Medical Physiology: A Systems Approach (Lange Medical Books)

Medical Physiology A Systems Approach Hershel Raff, PhD Professor Departments of Medicine and Physiology Medical College of Wisconsin Endocrine Research Laboratory Aurora St. Luke’s Medical Center Milwaukee, Wisconsin

Michael Levitzky, PhD Professor of Physiology and Anesthesiology Louisiana State University Health Sciences Center New Orleans, Louisiana

Medical New York Chicago San Francisco Lisbon London Madrid Mexico City Milan New Delhi San Juan Seoul Singapore Sydney Toronto

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To our students, mentors, colleagues, and families.

iv

KEY FEATURES

v

About the Authors Hershel Raff

Michael Levitzky

Hershel Raff received his Ph.D. in Environmental Physiology from the Johns Hopkins University in 1981 and did postdoctoral training in Endocrinology at the University of California at San Francisco. He joined the faculty at the Medical College of Wisconsin in 1983, and rose to the rank of Professor of Medicine (Endocrinology, Metabolism, and Clinical Nutrition) and Physiology in 1991. He is also Director of the Endocrine Research Laboratory at Aurora St. Luke’s Medical Center. At the Medical College of Wisconsin, he teaches physiology and pharmacology to medical and graduate students. He was an inaugural inductee into the Society of Teaching Scholars, received the Beckman Basic Science Teaching Award and the Outstanding Teacher Award, and has been one of the MCW’s Outstanding Medical Student Teachers each year the award has been given. Dr Raff was elected to Alpha Omega Alpha (AOA) Honor Medical Society as a faculty teacher in 2005. He is also an Adjunct Professor of Biomedical Sciences at Marquette University. He is Associate Editor of Advances in Physiology Education. He was Secretary-Treasurer of the Endocrine Society and is currently Chair of the Publications Committee of the American Physiological Society. He was elected a Fellow of the American Association for the Advancement of Science in 2005. Dr. Raff ’s basic research focuses on the adaptation to low oxygen (hypoxia). His clinical interest focuses on pituitary and adrenal diseases, with a special focus on the diagnosis of Cushing’s syndrome. Dr. Raff is also a co-author of Vander’s Human Physiology (McGraw-Hill) currently in its 12th Edition, and Physiology Secrets, currently in its 2nd Edition.

Michael Levitzky is Professor of Physiology and Anesthesiology at the Louisiana State University Health Sciences Center and is Director of Basic Science Curriculum at the LSU School of Medicine in New Orleans. He received a B.A. from the University of Pennsylvania in 1969 and a Ph.D. in Physiology from Albany Medical College in 1975. He joined the faculty of the LSU School of Medicine in 1975, rising to the rank of Professor in 1985. He has also been Adjunct Professor of Physiology at Tulane University School of Medicine since 1991. Dr. Levitzky teaches physiology to medical students, residents, fellows, and graduate students. He has received numerous teaching awards from student organizations at both LSU and Tulane. He received the inaugural LSUHSC Allen A. Copping Award for Excellence in Teaching in the Basic Sciences in 1997 and the American Physiological Society’s Arthur C. Guyton Teacher of the Year Award in 1998. He was elected to the Alpha Omega Alpha (AOA) Honor Medical Society as a faculty teacher in 2006. Dr. Levitzky has served the American Physiological Society as a member of the Education Committee and as a member of the Steering Committee of the Teaching Section. He served as a member of the National Board of Medical Examiners United States Medical Licensing Examination (USMLE) Step 1 Physiology Test Material Development Committee from 2007-2011. He is the author or co-author of several other textbooks, one of which, Pulmonary Physiology (Lange/McGraw-Hill), is currently in its 7th edition.

vi

Contents Contributors xi Preface xiii S E C T I O N

I

INTRODUCTION

10. Cardiac Muscle Structure and Function 93 Kathleen H. McDonough

1

1. General Physiological Concepts 1 Hershel Raff and Michael Levitzky

S E C T I O N

David Landowne

3. Cell Membranes and Transport Processes 15 David Landowne

4. Channels and the Control of Membrane Potential 33 David Landowne

5. Sensory Generator Potentials 43 David Landowne

6. Action Potentials 47

12. Introduction to the Nervous System 105 Susan M. Barman

13. General Sensory Systems: Touch, Pain, and Temperature 115 Susan M. Barman

14. Spinal Reflexes 125 Susan M. Barman

15. Special Senses I: Vision 133 Susan M. Barman

16. Special Senses II: Hearing and Equilibrium 147 17. Special Senses III: Smell and Taste 159

7. Synapses 59

Susan M. Barman

David Landowne

18. Control of Posture and Movement 167 Susan M. Barman

III 79

8. Overview of Muscle Function 79 Kathleen H. McDonough

9. Skeletal Muscle Structure and Function 83 Kathleen H. McDonough

105

Susan M. Barman

David Landowne

MUSCLE PHYSIOLOGY

IV

CNS/NEURAL PHYSIOLOGY

9

2. Cells and Cellular Processes 9

S E C T I O N

Kathleen H. McDonough

S E C T I O N

II

CELL PHYSIOLOGY

11. Smooth Muscle Structure and Function 99

19. Autonomic Nervous System 177 Susan M. Barman

20. Electrical Activity of the Brain, Sleep–Wake States, and Circadian Rhythms 185 Susan M. Barman

21. Learning, Memory, Language, and Speech 191 Susan M. Barman

vii

viii

CONTENTS

S E C T I O N

37. Acid–Base Regulation and Causes of Hypoxia 375

V

CARDIOVASCULAR PHYSIOLOGY 199

Michael Levitzky

38. Control of Breathing 385 Michael Levitzky

22. Overview of the Cardiovascular System 199 Lois Jane Heller and David E. Mohrman

S E C T I O N

VII

RENAL PHYSIOLOGY

23. Cardiac Muscle Cells 211 Lois Jane Heller and David E. Mohrman

24. The Heart Pump 223 Lois Jane Heller and David E. Mohrman

25. Cardiac Function Assessments 235 Lois Jane Heller and David E. Mohrman

397

39. Renal Functions, Basic Processes, and Anatomy 397 Douglas C. Eaton and John P. Pooler

40. Renal Blood Flow and Glomerular Filtration 409 Douglas C. Eaton and John P. Pooler

26. Peripheral Vascular System 251 David E. Mohrman and Lois Jane Heller

41. Clearance 417 Douglas C. Eaton and John P. Pooler

27. Vascular Control 263 David E. Mohrman and Lois Jane Heller

42. Tubular Transport Mechanisms 423

28. Venous Return and Cardiac Output 275

Douglas C. Eaton and John P. Pooler

David E. Mohrman and Lois Jane Heller David E. Mohrman and Lois Jane Heller

30. Cardiovascular Responses to Physiological Stress 295

VI

PULMONARY PHYSIOLOGY

44. Basic Renal Processes for Sodium, Chloride, and Water 437 Douglas C. Eaton and John P. Pooler

Lois Jane Heller and David E. Mohrman S E C T I O N

43. Renal Handling of Organic Substances 429 Douglas C. Eaton and John P. Pooler

29. Arterial Pressure Regulation 285

45. Regulation of Sodium and Water Excretion 449 Douglas C. Eaton and John P. Pooler

305

46. Regulation of Potassium Balance 463 Douglas C. Eaton and John P. Pooler

31. Function and Structure of the Respiratory System 305 Michael Levitzky

32. Mechanics of the Respiratory System 313 Michael Levitzky

47. Regulation of Acid–Base Balance 471 Douglas C. Eaton and John P. Pooler

48. Regulation of Calcium and Phosphate Balance 485 Douglas C. Eaton and John P. Pooler

33. Alveolar Ventilation 331 Michael Levitzky

34. Pulmonary Perfusion 341 Michael Levitzky

35. Ventilation–Perfusion Relationships and Respiratory Gas Exchange 353 Michael Levitzky

36. Transport of Oxygen and Carbon Dioxide 363 Michael Levitzky

S E C T I O N

VIII

GI PHYSIOLOGY

491

49. Overview of the GI System—Functional Anatomy and Regulation 491 Kim E. Barrett

50. Gastric Secretion 507 Kim E. Barrett

CONTENTS

51. Pancreatic and Salivary Secretion 517 Kim E. Barrett

52. Water and Electrolyte Absorption and Secretion 527 Kim E. Barrett

53. Intestinal Mucosal Immunology and Ecology 535 Kim E. Barrett

54. Intestinal Motility 543 Kim E. Barrett

55. Functional Anatomy of the Liver and Biliary System 559 Kim E. Barrett

56. Bile Formation, Secretion, and Storage 565 Kim E. Barrett

57. Handling of Bilirubin and Ammonia by the Liver 575 Kim E. Barrett

58. Digestion and Absorption of Carbohydrates, Proteins, and Water-soluble Vitamins 583 Kim E. Barrett

59. Lipid Assimilation 593 Kim E. Barrett S E C T I O N

IX

ENDOCRINE AND METABOLIC PHYSIOLOGY 601 60. General Principles of Endocrine Physiology 601

62. Anterior Pituitary Gland 623 Patricia E. Molina

63. Thyroid Gland 633 Patricia E. Molina

64. Parathyroid Gland and Calcium and Phosphate Regulation 643 Patricia E. Molina

65. Adrenal Gland 655 Patricia E. Molina

66. Endocrine Pancreas 671 Patricia E. Molina

67. Male Reproductive System 683 Patricia E. Molina

68. Female Reproductive System 695 Patricia E. Molina

69. Endocrine Integration of Energy and Electrolyte Balance 715 Patricia E. Molina

S E C T I O N

X

INTEGRATIVE PHYSIOLOGY 70. Control of Body Temperature 729 Hershel Raff and Michael Levitzky

71. Hypoxia and Hyperbaria 735 Michael Levitzky and Hershel Raff

72. Exercise 745 Michael Levitzky and Kathleen H. McDonough

73. Aging 753 Hershel Raff

Patricia E. Molina

61. The Hypothalamus and Posterior Pituitary Gland 613 Patricia E. Molina

729

Answers to Study Questions Index 761

757

ix

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Contributors

Susan M. Barman, PhD Professor Department of Pharmacology & Toxicology and Neuroscience Program Michigan State University East Lansing, Michigan

Kathleen H. McDonough, PhD Professor Department of Physiology Associate Dean, School of Graduate Studies Louisiana State University Health Sciences Center New Orleans, Louisiana

Kim E. Barrett, PhD Professor of Medicine and Dean of Graduate Studies University of California, San Diego La Jolla, California

Patricia E. Molina, MD, PhD Richard Ashman, PhD Professor and Head of Physiology Department of Physiology Louisiana State University Health Sciences Center New Orleans, Louisiana

Douglas C. Eaton, PhD Distinguished Professor and Chair of Physiology and Professor of Pediatrics Department of Physiology and Center for Cell & Molecular Signaling Emory University School of Medicine Atlanta, Georgia Lois Jane Heller, PhD Professor Department of Physiology and Pharmacology University of Minnesota Medical School Duluth, Minnesota David Landowne, PhD Professor Department of Physiology and Biophysics University of Miami, Miller School of Medicine Miami, Florida

David E. Mohrman, PhD Associate Professor, Emeritus Department of Physiology and Pharmacology University of Minnesota Medical School Duluth, Minnesota John P. Pooler, PhD Professor of Physiology Emeritus Emory University School of Medicine Atlanta, Georgia Hershel Raff, PhD Professor Departments of Medicine and Physiology Medical College of Wisconsin Endocrine Research Laboratory Aurora St. Luke’s Medical Center Milwaukee, Wisconsin

Michael Levitzky, PhD Professor of Physiology and Anesthesiology Louisiana State University Health Sciences Center New Orleans, Louisiana

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Preface

Medical Physiology: A Systems Approach is intended to provide first-year medical and graduate students and advanced undergraduate students with the basis of the major physiological processes necessary for understanding both health and disease. The curriculum of many medical schools is changing; most medical schools have undergone, or are in the midst of, a transition from the block approach, with each discipline having its own course, to a vertically integrated structure. One of the goals of an integrated curriculum is the presentation of much more clinical material during the first two years of medical school as well as the reinforcement of basic concepts in the two primarily clinical years. As a result, there is an increasing focus on the essential concepts necessary to understand pathophysiology. Therefore, this book is considerably shorter than the fulllength, standard physiology textbook. It focuses on major physiological concepts and clinical correlates, and leaves the minute details to larger books. Most of this book evolved from the Lange Physiology Series of monographs. The section on the central nervous system arose from the 23rd edition of Ganong’s

Review of Medical Physiology. Finally, the Introduction, Muscle Physiology, and Integrative Physiology sections are new. Each chapter begins with a list of objectives and concludes with a chapter summary. Most chapters also end with a clinical correlation that reinforces the major physiological principles just learned, and illustrates their importance to understanding disease states. Each chapter ends with multiple-choice questions designed to test the knowledge of some of the major concepts covered in the chapter. The authors are indebted to our mentors who provided us with a foundation for advances in physiological education in the 21st century. We also thank our students for providing a sounding board for the pedagogical approaches exploited in this book. The authors are thankful to Michael Weitz, Karen Davis, and Brian Kearns at McGraw-Hill for their outstanding editorial help. Finally, we give special thanks to our families: Judy and Jonathan; and Elizabeth, Edward, and Sarah. Hershel Raff Michael Levitzky

xiii

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SECTION I INTRODUCTION

C

General Physiological Concepts Hershel Raff and Michael Levitzky

1

H A

P

T

E

R

O B J E C T I V E S ■ ■ ■ ■ ■ ■ ■

Understand the general properties of a eukaryotic cell. Explain the general organization of the internal organs of the body. Compare and contrast the composition of extracellular versus intracellular fluid. Describe the different types of membrane transport. Understand the general concepts of pressure, flow, resistance, and compliance. Explain mass balance. Define negative and positive feedback.

INTRODUCTION Physiology is the science of the function of organisms. The object of physiology is to explain how the organ systems, cells, and even molecules interact to maintain normal function. The hallmark of physiology is the concept of homeostasis, which is the maintenance of a normal internal environment in the face of external and internal perturbations so that the functions of the cells and organ systems of the body are maintained. This is accomplished primarily by feedback systems such that when a system is disturbed, a variety of local responses, systemic reflexes (automatic, rapid reactions to stimuli), and long-term adjustments are activated to return the system to its normal set point. By understanding how things work under normal conditions, one can appreciate when and why there is a malfunction. This is called pathophysiology—a lasting disturbance in normal function

Ch01_001-008.indd 1

caused by disease or injury. Therefore, physiology is one of the foundations of the health sciences.

THE CELL The basic building block of the organs of the body is the cell. The details of cell physiology are covered in Section 2. Figure 1–1 shows the general structure of a nucleated (eukaryotic) cell. It is surrounded by a cell membrane that is composed of a lipid bilayer, membrane proteins, and carbohydrates in association with lipids (glycolipids) or proteins (glycoproteins). The cell membrane is the gatekeeper for anything that enters or leaves the cell and is a barrier that helps to maintain the internal composition of the cell. Some membrane proteins and glycoproteins function as sensors, or receptors, which sense the external environment and

1

11/26/10 9:50:25 AM

2

SECTION I Introduction

Secretory granules Golgi apparatus

Centrioles

Rough endoplasmic reticulum

Smooth endoplasmic reticulum

Lysosomes Nuclear envelope

Lipid droplets Mitochondrion

Globular heads

Nucleolus

FIGURE 1–1

Diagram showing a hypothetical cell in the center seen with a light microscope. (Adapted with permission from Fawcett DW, et al.

The ultrastructure of endocrine glands, Recent Prog Horm Res. 1969;25:315–380.)

chemical signals, and then signal the interior of the cell, usually through chemical second messengers or changes in electrical activity of the membrane. Other membrane proteins function as transporters that regulate the entry or exit of substances into or out of the cell. The lipid bilayer structure and associated proteins of the cell membrane are shown in Figure 1–2. The inside of the cell is composed of cytosol, which is a liquid consisting primarily of water in which proteins, metabolites, fuel, and inorganic ions (called electrolytes) are dissolved. Also dispersed in the cytosol are a variety of subcellular particles and organelles. Altogether, the combination of cytosol and the intracellular structures is called the cytoplasm. The organelles include the endoplasmic reticulum, which is an extensive network of membranes inside of which are proteins and other important chemicals. The endoplasmic reticulum is important in many metabolic functions and the packaging of secretory products. The ribosomes are involved in translation, which is the synthesis of proteins from messenger RNA (mRNA). These ribosomes are associated with endoplasmic reticulum in a combined structure called the rough endoplasmic reticulum (RER). The Golgi apparatus is associated with endoplasmic reticulum; the Golgi apparatus packages material synthesized in the RER. Lysosomes are intracellular, membrane-surrounded structures that contain digestive enzymes located in granules that are involved in intracellular metabolism. Secretory granules contain molecules that the cell will release into the extracellular fluid by exocytosis, in

response to stimuli. Some cells contain numerous lipid droplets, because fat is hydrophobic and does not dissolve readily in the aqueous environment of the cytosol. Mitochondria have two lipid bilayer membranes in apposition, and are the energy-

Extracellular fluid Carbohydrate portion of glycoprotein

Transmembrane proteins

Phospholipids

Channel Integral proteins

Peripheral protein Polar regions

Nonpolar regions

Intracellular fluid

FIGURE 1–2 Organization of the phospholipid bilayer and associated proteins in a biological cell membrane. (Reproduced with permission from Widmaier EP, Raff H, Strang KT: Vander’s Human Physiology, 11th ed. McGraw-Hill, 2008.)

CHAPTER 1 General Physiological Concepts

plasm and nucleus that respond to signals that enter the cell. Examples of such signals are steroid hormones such as estrogen and testosterone that are lipophilic (“fat-loving”) and, as a result, can readily diffuse through the cell membrane to exert an intracellular action.

generating organelles. The cytoplasmic organelles are held in position by filaments and microtubules, arising from the centrosomes, which are also important in the movement of chromosomes during cell division. Finally, the nucleus, also surrounded by a lipid bilayer membrane called the nuclear envelope, contains chromatin that is composed of DNA containing the nucleic acid code for cellular differentiation, function, and replication. DNA contains the genes that encode mRNAs that are produced from DNA by transcription. Also contained within the nucleus is the nucleolus, which is the site of ribosome synthesis. As you will learn in many chapters in this book, the cell membrane contains many different types of receptors that sense extracellular signals that are transduced into intracellular signals. In addition, there are receptors within the cyto-

GENERAL STRUCTURE OF THE BODY Figure 1–3 is a diagrammatic representation of the human body. The organs (e.g., brain and heart) receive nutrients and eliminate waste products via the circulatory system. The heart is illustrated as two parts—right and left—as a functional

Central nervous system

Afferent and efferent nerves

Right

Venous blood

O2 CO2

Atmosphere

O2 CO2

Lung

Left Heart

Heart Tissues

Arterial blood

Nutrients

Waste products Endocrine glands Hormones

Liver

GI tract

Synthesis

Metabolism

Kidney

Food & water intake

Nutrients

Bile

Waste

Reabsorption

Filtration Waste Feces Urine

3

FIGURE 1–3 General organization of the major organs of the body. Arrows show the direction of blood flow and flux of gases, nutrients, hormones, and waste products.

4

SECTION I Introduction

depiction even though it is actually one organ. The right side of the heart receives partially deoxygenated blood returning from the tissues and pumps blood to the lungs. In the lungs, oxygen diffuses into the blood from the gas phase for use in cellular respiration in the body, and carbon dioxide, a waste product of cellular respiration, is eliminated by diffusion from the blood into the gas phase. The left side of the heart receives oxygenated blood from the lung and pumps the blood into the arterial tree to perfuse the organs of the body. Nutrients, minerals, vitamins, and water are taken in by the ingestion of food and liquids and absorption in the gastrointestinal (GI) tract. The liver, usually considered part of the GI system, processes substances absorbed into the blood from the GI tract, and also synthesizes new molecules such as glucose from precursors. Metabolic waste products are eliminated by the GI system in the feces and by the kidney in the urine. The two main integrative controllers of the internal environment are the nervous and endocrine systems. The nervous system is composed of the brain, spinal cord, sensory systems, and nerves. The endocrine system is composed of ductless glands and scattered secretory cells distributed throughout the body that release hormones into the blood in response to metabolic, hormonal, and neural signals. It is the function of the nervous and endocrine systems to coordinate the behavior and interactions of the organ systems described throughout this book. Water is the most abundant molecule in the body, constituting about 50–60% of the total body weight. All cells and organs exist in an aqueous environment. The intracellular water is the main component of the cytosol. Water is also the main component of the extracellular fluid. The extracellular fluid includes the interstitial fluid, which bathes the cells of the body, the blood plasma, which is the liquid component of the blood, cerebrospinal fluid, which is found only in the central nervous system, synovial fluid, which is found in joints such as the knee, and lymph, which is a liquid formed from interstitial fluid that flows back to the circulatory system via the lymphatic system. There are significant differences in the composition of intracellular and extracellular fluids that are very important in many aspects of cellular function (Table 1–1).

GENERAL PHYSICAL FACTORS AND CONCEPTS It is not an accident that physiology and physics come from the same Greek word physis (nature). It is important that students of physiology understand the physical forces and factors that govern body function.

MEMBRANE TRANSPORT There are several different mechanisms by which molecules cross the cell membrane either coming into or going out of the cell. These are all described in detail in Section 2. The simplest is diffusion in which the rate at which a molecule crosses

TABLE 1–1 Composition of extracellular and intracellular fluids. Extracellular Concentration (mM)

Intracellular Concentration (mM)

Na+

140

12

+

5

150

1

0.0001

1.5

12

100

7

HCO3

24

10

Amino acids

2

8

Glucose

4.7

1

Protein

0.2

4

K

Ca

2+

Mg Cl

2+

− −

The intracellular concentrations are slightly different for different tissues. The Ca2+ concentrations shown are the free, biologically active ions not bound to proteins. Total Ca2+ (bound plus free) are considerably higher in extracellular (2.5 mM) and intracellular (1.5 mM) fluids. Reproduced with permission from Widmaier EP, Raff H, Strang KT: Vander’s Human Physiology, 11th ed. McGraw-Hill, 2008.

the cell membrane is governed by the concentration gradient and the ease with which each molecule can go through the cell membrane (permeability); energy expenditure is not directly required for diffusion, which is why it is sometimes called passive diffusion. There are also protein transporters located in the cell membrane that mediate facilitated diffusion of molecules that are too large or hydrophilic to permeate the membrane by simple diffusion. Facilitated diffusion does not require energy and moves molecules down a concentration gradient. By contrast, active transport is a process of moving molecules across a cell membrane against a concentration gradient; it can be thought of as a pump that uses energy to do work. The movement of water molecules across the cell membrane also occurs by diffusion from a higher to a lower water “concentration.” This is termed osmosis; water moves from a compartment with fewer osmotically active particles (higher water concentration) to a compartment with more osmotically active particles (lower water concentration). Examples of osmotically active particles are ions such as sodium, potassium, and chloride, and organic molecules such as glucose and amino acids.

BUFFERING AND pH One of the most tightly controlled variables in the body is the hydrogen ion concentration of the intracellular and extracellular fluids. This is because most proteins have optimal function within a very narrow range of pH. Remember that the pH is the negative logarithm (base 10) of the hydrogen ion concentration in molar units—when pH is low, the fluid is acidic; when pH is high, the fluid is alkaline. The body has several mechanisms for

CHAPTER 1 General Physiological Concepts maintaining a normal pH. These are extensively covered in Sections 6 and 7. The body can rid itself of acid by increasing the elimination of carbon dioxide from the lungs. This is because carbon dioxide and hydrogen ion are linked through chemical reactions to bicarbonate, one of the main buffers in the body. A buffer is an ionic compound that attenuates changes in pH by combining with or releasing hydrogen ions. The kidneys can also remove hydrogen ion from the body via the complex processes involved in producing urine. Finally, changes in intracellular and extracellular pH can be prevented by a variety of buffers in addition to bicarbonate.

HYDROSTATIC FORCES AND PRESSURE, RESISTANCE, AND COMPLIANCE Pressure is defined as force per unit of area. The pressure at the bottom of a column of liquid increases with the height of the column and is also dependent on the density of the liquid and on gravity. The pressure at any point in a column of liquid is called the hydrostatic pressure, and is the pressure difference between that point and the top of the column. Hydrostatic pressure differences have many important physiologic consequences, particularly in blood vessels, as will be seen in Section 5. The flow of a fluid (a liquid or a gas) is quantified as the volume of the fluid moving through a vessel per unit of time. The relationships among pressure, flow, and the resistance offered by the vessels through which a fluid flows can be complex, but are simplified as follows. The rate of flow of liquid through a tube is proportional to the difference in pressure between the two ends of the tube and inversely proportional to the resistance to flow through the tube. Resistance cannot be determined directly, but is calculated from the pressure and flow. If the resistance does not change, increasing the pressure difference through a tube will increase the flow. If the pressure difference from one end of the tube to the other does not

NET GAIN TO BODY

change, increasing the resistance will decrease the flow. If the flow through the tube does not change, increasing the resistance will increase the pressure difference between the ends of the tube. The pressure difference between the two ends of the tube represents energy conversion to heat by the internal friction of the fluid with itself and with the wall of the vessel. You will notice that the relationship between pressure, flow, and resistance for liquid flowing through a tube is analogous to Ohm’s law for electricity in which the voltage drop across a circuit (analogous to a pressure drop in a tube with liquid flowing through it) is proportional to the product of current (analogous to flow) and resistance. Most of the vessels or chambers in the body will stretch passively if the pressure difference across their walls increases. This results in an increased volume of the vessel. This ability to stretch in response to an increased transmural (across the wall) pressure difference is called compliance. A less specific term for compliance is distensibility. The inverse of compliance is elastance. Elastance can therefore be thought of as the resistance to stretch when the transmural pressure difference increases or as the ability of a vessel to return to its original volume after the increased transmural pressure difference is removed. It is directly related to Hooke’s law of elasticity for mechanical springs.

MASS BALANCE AND METABOLISM In order to achieve the steady state that defines homeostasis, any substance taken in by the body must be nearly equal to the amount of the substance leaving the body plus that removed by metabolism (Figure 1–4). The influx of a substance is the sum of uptake in the lung, absorption in the GI tract, synthesis in the body (e.g., liver synthesis of glucose from molecular precursors), and release from cells (e.g., fatty acid release from adipose tissue). The efflux of a substance is

DISTRIBUTION WITHIN BODY

NET LOSS FROM BODY Metabolism

Food

GI tract

Storage depots

Air

Lungs

POOL

Synthesis in body

Reversible incorporation into other molecules

Excretion from body via lungs, GI tract, kidneys, skin, menstrual flow

FIGURE 1–4 Concept of mass balance. The central compartment is usually extracellular fluid (which includes blood plasma). It receives substances from intake, synthesis, and release from cells. It loses substances by excretion, metabolism, and uptake into cells. In the steady state, when a substance is said to be “in balance,” intake and excretion are nearly equal. (Reproduced with permission from Widmaier EP, Raff H, Strang KT: Vander’s Human Physiology, 11th ed. McGraw-Hill, 2008.)

5

6

SECTION I Introduction

the sum of metabolism, uptake into cells, losses via the GI tract, respiratory system, sweat, and urinary excretion. In the steady state, the difference between total influx and efflux should be very close to zero. From minute to minute, there are obviously large differences between influx and efflux, but over days to weeks when the substance is usually in balance, the difference should be close to zero. Examples of this are sodium balance described in Section 7 and calcium and phosphate balance described in Section 9.

EXCITABILITY As you will learn in Sections 2–4, living cells have an electrical charge difference across the cell membrane created primarily by differences in ion concentration and movement between the outside and inside of the cell (see Table 1–1). As a result, the membranes have a resting electrical potential that can be changed by a variety of inputs. Dramatic changes in ion flux across the cell membrane lead to large changes in electrical potential that can result in major cellular responses. For example, muscular contraction described in Section 3 results from the depolarization of the muscle cell membrane that is transduced into a chemical signal within the cell that leads to the generation of force and movement.

CELL–CELL INTERACTIONS As you will learn in Sections 2–4, 8, and 9, cells interact with each other locally. One mechanism is by direct contact between cells via tight junctions and gap junctions. Another is the synapse, in which neurons can release chemicals called neurotransmitters to alter the function of a neighboring cell. Finally, there are a variety of chemical signals by which cells can communicate with neighboring cells by diffusion. An example of this is paracrine signaling by which humoral factors are released by one cell, diffuse through the interstitial fluid, and bind to a receptor on a neighboring cell within the same tissue.

The main focus of physiology is the understanding of the mechanisms by which cells, organs, and organ systems maintain homeostasis. This is accomplished primarily by negative feedback. The general concept is that the body tries to increase a variable when it is below its optimum (termed the set point), and decrease a variable when it is above its optimum. This is analogous to the thermostat that controls room temperature by adjusting the heating and/or cooling of the room. For example, if you open a window on a cold day, the room temperature decreases from the set point of the thermostat. This is called perturbation. The thermostat contains a sensor that detects the difference between the room temperature and the set point. The thermostat signals the furnace to generate heat, and the room temperature is returned toward normal. The difference between the low point in room temperature and the final room temperature at steady state is called the correction. Because the window is left open in this example, room temperature does not quite return to the set point; the remaining difference between the final room temperature and its thermostatic set point is called the error. The ability of the control system to restore the system to its set point is called gain, which is represented by the following equation: Correction Gain = ____________ Remaining error

Final blood pressure

100 95

100-95=5 Remaining error 95-75=20 Correction due

to reflexes

75

Mean arterial blood pressure (mm Hg)

Nadir

(1)

A classic example of this is shown in Figure 1–5 that shows the response of the cardiovascular system to rapid blood loss (hemorrhage). In this example, the rapid loss of 1 L of blood leads to a decrease in mean blood pressure from the set point of 100 to 75 mm Hg. As you will learn in Chapter 29, there are sensors in the cardiovascular system called baroreceptors that detect blood pressure. These sensors change their neural input to the brain to activate systemic reflexes to restore blood pressure to normal. In this example, these reflexes restore blood pressure to 95 mm Hg. The correction, therefore, is 20 mm Hg and the remaining error is 5 mm Hg. Using equation (1), this gives a gain of about 4. Although clinicians do not usually calculate gain when taking care of patients, it is a convenient way

Rapid blood loss

Set point

FIGURE 1–5 Moderate hemorrhage as an example of the gain of a feedback control system. The higher the gain of a system, the better able it is to restore a controlled variable to its set point in response to a perturbation.

CONTROL SYSTEMS

Gain=

Correction 20 = =4 5 Remaining error

Time (min)

Original perturbation

CHAPTER 1 General Physiological Concepts to think of the ability of reflexes to restore a perturbed system to normal via negative feedback. The higher the gain, the higher the ratio of correction to remaining error and the better the control system is at restoring the system to its set point. For example, as you will learn in Chapter 70, the control of body temperature has a very high gain. Included in many feedback systems is a change in behavior. For example, drinking extra water when blood volume is decreased helps to restore plasma volume. Putting on warm clothes and curling up helps to minimize heat loss in a cold environment. Finally, set points of control systems can change. Examples of this are resetting of the baroreceptor set point during chronic increases in blood pressure (hypertension) that you will learn about in Chapter 29, and during the acclimatization to the low ambient oxygen of high altitude (hypoxia) that you will learn about in Chapter 71. Although most control systems of the body are negative feedback, there are a few examples of positive feedback, which are feedback loops that amplify themselves. You will learn about several examples of this in Chapter 68. One is the stimulation of the anterior pituitary hormone LH by estrogen just before ovulation that causes a large increase in LH, which then stimulates more estrogen release, and so on. Another example is the birth of a baby during which stretch of the cervix stimulates the release of oxytocin from the posterior pituitary gland that, in turn, stimulates stronger uterine contractions. This causes additional cervical stretch, more oxytocin release, and greater uterine contractions. Positive feedback is also responsible for detrimental effects in the body. One example is heart failure during which the pumping of the heart decreases due to, for example, an infection of the heart muscle. The resultant decrease in blood pressure leads to reflexes that stimulate the heart to pump harder in an effort to raise blood pressure. This additional stress on the heart actually makes it work less well, and the heart failure feeds on itself. Another important concept in homeostatic control is potentiation. This is when one substance augments the response to another substance, even though the first substance does not exert a significant response on its own. An example of this that you will learn in Chapters 49 and 66 is the release of the GI hormones from the intestine in response to a meal. These hormones can potentiate the pancreatic insulin response to absorbed glucose. This is an example of feedforward potentiation, because these GI hormones “announce” the impending increase in blood glucose before glucose absorption actually occurs in the small intestine. When glucose finally arrives via the bloodstream at the pancreas, there is a potentiated insulin response such that hyperglycemia is prevented.

CHAPTER SUMMARY ■

■

The cell is surrounded by a membrane that regulates the intracellular composition and the flux of molecules in and out of the cell. Water is the most abundant molecule in the body, and its concentration and balance is highly regulated.

■

■

■

■ ■

7

There are significant concentration gradients between intracellular and extracellular fluid for sodium, potassium, calcium, magnesium, chloride, and bicarbonate, as well as organic compounds. Molecules can enter the cell by passive diffusion, and through transporters that do not (facilitated transport) and do directly use cellular energy (active transport). The rate of flow of a liquid through a tube is determined by the pressure difference between the inflow and outflow, and the resistance to flow of the tube. Most important substances in the body are in balance, with the influx and efflux being approximately the same over time. Most systems are controlled by negative feedback with the controlled variable being able to shut off its own release much like a thermostat controls room temperature.

STUDY QUESTIONS 1. Which of the following organelles is primarily response for generation of energy? A) Golgi apparatus B) mitochondria C) lysosomes D) ribosomes 2. Which of the following has an intracellular fluid concentration much higher than its extracellular fluid concentration? A) sodium ion B) chloride ion C) glucose D) potassium ion 3. Which of the following would result in an increase in flow of a liquid through a tube? A) increase in resistance B) increase in pressure at the downstream end of the tube C) increase in pressure at the inflow end of the tube D) increase in length of the tube 4. Which of the following has the highest feedback gain? A) starting blood pressure = 100; low point in blood pressure = 70; final blood pressure after feedback correction = 90 B) starting body temperature = 37.2°C; high point in body temperature = 38.9°C; final body temperature after feedback correction = 37.4°C C) starting blood glucose = 80 mg/dL; high point in blood glucose = 110 mg/dL; final blood glucose after feedback correction = 85 mg/dL D) starting plasma osmolality = 280 mOsm/kg; low point in plasma osmolality = 270 mOsm/kg; final osmolality after feedback correction = 278 mOsm/kg

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SECTION II CELL PHYSIOLOGY

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Cells and Cellular Processes David Landowne

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O B J E C T I V E S ■ ■ ■

Recognize and describe the types of electrophysiological events. Describe the types of membrane channels and their roles. Describe physiological control systems.

INTRODUCTION Life is cellular, and cells are the fundamental units of life. Without cells, there would be no living beings. All the cells of a given individual are ultimately derived from a single fertilized ovum. Most of the cells of multicellular organisms reside within their tissues and organs. This chapter concentrates on the cellular processes and leaves the discussion of their higher organization to chapters concerned with the various organ systems. Drugs, toxins, and diseases are introduced to illustrate the cellular processes.

COMMUNICATION Dynamic cell processes support sensory perception of the environment, communication, and the integration of information within and between cells, as well as their expression, or actions on the environment. These are the processes that enable the cell to contribute to the functioning of tissues, organs, and individuals. These processes make up one of the phenomena of cells—excitability. The others, reproduction and metabolism, are not covered in depth here. Perception, integration, and expression can be best considered as physio-

Ch02_009-014.indd 9

logical events in terms of inputs, processes, and outputs (Figure 2–1). Complex processes can be broken down into simpler ones, with the outputs of one or more processes becoming the inputs to the next one. In order to survey the processes discussed here, it is useful to consider a three-cell model of the body. Figure 2–2 shows a sensory neuron or nerve cell, a motor neuron, and a skeletal muscle cell. These cells represent the hardware the body uses to carry out the dynamic cell processes described in the previous paragraph. The cells have specialized portions for the different processes. Starting from the left, the sensory cell has one end that is specialized for the transduction of a stimulus into a cellular signal. The various senses have different specializations to accomplish this transduction. Besides the classic five senses (touch, hearing, vision, taste, and smell), there are sensors or proprioceptors inside the body that sense internal parameters—for example, body temperature, blood pressure, blood oxygen levels, or the lengths of various muscles. If it is sufficiently large, the initial signal causes another signal to propagate over the axon (the long cylindrical portion of the nerve cell) until it reaches the other end, where the sensory neuron makes a synaptic connection with dendrites of the motor neuron, located in the central nervous system (CNS). The message is transmitted from the presynaptic cell

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SECTION II Cell Physiology

Input

Output

Process

FIGURE 2–1 The input–process–output structural framework is a specification of causal relationships in a system. Complex systems can be considered as composed of simple units. (Modified with permission from Landowne D: Cell Physiology. New York: Lange Medical Books/McGraw-Hill, 2006.)

to the postsynaptic cell, where it is integrated or evaluated along with messages from other neurons that synapse on the same motor neuron. In the complete organism, this integration and comparison occurs in many cells and at different levels within the CNS, so the decision to move or not move can be made considering more than one input and also anything the organism has learned from the past. If the motor neuron is sufficiently excited, it will send another message along the axon that leads to a synapse on a muscle cell. In healthy people, this neuromuscular synapse leads to a signal that propagates over the length of the muscle cell and activates contraction, which can act on the environment. Other actions on the environment are effected by the secretions of various glands; these too may be controlled by synaptic connections. These muscles and glands may act internally (e.g., to control heart rate or blood pressure) or externally (for locomotion or communication with other people). These signals are all electrical; they all represent changes in the electrical potential difference across the various cell mem-

branes. Every living cell has a surface membrane that separates its intracellular and extracellular spaces. All cells, not just those of nerve and muscle, are electrically negative inside the cell with respect to outside. This is called the membrane potential. When the cells are “resting”—that is, not signaling—their membrane potential is called the resting potential. Chapter 4 is about the origins of the resting potential. Even though the signals described above are changes in potential, they are generally referred to as named potentials. On the left in Figure 2–2, there is the sensory generator potential, which has two properties to distinguish it from the next signal, the action potential. The sensory generator potential is local; it occurs only within a few millimeters of the sensory ending. The action potential is propagated; it travels from the sensory ending to the presynaptic terminal, perhaps more than a meter away. The sensory generator potential is also graded; a larger-amplitude stimulus produces a larger-amplitude sensory generator potential. In contrast, the action potential has a stereotyped amplitude and duration; it is all-or-none. The information about the stimulus is encoded in the number of action potentials, or the number per second. A larger-amplitude stimulus will result in a higher frequency of action potentials, each with the same stereotyped amplitude. Because the all-or-none character of neurons is similar to the true-or-false character of logical propositions, cyberneticists (people who study control and communication in the animal and the machine) have considered that neural events and the relations among them can be treated by means of propositional logic. Chapters 5 and 6 are about sensory generator potentials and action potentials, respectively. The presynaptic terminals contain a mechanism to release the contents of vesicles containing chemical transmit-

Hardware

Sensory ending

Axon

Synapse

Axon

Muscle

Signals (potentials)

Sensory generator Local

Action

Synaptic

Action

Endplate

Propagated

Local

Propagated

Local

Graded

All-or-none

Graded

All-or-none

Graded

Channels

Mechano sensitive

Voltage sensitive

Chemo sensitive

Voltage sensitive

Chemo sensitive

Cybernetics

Input

Transmission

Process

Transmission

Output

FIGURE 2–2 The cellular processes of a hypothetical three-celled organism. Different types of channels underlie different physiological processes that support the input–process–output functions of animals, including humans. (Modified with permission from Landowne D: Cell Physiology. New York: Lange Medical Books/McGraw-Hill, 2006.)

CHAPTER 2 Cells and Cellular Processes ters that diffuse across the narrow synaptic cleft and react with the postsynaptic cell to produce a postsynaptic potential. The postsynaptic potential is also local and graded. It is only seen within a few millimeters of the site of the presynaptic ending and its amplitude depends on how much transmitter is released. There are excitatory postsynaptic potentials (EPSPs) and inhibitory postsynaptic potentials (IPSPs), depending on whether the postsynaptic potential makes the cell more or less likely to initiate an action potential. If there is sufficient excitation to overwhelm any inhibition that may be occurring, an action potential will be initiated in the postsynaptic cell. There are many presynaptic cells ending on each postsynaptic neuron as well as various different transmitters in different synapses. These transmitters, the release mechanism, and the resulting postsynaptic potentials are discussed in Chapter 7. The action potential in the motor neuron and the synapse with the muscle cell are very similar to the neuron to neuron synapse discussed above. In the light microscope, the neuromuscular junction looks like a small plate; hence, the junction is often called an endplate and the postsynaptic potential an endplate potential. The neuromuscular junction differs from most other synapses because there is only one presynaptic cell, its effect is always excitatory, and—in healthy people—the endplate potential is always large enough to initiate an action potential in the muscle cell. The muscle action potential propagates along the length of the cell and into the interior by small transverse tubules, whose membranes are continuous with the surface membrane. The action potential excitation is coupled to the muscular contraction by processes described in Chapter 10. That chapter also discusses the control of cardiac and smooth muscle cells. The resting potential, the sensory generator potentials, the action potentials, and the synaptic potentials all occur by the opening and closing of channels in the cell membranes. These channels are made of proteins that are embedded in and span the membrane connecting the intracellular and extracellular spaces. Each has a small pore through the middle, which may be opened or closed and is large enough to allow specific ions to flow through and small enough to keep metabolites and proteins from flowing out of the cell. There are many channels, and a good part of Chapter 3 is devoted to their description. They are generally named either for the ion that passes through them or for the agent that causes them to open. There are three classes of channels that act to produce the changes in potential described in Figure 2–2. All these channels will be discussed individually in Chapter 3 and then again in the context of the various potentials in subsequent chapters. Mechanosensitive channels subserve the sensations of touch and hearing and the many proprioceptors that provide information on muscle length, muscle tension, joint position, the orientation and angular acceleration of the head, and blood pressure. These channels open when the membrane of the sensory ending is stretched, sodium ions flow through the channels, and the membrane potential changes.

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Voltage-sensitive channels underlie action potentials. They open in response to a change in membrane potential. When they are open, ions flow through them, and this changes the membrane potential as well. The generator potential or the synaptic potentials activate these channels, and then they open the remaining adjacent voltage-sensitive channels. This accounts for the propagation and all-or-none, stereotyped quality of the action potentials. Nerve and skeletal muscle action potentials are produced by the successive activation of voltage-sensitive sodium channels, followed by voltage-sensitive potassium channels. There are also voltage-sensitive calcium channels in the presynaptic nerve endings. When the action potential reaches the presynaptic terminal, these calcium channels open and permit calcium to enter the cell. The calcium binds to intracellular components and initiates the release of synaptic transmitters. Chemosensitive channels are responsible for the synaptic potentials. The transmitters bind to these channels, causing them to open. There are different channels for different transmitters and also different channels for EPSPs and IPSPs. Chemosensitive channels also subserve the chemical senses of smell and taste. There are also channels that open or close in response to intracellular chemicals such as adenosine triphosphate (ATP) or the cyclic nucleotides, cyclic adenosine monophosphate (cAMP) or cyclic guanosine monophosphate (cGMP). Vision is supported by a reaction series whereby light absorption leads to a decrease in cGMP, which produces a closure of cyclic nucleotide–gated (chemosensitive) channels. When sodium ions stop flowing through these channels, the membrane potential changes. From a cybernetic viewpoint, Figure 2–2 indicates that the body has mechanisms to input information, to transmit it within the body, to process the information, and to provide output. This type of analysis appears frequently in physiology. Much of what you will learn can be broken into various steps where the output of one process becomes the input for the next. For example, the sensory generator potentials are an input to the action potential–generation process and the action potential is the input to the voltage-sensitive calcium channel, which permits calcium to enter the presynaptic terminal. This calcium is the input for the transmitter release process, and so on.

CONTROL Although most of this book focuses on isolating the different processes so as to analyze them more easily, an understanding of the value and true significance of each physiological quality must refer to the whole organism. A recurring theme throughout all of physiology is the maintenance of a stable internal environment through homeostasis. Many internal properties (e.g., body temperature or blood glucose levels) are homeostatically controlled within narrow limits by feedback control systems. Homeostasis is a property of many complex open systems. Feedback control is the central feature of organized activity.

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SECTION II Cell Physiology

Desired value

Comparator Effector

Controlled parameter

Sensor A From higher centers

Motoneuron Muscle

Sensory neuron

Muscle spindle

B

FIGURE 2–3 Homeostasis and feedback control. A and B) By having inputs that sense the output and feed information back to the controller, machines and humans can gain control of their operating conditions. (Modified with permission from Landowne D: Cell Physiology. New York: Lange Medical Books/McGraw-Hill, 2006.)

A homeostatic system (e.g., a cell, the body, an ecosystem) is an open system that maintains itself by controlling many dynamic equilibria. The system maintains its internal balance by reacting to changes in the environment with responses of opposite direction to those that created the disturbance. The balance is maintained by negative feedback. Perhaps the most familiar negative feedback control system is the thermostat that controls the temperature of a room, which was described in Chapter 1. The basic steps (Figure 2–3A) in negative feedback control of any measurable parameter are the measurement by a sensor, communication of that measurement to a comparator, making the comparison, and communicating the comparison to an effector that changes the parameter of interest. The feedback is called negative because the signal to the effector is in the opposite direction to any disturbance and reduces the difference between the measured value and the desired value. The three cells in Figure 2–2, arranged as a negative feedback loop (Figure 2–3B), represent the process used to control the length of muscles both to maintain posture and to achieve movement in response to signals from the brain. This feedback loop can be easily demonstrated by the stretch reflex—that is, the knee-jerk reflex (see Chapter 14). When a muscle is

stretched, mechanosensitive channels in sensory organs open, changing membrane potentials in the sensory endings that induce action potentials to propagate to the spinal cord. Transmitter is released, which excites the nerve leading back to the muscle, where the synaptic process is repeated and the muscle shortens to compensate for the initial stretch. There are a few positive feedback systems that are physiologically important. A positive feedback system is unstable; the signal from the sensor increases the effect, which increases the signal from the sensor in a “vicious cycle,” which is limited only by the availability of resources. The all-or-none property of action potentials is due to a positive feedback loop. Some other examples of positive feedback were described in Chapter 1.

CHAPTER SUMMARY ■

■

Communication in excitable cells occurs via electrical signals within the cells and via chemical signals at synapses between the cells. There are two classes of electrical signals: those that are local and graded and those that are propagated and stereotyped, or all-or-none.

CHAPTER 2 Cells and Cellular Processes ■ ■

■ ■

The chemical transmitters are released presynaptically and produce an electrical signal in the postsynaptic cell. Three classes of ion channels produce the electrical signals: mechanosensitive, chemosensitive, and voltage-sensitive channels. Homeostasis by negative feedback control is an important feature of living systems. There are three basic elements of a negative feedback loop: a sensor, a comparator, an effector, and two communication links connecting them.

STUDY QUESTIONS 1. Which of the following changes in electrical potential require voltage-sensitive channels? A) excitatory synaptic potentials B) mechanical sensory generator potentials C) propagated action potentials D) light sensory generator potentials E) inhibitory synaptic potentials

2. Negative feedback control systems do not A) improve the reliability of control. B) require the sensing or measurement of the controlled process. C) require communication between separate parts of the system. D) regulate blood pressure and body temperature. E) cause the all-or-none property of the action potential.

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Cell Membranes and Transport Processes David Landowne

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Describe the molecular composition of biological membranes. Describe the functional biophysical properties of biological membranes. Describe classes of ion channels, their molecular structure, and their biophysical properties. Describe the molecular organization, properties, control, and functional roles of cell–cell channels. Describe the movement and transport of substances across biological membranes by passive processes. Describe the movement and transport of substances across biological membranes by active processes. Describe the physiological importance of two examples of active transport and two examples of passive transport. Define osmotic pressure. Calculate the osmolarity of simple solutions. Calculate the changes in osmolarity in body compartments caused by drinking various simple solutions. Describe physiological mechanisms to regulate osmolarity.

Every living cell has a surface membrane that defines its limits and the connectivity of the intracellular and extracellular compartments. Cell membranes are about 10-nm thick and consist of a 3–4-nm-thick lipid bilayer with various embedded proteins that may protrude into either compartment (see Figure 1–2). Membranes also delimit intracellular organelles, including the nuclear envelope, Golgi apparatus, endoplasmic reticulum (ER), mitochondria, and various vesicles (see Figure 1–1). The lipid bilayer is impermeable to charged or polar substances. The proteins handle the transport of specific ions or molecules across the membranes and thus control the composition of different solutions on either side. They support communication across the membranes and along the surface of the cell and provide mechanical coupling between cells.

Ch03_015-032.indd 15

LIPIDS Most of the membrane lipids are glycerophospholipids, which have a glycerol backbone with two of its three –OH groups esterified by fatty acids and the third esterified to a phosphate group, which is in turn esterified to a small molecule that gives its name to the whole molecule (Figure 3–1). The most common glycerophospholipids are phosphatidylcholine (PC), phosphatidylethanolamine (PE), and phosphatidylserine (PS). Membranes also contain phosphatidylinositol (PI), which plays an important role in signaling within the cytoplasm. Notice that PS and PI have a net negative charge. Animal cell membranes may also contain sphingolipids, including the phosphosphingolipid, sphingomyelin, which has

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16

SECTION II Cell Physiology

R O O P O– O

+

N(CH3)3 HCH

Phosphatidylcholine (PC)

HCH O

O

C=O

C=O

+

NH3 HCH

Phosphatidylethanolamine (PE)

HCH +

NH3

COO–

Phosphatidylserine (PS)

HCH

OH OH OH

HO

OH

Phosphatidylinositol (PI)

FIGURE 3–1 Glycerophospholipids. Along with cholesterol, these form the bilayer that separates the inside of cells and supports the embedded membrane proteins. (Modified with permission from Landowne D: Cell Physiology, New York: Lange Medical Books/McGraw-Hill, 2006.)

two acyl chains and a phosphate-linked choline head linked to a serine backbone, and glycosphingolipids, which have sugars in the head group. Membranes also contain cholesterol, which has a steroid ring structure. All of these lipids are amphipathic because they have hydrophilic, or “water-loving,” head groups and hydrophobic, or “water-fearing,” acyl tails. The –OH group of cholesterol is hydrophilic and the rest is hydrophobic. A hydrophobic effect arises from the lack of interactions of hydrocarbons with water and the strong attraction of water for itself. Thus, when placed in an aqueous environment, these lipids spontaneously assemble into closed bilayer membrane vesicles. The lipids are relatively free to diffuse laterally within the plane of the membranes, but—with the exception of cholesterol—they are unlikely to flip-flop from one half of the bilayer to the other owing to the hydrophilicity of the head groups. The bilayer is asymmetrical, with the cholinecontaining phospholipids, PC and sphingomyelin, in the outer half and the amino-containing phospholipids, PE and PS, in the inner half. In addition, the glycosphingolipids are in the noncytoplasmic half and PI is facing the cytoplasm. The asymmetrical arrangement is produced as the membranes are assembled in the ER. The phospholipids are synthesized and inserted on the cytoplasmic side of the membrane; then a phospholipid translocator or “flippase” transfers PC to the noncytoplasmic side. Sphingomyelin and the glycosphingolipids are produced in the Golgi apparatus on the noncytoplasmic side.

The ease of lateral diffusion, or membrane fluidity, is increased by the presence of unsaturation or double bonds in the hydrocarbon tails. This forms a kink in the tail and therefore looser packing. At the concentrations generally found in biological membranes, cholesterol reduces the fluidity because of its rigid ring structure. Glycosphingolipid head groups tend to associate with each other and reduce fluidity. Lipid protein interactions may also reduce fluidity. There are cholesterol– sphingolipid microdomains, or “lipid rafts,” involved in intracellular trafficking of proteins and lipids.

PROTEINS The intrinsic proteins of the membrane support the selective movement of ions and small molecules from one side of the membrane to the other, sense a ligand on one side of the membrane and transmit a signal to the other side, and provide mechanical linkage for other proteins on either side of the membrane. The proteins that move materials across the membrane can be functionally divided into channels, pumps, and transporters. Channels may be specific and may open and close, but, when open, they facilitate the movement of materials only with their electrochemical gradients. Ion channels control the flow of electrical current through the membrane. Pumps move ions against their electrochemical gradient at the expense of consuming ATP. The pumps maintain the gradients that allow the channels and transporters to do their jobs. Transporters can link the

CHAPTER 3 Cell Membranes and Transport Processes movement of two (or more) substances and can move one of them against its gradient at the expense of moving the other one with its gradient. A protein is the product of translating a gene; it is a folded, linked sequence of alpha amino acids chosen from a palette with 20 possible different side chains. The peptide link between amino acids –CO–NH– has a planar transconformation; the folding occurs according to the torsion angles between the amino group and the alpha carbon (Φ) and between the alpha carbon and the carboxyl group (ψ). The alpha helix axis and the beta sheet are secondary structures, with particular torsion angles, that are found in proteins. The conformation or tertiary structure of the entire protein is the three-dimensional relationship of all its atoms. Proteins have regions of various secondary structures connected by linkers with less easily characterized structure. Most of the proteins discussed in this book have more than one conformation. For example, a channel may be open or closed. The local secondary structures do not change very much during these conformational changes; rather, change occurs in the relationship between larger portions of the molecule. There is also a supermolecular or quaternary level of organization. Some channels are made of a single polypeptide chain, while others are made of four to six chains. Many channels also have accessory proteins that modulate their function. In addition, the lipid matrix imposes structural restrictions on the embedded proteins. In general, proteins are amphipathic and have regions that are more hydrophobic or hydrophilic, depending on the nature of the side chains. The membrane proteins discussed here have one or more transmembrane (TM) alpha-helical segments with hydrophobic side chains in contact with the hydrocarbon of the lipid. If more than one helix is involved, it is possible to have hydrophobic residues facing the lipid and other groups facing each other in the more interior parts of the protein. The general pattern is for the protein to cross the membrane several times, with intracellular and extracellular loops between TM segments. There is also an N-terminal region before the first segment and a C-terminal region after the last; an example is shown in Figure 3–3. The N-terminal region can be on either side, but the C-terminal region is usually cytoplasmic. Either or both terminal regions can be quite large compared to the TM regions. The TM folding occurs as the protein is synthesized in the ER. The noncytoplasmic portions of the protein may be glycosylated in the Golgi apparatus before being inserted in the surface membrane. Subunit assembly may also occur in the ER or Golgi apparatus. For most membrane proteins, only the primary sequence is known. Secondary structure can be predicted by sequence analysis. The presence of putative hydrophobic helices of sufficient length is taken as a suggestion of a TM segment. A topology or pattern of loops and TM segments can be predicted; such a prediction has been tested for many proteins by preparing antibodies for the putative extracellular portions. Sequence

17

analysis of entire genomes suggests that about 20% of the proteins contain one or more TM segments and are thus membrane proteins. Only a few membrane proteins have been crystallized and subjected to x-ray diffraction analysis. These crystals must include lipid or detergent molecules to satisfy the hydrophobic needs of the TM segments. Most of the solved structures are of bacterial proteins that have been genetically modified to enhance crystallization. A strong sequence homology between the crystallized molecule and part of the human protein is taken to indicate that they have similar structures. Channels, pumps, transporters, receptors, and cell adhesion molecules come in many varieties to serve many roles. The following five sections will describe a taxonomy and the anatomy of examples of each functional class. It may be useful to return to this section while reading the later part of this chapter and those parts of the rest of the book that describe the role of these molecules in physiological processes.

CHANNELS In the previous chapter, channels were distinguished by the mechanism by which they open. There are mechanosensitive channels involved in sensory processes, voltage-sensitive channels involved in action potential propagation, and chemosensitive channels involved in synaptic transmission. There are also channels that are usually open, such as channels that maintain resting potential, water channels, and specialized cell–cell channels that connect the cytoplasm of one cell with the cytoplasm of another. This section describes some channels that support various cell processes discussed later in the book. It is not exhaustive; many channels and many classes of channels are not mentioned. This is a “golden age” for ion channels. Electrophysiology and molecular and structural biology are revealing some amazing membrane proteins. Many ion channels are selective and are named according to the ion that passes through them. The first channel to be crystallized is the resting potential potassium channel, also known as the inward rectifier or Kir. The reason for this name is discussed in the next chapter, along with its function. Kir is a tetramer with four identical subunits arranged with radial symmetry and a pore that permits ion flow at the axis (Figure 3–2A). Each monomer has two TM segments with an extracellular P loop in between (Figure 3–2B; see also Figure 3–4, segments 5 and 6). The four P loops dip back into the membrane and together form the lining of a pore that goes about one third of the way through the membrane. This pore empties into a larger intramembranous cavity that communicates with the cytoplasmic space. The eight helices form a wall for the cavity and also surround the inserted P loops. The TM helices form a conical structure with the point toward the cytoplasm. The selectivity of the pore for potassium ions depends on the specific amino acids forming the lining. VGYGD is the

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SECTION II Cell Physiology

A

B

C

FIGURE 3–2 The crystal structure of an inward rectifier K channel (Kir). A) Top view of a ribbon-structure representation with stick-and-ball for the GYG sequences. B) Side view with two monomers removed; the GYG sequence is a space-filling representation. C) Close-up view of two VGYGD sequences and an ion. (Modified with permission from Landowne D: Cell Physiology, New York: Lange Medical Books/McGraw-Hill, 2006.)

K-channel signature sequence (Figure 3–2C); it has been found in K channels from more than 200 organisms. This portion of the molecule is the selectivity filter because it accepts K+ ions and excludes other ions. The pore is lined with the carbonyl oxygen groups; these are in the same relation to each other as the oxygen of the water molecules that coordinate around K+ ions in solution because of its positive charge and the oxygen’s electronegativity. Two of the coordinating oxygens from glycines just below the tyrosines can be seen in Figure 3–2C. Ions with different charges or radii will coordinate water differently and thus will be less likely than K+ ions to leave the water and enter the K channel. It is thought that Figure 3–2 represents a closed Kir channel. The structure of another prokaryotic 2-TM channel has been solved; its inner helices are bent and splayed open, creating a wide entryway. This second Kir channel responds to Ca2+ on its intracellular side by increasing its open probability. The Ca2+ binds to the regulator of K conductance (RCK) domain in the C-terminal part of the protein, not shown in Figure 3–2, inducing a conformational change that splays the inter-

nal helices. Ca2+ and cyclic nucleotides increase the open probability of some other 2- and 6-TM channels by a similar mechanism. There are eight subfamilies of 2-TM Kir channels in the human genome. Several are important in cardiac electrophysiology. Kir2 (or IK1) is the original inward rectifier discovered in cardiac muscle; it is responsible for maintaining the resting potential. Kir3 channels open via G protein–coupled receptors (GPCRs); in the heart, they are referred to as KACh. Kir6 channels open when the ADP/ATP ratio rises. In the heart, they are referred to as KATP.

MECHANOSENSITIVE CHANNELS Mechanosensitive channels are a diverse class of structurally unrelated channels that subserve many different functions in different cells. Mechanosensation is important for touch and hearing and also for sensing blood pressure and for proprioception, providing information about position,

CHAPTER 3 Cell Membranes and Transport Processes

G Y G

P S1

S2

+ + S4 + +

S3

S5

19

S6

C N

FIGURE 3–3 The topology of one monomer of voltage-dependent K channels (KV). The six transmembrane helices (S1–S6) are characteristic of all voltage-dependent ion channels. (Modified with permission from Landowne D: Cell Physiology, New York: Lange Medical Books/ McGraw-Hill, 2006.)

orientation, velocity, and acceleration of the body and its parts. The channels are associated with accessory molecules and cellular structures that enhance their particular functions. Somatic nonsensory cells also respond to mechanical stress without informing the nervous system—for instance, to compensate for osmotic swelling or modulate secretion or contraction. Many mechanosensitive channels are relatively nonselective cation channels. Some are very large and permit electrolytes and small metabolites, but not proteins, to cross the membrane. The two structures that have been solved are bacterial. One is a homopentamer, with each subunit containing two TM helices. The other is a heptamer, with each subunit containing three TM helices. These are beautiful structures, but they do not shed much light on the many other forms of mechanosensitive channels.

VOLTAGE-SENSITIVE CHANNELS Voltage-sensitive K channels (KV) are responsible for the return to the resting state, which ends an action potential. KV has a core structure similar to that of Kir and an additional four TM helices on each subunit (see Figure 3–3). The fourth TM segment (S4) is distinguished because it has between four and eight positively charged side chains (Arg or Lys). S4

P S1

S2

S3

+ + + +

S4

S5

S6

is a signature feature of voltage-sensitive channels. It is thought to be the voltage sensor that moves toward the extracellular surface when the membrane potential changes and causes the conformational changes that lead to channel opening. There are nine subfamilies of KV channels and several more 6-TM-channel subfamilies, including the Ca-activated K channels, the hyperpolarization-activated channels important for pacemaker activity in the heart, and cyclic nucleotide–gated channels. The last two families are nonselective cation channels. Voltage-sensitive Na channels (NaV) are responsible for the upstroke of the action potential and support its propagation. Voltage-sensitive Ca2+ channels (CaV) couple membrane potential changes with an increase in intracellular Ca2+ concentration, which acts as a second messenger to control a variety of intracellular processes. NaV and CaV channels have a structure similar to the KV channels except that they are single larger molecules incorporating four domains, each with slightly different 6-TM segments (Figure 3–4). The selectivity filters have four different walls. The CaV channel has four characteristic glutamates (EEEE) in its pore lining, one on each domain. The NaV channel has a DEKA pattern on the four walls of its pore. These side chains must be exposed to the lumen of the pore. The charges they expose to the lumen and the size of the pore determine the selectivity of the channel.

P S1

S2

S3

+ + + +

S4

S5

S6

P S1

S2

S3

+ + + +

S4

S6

P S1

S2

S3

S4

S5

S6

C

N

FIGURE 3–4

S5

The topology of voltage-dependent Na channels (NaV). Four slightly different domains are linked together in one protein.

(Modified with permission from Landowne D: Cell Physiology, New York: Lange Medical Books/McGraw-Hill, 2006.)

20

SECTION II Cell Physiology

CHEMOSENSITIVE CHANNELS There are many different chemosensitive or ligand-gated channels. These control the flow of ions and thus generate electrical signals in response to specific chemicals, such as acetylcholine (ACh), glutamate, or ATP. They can be grouped into three different superfamilies according to the stoichiometry and membrane topology of their subunits. Many of these were first discovered pharmacologically by noticing that certain compounds, called agonists, produced membrane currents or altered the electrical activity of cells and other compounds; antagonists could block these effects. For some agonist-induced currents, the ligand binds the same molecule that contains the pore. These are the ligand-gated channels, which are sometimes called ionotropic ligand receptors to distinguish them from metabotropic ligand receptors, where the ligand binds a GPCR and triggers a biochemical cascade that may include opening of other channels, for example, KACh, described above. The ACh receptor channels (AChRs) are referred to as nicotinic AChRs, or nAChRs. The term nicotinic indicates these receptor bind nicotine, which also opens the channels. nAChRs are distinguished from muscarinic AChRs, which are not channels but rather GPCRs. nAChRs are found on the postsynaptic membranes at skeletal neuromuscular junctions and in the autonomic and central nervous systems. The best-studied nAChRs are heteromeric pentamers (Figure 3–5). The monomers have four TM segments each and

a large extracellular N-terminal region. At the neuromuscular junction, the nAChR has two alpha subunits, with Ach-binding sites at the interface between subunits and far from the lipid membrane. ACh binding induces a conformational change that opens the pore formed at the level of the lipid membrane and lined by the second TM segment of each of the monomer’s five subunits. The open channels are highly permeable to both Na+ and K+, slightly permeable to Ca2+, and not permeable to anions. They are not as selective as the Kir or voltage-sensitive channels. Functionally, the Na permeability is most important, as discussed in Chapter 7. The CNS postsynaptic receptors for glycine (glyR), gammaaminobutyric acid (GABAAR), and serotonin (5HT3R) have similar pentameric architecture, although some are homomeric, as are some nAChRs. glyRs and GABAARs are selectively permeable to anions and produce inhibitory postsynaptic potentials (IPSPs.) 5HT3Rs are cation-selective, similar to nAChRs, and produce excitatory postsynaptic potentials (EPSPs). The most common CNS EPSP channels are glutamate receptors (gluR), which have an architecture (Figure 3–6) reminiscent of an inverted Kir molecule with extra TM segments. gluRs are heteromeric tetramers with three TMs per subunit. They have a large extracellular region with four glutamatebinding sites and a cytoplasmic-facing P loop. Several functionally different gluRs are discussed in more detail in Chapter 7. They are all cation-selective; some allow Ca2+ entry and others do not.

N N

C Out Out

In In

C β

α γ

α δ

FIGURE 3–5 The topology of one monomer of nicotinic acetylcholine receptor channels (nAChR), with a top view showing the arrangement of the five monomers. (Modified with permission from

FIGURE 3–6 The topology of one monomer of glutamate receptor channels (gluR), with a top view showing the arrangement of the four monomers. (Modified with permission from Landowne D: Cell

Landowne D: Cell Physiology, New York: Lange Medical Books/McGraw-Hill, 2006.)

Physiology, New York: Lange Medical Books/McGraw-Hill, 2006.)

CHAPTER 3 Cell Membranes and Transport Processes The ATP-sensitive channels or P2X receptors (P2XRs) have two TMs per subunit and three subunits per channel. “P” refers to the purine sensitivity; adenine is a purine. P2 distinguishes them from P1 receptors, which are sensitive to adenosine and act through adenylyl cyclase (AC). The P1 receptors are often referred to as A receptors (A for adenosine); they are GPCRs. Caffeine is an antagonist of some of the A receptors. P2 receptors prefer ADP or ATP to adenosine. P2XRs are channels and P2YRs are GPCRs. Purinergic receptors are best known as regulators of blood flow in tissues; they have also been implicated in several sensory processes. Two additional channel families have chemosensitive members but also have important members without known ligands. These are the epithelial sodium channel (ENaC) and the inositol triphosphate (IP3) receptor (IP3R) family. ENaCs are important in the reabsorption of sodium from the nascent urine in the tubules of the nephron. They are thought to be heteromeric tetramers each with two TM segments; they are not voltage-dependent. It is known that they are regulated by control of their insertion and removal from the membrane, and there may be an unknown ligand for this channel. There are structurally related channels in invertebrates that have known ligands. IP3Rs and the related ryanodine receptors (RyR) are found in the membrane of the ER. When open, they permit the release of Ca2+ from the ER. IP3 is a second messenger produced by the action of phospholipase C (PLC) on the membrane lipid phosphotidylinositol, which has been previously phosphorylated to be PIP2. RyRs also control the release of calcium, primarily in muscle, from the sarcoplasmic reticulum. Ryanodine refers to a toxin that partially opens these channels. RyRs are opened by direct interaction with a modified CaV channel in skeletal muscle and by intracellular Ca2+ in cardiac muscle. The functions of IP3Rs and RyRs are discussed in further detail in Chapters 9 and 10. RyRs are homotetramers with an enormous 20-nm-diameter cytoplasmic N-terminal region. The total molecular weight for the tetramer is above 2,000 kDa, about 10 times larger than NaV or KV channels. IP3R channels are also homotetramers about half the size of RyRs. It has been predicted that IP3Rs have 6 TM segments per monomer and RyRs have 4–12.

CELL–CELL CHANNELS In most tissues, there are channels that connect the cytoplasm of one cell to the cytoplasm of its neighbor. The exceptions are free-floating cells in the blood and skeletal muscle cells. These channels are mostly between cells of the same type, but there are some cells of different type with junctions between them. These channels were originally detected electrically by showing that current could pass from one cell to another through an electrical synapse. Later they were associated with an anatomic structure called the gap junction, named for its appearance in electron micrographs. Actually this gap is spanned by matching arrays of proteins from each cell, with up to thousands of cell–cell channels per gap junction. Each cell–cell channel is made of two hemichannels, one from each cell (Figure 3–7). They are also called connexons. A hemichannel is a homomeric or heteromeric hexamer of proteins called connexins. There are more than 15 different connexins with molecular weights between 25 and 50 kDa. They all have four TM segments and two extracellular loops and their N- and C-terminals are in the cytoplasm. Some but not all connexins can form hybrid channels joining different hemichannels on the two cells.

Out

In

N

C

In

WATER CHANNELS Some cells require more permeability to water than is provided by the lipid bilayer. Red blood cells, which must quickly change shape to pass through narrow capillaries, and many epithelial cells, most notably those in the kidney, have specialized water channels or aquaporins (AQPs), which permit the passage of water but exclude ions. The AQPs are found as tetramers with four functional pores, one in each subunit. The subunits have six TM segments and two regions similar to the P loop of KV channels. One of the loops faces the extracellular surface and the other faces the cytoplasm, and they meet in the middle of the membrane. The functions of AQPs and ENaCs are discussed toward the end of this chapter.

21

Out

In

FIGURE 3–7

The topology of connexin, a monomer of cell–cell channels, top view showing the arrangement of six monomers in a hemichannel and side view showing two cell membranes with aligned hemichannels. (Modified with permission from Landowne D: Cell Physiology, New York: Lange Medical Books/ McGraw-Hill, 2006.)

22

SECTION II Cell Physiology

The pore is much larger than the ion channels described above. It is about 1.2 nm and is permeable to anions, cations, and small metabolites as well as second messengers such as ATP, cAMP, or IP3 but not proteins. Experimentally, the pore is permeable to molecules with molecular weights below 1 kDa. Cell–cell channels allow cells in a tissue to work in a coordinated manner. If a cell is damaged, it can close its cell–cell channels leading to its neighbors and thus prevent the loss of small molecules from the whole tissue. This gating is controlled by intracellular Ca2+, H+, or transjunctional voltage. Different connexons have relatively different sensitivity to these three changes. Gating can also be induced by octanol and anesthetics such as halothane. In some situations unpaired connexons, or the related pannexons, can open and allow small molecules to move from the cytoplasm to the extracellular space. Pannexons have been suggested to have a role in inflammation and the response to ischemia by allowing the release of ATP to signal to cells near a site of tissue insult.

Out

Na/K PUMP The Na/K pump, often referred to more simply as the Na pump, moves three Na+ ions out of the cell and two K+ ions into the cell in a cycle that converts one ATP molecule to ADP + Pi. At maximum speed, the pump completes about 100 cycles per second (cps), which means the movement of ions per molecule is much less than a NaV channel, which may allow 1,000 ions/ms to flow into the cell. The NaV channels are open only briefly when the cell is active; the pump runs continuously to recover from the activity. Pump activity increases when intracellular Na+ or extracellular K+ increase and the pump acts homeostatically to restore the original levels. The Na pump is a heterodimer with an alpha subunit that has the Na+, K+, and ATP-binding sites and a beta subunit thought to be important for membrane insertion. The beta subunit has 1 TM segment; the alpha subunit probably has 10. Intracellular

3Nao

E2 3Na

2K

In P

P

P

Out Occluded 3Na

In

2K

P ATP

ADP

PUMPS Ions move across cell membranes via channels, pumps, and transporters. These are three fundamentally distinct mechanisms and the student should be careful not to confuse them. Pumps create and maintain ionic gradients, moving ions against the gradient at the expense of ATP. Channels use these gradients to produce the various electrical signals. Transporters use one or more gradients; the with-gradient movement of an ion (often Na+) is coupled to the against-gradient movement of another substance. Because they consume ATP, pumps are often referred to as ATPases. Five pumps will be described in detail: the Na/K pump, the Ca pump, and three types of proton pump. The first three of these are called P-type pumps, because they are autophosphorylated during the reaction cycle, or E1–E2 pumps, because they have two major conformational states.

2Ko

Out E1 In

2Ki

3Na

ATP

3Nai

2K

ATP

FIGURE 3–8 The Na/K pump cycle. Operating in the clockwise direction the pump moves three Na+ out and then moves two K+ in at the expense of converting one ATP to ADP. (Modified with permission from Landowne D: Cell Physiology, New York: Lange Medical Books/ McGraw-Hill, 2006.)

Na+ and ATP bind to the E1 form of the alpha subunit, which is then phosphorylated and converts to the E2 form (Figure 3–8, lower left, proceeding clockwise). The E2 form releases the Na+ into the extracellular space and binds extracellular K+. The crystal structure of the E2-2K+–Pi form has recently been solved. The overall structure of domains and helices is similar to the Ca pump described below but there are differences related to the specific functions of each pump. The cycle continues when the phosphate is hydrolyzed off the protein; the protein changes back to the E1 form, releases the K+ inside the cell, and then binds the next Na load. As the Na+ and K+ alternately move through the membrane, the pump passes through an occluded state where the ions are not accessible to either solution. Digitalis and ouabain, a related cardiac glycoside, stop the action of the pump by binding extracellularly to the E2 form near the K+-binding location. Digitalis is used to treat a variety of cardiac conditions. It is a relatively dangerous drug and must

CHAPTER 3 Cell Membranes and Transport Processes be used cautiously so as to block only some of the pump molecules and leave others functional. The danger is complicated because extracellular K+ antagonizes the binding of digitalis by driving the pump toward the E1 form; the prudent clinician will monitor blood potassium levels during digitalis treatment. The Na pump is electrogenic, because each cycle moves one net charge out of the cell. This current has only a small effect on the membrane potential compared to ion flow through channels, which is discussed in the next chapter. The net movement of Na+ out of the cell prevents NaCl from accumulating in the cell. If the pump is blocked with cardiac glycosides, the cell will swell because of the osmotic influx of water following the NaCl.

Ca PUMP There are two important Ca pumps, one that pumps Ca2+ from the cytoplasm into the extracellular space and another, the SERCA pump, that pumps Ca2+ from the cytoplasm into the lumen of the sarcoplasmic or ER. They are thought to have similar mechanisms; both are P-type E1–E2 pumps that move two Ca2+ ions out of the cytoplasm and two or three H+ ions into the cytoplasm for each ATP consumed. The SERCA pump structure has been solved in several different states. It is a tall molecule, about 15-nm high and 8-nm thick, mostly extending out of the membrane on the cytoplasmic side. There are 10 TM segments. The cytoplasmic headpiece consists of the actuator (A), nucleotide binding (N), and phosphorylation (P) domains. The three cytoplasmic domains are widely split in the E1 • 2Ca state but gather to form a compact headpiece in the other states. This motion is transmitted to the membrane portion through helices 1–3, attached to the A domain, and 4 and 5, attached to the P domain, to allow the Ca2+ to be released on the noncytoplasmic side. The distance between the Ca2+-binding sites and the phosphorylation site is greater than 5 nm.

H/K PUMP The H/K pump secretes acid into the stomach by pumping two H+ ions out of the parietal cells of the gastric glands and two K+ ions into the cell while splitting one ATP molecule. Similar pumps also operate in epithelial cells in the intestine and kidney. This is an E1–E2 P-type pump and has a beta subunit, similar to the Na/K pump. The H/K pump is inhibited by omeprazole (Prilosec) and other similar drugs used in the treatment of frequent heartburn.

F-TYPE H PUMPS The most significant F-type H pump usually runs in reverse as the F0–F1 ATP synthase found in mitochondria. This protein complex allows protons to flow with their electrochemical gradient and converts the flow of 10 protons to form three ATPs from ADP. The hydrogen gradients are produced by oxidative metabolism in mitochondria.

23

TABLE 3–1 Localization of membrane pumps. Pump

Cell Type

Membrane

Inhibitor

Na/K

All

Surface

Digitalis

Ca

All

Surface and ER

Thapsigargin

H/K

Gut, kidney

Surface

Omeprazol

F-type H

All

Mitochondria

Oligomycin

V-type H

All

Surface and vesicles

Bafilomycin

The pump has 8 different subunits and more than 20 polypeptide chains. The F0 portion spans the membrane and carries the H ions; the F1 extends into the mitochondrial matrix. Part of the complex rotates about an axis perpendicular to the plane of the membrane, similar to a turbine, as the H ions flow through. Another portion, the stator, stays fixed in position, and the interaction between the rotator and the stator produces a sequence of conformational states that favor the synthesis of ATP. In the presence of high ATP, low ADP, and no proton gradient, the process can be reversed to pump H+.

V-TYPE H PUMPS V-type H pumps are also protein complexes of up to 14 subunits with rotors and stators. They move protons into vacuoles and other intracellular organelles such as lysosomes, the Golgi apparatus, and secretory vesicles. The H+ gradient produced across synaptic vesicle membranes is used to drive the packaging of neurotransmitters (see Figures 7–3 to 7–5). These pumps are responsible for the H+ that is secreted by osteoclasts to dissolve bones and also for H+ secretion in the kidney and epididymus (Table 3–1).

TRANSPORTERS Transporters move ions and other small molecules across the membrane and are not channels or pumps. Sometimes the word transporter is used in the general sense to include all transport mechanisms and secondary transporter is used to distinguish this group. Transporters undergo a conformational change as they transport; in this aspect they are similar to pumps and different from an open channel. Unlike a pump, they do not consume ATP. Most transporters are thought to have 12 TM segments in two groups of 6 with a larger cytoplasmic loop between them. Some have a 2-fold pseudosymmetry and P loops facing both surfaces. There are three general categories of transporters: uniporters, symporters or cotransporters, and antiporters or exchangers (Figure 3–9). The glucose transporter (GLUT) is a uniporter that facilitates the diffusion of glucose with its concentration gradient into many cells that are consuming glucose. It also facilitates movement of glucose from cells that are releasing

24

SECTION II Cell Physiology The Cl/HCO3 exchanger, also known as the anion exchanger (AE), is important for moving CO2 from the tissues to the lungs. CO2, produced by metabolism in the cells, is converted to bicarbonate by carbonic anhydrase in the red blood cells, and the HCO3– moves into the plasma exchanging for chloride via AE. The process is reversed as the blood passes through the lungs and the CO2 moves into the air to be exhaled. This process will be covered in Chapter 37. Uniporter

FIGURE 3–9

Symporter

Antiporter

Three types of transporters. (Modified with

permission from Landowne D: Cell Physiology, New York: Lange Medical Books/ McGraw-Hill, 2006.)

glucose by breaking down glycogen and from basal surfaces of epithelial cells that line the intestines and kidney tubules (see Figure 3–14). The Na–glucose cotransporter (SGLT) is a symport that carries glucose into intestinal and kidney epithelial cells across their apical surfaces against the glucose concentration gradient. The energy required for this transport comes from the movement of one or two sodium ions with their electrochemical gradient for each transported glucose molecule. A Na/glutamate cotransporter recovers glutamate that is used as a neurotransmitter at CNS synapses (see Figure 7–4). It couples the downhill movement of three Na+ ions and one K+ ion to the uphill transport of one glutamate. The structure of a bacterial glutamate transporter, which is thought to be similar to that of humans, has recently been solved. It has eight TM segments and two P loops, one facing the cytoplasm and one facing the outside. It is thought that relatively small movements of the protein can transfer the glutamate from one P loop to the other and thus across the membrane. There is an H/glutamate antiporter that uses the H+ gradient, established by a V-type pump, across the membrane enclosing synaptic vesicles to concentrate glutamate inside the vesicle (see Figure 7–4). There are many other Na-driven cotransporters to move other small molecules into cells and H-driven transporters to move some material into vesicles. Some of these transporters are targets for pharmacologic intervention. For example, fluoxetine (Prozac) acts on a Na/serotonin cotransporter. Others are discussed further in Chapter 7. Some anions are cotransported with sodium; for example, the Na/I symporter concentrates iodine into thyroid follicle cells. The Na/Ca exchanger (NCX) is an important regulator of intracellular Ca2+ concentration. Three sodium ions moving with their electrochemical gradient into the cell can move one calcium ion out, or vice versa; all of the exchangers can run either way depending on the relative gradients. The effect of digitalis on cardiac muscle is to raise intracellular Na by inhibiting the Na/K pump. Elevated Nai+ means that there is less inward gradient for Na+ and therefore less Ca2+ efflux via NCX. This increases Cai2+ and produces a stronger contraction (see also Chapter 23).

ABC TRANSPORTERS This mixed group of 12 TM transport proteins contains a characteristic ATP-binding cassette (ABC) amino acid sequence and, in the absence of more specific information, is assumed to consume ATP while transporting some material across the membrane. Two ABC transporters deserve mention here, the multidrug resistance (MDR) transporter, which is a pump, and the cystic fibrosis transmembrane regulator (CFTR), which is a channel. MDR1 extrudes hydrophobic drugs across the cell membrane. It is thought to act somewhat like the flippase and extrudes the drugs without much specificity. A wide variety of cells in the GI tract, liver, and kidney express MDR proteins. These can frustrate the physician who is attempting to provide drugs to treat cancer among these cells. CFTR is a protein that, when mutated, leads to cystic fibrosis. The wild-type protein is a chloride channel that requires phosphorylation by protein kinase A (PKA) and additional ATP hydrolysis by the activated CFTR protein in order to open. The Cl− moves with its electrochemical gradient. Cystic fibrosis occurs because of the lack of Cl− transport in the pancreatic duct (hence cystic). The decreased Cl− leads to decreased water and the protein-rich secretion thickens and can block the ducts that then become fibrotic. Before the development of oral replacement therapy for the missing pancreatic enzymes, many CF patients died of complications of malnutrition. Now the major problem is the thickening of mucus in the lungs because of insufficient fluid secretion.

MEMBRANE RECEPTORS The word receptor comes from pharmacologic studies, where it designates the site of action or the molecule that a small molecule of interest, perhaps a hormone or neurotransmitter, acts on. Here it is used in a more restrictive sense to mean molecules that span the membrane, are acted on the external surface by the small molecule, and trigger some action inside the cell when the small molecule is present. There are also intracellular receptors, for example, the steroid hormone receptor. Steroid hormones and related drugs can cross the lipid bilayer and bind these intracellular proteins. Chemosensitive channels are excluded as well, although some pharmacologists like to call them ionotropic receptors. There are two major categories of these membrane receptors: the GPCRs and the enzyme-linked or catalytic receptors.

CHAPTER 3 Cell Membranes and Transport Processes

Agonist

AC

Effector

GPCR

P

β/γ G protein

25

α ATP

cAMP

PKA

FIGURE 3–10 The Gαs signaling pathway. Binding of agonist to the G protein–coupled receptor causes the dissociation of the α subunit, which causes adenylyl cyclase to raise cAMP levels. This, in turn, causes protein kinase A to phosphorylate an effector protein (in this case a channel). (Modified with permission from Landowne D: Cell Physiology, New York: Lange Medical Books/McGraw-Hill, 2006.)

G PROTEIN–COUPLED RECEPTORS GPCRs have seven TM segments with an extracellular N terminus. They are coupled to a trimeric GTP-binding protein complex. When a hormone or neurotransmitter interacts with a GPCR, it induces a conformation in the receptor that activates a heterotrimeric G protein on the inner membrane surface of the cell (Figure 3–10). In the inactive heterotrimeric state, GDP is bound to the Gα subunit. On activation, GDP is released, GTP binds to Gα, and subsequently Gα–GTP dissociates from Gβγ and from the receptor. Both Gα–GTP and Gβγ are then free to activate other membrane proteins. Most Gα and Gγ are lipidated; they have a covalently attached lipid anchor into the membrane bilayer. The duration of the G-protein signal is determined by the intrinsic GTP hydrolysis rate of the Gα subunit and the subsequent reassociation of Gα–GDP with Gβγ. There are more than 2,000 predicted GPCRs in the human genome, more than 5% of all the genes. More than 800 are olfactory receptors; others detect almost all neurotransmitters and many hormones. Light also is detected by GPCRs in the eye (Figure 5–2). Different cells have different palettes of GPCRs coupled to different G proteins controlling different sets of intracellular reactions. There are only about 16 different Gα subunits and even fewer Gβγ. Three classes of Gα subunits initiate most of the subsequent events described in this book. Gαs stimulates adenylyl cyclase (AC), Gαi inhibits AC and its associated βγ directly activates KAch channels, and Gαq stimulates a phospholipase (PLCβ). AC produces cAMP that can directly influence some channels. cAMP also activates protein kinase A (PKA) by dissociating the regulatory subunits from the catalytic subunits. The PKA phosphorylates many proteins, thus altering the activity of the cells. PLCβ splits the membrane

phospholipid PI to produce IP3 and diacylglycerol (DAG). As described above, IP3 binds the IP3R channels, which increases Cai, which in turn triggers various reactions. Several examples of GPCR-initiated cascades are described more fully in later chapters. The toxins that underlie two infectious diseases, cholera and pertussis, ADP-ribosylate Gα subunits leading to constitutive activation. In cholera, activated Gα in intestinal epithelial tissue stimulates AC, cAMP levels increase, and CFTR chloride channels open, leading to a watery diarrhea. People with cystic fibrosis can be resistant to cholera because they have fewer functional chloride channels. The cellular pathogenesis of pertussis is not clear.

ENZYME-LINKED RECEPTORS Most enzyme-linked receptors are receptor tyrosine kinases (RTK) and act by phosphorylating tyrosine side chains on other proteins, which may in turn phosphorylate other proteins. Some enzyme-linked receptors are not kinases themselves but are coupled to an associated protein that phosphorylates other proteins. Some enzyme-linked receptors are guanylyl cyclases, tyrosine phosphatases, or serine kinases. Most growth and differentiation factors act by binding specific RTKs. The insulin receptor is an RTK that phosphorylates a family of substrates known as insulin-receptor substrates; these stimulate changes in glucose, protein, and lipid metabolism and also trigger the Ras signaling pathway, activating transcription factors that promote growth. Interferon receptors and the CD4 and CD8 molecules on the surface of T lymphocytes are examples of receptors that are coupled to cytoplasmic tyrosine kinases.

26

SECTION II Cell Physiology

CELL ADHESION MOLECULES Most cells except red blood cells have integral membrane proteins that attach to the extracellular matrix or with adhesion molecules on neighboring cells. These molecules hold the tissue together and can allow the transmission of mechanical forces from one cell to another. They can act as signals during development, so one cell can recognize another. Many also act as receptors, informing the inside of the cell that they have bound something. Some are controlled from the inside, binding only when some signal has been received. The integrins are examples of cell-matrix adhesion molecules. They have a single TM segment and link cells to fibronectin or laminin in the extracellular matrix. Cadherins are Ca-dependent cell–cell adhesion molecules; they are glycoproteins with a single TM segment and are thought to bind homophilically (to another copy of the same molecule) to cadherins on the other cell. Cadherins have been found at many neuron–neuron synapses. There is a large family of cell adhesion molecules, of which the N-CAMs are the best understood. N-CAMs are found on a variety of cell types and most nerve cells. Like cadherins, N-CAMs have a single TM segment and bind homophilically, but they differ in that they do not require Ca2+ for binding. Intercellular adhesion molecules (ICAMs) are a related class expressed on the surface of capillary endothelial cells that have been activated by an infection in the surrounding tissue. They bind heterophilically (to a different molecule) to integrins on white blood cells and help them move to the site of infection. Selectins are carbohydrate-binding proteins on the endothelial cell membrane that recognize sugars on the surface of the white blood cell and form the initial binding, which is strengthened by the ICAMs.

TRANSPORT ACROSS CELL MEMBRANES From a functional point of view, discussion of the transport of materials across cell membranes can be divided into passive transport, where the materials move with their concentration

Flux

gradient, and active transport, which creates or maintains these gradients.

PASSIVE TRANSPORT Simple Diffusion Some materials can move with their concentration gradient by simple diffusion though the lipid bilayer. Small, uncharged molecules such as O2, CO2, NH3, NO, H2O, steroids, and lipophilic drugs can enter or leave cells by simple diffusion. The net flux of these compounds through the membrane is proportional to difference in their concentrations on the two sides, or as expressed in the following equation: J1→2 = –P(C2 – C1) = –PΔC

(1)

Using the centimeter–gram–second (CGS) system of units, J1→2 is the number of moles that move through a square centimeter of membrane from side 1 into side 2 each second and C1 and C2 are the numbers of moles of the material per cubic centimeter of solution on the two sides. P, the proportionality constant, is called the permeability of the membrane to this material in centimeters per second. The equation is written with the leading minus sign as an aid to remembering that the flux is moving with the concentration gradient. This relationship is shown graphically in Figure 3–11. Equation (1) is Fick’s first law. It can be used to describe the flux by simple uncharged substances through any membrane. For example, it is useful to describe the movement of oxygen from the air into the alveoli of the lungs and into the blood, across the cells of the alveolar epithelium and the capillary endothelium. A charged species will also be influenced by the electrical potential difference across the membrane in a manner to be discussed in the next chapter. If there is no potential difference across the membrane, Fick’s law is also applicable to charged substances. Permeability describes a property of a particular membrane in relation to a particular substance. The membrane is considered permeable, while the substances are said to be permeant or to permeate. The permeability will be proportional to the ability of the substance to partition into the

Flux

Vmax

Concentration

FIGURE 3–11

Km

Concentration

The concentration dependence of simple diffusion (left) and facilitated diffusion (right). (Reproduced with permission from

Landowne D: Cell Physiology, New York: Lange Medical Books/McGraw-Hill, 2006.)

CHAPTER 3 Cell Membranes and Transport Processes membrane and to diffuse within the membrane. The permeability will be inversely proportional to the thickness of the membrane. It is usually not easy or necessary to know these three factors separately, but one should appreciate that thickening of the complex membrane between the alveolus and the pulmonary capillary blood will reduce the movement of oxygen into blood. It is sometimes convenient to think of Fick’s law as saying that the net influx of a substance is equal to the unidirectional influx (PC0) minus the unidirectional efflux (PCi). The permeability is a measure of the ease with which a solute crosses through a membrane. Plain lipid bilayers are relatively permeable to small, uncharged molecules; the permeability to water is about 10−3 cm/s. Thus, water equilibrates across a cell membrane in a few seconds. Urea is moderately permeable (P = 10−6 cm/s), and its equilibration time is a few minutes. Hydrophilic small organic molecules such as glucose or uncharged amino acids are less permeable, with P = 10−7 and equilibration times of hours; ions are essentially impermeable, with P = 10−12 cm/s and equilibration times of many years.

27

ACTIVE TRANSPORT Pumps provide primary active transport, moving materials against their electrochemical gradients at the expense of ATP. The Na/K pump moves Na+ out of the cell and K+ into the cell; both ions are moving against their respective gradients. The SERCA pump moves Ca2+ against its gradient from the cytoplasm into the lumen of the ER. Cotransporters and exchangers can provide secondary active transport, using a gradient produced by primary active transport to move another material against its gradient. Many transporters couple the movement of Na+ or H+ with its electrochemical gradient with the movement of another substance against its gradient. The Na-GLUT and the H/glutamate antiporter are two examples of secondary transport mechanisms. The flux by pumps and transporters can be described by equations similar to equation (2), modified to include the affinity for each substance and for ATP. When more than one ion at a time is involved in the reactions at one pump or transporter molecule, the equation must also be modified to reflect this cooperativity. Thus, the efflux of sodium through the Na/K pump has a sigmoidal relationship to the internal Na+ concentration.

Facilitated Diffusion Many substances, such as glucose or urea, easily enter cells in spite of the fact that the lipid bilayer is relatively impermeable to them. The flux of these materials is described by Fick’s law only for low concentrations. At higher concentrations, the flux saturates at a maximum value (see Figure 3–11). This behavior can be described by the Michaelis–Menten equation, which is also used to describe enzyme kinetics. The unidirectional flux is given by the following equation: J

C

max J = _____ C+K

(2)

m

where Jmax is the maximum flux and Km the affinity or the concentration at which the flux is half its maximum value. This saturable property of the flux suggests that there are a fixed number of sites at which the flux can take place. Also, as in the case of enzymes, it may be possible to demonstrate the competition of different substances for the same site or noncompetitive inhibition of the transport sites. The sites are selective for a particular substance or group of substances that they will transport or that allow competition for transport. Selectivity, affinity, and Jmax are three independent qualities of the sites; they will be found with different values in different systems. Facilitated diffusion is now understood in terms of channels or transporters. Most channels have low affinity or high Km values; they are not saturated under normal physiological conditions. Three glucose uniporters, GLUT1, GLUT3, and GLUT4 (which is regulated by insulin), are found in many tissues and have a high affinity for glucose; they are saturated at all physiological concentrations. GLUT2, which is found in tissues carrying large glucose fluxes (such as intestine, kidney, and liver), has a low affinity for glucose, and the influx through GLUT2 transporters increases as the glucose concentration increases.

OSMOSIS Life is intimately associated with the movement of water. Our bodies are mostly water and are vitally dependent on its supply. Water is a small but abundant molecule. It is not much larger than an oxygen atom, about 0.2 nm across—small enough to intercalate between other molecules, even in some crystals. A mole of water is 18 mL; thus, pure water is 55 mol/L. This concentration is several hundred-fold higher than the Na+, K+, or Cl− concentrations in the body that are the next highest. More than 99% of the molecules in the body are H2O. Because the molecules are small, they move easily; because they are so abundant, their movements are important to our health. There are two or three distinct mechanisms for water movement: bulk flow, molecular diffusion, and, perhaps, molecular pumping. When you pull the plug in a bathtub or your heart beats, there is bulk flow of fluid in response to an external mechanical force—a push or a pull. The driving force for bulk flow is the mechanical pressure commonly produced by pushing or by gravity. Molecular diffusion or osmosis is a passive process by which water diffuses from areas of high water concentration to those of low. There is a high water concentration where there is low solute concentration, and vice versa. Water can diffuse across most cell membranes directly through the lipid bilayer or by traveling through AQPs. Many cells produce AQPs, because simple diffusion does not permit adequate water flux. Some kidney cells insert AQPs in response to antidiuretic hormone (ADH), so as to increase water flow from the forming urine back into the blood, thereby conserving water. This passive type of water movement is called osmotic flow, and the associated driving force is the concentration gradient of the water.

28

SECTION II Cell Physiology

Water may also be transported across membranes at the expense of energy by the Na–glucose cotransporter (SGLT). The TM transport of two Na+ ions and one sugar molecule has been associated with the influx of 210 water molecules, independent of the osmotic gradient. The energy could come from allowing Na+ to move with its concentration gradient. This molecular pumping would be a secondary active transport mechanism and might account for almost half the daily uptake of water from the small intestine. Osmotic pressure is the mechanical pressure needed to produce a flow of water equal and opposite to the osmotic flow produced by a water concentration gradient. In animal cells, this pressure does not develop across the cell membrane because the cells will change their volume in response to osmotic flow. The concept of osmotic pressure is similar to (and historically preceded) the Nernst equilibrium potential, an electrical potential that produces a flow of ions equal and opposite to a flow produced by a concentration gradient. The Nernst potential is discussed in Chapter 4. If two different solutions are in contact, the osmotic pressure, π, between them is: π = RTΔc

(3)

where R is the molar gas constant (Avogadro’s number times Boltzmann’s constant), T the absolute temperature, and Δc the concentration difference of all of the impermeable solutes. The concentration difference refers to the summated molar concentration of all the particles created when the solute is dissolved in water. It is measured as the osmolarity, that is, the sum of the moles of each component of the solution. A 2-mM solution of MgCl2 contains 6 milliosmoles (mOsm) per liter of solution, 2 for the Mg2+ and 2 for each Cl−. The osmolarity of this solution is 6 mOsm. A 3-mM NaCl solution and a 6-mM urea solution have the same osmolarity because they have the same number of particles per liter of solution. They are said to be isosmotic. The osmolality of a solution can be measured by the change it produces in the freezing point or vapor pressure. Osmolality refers to moles of solute per kilogram of solvent, whereas osmolarity refers to moles of solute per liter of solution. Because 1 L of any body fluid contains very close to 1 kg of water, the distinction is moot in clinical situations, and you may hear

300 mM NaCl

150 mM NaCl

300 mM urea

Cell volume

150 mM NaCl

the terms used interchangeably. Also, the actual pressures are rarely discussed; rather, the osmoles are mentioned directly. Tonicity is a concept that is related to osmolarity but is a special case for cells. A solution is said to be isotonic if it causes neither shrinking nor swelling of cells. A 150-mM NaCl solution (9 g/L or 0.9%) is isotonic for mammalian cells and also isosmotic to the cell contents. A 300-mM urea solution is also isosmotic to the cell contents, but a cell placed in this solution will swell and eventually lyse or burst (Figure 3–12). The urea solution is hypotonic; it has insufficient tonicity to keep the cell from swelling. It differs from the NaCl solution because the urea can cross the cell membrane. The addition of a permeable material to a solution increases its osmolarity but not its tonicity. The addition of more impermeable solutes makes a hypertonic solution; a 300-mM NaCl solution is hypertonic and will cause cells to shrink. If a moderately permeable solute is added to an isotonic solution (e.g., 300-mM urea + 150-mM NaCl), the cells will transiently shrink and then return to their original volume (Figure 3–13). The rate at which they shrink is proportional to the water permeability of the membrane; the rate at which the volume recovers is proportional to the urea permeability. If the original 150-mM NaCl solution is replaced, the opposite effects will occur. The cells will swell as water rushes in and then return to their original volume as the urea (and water) leaves the cell. In some cases, it is convenient to consider a reflection coefficient as a description of the permeability of solutes. Water movement across capillary walls depends on the mechanical or hydrostatic pressure difference and on the difference in colloid osmotic pressure due to differences in protein concentration in the plasma and the interstitial fluid. If the capillary wall is completely impermeable to the proteins, it is said to have a reflection coefficient of 1.0. If the walls become leaky, the reflection coefficient decreases, proteins enter the interstitial space, and water follows. Water movement in the whole body is concerned with two compartments, intracellular and extracellular. The extracellular compartment has two subcompartments: the plasma fluid in the blood vessels and the interstitial fluid that bathes the rest of the cells. The plasma and the interstitial fluid are separated by the capillary walls, which are freely permeable to all the small molecules and ions but normally prevent the plasma

Time

FIGURE 3–12

Cells shrink in hypertonic solutions and swell in hypotonic solutions. (Modified with permission from Landowne D: Cell Physiology,

New York: Lange Medical Books/McGraw-Hill, 2006.)

CHAPTER 3 Cell Membranes and Transport Processes

150 mM NaCl + 300 mM urea

150 mM NaCl

Cell volume

150 mM NaCl

29

Time

FIGURE 3–13

The addition of urea causes transient shrinking but does not change the steady-state tonicity. (Modified with permission

from Landowne D: Cell Physiology, New York: Lange Medical Books/McGraw-Hill, 2006.)

proteins from entering the interstitial fluid. The proteins have an overall net negative charge at blood pH. The equilibrium that arises with impermeable proteins and freely permeable ions is called the Gibbs–Donnan equilibrium. This effect produces small ion concentration gradients (<3%) and a small potential (a few millivolts, lumen-negative) across the capillary walls. For most clinical purposes, these can be ignored and the ionic concentrations in the plasma, which are easily measured, can be considered to represent the extracellular fluid in general. The plasma proteins are osmotically important; they tend to keep water in the blood vessels. The balance between the hydrostatic pressure and this “colloid” osmotic pressure is described by the Starling hypothesis discussed in detail in Chapter 26. It regulates the flow of water across capillary endothelia. Edema represents the loss of this balance. Intracellular proteins promote the entry of water into cells that is counteracted by the extrusion of sodium ions by Na/K pumps. Cell membranes are not freely permeable to ions and the intracellular compartment is not in Gibbs–Donnan equilibrium with the extracellular space. Short-term changes in the volumes and osmolarity of body compartments can be calculated using the following four principles: in every compartment, the volume times the osmolarity is the total number of osmoles. Water will move between the compartments to make the osmolarity equal in all compartments. The total amount of water and the total number of osmoles is the sum of the amounts in the compartments. Any added impermeant osmotically active substances will remain extracellular; added water will distribute among the compartments according to the first three principles. These calculations do not include the effects of the renal system (Chapter 45) that will act to restore the original volumes and osmolarities. For example, consider a 70-kg medical student with 16 L of extracellular fluid and 24 L of intracellular fluid for a total of 40 L. If the osmolarity of these compartments is 300 mosm, the extracellular compartment contains 16 × 0.3 = 4.8 osm and the intracellular compartment contains 7.2 osm, for a total of 12 osm. If this student should happen to swallow 1 L of seawater containing 1 osm of salts, mostly NaCl, the total water increases to 41 L and the total number of osmoles increases to

13, so the new osmolarity is 13/41 = 317 mosm. The extracellular compartment will have 5.8 osm, so its new volume will be 5.8/0.317 = 18.3 L. The new intracellular volume will be 7.2/0.317 = 22.7 L. Notice that water moved out of the cells to dilute the seawater.

TRANSPORT ACROSS EPITHELIAL CELLS Many epithelial cell layers functionally separate two solutions with different compositions and act in a coordinated way to selectively transport solutes and water across the layer. This is achieved by having tight junctions between the sides of the epithelial cells so that the sheet of cells is impermeable to substances that cannot pass through the cell membranes and by incorporating selective pumps and channels appropriately on the two surfaces of the sheet. The two sides may be called by different names in different epithelia. The apical membrane faces the lumen or outside of the body; it can be known as the luminal or mucosal membrane or the brush border after the appearance of its microvilli. The basolateral membrane that faces the inside of the body can be known as the serosal or peritubular membrane. Figure 3–14 shows pathways for Na+ and glucose transport across epithelial cell layers. Na/K pumps in the basolateral membrane keep the intracellular Na+ low by moving it into the extracellular fluid. Na+ can enter the cell by moving with its concentration gradient through ENaC channels on the apical membrane and leave via the pump on the other side. Glucose may be brought into the cell through the apical membrane, against its concentration gradient by the SGLT, and then move with its concentration gradient through the glucose uniporter (GLUT) on the basolateral surface. When solutes are moved across epithelial membranes, water may flow osmotically, “following” the solute. This effect is important for rehydration therapy to combat the water loss of diarrhea. Adding glucose and salt to the drinking water will stimulate SGLT to move Na+, glucose, and water into the cell. The Na/K pump and GLUT transporter will then move the solutes into the body and the water will follow.

30

SECTION II Cell Physiology

Tight junction

ENaC Na/K pump

Na

Na K

Lumenal apical mucosal

ATP

Basal serosal

ADP

Na Glucose SGLT

Glucose GLUT

FIGURE 3–14 Sodium and glucose are transported through epithelial cell layers by a combination of pumps, channels, and transporters. (Modified with permission from Landowne D: Cell Physiology, New York: Lange Medical Books/McGraw-Hill, 2006.)

Water and water-soluble material may move across epithelia by transcytosis or by receptor-mediated endocytosis. The substance is taken up into vesicles by endocytosis on one surface and either released unchanged by exocytosis on the other surface or broken down in endosomes and the products released by transporters. Transcytosis occurs across capillary endothelia; receptor-mediated endocytosis is important in the kidney and liver.

CLINICAL CORRELATION As she passed her coach and friends at the 15-mile mark of the Boston Marathon, the 28-year-old runner smiled and waved cheerily. She looked good as she passed Heartbreak Hill, about 6 miles from the finish. Two miles later, she stopped to drink a cup of fluid. Another runner remembers her saying she felt dizzy and disoriented. She began to falter and told a friend running next to her that she felt rubber-legged, and then tumbled to the pavement. When she reached the hospital, she was unresponsive with stable vital signs. After endotracheal intubation, a blood serum sodium value was found to be very low at 113 mmol/L. Computed tomography of the brain and chest radiography showed diffuse cerebral and pulmonary edema. She was given intravenous isotonic saline (150 mmol/L) but never regained consciousness. Diffuse cerebral edema was found at postmortem examination. A few days later, the newspapers reported she died from a condition called hyponatremic encephalopathy.

Hyponatremia, defined by a blood sodium concentration less than 135 mmol/L, may lead to hypotonic encephalopathy with fatal cerebral edema. Of 488 runners in the 2002 Boston Marathon providing a usable blood sample at the finish line, 13% were hyponatremic and 0.6% had critical hyponatremia (120 mmol/L or less). The study concluded that hyponatremia occurs in a substantial fraction of nonelite marathon runners and can be severe. It is usually caused by drinking excessive amounts of fluid that exceed the kidney’s capacity to excrete water during exercise. Considerable weight gain during the race, a long racing time, and body mass index extremes were associated with hyponatremia, whereas female sex, composition of fluids ingested, and use of nonsteroidal anti-inflammatory drugs were not. Mild cases can be managed by restricting fluids until the onset of urination. Manifestations of hyponatremic encephalopathy indicate the need for emergent treatment with hypertonic solutions such as 3% saline (513 mmol/L). Na+ and Cl− account for most of the osmotic strength of the serum. If Na+ levels are low, the serum will be hypotonic and water will move into all the cells of the body causing them to swell (edema). This can have serious effects in the brain because it is in the closed space of the cranium and the swollen tissue will restrict blood flow and therefore oxygen supply. Swelling may cause herniation of the brain through the tentorium and foramen magnum, compressing the brainstem and causing respiratory arrest. Blood sodium level is influenced by salt and water intake, sweating, and urinary secretion and is regulated by the endocrine system. The recommendation for marathon runners is to drink only when thirsty.

CHAPTER 3 Cell Membranes and Transport Processes

■

■

■

■ ■

■ ■

■

■

■ ■

■ ■ ■ ■ ■ ■

A lipid bilayer surface membrane with embedded proteins separates and connects cells with the surrounding extracellular environment. Cell membrane lipid molecules are amphipathic, with hydrophobic groups facing the interior of the membrane and hydrophilic groups facing both aqueous interfaces. Cell membrane proteins carry out specific functions by acting as channels, pumps, transporters, receptors, or cell adhesion molecules. Cell membrane proteins are amphipathic, generally with one or more hydrophobic TM helices. Ion channels are membrane proteins with a pore that selects for the type of ion(s) that passes through the channel with their electrochemical gradient. Mechanosensitive channels are generally cation-selective and have diverse structures. Voltage-sensitive channels have a 4-fold symmetry. Each of the parts has six transmembrane helices, one of which carries multiple positively charged amino acids. There are many different families of chemosensitive or ligand-gated channels corresponding to the different chemical ligands. Cell–cell channels connect the interior of one cell to the interior of an adjacent cell by an aqueous path that permits the passage of ions and other small molecules. Pumps move ions or other molecules against their gradients at the expense of ATP. Transporters move some ions or other molecules against their gradients at the expense of having other ions move with their gradients. GPCRs initiate intracellular G-protein cascades under the control of extracellular activators. Some materials can simply diffuse with their concentration gradients through the membrane lipids. Many substances have specific facilitated diffusion mechanisms characterized by an affinity and a maximum transport velocity. Osmotic pressure is proportional to the osmolarity or the total concentration of all solutes. Tonicity describes a solution’s ability to prevent the shrinking or swelling of cells. Substances may be transported through epithelial cell layers by combinations of pumps and transporters arranged on opposite sides of the cells.

STUDY QUESTIONS 1. Cell membranes A) consist almost entirely of protein molecules. B) are impermeable to fat-soluble substances. C) contain amphipathic phospholipid molecules. D) are freely permeable to electrolytes but not to proteins. E) have a stable composition throughout the life of the cell.

2. In an intestinal epithelial cell, glucose transport from the intestinal lumen to the blood involves which of the following processes? A) secondary active transport B) facilitated diffusion C) active transport D) secondary active transport and facilitated diffusion E) Active transport and secondary active transport 3. A solution is prepared by adding 10 g of NaCl (formula weight = 58.5) to 1 L of distilled water. An isotonic solution is 300 mOsm. The prepared solution is A) very hypotonic (with less than 50% normal tonicity). B) slightly hypotonic (about 10% low). C) isotonic (within 1%). D) slightly hypertonic (about 10% high). E) very hypertonic (more than twice normal tonicity). 4. Drinking isotonic saline solution will decrease A) extracellular volume. B) extracellular osmolarity. C) intracellular volume. D) intracellular osmolarity. E) none of the above.

Rate of transport

CHAPTER SUMMARY

Concentration gradient 5. The above diagram is typical for the concentration gradient dependence of A) the rate of secondary active transport. B) the rate of primary active transport. C) the rate of transport by passive diffusion. D) the rate of transport by facilitated diffusion. 6. Which one of the following is least likely to affect Na/K pump activity? A) cardiac glycosides B) second messengers (e.g., cAMP and diacylglycerol) C) intracellular Na+ concentration D) extracellular Mg2+ concentration E) extracellular K+ concentration

31

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C

Channels and the Control of Membrane Potential David Landowne

4

H A

P

T

E

R

O B J E C T I V E S ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■

Describe how membrane potentials are measured and provide typical values for different cells. Discuss the relationship between the separation of charge across the membrane and the membrane potential. List the approximate concentrations of the major ions in the intracellular and extracellular compartments. Describe the three factors that control the movement of ions through membranes. Determine whether an ion will move into or out of cells given the membrane potential and the concentration gradient of the ion. Discuss how the membrane potential changes when ions flow across cell membranes. Explain the steps that occur during the generation of a Nernst potential. Explain the steps that occur during the generation of a resting membrane potential. Discuss why the net flux of charge is 0 in the resting state even though ions are moving through the membrane. Discuss the role of the Na/K pump in the generation of the membrane potential. Define single-channel recording and describe currents through single K channels. Describe the two types of the spread of electrical information in nerve and muscle cells. Discuss why the cell membrane acts as a capacitor and what properties this confers on nerve and muscle cells. Discuss the difference between length (space) and time constants and the relationship of these constants to nerve conduction. Explain the steady-state and transient cable properties of nerve and muscle cells.

INTRODUCTION All living cells have an electrical potential difference across their surface membranes. Cells act as miniature batteries; the battery cell is named after the biological cell. At rest, the inside of cells is negative to the outside by about 0.01–0.1 V or

Ch04_033-042.indd 33

10–100 mV. Concentration gradients of ions across the membrane are the immediate supplier of the energy to create and maintain the resting potential. The resting potential is necessary for electrical excitability of nerve and muscle cells, sensory reception, CNS computation, and to help regulate transfer of ions across the membrane.

33

11/26/10 9:41:01 AM

34

SECTION II Cell Physiology

0 mV Microelectrode In

FIGURE 4–1 Membrane potentials are measured with microelectrodes filled with electrolyte solutions. (Modified with permission

Out

In

Out

−90 mV

Oscilloscope

from Landowne D: Cell Physiology. New York: Lange Medical Books/McGraw-Hill, 2006.)

Muscle

MEASURING MEMBRANE POTENTIALS Figure 4–1 shows how resting potentials are measured. A muscle is secured to the bottom of a dish that is filled with an isotonic salt solution with an ionic composition similar to that of blood. A microelectrode with a fine tip pulled out of glass and filled with 3-M KCl is positioned over one of the muscle cells. A chlorided silver wire in the microelectrode is attached to one terminal of a voltage-measuring device that displays a trace of voltage versus time. The other terminal is attached to another chlorided silver wire placed in the dish; this is called the ground wire. When the microelectrode is in the solution, it is at the same potential as the ground wire and the oscilloscope reads 0 mV. When the microelectrode is advanced a few micrometers into the muscle cell, the trace on the oscilloscope abruptly jumps to about −90 mV and stays there as long as the microelectrode remains in place. When the electrode is withdrawn, the trace returns to 0 mV. The experiment can be repeated. If a second microelectrode is inserted, it measures the same potential, showing that the electrodes are not somehow creating the potential. When the microelectrode is inside the cell, the KCl is in contact with the cytoplasm that is in contact with the membrane. The ground wire is in contact with the external solution, which is in contact with the outside of the membrane. The potential difference is across the membrane; it is called the membrane potential. The particular membrane potential measured when the cell is at rest—that is, not active—is also called the resting potential. Different cells have different resting potentials. Skeletal and cardiac muscle cells have a resting potential of about −90 mV. Sensory and motor neurons have a resting potential of about −70 mV; smooth muscle cells, about −60 mV; and red blood cells, about −10 mV.

150 mmol/L of cations and anions (Table 4–1) with exactly balanced positive and negative charges except for the layer within about 1 nm from the surface of the membrane. The bulk solutions on both sides are electrically neutral. The excess charges of opposite sign experience an attractive force for each other but are prevented from reaching each other because they cannot easily leave the aqueous solutions and enter the oily lipid membrane. Any charge within the membrane also experiences this force, tending to pull positive charges inward and push negative charges outward. The voltage across the membrane is the electrical measurement of this electromotive force or this potential for movement of charges if they happen to be within the membrane. The voltage is directly proportional to the amount of charge (Q) that is separated. The ratio of separated charge to the voltage is called the membrane capacitance: Q

C = __ V

(1)

Electrical charge is measured in terms of coulomb (C); there are 96,484 C/mol of charge (this is Faraday’s constant). The unit of capacitance is the farad (F); 1 C/1 V is 1 F. Capacitance is the ability to store separated charges. Many small computers use a capacitor to store enough charge to allow some minimal function to remain for a short time while the battery is being

SEPARATION OF CHARGE The resting membrane potential is a reflection of the separation of charges across the membrane. There are a few excess negative charges (about 1 pmol/cm2) on the inner surface and the same number of excess positive charges on the outer surface (Figure 4–2). The solutions on the two sides contain about

FIGURE 4–2 The separation of charge. Left: A single layer of charges separated by the membrane. Right: Adding a representation of the mobile charges in the bulk solutions. (Modified with permission from Landowne D: Cell Physiology. New York: Lange Medical Books/McGraw-Hill, 2006.)

CHAPTER 4 Channels and the Control of Membrane Potential

TABLE 4–1 Concentrations of some ions of importance across a muscle cell membrane.a Extracellular concentration (mM)

Ion

Intracellular concentration

Eion (mV)

145

12 mM

+65

4

155 mM

−95

2.5

100 nM

+132

−90

Cations Na+ +

K

2+

Ca

Anions

a

Cl−

132

4 mM

A−

~0

155 mM

HCO3−

22

8 mM

35

ent muscles for Na+, K+, and Cl− values. External Ca2+ is normally about 2.5 mM, but internal Ca2+ can change dramatically with activity, increasing above 1 μM when the muscle is contracting. The cell membrane is permeable to all of the ions listed in Table 4–1 except A−; they can move through the membrane via various channels. The active transport of Na+, K+, and Ca2+ maintains the gradients. If the cell membrane is damaged or there is not an adequate supply of ATP, the cell will gain Na+ and Ca2+ and lose K+. The membrane is not very permeable to ions; compared with water, their permeability is insignificant. However, it is the control of this ionic permeability that regulates the membrane potential and small (by chemical standards) movements of ions that change the membrane potential.

−26

−

A represents impermeant anions inside the cell. Many are polyvalent; all together, they contribute less than 155 mOsm to the osmotic pressure. There are also other uncharged osmolytes in the cell.

changed. The membrane stores the opposite charges by keeping them separated. The membrane capacitance is about 1 μF/cm2. One picomole of univalent ions carries about 100 nC of charge. Putting these values into equation (1) means separating 1 pmol/cm2 of univalent ions will produce a 100-mV membrane potential.

GENERATION OF THE RESTING POTENTIAL The membrane separates two solutions with quite different ionic compositions. The extracellular concentrations are thought to represent the concentration of these ions in seawater at the time the ancient ancestor left the sea. They are about one third the concentration in seawater today. The generation of the resting potential and all of the changes in potential (such as the action potential and the synaptic potentials) depend on the concentration gradients of ions across the cell membrane. Table 4–1 presents some typical values for a skeletal muscle. Both sides are electrically neutral; the sums of positive and negative charges are equal. The external solution has relatively high Na+ and Cl− concentrations and modest K+ and Ca2+ concentrations, whereas the internal solution is high in K+ and low in Na+ and Cl− and very low in Ca2+; it has a high concentration of other anions (A−), such as phosphate groups on proteins or nucleic acids and negatively charged amino acids on proteins. There is an inward concentration gradient for Na+ and Cl− and an outward concentration gradient for K+. The sodium gradient is about 10-fold; Cl−, about 30-fold; and K+, about 40-fold. Table 4–1 indicates a 25,000-fold inward concentration gradient for Ca2+. Exact numbers are given in this table to facilitate the calculation of examples later in this chapter. There is a normal variation of about 10% in different people or differ-

FACTORS THAT CONTROL ION MOVEMENTS The movement of ions through the membrane is proportional to the net driving force on them. The net driving force is the electrochemical gradient or the difference between the driving force due to the concentration gradient and the force due to the voltage gradient or membrane potential. Movement of charged particles is an electrical current. The current, I, carried by a particular ion, x, is related to the driving force by the following expression: Ix = gx (V − Ex)

(2)

where Ex is the chemical driving force for ion x expressed as an electrical potential; this is described more fully below. V is the membrane potential and (V − Ex) is the driving force on ion x. The membrane conductance for ion x is gx. The overall membrane conductance for ion x is proportional to the number of channels for that ion, N; the probability that a channel is open, Po; and the conductance of a single open channel, γ; or: gx = NPoγ

(3)

The conductance is proportional to the permeability of the membrane (the ease with which ions move through it). The conductance is also proportional to the concentration of the conducting ion(s). In the absence of sodium ions, a sodium channel may be permeable (if it is open), but it will not conduct any current. The voltage gradient pushes or pulls an ion because the ion is charged. The concentration gradient is a conjugate force; ions tend to move from a high concentration to a low concentration. More ions will hit an open channel from the side with higher concentration than the side with lower concentration, so there will be a flow with the concentration gradient in proportion to the gradient. To determine the net flux of an ion through the membrane it is necessary to know the concentration gradient, the voltage gradient (the membrane potential), and the conductance for the ion. Unless all three factors are known, it is not possible to predict the flux of the ion. The two forces on the ion from the

36

SECTION II Cell Physiology Cl−

Na+

C V

C V

Cl− −90 mV

ECI =

K+

C

V

Na+ −90 mV

132 60 mV log 4 −1

ECI = −90 mV

ENa =

145 60 mV log 12 +1

ENa = +65 mV

K+ −90 mV

EK =

4 60 mV log 155 +1

EK = −95 mV

FIGURE 4–3 The driving force on ions crossing through the membrane, voltage gradients (V), and concentration gradients (C) for the three most common ions in the solutions in the intracellular and extracellular fluids. (Modified with permission from Landowne D: Cell Physiology. New York: Lange Medical Books/McGraw-Hill, 2006.)

voltage and concentration gradients may act in the same direction or in opposite directions.

THE NERNST EQUILIBRIUM POTENTIAL For any particular concentration gradient, it is possible to pick a voltage gradient that is equal and opposite, so that the term in parentheses in Eq. (2) is zero and there is no net current. This is called the electrochemical equilibrium potential or the Nernst potential and is given by: C Ci

RT __o Ex = ___ ln Fz e

(4)

where Ex is the Nernst potential (or the equilibrium potential or diffusion potential) for the ion, Co and Ci the concentrations on the outside and inside of the cell, z the charge of the ion or the valence, R the molar gas constant, T the absolute temperature, and F the Faraday’s constant. RT is the thermal energy of the material at temperature T and RT/F is this energy expressed in electrical units. At room temperature, RT/F is about 25 mV. At body temperature, 37°C, the equation can be simplified to: Co 60mV __ Ex = _____ z log10 C

(5)

i

with z = +1 for Na+ or K+, +2 for Ca2+, –1 for Cl−, and so on. The equilibrium potential for an ion is the potential at which the net flux is zero. It can be calculated theoretically using the formula of equation (5) without knowledge of the actual membrane potential. It is a way to express the concentration gradient in electrical terms, so that the concentration gradient can be compared to the voltage gradient. The Nernst potentials for the various ions in Table 4–1 are listed in the last column. Figure 4–3 compares three of these equilibrium potentials with a resting potential of –90 mV.

For chloride, the concentration gradient is inward; Cl− would like to move into the cell because there is a higher concentration outside. The –90-mV resting potential exerts an outward force on the negatively charged chloride ions. These two are equal and opposite, that is, (V – ECl) = –90 – (–90) = 0 mV, and chloride ions are in electrochemical equilibrium. For sodium, the concentration gradient is also inward, but the negative membrane potential exerts an inward force on the positively charged Na+. Both forces are inward and sodium ions are far from equilibrium, that is, (V – ENa) = –90 – (+65) = –155 mV. If the membrane were permeable to Na+, it would readily enter. For potassium, the concentration gradient is outward while the force from the voltage gradient is inward. The magnitude of the concentration gradient is slightly larger than that of the voltage gradient, that is, (V – EK) = –90 – (–95) = + 5 mV. Potassium ions are not at equilibrium; they have a tendency to leave the cell. Chloride is the only ion in Table 4–1 that is at equilibrium. Cl− are distributed at or very near equilibrium in skeletal muscle cells but not in most nerve cells.

GENERATION OF THE NERNST POTENTIAL The resting potential has its particular value because of the K+ and Na+ gradients and because the resting membrane is much more permeable to K+ than to Na+. This is more easily understood by first considering a membrane separating the same gradient that is permeable only to K+. Such a membrane could be constructed by reconstituting biological K channels into an artificial lipid bilayer (Figure 4–4). When the solutions are first added to the compartments, there is zero membrane potential. K+ will start to move with its concentration gradient and thereby move positive charge from

CHAPTER 4 Channels and the Control of Membrane Potential

A

B

4 mM

K+

155 mM K+ Cl−

Cl−

FIGURE 4–4 K+ flowing with its concentration gradient through an artificial bilayer that is permeable only to K+. Cl− is impermeant and a separation of charge develops. (Modified with permission from Landowne D: Cell Physiology. New York: Lange Medical Books/ McGraw-Hill, 2006.)

compartment B to compartment A, leaving an excess negative charge on side B and producing an excess positive charge on side A. This separation of charge means that there is now a membrane potential with side B negative to side A (or, equivalently, side A positive with respect to side B). As side B becomes more negative, the further net flow of K from B to A will be reduced, until eventually sufficient charge will have been separated so that the flux due to the increasing electrical attraction is equal and opposite to the flux due to the concentration gradient. At this point electrochemical equilibrium will have been reached and the membrane potential will be equal to the Nernst potential—in this example, –95 mV with side B negative to side A. This could also be expressed by saying that the Nernst potential is +95 mV, with side A positive to side B. This is a property of equation (5), because log A/B = –log B/A. Notice that less than 1 pmol/cm2 flux of positive charge is required to establish the membrane potential. The bulk concentrations of K+ on the two sides of the membrane have not changed significantly. The change in concentrations is undetectable by ordinary chemical experiments.

THE RESTING POTENTIAL The example above can be extended to explain the resting potential in a muscle cell by considering the situation that would occur if the membrane potential were artificially held at zero

Na

K

37

electronically and then released. Such a condition can be arranged with the voltage-clamp apparatus in described Chapter 6. In order to understand the process, it is necessary to know the concentration gradients listed in Table 4–1 and also that the permeability of the membrane to K+ is 50–100 times greater than its permeability to Na+. Starting at 0-mV membrane potential, K+ will start to move out of the cell while Na+ will start to move in, both moving with their concentration gradients. However, more K+ will move than Na+ because the permeability to K+ is much greater than the permeability to Na+, so a net positive charge will move out of the cell, making the inside of the cell negative with respect to the outside. The developing negative membrane potential opposes the further efflux of K+ and acts to increase the influx of Na+. This trend will continue, with the membrane potential becoming more and more negative until three Na+ are entering through the Na channels for every two K+ that are leaving through the K channels. At this point a steady state will be reached because the Na/K pump is extruding three Na+ and taking up two K+ on each ATP-consuming cycle. There is no net flux in this steady state, so the membrane potential will not change as long as the ATP supply is adequate (Figure 4–5). It is important to realize that the major role of the pump is indirect; the pump is very important for maintaining the gradients but contributes only a few millivolts directly to the membrane potential. If the “starting at 0 mV” experiment were repeated with the pump blocked by ouabain (a cardiac glycoside similar to digitalis) or the absence of ATP, the initial processes would be the same and the process would continue until the influx of sodium were equal to the efflux of potassium. At this point the membrane potential would stop becoming more negative and then, very slowly, start to move back toward 0 mV as the concentrations on the two sides of the membrane changed over several hours. Using the figures in Table 4–1, it is possible to estimate the immediate difference in membrane potential that can be attributed to the running pump. When the membrane potential is –90 mV, there is a 5-mV net driving force on K+. If the membrane potential became 2.5 mV less negative to –87.5 mV, the driving force on K+ would be increased by 50%, so that three K+ would leave for every two that left at –90 mV. There would

3 Na 2 K

FIGURE 4–5 Ions flowing with their concentration gradient through channels and actively transported against their concentration gradient by pumps. (Modified with permission from Landowne D: Cell Physiology. New York:

ATP

ADP

Lange Medical Books/McGraw-Hill, 2006.)

38

SECTION II Cell Physiology

be a 2.5-mV decrease in the driving force on Na+, but this is less than 2% of the 155-mV driving force, so it would make a negligible change in the Na+ influx, and three Na+ would enter for every three K+ leaving. Thus, about 87.5 mV of the resting potential comes from the gradients and an additional 2.5 mV comes directly from the pump. If the concentrations and the ionic conductances are known, the membrane potential can be calculated using equation (4) to find the Nernst potentials and equation (2) to find the currents. When the membrane potential is not changing, there is no net current. If the pump is not running and the membrane only conducts Na+ and K+, INa = –IK or gNa(V – ENa) = –gK(V – EK), which can be rearranged to solve for V: g E +g E

Na Na K K V = _________ g +g Na

(6)

K

The membrane potential is the weighted average of the equilibrium potentials; the weighting is by their respective conductances. If gK >> gNa, the membrane potential will be near EK; if gNa >> gK, it will be near ENa, and if they are equal, it will be halfway between. If the membrane is permeable only to these two ions and there is no external source of electrical current, the membrane potential will always be between EK and ENa. These concepts will become more useful when the conductances change, as seen in the next three chapters. Because the resting membrane is preferentially permeable to potassium, the resting potential is sensitive to the external potassium concentration (Figure 4–6). Increasing external K will bring the membrane potential closer to zero or depolarize the membrane. The resting membrane in its normal ionic environment is considered polarized. A change of potential in the positive direction, toward 0 mV, is a depolarization. A change in the other direction, making the membrane potential more negative, is a hyperpolarization.

Increased Ko depolarizes membranes because it reduces the K+ gradient across the membrane and makes EK closer to zero. This reduces the tendency for K+ to leave the cell, so the balance is reached at a less negative potential. Increased Ko+ is a dangerous, potentially lethal condition because excitable cells require the normal resting potential to remain excitable. Doubling the blood K+ level (hyperkalemia) is likely to compromise cardiac muscle function.

Kir CHANNELS SUPPORT THE RESTING POTENTIAL Some cells, notably cardiac and skeletal muscle cells, have Kir channels that are open, thus conducting, at the resting potential and are thought to be the major contributor to the resting K conductance. These were named inward rectifiers when experiments demonstrated that the inward current through them, when the membrane potential was hyperpolarized beyond EK, was larger than the outward current seen when the membrane was depolarized. It is perhaps an unfortunate name because, in normal life, the membranes never experience such a large hyperpolarization. The important aspects of this channel’s function are to be open for outward movement of potassium near the resting potential and then to become nonconducting when the cell is depolarized. This blocking in the depolarized state will be seen to be important for cardiac muscle action potentials, as described in Chapter 6. Kir is not a voltage-sensitive channel. The blocking comes about because Mg2+ or other polyvalent cations in the cytoplasm attempt to go through the channel when they are depolarized and get stuck, thus preventing K+ from using the channel. If the channels are studied under conditions without polyvalent cations, they conduct K+ equally well in both directions.

0

Membrane potential (mV)

−20 −40 −60 −80 −100

EK = 60 mV log [K]o/155

−120 −140 −160

1

10 [K]o mM (note log scale)

100

FIGURE 4–6 The observed membrane potential as a function of the external K+ concentration. The solid line is the theoretical prediction for a membrane that is permeable only to K+. Notice the logarithmic concentration scale. (Modified with permission from Landowne D: Cell Physiology. New York: Lange Medical Books/McGraw-Hill, 2006.)

CHAPTER 4 Channels and the Control of Membrane Potential

GOLDMAN–HODGKIN–KATZ EQUATION If permeabilities are known, rather than conductances, a membrane potential can be calculated using the theoretical Goldman–Hodgkin–Katz (GHK) or constant field equation: P Na + + P K + + P Cl − PNaNai + PKKi + PClClo

Na o K o Cl i V = 60mV log10_________________ + + −

(7)

As in equation (6), the GHK equation simplifies to the Nernst equation if only one permeability is greater than zero. The GHK equation has been useful to describe experimental results when some of the concentrations are set to zero, which makes the Nernst potentials in equation (6) meaningless. The relationship between permeability and conductance can be set on a quantitative basis by considering the condition when the membrane potential is zero and then, after multiplying the chemical flux by Faraday’s constant, equating equations (3–1) and (4–2) to obtain the electrical current. Thus, we have: gxEx = PxF ΔCx

(8)

CHANGES IN MEMBRANE POTENTIAL The membrane potential will change if current is injected into the cell by opening channels that allow ions to flow with their electrochemical gradients. It takes time to change the membrane potential; it will not jump instantaneously to a new value. Many nerve and muscle cells are quite long, more than 1 m for some nerve cells. The effect of a localized current will spread passively from the site of injection but may not change the potential of the entire cell. These temporal and spatial effects are shared by electrical cables and are referred to as the cable properties. They can be understood by considering the membrane capacitance, the membrane resistance, and the longitudinal cytoplasmic resistance between different parts of the cell. The passive spread by cable properties must be distinguished from the active spread by action potentials. The passive effects occur without any change in the number of open channels. If sufficient current enters a nerve axon and depolarizes it above threshold, an action potential will be elicited and will propagate without loss of amplitude over the entire length of the cell. The action potential is regenerated as it propagates. As the wave of opening sodium channels moves, energy is supplied to the process from the Na+ gradient all along the axon. In contrast, a smaller depolarization or a hyperpolarization that does not open Na channels will spread only a few millimeters, becoming progressively smaller when measured at a greater distance from the stimulus. The membrane capacitance is the ratio of the charge separated to the membrane potential—equation (1). The capacitance is related to the membrane geometry by the following equation: K × area C = ________ Thickness

(9)

39

where K is a constant describing the material composition of the membrane. If the area is larger, it will take a greater amount of charge to change the potential. The thinner the membrane, the closer the charges are to each other and the more charges will have to be moved to change the potential. The capacitance of a typical membrane is about 1 μF/cm2; this value is often used to estimate the size of a cell by measuring its capacitance. The membrane resistance is the reciprocal of the membrane conductance: 1 Rm = __ g m

(10)

The longitudinal resistance is proportional to the length and inversely proportional to the cross-sectional area: ρ × length

Rl = ________ Area

(11)

where ρ is the resistivity of the cell contents.

PASSIVE PROPERTIES OF A SMALL ROUND CELL When pulse of current is injected into a small round cell (which can be assumed to have the same membrane potential over its entire surface), the membrane potential does not change instantaneously. Instead, it changes with an exponential time course with a characteristic time constant (τ), the time it takes to discharge the change in voltage to 1/e = 37 percent of its value (or the time it takes to charge to 63 percent of its final value) (Figure 4–7). Initially the injected charges are adding to the stored charges that were causing the original membrane potential. Later, when the membrane potential has reached a new steady state, current equal to the injected current is leaking back out through membrane channels. When the pulse is terminated, the excess stored charge leaks out through the channels and the membrane potential decays exponentially to its original value. The time constant of these exponential changes is the product of the cell’s membrane resistance and capacitance. Many cells have time constants in the range of 1–20 milliseconds. These time constants limit how rapidly the membrane potential can change and permit temporal summation of synaptic events in the central nervous system (see Chapter 7).

PASSIVE PROPERTIES OF A LONG CYLINDRICAL CELL An extended cell or a tissue with cells that are electrically connected by gap junctions may have different membrane potentials at different locations. If there is a local change in permeability, current will flow into or out of the cell and the membrane potential will change at that location and, to a lesser extent, at nearby locations. With a prolonged steady current, which lasts much longer than the time constant described in the previous

40

SECTION II Cell Physiology

I

V

In C

I

R

V

Out A

B

I

ΔV = IR[1 −exp(−t/τ)] V

63%

37%

τ

ΔV = IR exp(−t /τ)

τ

C

FIGURE 4–7 A spherical cell (A), its equivalent circuit (B), and the voltage response to an injected pulse of current (C). (Modified with permission from Landowne D: Cell Physiology. New York: Lange Medical Books/McGraw-Hill, 2006.)

section, there will be a steady change in potential that is largest at the point of current entry and falls off exponentially with distance with a characteristic length constant (λ) or space constant, the distance it takes for the potential to drop to 37 percent of its

I

value at the site of injection (Figure 4–8). Typical length constants for nerve and muscle cells are 0.1–2.0 mm. A 10-μm cell is approximately isopotential, but a 150-cm-long nerve cell requires an active propagation mechanism to be able to communicate electrical activity from end to end. The voltage change declines because some of the injected current leaks out of the cell and is not available to depolarize the adjacent regions. The amount that leaks out is proportional to the voltage change, so the decline is exponential. The length constant depends on the ratio of the membrane resistance to the longitudinal axoplasmic resistance. As the distance from the injection increases, the amplitude of the transient response decreases and the rise time becomes longer and more sigmoidal (Figure 4–9). Initially most of the charge entering the cell goes to the membrane immediately adjacent to the source; only later it is enough available to charge the distal membrane. When the pulse is terminated, all responses decay at the same rate. Synapses are distributed on the dendritic tree at different distances from the cell body. The more distant synapses will have less effect on the cell’s activity; the amplitude of the effect will be lower and its time course will be slower. Passive spread is important for action potential propagation; it is the mechanism of connection between the active region and the adjacent resting region. Action potentials propagate more rapidly in larger-diameter axons because they have lower longitudinal resistance and longer length constants. The passive properties, membrane capacitance, membrane resistance, and longitudinal resistance, are referred to as cable properties because they also determine the ability of under-

V1

V2

V3

A RI

In

I

C

RI

Rm

RI

Rm

Rm

RI

Rm

Out B 1

ΔV(x) = ΔVo exp(−x/λ) 2

3

37% λ

Distance x

C

FIGURE 4–8

A long cell (A), its equivalent circuit (B), and the steady-state distribution of its membrane potential in response to a steady injection of current (C). (Modified with permission from Landowne D: Cell Physiology. New York: Lange Medical Books/McGraw-Hill, 2006.)

CHAPTER 4 Channels and the Control of Membrane Potential

I

V2

V1

41

V3

I 1 2 V

FIGURE 4–9

3

The transient voltage responses at three distances from the site of an injected pulse of current. (Modified with permission

from Landowne D: Cell Physiology. New York: Lange Medical Books/McGraw-Hill, 2006.)

water cables to transmit signals. The length constant for undersea cables is several kilometers; for nerve axons it ranges from about 0.1 to 20.0 mm depending on the diameter. Undersea cables rely on repeater amplifiers for longer distances; nerves use voltage-dependent sodium channels, as described in Chapter 6. When cell–cell junctions join cells, they can operate electrically as if they were all one cell. Many of the cells in the heart are coupled and action potentials propagate from one cell to another supported by the passive spread of depolarization via the cell–cell junctions. There are also cell–cell junctions between some neurons in the CNS. For some it is helpful to visualize a hydraulic analogy of these electrical phenomena. Electrical voltage is analogous to water pressure and electrical current to solution flow. The long cell is similar to a leaky hose, with lower membrane resistance corresponding to more leaks and lower longitudinal resistance corresponding to larger hose diameter.

CHAPTER SUMMARY ■

■ ■

■

An electrical membrane potential is directly proportional to the separation of positive and negative charges across the cell membrane. The ratio of separated charge to voltage is the membrane capacitance. Cell membranes separate solutions with quite different ionic compositions. The movement of ions is directly proportional to the net driving force on the ions. The net driving force is the electrochemical gradient or the difference between the effect of the membrane potential and the effect of chemical gradient. The effect of the chemical gradient can be expressed by the Nernst equilibrium potential.

■

■

■

■

■

■

Only a very small number of ions must be separated to produce the membrane potential. This is negligible compared with the concentrations available on both sides. The resting membrane potential is a steady state with ions moving with their electrochemical gradient through channels and an equal number being pumped against their electrochemical gradient at the expense of ATP. The GHK equation can be used to calculate the membrane potential if the permeabilities to the various ions and their concentrations are known. When current flows through the membrane, the membrane potential changes in time and in space, governed by the “cable properties.” When a pulse of current is injected into a cell, there is a characteristic time required for the membrane potential to change. When a steady current is injected into a long cell, the potential change is largest at the injection site and decreases characteristically away from the site.

STUDY QUESTIONS 1. If all the Na–K pumps in the membrane of a muscle cell were stopped, all of the following changes would be expected for the muscle cell except A) immediate loss of the ability of the cell to carry action potentials B) gradual decrease in internal K+ concentration C) gradual increase in internal Na+ concentration D) gradual decrease in resting membrane potential (the potential would become less negative) E) gradual increase in internal Cl− concentration.

42

SECTION II Cell Physiology

2. If the potassium ion concentration on the outside of a resting skeletal muscle cell is doubled to twice of the normal value by adding K+ and Cl− in equal amounts, what would be the best estimate of the effect on the resting membrane potential? A) hyperpolarize about 100 mV B) depolarize about 5 mV C) hyperpolarize about 15 mV D) depolarize about 20 mV E) no measurable effect 3. The following cell in an organism called the Europa louse was recovered from a moon of Jupiter with a space probe. The intracellular and extracellular concentrations of all the ions are given as follows: Extracellular +

Intracellular

Rb = 100 mM

Rb+ = 1 mM

SO42− = 50 mM

SO42− = 0.5 mM

The cell membrane is permeable to Rb+ and not to SO42− or water. What is the resting membrane potential? (The sign refers to the potential inside of the cell.) A) +30 mV B) +60 mV C) +120 mV D) −30 mV E) −60 mV

4. A scientist is recording from the soma of a neuron with an intracellular microelectrode to study synaptic inputs on the dendrites. The letters a, b, and c below indicate the synaptic potentials recorded from three different synaptic inputs. For identical synaptic inputs to the dendrites, which synaptic potential was generated by the synapse at a location on the dendrites closest to the soma?

A)

B)

C)

C

Sensory Generator Potentials David Landowne

5

H A

P

T

E

R

O B J E C T I V E S ■ ■ ■

■

List eight sensations and the names of the specialized sensory receptor cells responsible for generating these sensations. Describe sensory adaptation in these receptors. Draw a schematic cartoon of (a) a Pacinian corpuscle and its sensory ganglion cell (including cell body and central process); (b) a cochlear hair cell and its synapses; and (c) a photoreceptor and its synapses. List three or more differences between ion channels that underlie action potentials, resting potentials, and receptor potentials.

Animals have developed a wide variety of sensory organs capable of monitoring chemicals, light, sound, and other mechanical events in the external and internal environments. In all of these organs there are mechanisms to convert information about the environment into electrical signals within the nervous system. This chapter is concerned about the conversion process and some general properties of all receptors. More details about the sensory organs and the systems that process the nerve signals are provided in Section 4: Chapters 13, 15, 16, and 17. Transducers can convert one type of energy to another. The cells or portions of cells that perform the initial step of sensory transduction convert light or mechanical energy or the presence of specific chemical conditions into a change in the membrane potential called the receptor potential or sensory generator potential. In small sensory cells, this generator potential directly controls the synaptic release process to be described in Chapter 7. In longer cells, the generator potential will initiate an action potential that propagates to a distant presynaptic ending and then trigger the release process. The information about the stimulus energy that was transduced into a generator potential is then encoded in the frequency of action potentials. Each sensory cell has an appropriate stimulus, called its adequate stimulus. The CNS interprets signals coming from this cell in terms of its adequate stimulus. The adequate stimulus for photoreceptors in the eye is visible light. If an electric

Ch05_043-046.indd 43

shock or sufficient pressure is applied to the eye, a person will report flashes of light, even if the room is dark. Each cell also has a receptive field that is the region in stimulus space that evokes a response in that cell. The receptive field of a photoreceptor in the retina is a particular location in the visual space in front of the eye and a range of colors to which that receptor is sensitive. The receptive field for a somatosensory nerve in the skin is the area of skin that elicits a response. The receptive field for an olfactory neuron is the range of chemicals it can detect. Cells in the CNS concerned with sensory information also have receptive fields. Different cells handle sensory information from the feet than that from the hands. The incoming information arrives on “labeled lines”; the CNS processors know from whence it comes. There are several locations in the brain that have receptive fields including the same location in visual space. The receptive fields of these higher-order cells are more complex, as signal processing has occurred comparing the output from one lowerorder cell with that of others. Mechanosensory transduction is direct, by mechanosensitive channels in the membrane. The sensory cell often has molecules or structures to focus the mechanical energy or filter out undesired mechanical disturbances, and there may be an elaborate organ—such as that comprising the outer, middle, and inner ear—to deliver the desired mechanical energy to the appropriate cell. In the end, a relatively nonspecific cation channel opens and both Na+ and K+ move with their concentration

43

11/26/10 9:41:42 AM

44

SECTION II Cell Physiology

FIGURE 5–1

The changes in membrane potential of a mechanosensory nerve ending to stimuli of three different amplitudes. (Modified with permission from Landowne D: Cell Physiology, New

York: Lange Medical Books/McGraw-Hill, 2006.)

gradients. In skin mechanoreceptors, such as the Pacinian corpuscle discussed below, there is a greater driving force on Na+, so more Na+ than K+ moves and the cell depolarizes. The number of mechanosensitive channels that open is proportional to the amount the membrane is stretched by the stimulus. A larger stimulus will open more channels and produce a larger depolarization (Figure 5–1). If the depolarization is large enough, action potentials will be initiated and will propagate toward the CNS. The situation is more complex in the ear, because the sensory cells (called sensory hair cells, for the hairlike appearance of the modified cilia on their apical surface) are part of an epithelium that separates two different solutions. However, mechanical

disturbance of these cells by the appropriate sound also leads to inward current carried by K+ through mechanosensitive channels on the cilia and depolarizes the cell. The sensory hair cells are short and synapse with auditory nerve cells in the ear. The hair cells do not have action potentials; they are short compared to their length constant, so they can rely on passive spread to open CaV channels to release transmitters. Some taste chemosensation is supported directly by chemosensitive channels, as in the glutamate receptors for the umami taste (the distinctive savory taste of glutamate); these are relatively nonselective cation channels that depolarize the cells. Others use channels even more directly; Na+ moving through epithelial sodium channels (ENaCs) depolarizes cells to provide the salty taste sensation. Odors are detected by G protein– coupled receptors (GPCRs) whose G proteins activate adenylyl cyclase, thus elevating levels of cyclic adenosine monophosphate (cAMP). The cAMP opens a cyclic nucleotide–gated (CNG) nonspecific cation channel that depolarizes the cell. CNG channels are tetramers with six TM segments and are structurally similar to KV channels but lack the latter’s exquisite selectivity for K ions and the voltage sensitivity. Light transduction also involves GPCRs with seven TM segments: rhodopsin in the rods and three other opsins in the cones tuned for short, medium, and long (or blue, green, and red) wavelengths. The chromophore that absorbs the light is 11-cis retinal (MW 284). Absorption of a photon triggers conversion of the retinal to the all-trans isomer, which causes a conformational change in the opsin protein informing the G protein that

Disk membrane

Rhodopsin (GPCR)

Phosphodiesterase

β/γ Transducin (G protein)

α

cGMP

hν

GMP

cGMP Na

FIGURE 5–2 The processes linking light absorption by rhodopsin and the closing of cyclic nucleotide–gated channels. Light induces a conformational change in rhodopsin that causes the subunits of transducin to dissociate. The alpha subunit stimulates a phosphodiesterase that degrades cGMP. In the absence of cGMP a channel that was allowing the entry of Na+ closes and the cell hyperpolarizes. (Modified with permission from Landowne D: Cell Physiology, New York: Lange Medical Books/McGraw-Hill, 2006.)

CHAPTER 5 Sensory Generator Potentials an event has taken place (Figure 5–2). The G protein is called transducin; it was the first G protein to be identified and was named before the family was well known. Transducin activates a phosphodiesterase that hydrolyzes cyclic guanosine monophosphate (cGMP). In the dark, there is a CNG channel that is open and carrying inward current. The channel closes when the cGMP level drops; when the light is on, the dark current decreases and the cell hyperpolarizes. There is amplification along this chemical pathway, so one photon leads to the closure of many CNG channels. The hyperpolarization reduces a steady output of synaptic vesicles to pass the message on to the next cell in the pathway to the brain. The sensation of uncomfortably hot skin temperature has been linked to the direct activation of a channel called VR1, for vanilloid receptor. It is also known as the capsaicin receptor because it can be activated by the vanilloid capsaicin, the major piquant ingredient in hot peppers. VR1 is a member of the transient receptor potential (TRP) channel family; it has a six-TM architecture and is permeable to cations. Raising the temperature into the range of 42°C (107.6°F), which many human observers identify as painfully hot, opens this channel, depolarizes the sensory ending, and initiates a train of action potentials. Other members of the TRP family have been associated with temperature sensation and other functions, though not all with pain. Our everyday experience of our sense is not a direct representation of the stimuli but rather the result of processing that occurs in the nervous system. We do not see the world as flashes of light at different positions in our visual fields but rather as objects and surroundings. Pain is an experience that can arise from a wide variety of stimuli without necessarily telling us anything definite about the stimulus. A few specific nociceptors have been identified, but there are also many other receptors that may be associated with pain. Elevated K+ from damaged cells or the direct cutting of a nerve cell can induce action potentials that may be interpreted as pain. Acid-sensing ion channels (ASICs) in the ENaC family respond to lactic acid released in the heart and depolarize nerves that provide the sensory pathway for the painful experience of angina. P2X3 receptor channels, which can be activated by adenosine triphosphate (ATP) released by damaged cells, have been associated with pain from overstretched bladders, and P2X4 receptors have been associated with a neuropathic pain generated within the nervous system without obvious outside stimuli.

SENSORY ADAPTATION All senses except pain adapt; if they are presented with a maintained stimulus, the response will diminish in time. The Pacinian corpuscle adapts rapidly and responds to a sustained stimulus with only one or two action potentials at the start (Figure 5–3). When the stimulus is released, there is an offresponse and another action potential is initiated. Most of this adaptation takes place in the onionlike capsule of accessory

45

FIGURE 5–3

Fast and slow sensory adaptation. The colored bars indicate a steady level of stimulation. The rapidly adapting receptor on the left adapts completely after two impulses have occurred. In the slowly adapting receptor on the right, the rate of firing declines less rapidly. (Modified with permission from Landowne D: Cell Physiology, New York: Lange Medical Books/McGraw-Hill, 2006.)

cells that surrounds the nerve ending. When one side of the capsule is distorted by the stimulus, at first the distortion is transmitted to the nerve ending and the nerve depolarizes. Then the capsule balloons out to the sides, the forces on the nerve are relieved, and the nerve stops firing. When the stimulus is removed, the capsule rebounds to its original shape, transiently pushing the sides of the nerve in the process. The Pacinian corpuscle is tuned to provide maximum information about vibratory stimuli and to ignore steady pressure. Muscle spindle organs are sensory structures embedded in skeletal muscles, which provide information about the length of the muscle to the CNS (see Figure 2–3 and Chapter 14). Muscle spindles adapt rapidly to changes in length but also continue to fire during a sustained stimulus. The firing rate decreases slowly during the stimulus; muscle spindles are said to be slowly adapting (Figure 5–3). The nervous system responds to changes in the environment, and by reducing the messages indicating that a stimulus is still present, more attention can be given to any changes. Adaptation takes place at many levels—accessory tissue before the receptor potential, the receptor potential itself, the encoding mechanism that initiates action potentials, and at many higher synapses where the incoming message is integrated with other signals. Adaptation to light occurs by constricting the pupils, by photobleaching the pigments, and by feedback regulation of the steps in the biochemical cascade. Many senses have some form of efferent control. The sympathetic nervous system can release norepinephrine onto the Pacinian corpuscle, which will increase its sensitivity to mechanical stimuli. Muscle spindle organs (see Chapter 14) have efferent nerves (γ motor nerves) that set the range of lengths to which the sensory nerve is most sensitive. There are also motor hair cells in the ear that can selectively enhance the sensitivity of sensory hair cells to particular sounds (see Chapter 16). There are many controls on the eye to assure that the object of interest is suitably focused on an appropriate portion of the retina even as the head changes its position in space (see Chapter 15).

CHAPTER SUMMARY ■ ■

Each sensory cell has an adequate stimulus. Touch, hearing, and other mechanosensation occur via mechanosensitive channels.

46 ■ ■ ■ ■

SECTION II Cell Physiology Taste is mediated by chemosensitive channels and odor by GPCRs and CNG channels. Vision is also mediated by GPCRs—for example, rhodopsin—and CNG channels. Pain is mediated by ASICs and purine-activated channels. All senses except pain adapt.

10

Response impulse/s

Response impulse/s

STUDY QUESTIONS

5

10 5

10

5

30 50 Seconds A) Response impulse/s

Response impulse/s

10

10

50 30 Seconds C)

10

30 50 Seconds B)

10

50 30 Seconds D)

10 5

1. The graphs above show the frequency of action potentials (y-axis) recorded from a primary sensory afferent fiber during sensory stimulation. Which one of these graphs shows the response from a typical sensory fiber (excluding pain fibers) to a constant maintained stimulus applied beginning at 10 seconds and lasting throughout the recording (i.e., until 50 seconds)?

2. Which of the following sensory cells has a hyperpolarizing generator potential in response to its adequate stimulus? A) Pacinian corpuscle nerve ending B) muscle spindle nerve C) taste bud cell D) retinal cone cell E) olfactory nerve ending 3. Hair cells are the sensory receptor cells in the cochlea. They are excited by the vibration of the hair bundle. Vibration of the hair bundle causes which one of the following events? A) influx of K+ through mechanosensitive cation channels in the tips of the cilia B) influx of Ca2+ through cyclic nucleotide–gated (CNG) channels in the tips of the cilia C) long-lasting hyperpolarization of the hair cell D) a train of action potentials propagated from the cilia to the cell body of the hair cell

C

Action Potentials David Landowne

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O B J E C T I V E S ■ ■ ■ ■ ■ ■ ■ ■ ■

Describe the activation of action potentials. Explain the propagation of action potentials. Describe the membrane currents underlying action potentials. Describe the activity of channels producing action potentials. Explain the membrane basis of the action potential threshold and refractory period. Explain actions of calcium, local anesthetics, and neurotoxins on action potentials. Describe the relationship between channel activity and cardiac muscle contraction. Describe the membrane basis of intrinsic cardiac pacemakers. Describe the effects of acetylcholine and NE on cardiac action potentials.

ROLE OF VOLTAGE-SENSITIVE SODIUM CHANNELS Action potentials are changes in membrane potential that propagate along the surface of excitable cells. They are best known in nerve and muscle cells but also occur in some other cells, including egg cells associated with fertilization. Unlike some other changes in membrane potential, action potentials are characterized as being “all-or-none”; they have a threshold for excitation and a stereotyped duration. Immediately following an action potential, the excitable cell has a refractory period when it is more difficult or impossible to elicit a second action potential. Like most changes in membrane potential, action potentials are the result of changes in membrane permeability due to the activity of channels, or proteins embedded in the membrane lipid bilayer that facilitate the passive movement of specific ions with their electrochemical gradients. An action potential is a change in membrane potential from a resting potential of about –70 mV (the inside of the cell is negative) to about +30 mV and then back to the resting potential. Their duration

Ch06_047-058.indd 47

in nerve and skeletal muscles is on the order of 1 millisecond; in cardiac ventricular muscle cells, their duration is several hundred milliseconds. In nerve and skeletal muscles, the underlying permeability changes are a transient increase in sodium permeability followed, after a delay, by an increase in potassium permeability due, respectively, to the activation of sodium and potassium channels (Figure 6–1). Cardiac action

25 mV 10 mS/cm2 1 ms

FIGURE 6–1 An action potential (red trace) and the underlying changes in membrane conductance for Na+ (blue trace) and K+ (beige trace). (Modified with permission from Landowne D: Cell Physiology. New York: Lange Medical Books/McGraw-Hill, 2006.)

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SECTION II Cell Physiology

potentials are more complex and also involve the activation of calcium channels. Action potentials are all-or-none and propagate because the sodium channels are voltage-sensitive. Depolarization, the reduction of the membrane potential, from –70 to 0 mV, induces a conformational change within a few hundred microseconds in the sodium channel protein, which leads to in increase in permeability to sodium ions. Sodium ions rush into the cell through these open voltage-dependent Na (NaV) channels and bring positive charge with them, which further depolarizes the cell, opening more NaV channels (Figure 6–2). This positive feedback loop persists until all of the sodium channels have opened. Once the loop is started, it continues to completion. The depolarization spreads passively to adjacent regions of the membrane and activates nearby sodium channels. This wave of molecular conformational change and electrical activity propagates over the length or surface of the cell at velocities up to 120 m/s. Potential energy that is stored in the sodium concentration gradient is sequentially used along the propagation path. The propagation velocity is determined by the rate of molecular change and the electrical properties of the cell that control the spread of potential changes (cable properties). About 1 millisecond later, the sodium channels undergo a second conformational change and inactivate. In this third conformation, they are closed and sodium no longer passes

Change of channel conformation

Depolarization of membrane potential

Increase of sodium permeability

Entry of sodium into cell

FIGURE 6–2 The action potential’s positive feedback cycle. The cycle is started by a depolarization and continues until all of the sodium channels have been activated. (Modified with permission from Landowne D: Cell Physiology. New York: Lange Medical Books/McGraw-Hill, 2006.)

through. In addition, the NaV channels are unable to open again until the membrane is repolarized to the resting potential for a few milliseconds to allow recovery from inactivation (Figure 6–3). This automatic closing of the sodium channels limits the duration of nerve and skeletal muscle

Open

Activated

Resting closed

Inactivated closed

FIGURE 6–3 Sodium channels can be in different functional states. A depolarization first causes the channel to change from the resting state to the activated and open states and later to the inactivated state. Repolarization is required to go from the inactivated state back to the resting state. (Modified with permission from Landowne D: Cell Physiology. New York: Lange Medical Books/McGraw-Hill, 2006.)

CHAPTER 6 Action Potentials

Vi

Vm

49

Axon

Axial wire Vo Vc

I

FIGURE 6–4 A simplified voltage-clamp circuit for a squid giant axon. The membrane potential, Vm, is sensed as the difference between the inside potential, Vi, and the outside potential, Vo. Vm is compared to the command potential, Vc, and, if they are different a current flows through the axial wire and the cell membrane to make Vm equal to Vc. (Modified with permission from Landowne D: Cell Physiology. New York: Lange Medical Books/McGraw-Hill, 2006.)

action potentials. Loss of the ability to open again produces the refractory period. The outward movement of K+ carrying positive charge out of the cell produces the repolarization (the falling phase of the action potential). In some cells, voltage-dependent K channels (KV) channels—whose activation is slower than that of sodium channels—facilitate repolarization. In mammalian myelinated axons, the repolarizing current passes through the (nonvoltagesensitive) potassium channels that produce the resting potential. The axons seem to be an exception; the presynaptic nerve terminals and the cell bodies of most neurons have KV channels.

VOLTAGE CLAMPING This understanding of the action potential mechanism comes from the work of Alan Hodgkin and Andrew Huxley about 50 years ago. Working with giant nerve axons isolated from squid, they were able to break the positive feedback loop and

measure the effect of a change in membrane potential in the ionic permeabilities without any change to the membrane potential due to the movement of ions. Their technique was to include the nerve membrane in a negative feedback circuit (Figure 6–4). A pair of electrodes measures the membrane potential; this is then compared with a desired command potential. If the membrane potential is different from the command potential, a current is made to flow through the membrane in a direction that reduces the difference. Thus, the voltage across the membrane is clamped at a desired value. When the controlled voltage is a pulse from the resting potential to 0 mV, four different kinds of current can be identified (Figure 6–5). The first is the charge movement necessary to change the potential or change the charge on the membrane capacitance. Second, there is a small outward current called the gating current. Then there is an inward current that is replaced in a few milliseconds by an outward current, which lasts as long as the pulse.

0 mV −70 mV Ic

“Voltage clamped” membrane potential

IK

Ig

Outward INa Inward

Current with both potassium and sodium ions

FIGURE 6–5 The membrane currents (lower trace) in response to a voltage-clamp pulse (upper trace). Ic, capacity current; Ig, gating current; INa, sodium current; IK, potassium current. (Modified with permission from Landowne D: Cell Physiology. New York: Lange Medical Books/McGraw-Hill, 2006.)

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SECTION II Cell Physiology

0 mV −70 mV

“Voltage clamped” membrane potential

IK Outward Current without sodium ions Inward

Current without potassium ions

INa 1 ms Ig

Current without either ions

FIGURE 6–6

The separation of the currents by changing the solutions. The labels have the same significance as Figure 6–5.

(Modified with permission from Landowne D: Cell Physiology. New York: Lange Medical Books/McGraw-Hill, 2006.)

One can replace the contents of a segment of squid axon with a simple salt solution and maintain functioning channels. By changing the solutions bathing both sides of the membrane, one can separate the currents carried by Na+ (INa) and K+ (IK) and also see the gating current (Ig) still present in the absence of either ion (Figure 6–6). Notice that at 0 mV, the Na current is inward and the K current outward. The Na current activates or increases more rapidly than the K current. It inactivates or decreases during the pulse, even though the membrane potential is kept at 0 mV, whereas the K current remains for the duration of the pulse. If the potential is pulsed to other depolarized potentials, all four components of the current are present, although their amplitude and time course and, in the case of INa, direction may change (Figure 6–7). The Na current becomes more inward between the resting potential and about 0 mV. Larger pulses

produce less inward Na current until, at about +60 mV, no net current passes through the Na channels. Still larger pulses can drive outward Na current through the Na channels. The reversal of the current occurs at the sodium equilibrium potential, ENa. If the ratio of the sodium concentrations bathing both sides of the membrane is changed, this reversal potential also changes. With modest depolarizations, the inward current increases because larger pulses open more sodium channels. However, the less negative potential decreases the inward driving force on the sodium ions; after most of the NaV channels have been opened, still larger depolarizations decrease the Na current. When the membrane potential exceeds the sodium equilibrium potential, Na is forced out of the cell through the open NaV channels. In a free-running action potential, the membrane potential never exceeds the sodium equilibrium potential and there is always a net entry of Na into the cell.

+80 mV +60

1 mA/cm2 1 ms

+40

0 −20

−70

+80 mV +60 +40 0 −20

FIGURE 6–7 The current’s responses (upper traces) to voltage steps of varying amplitude (lower traces). Capacity current transients not shown. (Modified with permission from Landowne D: Cell Physiology. New York: Lange Medical Books/McGraw-Hill, 2006.)

CHAPTER 6 Action Potentials

51

The Hodgkin–Huxley equations are available in a commercial computer program called Neuron. The Web site (http://nerve.bsd.uchicago.edu/nerve1.html) has a JavaScript rendition that will allow you to manipulate the equations with most modern Web browsers.

1 mA/cm2 10 ms 0 mV −70

FIGURE 6–8

The recovery from inactivation shown by a two-pulse experiment with different amounts of time at the resting potential between pulses. Capacity current transients not shown. (Modified with permission from Landowne D: Cell Physiology. New York: Lange Medical Books/McGraw-Hill, 2006.)

The Na current activates and inactivates more rapidly as the size of the pulse is increased. If a second pulse is given immediately after the first, the gating current and the sodium current during the second pulse are smaller than during the first pulse (Figure 6–8). They both recover in parallel as the duration between pulses is increased. The rate of recovery from inactivation is also voltage-dependent, as the channels recover more rapidly at more hyperpolarized potentials. The K current increases and becomes more rapid as the membrane potential is increased. Above about +20 mV, the increase in amplitude becomes proportional to the change in potential, indicating that all of the channels are open and that only the driving force continues to increase. The gating current is a direct sign of the conformational changes in the NaV channel proteins. These molecules contain charged groups and dipoles that move or reorient when the electrical field changes, specifically the S4 TM helices shown in Figures 3–3 and 3–4. This movement can be measured as the gating current. As the pulse is made progressively more positive and more sodium channels open, the amplitude of the gating current grows and the currents become more rapid. Above about +20 mV, these two changes are complementary and the area under the gating current trace is constant, indicating that all of the channels are undergoing conformational changes and are doing so more rapidly at more positive potentials. The capacitance current increases linearly with the size of the pulse because it requires more charge to change the voltage by larger amounts. Hodgkin and Huxley separated the currents and showed how the ionic currents were proportional to the driving force on the ions. They created mathematical equations that emulated the amplitude and time course of the permeability changes and showed that these equations could predict the amplitude and time course of action potentials as well as their threshold, conduction velocity, refractory period, and several other features. Their concept of describing ionic current as the product of conductance times driving force is used to describe most of the remaining electrophysiological phenomena in all cells and tissues.

THRESHOLD The threshold arises because there are two different effects of small depolarizations. On the one hand, depolarization will increase the probability that NaV channels open and permit inward current, which will lead to further depolarization. On the other hand, depolarization moves the membrane potential further away from the potassium equilibrium potential, increasing the net driving force on potassium ions and thus producing an outward current through the resting potential potassium channels, which will lead to repolarization. If a sufficient number of sodium channels are opened so that the inward sodium current exceeds the outward potassium current, the cell has exceeded threshold and will continue to depolarize until all of the available sodium channels have opened. Treatments that reduce the sodium current—for example, reducing extracellular sodium concentration or reducing the number of NaV channels—will elevate the threshold.

REFRACTORY PERIODS During an action potential, most of the NaV channels activate or open and then inactivate and close into a state that differs from their condition before the action potential. In order to recover from inactivation and be available to open again, the NaV channels must spend some time with the membrane potential near the resting potential. They will not recover if the membrane remains depolarized. During this recovery, the axon is said to be refractory because it is resistant to stimulation. The refractory period is divided into two segments: an absolute refractory period when no stimulus, however large, can elicit a second action potential, followed by a relative refractory period when the axon can be stimulated again but requires a larger stimulus to elicit the second response than was needed for the first (Figure 6–9). During the absolute refractory period, so few NaV channels have recovered that even if all of the recovered channels were opened, there would be insufficient sodium current to exceed the outward potassium current, which tends to restore and maintain the resting potential. During the relative refractory period, a larger depolarization is required because a larger fraction of the available NaV channels must be opened to obtain the same number of channels opened in the first stimulus. In addition, in many nerve and muscle cells, there are more open potassium channels immediately following an action potential, which also makes the cell more difficult to excite a second time.

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SECTION II Cell Physiology

3

Relative threshold

Absolute

Relative

2

1

0

0

2

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ms

6

FIGURE 6–9 The absolute and relative refractory periods. The time axis begins with the occurrence of an action potential. During the absolute refractory period no stimulus, however large, can elicit a second action potential. During the relative refractory period a second action potential can be elicited but it requires a larger stimulus than that in the resting state. (Modified with permission from Landowne D: Cell Physiology. New York: Lange Medical Books/McGraw-Hill, 2006.)

MYELINATION

DISEASES

Vertebrate nervous systems present a specialization of nervous function not seen in invertebrates, namely myelination (Figure 6–10). Accessory cells wrap nerve axons with many layers of their own membrane, electrically insulating most of the cell. NaV channels cluster in the regions between these wraps, in the nodes of Ranvier. The Na current enters the cell only at these nodes; excitation “jumps” from node to node in what is called saltatory conduction. The spread between nodes is the same passive spread seen in unmyelinated nerve cells, but it is more effective, that is, it produces a more rapid conduction velocity. The myelin wraps increase the resistance between the axoplasm and the surrounding media, which, in turn, increases the length constant for passive spread. The myelin also increases the effective thickness, which decreases the effective capacitance and reduces the amount of charge required to change the potential. Both effects speed conduction.

There are many diseases or conditions of reduced or excessive excitation of cells. Perhaps the most familiar is the conduction of acute pain information, which is frequently treated with local anesthetics; these act by blocking the NaV channels. Some forms of epilepsy and some cardiac arrhythmias are also treated with NaV channel blockers. One type of long-QT (LQT) syndrome, a cardiac arrhythmia, has been linked to a mutation in one of the Na+ channel genes, and a hyperkalemic periodic paralysis (HyperKPP) has been linked to another. Other LQT syndromes have been associated with KV channels. Hypocalcemia is associated with increased excitability of nerves and skeletal muscle and may produce uncontrollable muscle contraction (tetany). Hypercalcemia renders nerves and muscles less excitable. Calcium binds to the membrane near the S4 voltage sensor (Figure 3–4) of the NaV channel and has an effect similar to hyperpolarization. The positive charge on the calcium ion repels the positively charged S4 helix, making it

FIGURE 6–10

The effect of myelination on the longitudinal spread of current. In the upper diagram Na+ is shown entering (colored arrow) at a node of Ranvier and the associated current loops are shown in black. In an unmyelinated nerve (lower diagram) the same current loops occur but over a shorter distance; hence, the action potential propagates more slowly. (Modified with permission from Landowne D: Cell Physiology. New York: Lange Medical Books/McGraw-Hill, 2006.)

CHAPTER 6 Action Potentials

DRUGS AND TOXINS

more difficult for the S4 to move outward and open the channel. The result is that, in low calcium conditions, the sodium channel opens in response to a smaller stimulus or even spontaneously at the resting potential. The calcium binding does not change the resting potential as measured with electrodes in the bulk compartments on both sides of the membrane. There are demyelinating diseases, such as multiple sclerosis (MS), where myelin is lost and conduction can become slower or fail altogether. MS is an autoimmune disease and is generally treated with synthetic corticosteroids such as prednisone. The symptoms can be eased by providing air conditioning or moving to a cooler climate. Cooling helps, somewhat paradoxically, because although it slows the opening of sodium channels and thereby slows the propagation velocity, it also slows the inactivation of NaV channels and increases the duration of the action potentials; thus, the greater Na+ influx makes the propagation more reliable. Reliability is often discussed in terms of the safety factor for propagation. In healthy individuals, the 100-mV action potential that arrives at the next node of Ranvier is about five times larger than the 20-mV depolarization required for initiating a new impulse at that node. In patients with MS, the action potential reaching the next node may be diminished to near or below the size needed to reinitiate the impulse. One effect of cooling nerves is to increase the safety factor for propagation.

1

2

3

4

5

++++−−−−+++++++++++++++ −−−−++++−−−−−−−−−−−−−−−

++++++++++−−−−+++++++++ −−−−−−−−−−++++−−−−−−−−−

+++++++++++−−−−++++++++ −−−−−−−−−−−++++−−−−−−−−

1

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After the identification of these specific Na+ and K+ conductances, they were shown to be molecularly separate because they differ in pharmacology and respond differently to various drugs. Tetrodotoxin (TTX), a poison found in the internal organs of puffer fish, selectively blocks nerve NaV channels at nanomolar concentrations. Local anesthetics such as lidocaine or benzocaine also block NaV channels. There is a greater diversity among KV channels and also among the drugs that block them. Tetraethyl ammonium (TEA) ions and 4-aminopyridine are among the KV channel blockers. There are also compounds that chronically activate NaV channels, such as veratridine, pyrethroid insecticides, and brevetoxin, one of the red-tide toxins.

EXTRACELLULAR RECORDINGS— COMPOUND ACTION POTENTIALS Action potentials can be recorded with a pair of wires placed on the surface of a nerve bundle, typically about 1 cm apart. When a nerve impulse passes these wires, a biphasic action potential is seen on the display (Figure 6–11). This is a differential recording of the same nerve impulse that would

++++−−−−++++ −−−−++++−−−−

++++ ++++−−−− −−−− −−−−++++

+++++++++++++ −−−−−−−−−−−−−

++++++++++++++−−−−+++++ −−−−−−−−−−−−−−++++−−−−−

+++++++++++++++−−−−++++ −−−−−−−−−−−−−−−++++−−−−

2

1

2

3

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1

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FIGURE 6–11 Externally recorded action potentials. Left: Biphasic action potential recorded from an intact axon. Right: Monophasic action potential recorded near the site of a crush injury. The potential is measured between the two circles above each diagram. The numbers on the traces indicate the timing of the associated diagram above. The colored region inside the nerve cell is propagating from left to right. (Modified with permission from Landowne D: Cell Physiology. New York:

4

Lange Medical Books/McGraw-Hill, 2006.)

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SECTION II Cell Physiology α δ

1 mV 10 ms

β

B 1 μV 50 ms C

γ

δ

FIGURE 6–12 A compound action potential. Left: High sweep speed. Right: Lower sweep speed, higher vertical gain. The letters refer to specific groups of axons within the nerve. (Modified with permission from Landowne D: Cell Physiology. New York: Lange Medical Books/McGraw-Hill, 2006.)

appear as in Figure 6–1 if the recording were made with an intracellular microelectrode. One deflection occurs as the impulse passes the first wire and the second occurs as it passes the second wire. They are in opposite directions because the two wires lead to opposing inputs for the display. If the nerve is crushed between the electrodes so that the impulse does not reach the second electrode, the response becomes monophasic. This type of recording with external electrodes is used clinically to test nerve integrity. A nerve bundle can also be stimulated with another pair of wires on a remote stretch of the same bundle. With appropriate equipment, stimulation and recording can be made through the skin without dissecting out the nerve bundle. When a nerve bundle is stimulated, more than one axon may be excited. The electrical recording of the combination of the action potentials produced is called a compound action potential. The compound action potential is also biphasic if the nerve is intact between the recording wires. Besides being biphasic, there are many differences between compound action potentials recorded with external electrodes and the single-cell action potential recorded with an electrode inside the cell and a reference electrode outside the cell. The compound action potentials are much smaller, on the order of 1 mV, and there is no sign of the resting potential because both wires are outside the nerve. The compound action potential is not all-or-none because a larger stimulus will bring more individual axons above threshold and the compound action potential’s amplitude is proportional to the number of axons firing. The compound action potential becomes smaller and longer at greater distances from the stimulating electrodes because the conduction velocity of the various axons is not exactly the same and the action potentials disperse as they travel away from the stimulation site. The threshold and conduction velocity of the various axons within a nerve bundle vary with the diameter of the axons. Large axons have a lower threshold to stimulation by external electrodes. (Of course, in life they are usually stimulated more selectively by a specific receptor or synaptic input.) The larger-diameter fibers have a lower threshold; more of the stimulating current flows through them because they have a lower internal resistance. Larger axons also have a more rapid conduction velocity, again because of their lower internal resistance.

Vertebrate peripheral axons are classified by their diameter (or conduction velocity or threshold to external stimulation). There are groups of nerve fibers with similar diameters. The groups of different diameters can be distinguished as separate elevations in the compound action potential (Figure 6–12). There is some correlation of function with diameter. For example, large myelinated motoneurons leading to skeletal muscles are Aα fibers and small unmyelinated fibers carrying pain information are C fibers. The larger fibers have faster conduction velocities and lower thresholds to external electrical stimuli.

CARDIAC ACTION POTENTIALS The heart is a pump made up of excitable muscle cells. The electrical activity of these cells controls their contraction. The function of these cells will be discussed further in the context of function of the heart in Chapter 23. The overall control of the heart’s pattern of contraction is by the spread of action potentials through a special conducting system of modified heart muscle cells (Purkinje fibers) and through the atrial and ventricular muscle cells themselves (see Figure 23–3). There are two types of action potentials in the heart distinguished by their rate of depolarization and their conduction velocity. The fast action potentials, with a rapid rate of depolarization and a rapid propagation velocity, are found in atrial and ventricular muscle cells and Purkinje fibers. The slow action potentials are normally found in the sinoatrial (SA) node and the atrioventricular (AV) node.

CARDIAC MUSCLE ACTION POTENTIALS In cardiac muscle action potentials, current from adjacent cells depolarizes the cell to a level where fast, voltage-dependent NaV channels open and rapidly depolarize the membrane toward the sodium equilibrium potential (phase 0 in Figure 6–13). These channels are similar to the sodium channels of nerve and skeletal muscle; they open in response to depolarization. They are also blocked by local anesthetics. After opening, they inactivate quickly and the membrane potential starts to return. However, the depolarization also opens voltage-activated L-type CaV channels that do not inactivate. This maintains the

CHAPTER 6 Action Potentials

1 2 Vm 50 mV 0

3

50 ms

4 IK

ICa 1 mA/cm2 INa

FIGURE 6–13 A ventricular muscle cell action potential (upper trace) and its underlying ionic currents. The INa and ICa currents are inward and the IK current is outward. (Modified with permission from Landowne D: Cell Physiology. New York: Lange Medical Books/ McGraw-Hill, 2006.)

action potential in the plateau phase (phase 2). Reducing external Ca2+ concentration or adding drugs that block calcium channels will reduce the plateau phase and also reduce the strength of muscle contraction. Cardiac muscle, unlike skeletal muscle, requires external Ca2+ for contraction (Figure 6–13). Cardiac muscle cells also differ from nerve and skeletal muscle by lacking the fast KV channel for quick repolarization. The potassium conductance system of the heart is rather complex; at least five different components have been identified on the basis of their kinetics and voltage dependence. Two of these are important to understand the plateau phase. During the plateau phase, the conductance is less than that during diastole, the period between action potentials. This is because of the inward rectifier channel (Kir), which is responsible for maintaining the resting potential and has a high conductance near and below the resting potential (at more negative potentials); it does not conduct during the plateau phase when the membrane is depolarized. The Kir channel rectifies, allowing current to flow and maintain the resting potential, but it does not allow much current to flow out during depolarization. The rectification is caused by Mg2+ or other polyvalent cations from the internal solution moving into the channel and plugging it when the cell is depolarized. The low conductance to K+ during the plateau phase means that the modest conductance to Ca2+ through the CaV channels maintains the membrane potential at depolarized levels during the plateau. Slow KV channels open very slowly during the action potential and are responsible for the downward slope during the plateau phase. When the membrane potential falls below a certain level, the CaV channels close and the repolarization toward the potassium equilibrium potential accelerates (phase 3). Since the membrane is no longer depolarized, the KV channels close.

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The description above is a simplified view of cardiac muscle action potentials. The complete story has several more K channels and must account for differences among muscle action potentials in different regions of the heart as well as age-related changes. There are two KV channels that open transiently just after the NaV channels and produce the initial partial repolarization (phase 1) from the peak to the plateau (IKto). There are at least two different slow voltage-dependent K channels with similar kinetics but distinct pharmacology (IKR and IKS). Some cardiac muscle cells have T-type calcium channels. In all cardiac cells, some current is carried by the sodium–calcium exchanger and by the Na/K pump. The regional and age-related differences in the action potentials are functionally and clinically important. The ventricular muscle’s action potentials near the endocardial (inner) surface have a longer duration than those near the epicardial (outer) surface. More work is done by the inner fibers, and they are more likely to be damaged in a heart attack. These differences must arise because of a different balance of Na, Ca, and K channel activities. The interactions between the effects of different channels are complex and are best explored with computer models. Clearly more research is necessary to understand the details.

SA AND AV NODE ACTION POTENTIALS The overall control of the heart’s pattern of contraction is normally initiated by action potentials that spontaneously arise 60–80 times/min from modified muscle cells in the SA node. Similar action potentials are also seen in the AV node, where they regulate the activation of the ventricles. In the absence of stimulation from the atria, the AV node’s cells spontaneously produce about 40 action potentials/min; in healthy hearts, however, the atrial cells drive them at the rate set by the SA node. The action potentials in the nodes lack the rapid upstroke and do not have as pronounced a plateau phase as the cardiac muscle action potentials. They are further characterized by the slow depolarization between action potentials: the pacemaker potential. These cells fire rhythmically; they are never at rest and have no true resting potential. The upstroke of the action potential is produced by a slow inward current carried primarily by Ca2+ (Figure 6–14). There is an initial phase through T-type CaV channels and a major phase through L-type CaV channels. The T-type channels are transient and have a low threshold for opening, near –60 mV. The L-type channels are long-lasting and have a higher threshold, near –30 mV. The L-type channels are similar to the CaV channels that maintain the plateau of the cardiac muscle action potentials; they are blocked by dihydropyridines. T-type channels have a different pharmacology. Reducing external Ca2+ concentration or adding Ca2+ channel blockers reduces the amplitude of the node’s action potentials. Outward K+ current gradually replaces the slow inward current and the cells repolarize toward EK. As the potential passes –50 mV, an inward hyperpolarization-activated current, If , appears,

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SECTION II Cell Physiology

Vm

50 mV 50 ms

IK

If 1 mA/cm2 ICa

FIGURE 6–14 The SA node’s action potentials (upper trace) and their underlying currents. The If and ICa currents are inward and the IK current is outward. (Modified with permission from Landowne D: Cell Physiology. New York: Lange Medical Books/McGraw-Hill, 2006.) competes with IK, and eventually begins to depolarize the cell again. If is carried mainly by sodium ions. When the potential again passes –60 mV, the CaV channels are again activated and the cycle is repeated.

EFFECTS OF SYMPATHETIC AND PARASYMPATHETIC INNERVATIONS The heart can beat spontaneously without neural input. In healthy individuals, however, the autonomic nervous system and circulating hormone levels regulate the heart rate and its strength of contraction. The autonomic nervous system controls many internal organs through its two divisions, the sympathetic and the parasympathetic nervous systems. These release norepinephrine (NE) and acetylcholine (ACh), respectively, into the heart. The autonomic nervous system can also cause the adrenal medulla to release epinephrine into the blood. Epinephrine has effects on the heart similar to those of NE. Some of the details about the autonomic synapses and their pharmacology are described in the next chapter. The cells in the SA and AV node cells have GPCRs that produce a stimulation (via Gαs) or inhibition (via Gαi) of adenylyl cyclase, which, in turn, raises or lowers cAMP levels in response to NE and ACh, respectively. The cAMP enhances the activity of the If channels. The end result is that NE increases If and thus depolarizes the cells more rapidly and increases the heart rate. ACh reduces If , slows the rate of depolarization, and reduces the heart rate (see Figure 23–4). Changing If also leads to a speeding or slowing of conduction through the AV node. These effects are discussed further in terms of heart function in Chapter 23. High ACh levels lead to the opening of another potassium channel (KACh). (It is a G protein–activated inward rectifier GIRK channel.) This channel further reduces the tendency to

depolarize between action potentials and can temporarily stop the heart.

NOREPINEPHRINE ALSO INCREASES CONTRACTILITY In the presence of NE, the plateau of the muscle action potentials is elevated and has a shorter duration (Figure 6–15). This shortening of the action potential shortens the duration of the muscle contraction, which is functionally important for the heart. At high heart rates, the time required to refill the heart limits its performance. By reducing the time that muscle force is being generated (systole), more time is left for filling (diastole). The shortening of the ventricular action potentials can be seen in the ECG as a shortening of the QT interval. NE increases the amplitude of the plateau by causing the action potential to open more L-type Ca2+ channels. This drives the membrane closer to the Ca equilibrium potential. The increased Ca influx leads to a greater strength of contraction by a mechanism described in Chapter 10. NE shortens the

NE elevates plateau NE shortens duration

50 mV 50 ms

FIGURE 6–15 The effects of norepinephrine on ventricular muscle cells’ action potentials. (Modified with permission from Landowne D: Cell Physiology. New York: Lange Medical Books/McGraw-Hill, 2006.)

CHAPTER 6 Action Potentials duration by making the KV channels open more rapidly. The effects on the K and Ca2+ channels are mediated via cAMP acting as a second messenger, stimulating protein kinase A (PKA) and phosphorylating the channels. This pathway also enhances the calcium reuptake mechanism by phosphorylating phospholamban. This speeds up muscle relaxation.

ACETYLCHOLINE REDUCES ATRIAL CONTRACTILITY The ACh-activated K channel (KACh) remains open during the action potentials; in atrial muscle and Purkinje fibers, it makes the plateau phase shorter and lower. The atrial contractions are weaker. ACh receptors are relatively sparse on ventricular muscle cells.

57

It is caused by mutations of the NaV channel of skeletal muscle that make them slowly inactivating; the myotonia results from abnormal reopenings of the NaV channels. Moderate elevation of extracellular potassium favors aberrant gating with persistent and prolonged reopenings. The Na current through these channels may cause skeletal muscle weakness by depolarizing the cells, thereby inactivating normal NaV channels, which are then unable to generate action potentials. Patients with HyperKPP are at increased risk for malignant hyperthermia induced by anesthesia during surgery. Other NaV channel mutations in heart muscle are linked to sudden death syndromes. Attacks can be stopped by ingesting a high sugar load or by thiazide diuretics, both of which reduce extracellular potassium. They can be prevented by a diet low in potassium and high in carbohydrates, and also with thiazides. The disease is a lifelong condition.

CLINICAL CORRELATION Since early childhood, a 42-year-old woman experienced stiffness of her muscles, particularly when loosening a tight handgrip or starting to walk. Cold exposure exacerbated these symptoms. Outdoors on a cold and windy day, her face stiffened in a grimace and she could not open her eyes or move them from side to side. These symptoms disappeared within a few minutes after she had entered a warm room. When she ate ice cream, her throat stiffened and she could not swallow. From age 16, she also had attacks of generalized weakness unrelated to cold. Sometimes she woke up at night severely paralyzed. She was more liable to have an attack when hungry. During pregnancy she had daily attacks of weakness; within a few days after delivery she improved. A neurologist performed diagnostic testing. The patient was given 60 mEq of potassium orally with a mixture of anions. Forty-five minutes later, she was so stiff that she could make no quick movements. About an hour later, she noticed increasing weakness and had to lie down. The paralytic attack reached its peak roughly half an hour later. At that time, she could not lift her head, arms, or legs, nor could she move her limbs on the examination table. Myotonia (difficulty of relaxing muscles) of her facial and extraocular muscles was intense. Respiration was mildly impaired. Reflexes were unchanged and sensation was normal. Improvement started half an hour later and was complete 3.5 hours from the start. Before, during, and after, her serum potassium values were: 4.5, 7.3, and 3.9 mEq/L (normal is 3.5–4.5 mEq/L). This disease also affected her son, sister, mother, maternal aunt, and maternal grandfather. The inheritance was due to a single autosomal, dominant gene with probably complete penetrance. This patient was suffering from familial HyperKPP, which occurs in approximately 1 in every 200,000 people.

CHAPTER SUMMARY ■

■ ■

■ ■ ■ ■ ■

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Depolarization opens NaV channels, which allows Na+ to rush in and produce further depolarization. This positive feedback loop produces the all-or-none quality and the propagation of action potentials. K+ leaving the cell repolarizes the membrane potential and terminates action potentials. Voltage clamping, or negative feedback control of the membrane potential, facilitates understanding of the currents underlying the action potential. The amplitude and direction of the sodium current vary with the amplitude of voltage-clamp steps in membrane potential. Depolarizing steps first activate and then inactivate Na+ current. They also activate K+ current after a delay. The gating current is a direct sign of the conformational changes in the sodium channel proteins. There is a threshold for action potential initiation. Following an action potential, excitable cells have an absolute refractory period when they will not produce a second action potential and then a relative refractory period when a larger stimulus is required to produce a second action potential. Myelination increases conduction velocity by increasing the length constant. Hypocalcemia (low extracellular calcium) makes excitable cells more excitable. Demyelinating diseases slow the conduction velocity and may block the propagation of action potentials. Action potentials appear differently when they are recorded with a pair of wires placed on the outside of a nerve bundle. Compound action potentials, the sum of many externally recorded action potentials, have properties that differ from those of single action potentials recorded with intracellular electrodes. In the heart, action potentials arise automatically in the SA node and then spread from cell to cell over the heart via gap junctions.

58 ■

■

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■

SECTION II Cell Physiology Cardiac muscle cells have KIR channels to maintain the resting potential, NaV channels for the upstroke of the action potential, CaV channels for the plateau phase, and slow KV channels for the repolarization. SA node cells use CaV channels for the upstroke of the action potential, KV channels for the repolarization, and a hyperpolarization-activated If channel to produce the slow “pacemaker” depolarization between action potentials. ACh and NE slow or speed the heart rate, respectively, via G protein–coupled receptors, which leads to a decrease or increase in If. NE increases the amplitude of the plateau and decreases the duration of ventricular muscle action potentials.

STUDY QUESTIONS 1. Hyperkalemia (high extracellular potassium concentration) can stop the heart because A) potassium ions bind to sodium channels, preventing their activity. B) potassium ions stimulate the sodium–potassium pump and thereby prevent cardiac action potentials. C) the membrane potential of heart cells depolarizes and its sodium channels inactivate. D) potassium ions rush out through the inward rectifier. E) potassium ions block the actin–myosin interaction in the heart. 2. Myelination of axons A) reduces conduction velocity to provide more reliable transmission. B) forces the nerve impulse to jump from node to node. C) occurs in excess in multiple sclerosis (MS). D) leads to an increase in effective membrane capacitance. E) decreases the length constant for the passive spread of membrane potential. 3. Consider the following three channels in ventricular muscle cells: sodium channel (NaV), inward rectifier potassium channel (Kir), and calcium channel (CaV). Choose the answer that best describes which of these channels is open during the plateau phase of the ventricular action potential. A) all three B) NaV and Kir only C) CaV and Kir only D) Kir only E) CaV only

4. There is an inward current (If ) associated with pacemaker activity in cells of the sinoatrial node. Stimulation of sympathetic nerves leading to the heart or application of norepinephrine produces A) a decrease of If , a decrease in heart rate, and an increase in strength of contraction. B) a decrease of If , an increase in heart rate, and an increase in strength of contraction. C) an increase of If , an increase in heart rate, and an increase in strength of contraction. D) an increase of If , a decrease in heart rate, and a decrease in strength of contraction. E) an increase of If , an increase in heart rate, and a decrease in strength of contraction. 5. Propagation of a nerve impulse does not require A) closure of potassium channels that maintain the resting potential. B) a conformational change in membrane proteins. C) a membrane depolarization that opens Na+ channels. D) current to enter the axon and flow within the axon. E) entry of sodium ions into the axon. 6. The compound action potential recorded with a pair extracellular electrodes from an intact bundle of nerve fibers A) propagates without change in size or shape. B) is all-or-none. If a threshold is exceeded, further increase in stimulus does not increase the response. C) has an amplitude of about 100 mV. D) is biphasic, showing both upward and downward deflections from the baseline. E) is not blocked by tetrodotoxin (TTX).

C

Synapses David Landowne

7

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P

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E

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Describe the steps in chemical synaptic transmission. Describe the biosynthesis and actions of acetylcholine, catecholamines (dopamine, norepinephrine, epinephrine), serotonin, histamine, and excitatory and inhibitory amino acids. Describe the biosynthesis and actions of neuropeptides. Describe the structure of the neuromuscular junction and the functions of the various substructures. Describe and explain the steps involved in neuromuscular transmission. Describe the actions and explain the mechanisms for the effects of Ca2+ and Mg2+ on transmitter release. Describe how acetylcholine interacts with receptors on the postsynaptic membrane and the fate of the acetylcholine. Describe the generation of the endplate potential and the effects and mechanisms of action of acetylcholine esterase inhibitors and blockers of acetylcholine receptors. Describe facilitation and posttetanic potentiation of transmitter release and how these processes can be used to explain certain features of myasthenia gravis and recovery from receptor blockade. Describe the structures and explain the functions of the various parts of neurons. Describe transport of materials up and down axons (orthograde and retrograde axonal transport) including mechanisms and materials. Calculate the time required for the regeneration of peripheral nerves. Describe the differences and similarities between synaptic transmission at a central synapse and at neuromuscular junctions. Describe the generation of IPSPs and EPSPs by ionotropic and metabotropic receptors. Describe the integration of information and repetitive firing in neurons and the concept of presynaptic inhibition.

INTRODUCTION A synapse is a specialized region where a neuron communicates with a target cell: another neuron, a muscle cell, or a gland cell. Most synapses are chemical; the presynaptic neuron releases a transmitter substance that diffuses across the

Ch07_059-078.indd 59

synaptic cleft and binds to a receptor on the postsynaptic cell. The postsynaptic receptor may be ionotropic, in which case it will open a selective pore and allow ions to flow to produce a postsynaptic potential (PSP), or it may be metabotropic and inform a G protein to initiate a chemical cascade, which may include the opening or closing of 59

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channels. A few synapses are electrical; current passes through cell–cell channels directly into the postsynaptic cell. Chemical synapses offer the possibility of amplification, signal inversion, and persistent effects; electrical synapses are faster and seem to be used when synchronization is more important than computation (information processing). Chemical synapses may be excitatory or inhibitory, depending on their effect on the postsynaptic cell. In the CNS, neurons receive both types of synapses and integrate the information coming into them before sending the processed message on to another cell. Chemical synapses are major pharmaceutical targets.

PRESYNAPTIC PROCESSES The presynaptic terminal must provide for the synthesis, packaging, and release of the various transmitters (Figure 7–1). The nonpeptide transmitters are concentrated inside vesicles by specific H/transmitter cotransporters. A V-type H+ pump, which consumes ATP, produces the H+ gradient. The transmitter concentration inside the vesicle can be quite high, on the order of 20,000 molecules in a 20-nm radius sphere, or about 30 mM. After release, transmitters are degraded or transported back into the presynaptic terminal for reuse. The vesicular membranes are also recycled. Some transmitters are small polypeptides that are synthesized on rough endoplasmic reticulum near the nucleus, packaged by the Golgi apparatus, and then transported in vesicles the length of the axon by an active process called axoplasmic transport. This process also brings other proteins to the presynaptic terminals.

Neurotransmitters can be chemically classified into five groups (Figure 7–2). They are all hydrophilic and contain groups that are charged at physiologic pH. Thus, they do not readily pass through lipid membranes and can be compartmentalized as needed.

ACETYLCHOLINE Acetylcholine (ACh) was the first recognized transmitter. It is used by spinal motoneurons to excite skeletal muscles; by the parasympathetic nerves to communicate with various end organs, including the vagus nerve slowing pacemaker regions of the heart; in sympathetic and parasympathetic ganglia; and in various locations in the CNS. There are two classes of postsynaptic ACh receptors (AChRs), which are named for other agonists that can also bind to them. Nicotinic AChRs are at neuromuscular junctions, sympathetic and parasympathetic ganglia, and in the CNS. Nicotinic AChRs are ionotropic receptors or heteromeric pentamers (see Figure 3–5). They are chemosensitive channels that are opened by nicotine and blocked by curare. Muscarinic AChRs occur in the heart, smooth muscles, gland cells, and CNS. They are metabotropic 7-TM GPCRs that are activated by muscarine and blocked by atropine. nAChRs tend to excite the postsynaptic cell; mAChRs may be excitatory or inhibitory. ACh is synthesized from acetyl-CoA and choline by the enzyme choline acetyl transferase (CAT), found in the presynaptic cytoplasm. ACh is concentrated into vesicles by an H/ ACh cotransporter (Figure 7–3). A Ca2+-activated process releases the vesicles. It is described below, after all of the transmitters have been discussed.

Fill

Dock

Fuse and release

Recycle

FIGURE 7–1

Synaptic vesicle docking, releasing of contents, and recycling. (Modified with permission from Landowne

D: Cell Physiology. New York: Lange Medical Books/McGraw-Hill, 2006.)

CHAPTER 7 Synapses

Cholinergic

Biogenic Amines

O

+

O

N(CH3)3

NH2 HOOC

HO

Dopamine HO

Peptidergic

Amino Acids COOH

HO

Acetylcholine

61

NH2 Glutamic acid

NH2 HOOC

HO

NH2

OH Endorphin Enkephalin Dynorphin Calcitonin gene related peptide (CGRP) Substance Y Substance P Vasopressin (ADH) Oxytocin Cholecystokinin (CCK) Vasoactive intestinal peptide (VIP)

γ-aminobutyric acid (GABA)

Norepinephrine HO

N(CH3)

HO

HOOC

NH2

OH Epinephrine

Glycine

NH2

HO

Purinergic ATP

NH Adenosine

Serotonin NH2

HN N NH N Histamine

Poisoning by botulinum toxin (Botox) blocks ACh release and results in a failure of neuromuscular transmission. Recently Botox injections have been used to treat dystonia, a movement disorder characterized by involuntary muscle contractions, and cosmetically to locally block facial muscles that wrinkle the skin. Excessive doses or systemic toxin delivery from contamination during food canning can lead to death. Black (or brown) widow spider venom (BWSV) also blocks neuromuscular transmission. It makes the presynaptic membranes permeable to Ca2+ and causes a massive release of vesicles, followed by a failure of transmission due to the lack of stored ACh. After release, ACh may be broken down into acetate and choline by acetylcholinesterase (AChE) in the extracellular space. A Na/choline cotransporter recaptures most of the choline; then ACh is resynthesized by CAT and repackaged. AChE inhibitors or anticholinesterases are used for medical purposes, as insecticides, and as nerve gases in chemical warfare. Their effect is to increase the amount and duration of ACh interaction with the postsynaptic receptors. The battlefield countermeasures are to block the postsynaptic receptors on the heart with atropine. The nerve

FIGURE 7–2

The neurotransmitters.

(Modified with permission from Landowne D: Cell Physiology. New York: Lange Medical Books/McGraw-Hill, 2006.)

gases are organofluorophosphates that irreversibly bind AChE but can be displaced by pyridine aldoxime methyl iodide (PAM).

AMINO ACIDS GLUTAMATE Glutamate is the major excitatory neurotransmitter of the CNS. It is a nonessential amino acid, but, because it cannot pass the blood–brain barrier, it must be synthesized in the CNS. There are several synthetic pathways but none specific for neurons. Ionotropic glutamate receptors, gluRs, are classified as NMDA-type if the synthetic agonist N-methyl-daspartate activates them or non-NMDA-type if it does not. Both types are heteromeric tetramers (see Figure 3–6) and permit the passage of Na+ and K+, but the NMDA gluRs also allow Ca2+ to enter the cell and have a special role in synaptic plasticity, described later. There are also metabotropic gluRs (mgluRs). All of these are normally activated by glutamate (Figure 7–4).

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Glia Cholinesterase

H+

Muscarinic GPCR

ATP ACh

Nicotinic channel

Presynaptic

ACh ATP

Choline Na

Cholinesterase Postsynaptic

K Na

FIGURE 7–3

A generalized schematic acetylcholine synapse. The presynaptic terminal has transporters for choline reuptake and ACh packaging. The postsynaptic membrane has ACh receptors and cholinesterase. The nearby glial cell membrane also has cholinesterase. ACh is hydrolyzed by the esterases and the choline part is taken back by the presynaptic terminal. (Modified with permission from Landowne D: Cell Physiology. New York: Lange Medical Books/McGraw-Hill, 2006.)

Glutamate is removed from the extracellular space by a Na/ glu cotransporter, the excitatory amino acid transporter (EAAT), which also countertransports K+. EAATs are in the presynaptic terminal membrane and also in the postsynaptic

membrane and nearby glial cell membranes. Inside the glia, glutamate can be converted to glutamine, released, and taken up by the presynaptic terminal by a Na/Cl-coupled cotransporter and finally reconverted into glutamate.

Na glu K gln Na

gln

Glia

mgluR GPCR

H+ ATP

Ionotropic channel

Presynaptic

glu ATP

K glu Na Postsynaptic

K Na

FIGURE 7–4

A generalized schematic glutamate synapse. In addition to the reuptake and packaging transporters, glutamate synapses have uptake transporters in the postsynaptic and glia cell membranes. There is also a glutamine (gln) pathway to move glutamate in the glial cell back to the presynaptic terminal. (Modified with permission from Landowne D: Cell Physiology. New York: Lange Medical Books/McGraw-Hill, 2006.)

CHAPTER 7 Synapses

63

Na GABA Cl Glia

GABAB GPCR

H+ ATP

GABAA channel

Presynaptic

GABA ATP

Cl GABA Na Postsynaptic

K Na

FIGURE 7–5

A generalized schematic GABA synapse. This is similar to the glutamate scheme but has GABA receptors and transporters.

(Modified with permission from Landowne D: Cell Physiology. New York: Lange Medical Books/McGraw-Hill, 2006.)

Excess extracellular glutamate kills neurons by allowing excess Ca2+ into the cells, which can lead to necrosis (cell death). This neurotoxicity is postulated to play a role in ischemic stroke, amyotrophic lateral sclerosis (ALS), Huntington’s disease, Alzheimer’s disease, and possibly some forms of epilepsy. Ischemia can raise extracellular glutamate by limiting oxidative metabolism, ATP, and sodium gradients, thus the movement of glutamate away from the receptors.

GABA AND GLYCINE Gamma-aminobutyric acid (GABA) and glycine are the major inhibitory neurotransmitters in the CNS. Glutamate decarboxylase (GAD) converts glutamate into GABA in the presynaptic terminal cytoplasm. GABA is packaged and released as other transmitters (Figure 7–5). There is a Na/ GABA cotransporter that removes GABA from the synaptic cleft. GABAA receptors and glycine receptors are pentameric heteromers in the nAChR superfamily; they are permeable to Cl– ions. GABAB receptors are GPCRs that activate Kir (or GIRK) channels. The CNS operates with a tonic level of inhibition that can be shifted with various drugs. Muscimol, from the mushroom Amanita muscaria, is a potent GABAAR agonist. Common tranquilizers such as diazepam (Valium) and barbiturates such as phenobarbital enhance the opening of GABAARs. Picrotoxin, a potent convulsant, blocks GABAAR. Strychnine, also a convulsant, blocks glyRs. Tetanus toxin produces a spastic paralysis by blocking the release mechanism for GABA and glycine.

BIOGENIC AMINES The catecholamines, serotonin, and histamine are all biogenic amines. The catecholamines are dopamine, norepinephrine (NE), and epinephrine (EPI). Most of the effects produced by these biogenic amines are via GPCRs, often without producing PSPs. All are concentrated into vesicles and released by similar mechanisms, but some are released by nerve swellings, which are in the vicinity of the receptors but not as closely apposed (see Figure 7–19). Non-nerve cells also release EPI and histamine.

CATECHOLAMINES Dopamine and NE are found in the CNS. NE is the principal final transmitter of the sympathetic nervous system and EPI is made and released by the adrenal medulla. All three are synthesized by the same pathway, starting with the hydroxylation of tyrosine to dihydroxyphenylalanine (DOPA), which is then decarboxylated to form dopamine. Adding a beta-hydroxyl group forms NE and, in the adrenal medullary cells, a subsequent transfer of an N-methyl group forms EPI. Tyrosine hydroxylase (TH) is the rate-limiting enzyme. TH and DOPA decarboxylase are in the presynaptic terminal cytoplasm. Dopamine is concentrated into vesicles, where dopamine beta-hydroxylase (DBH) converts it to NE. NE is taken back into the presynaptic terminal by a Na/Cl-coupled cotransporter; there, it is broken down by monoamine oxidase (MAO) in mitochondria and by catecholamine-O-methyl transferase (COMT) in the cytoplasm. Catecholamine receptors are GPCRs and are found in the CNS, smooth muscle, and heart. Adrenergic receptors respond

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to NE and/or EPI. There are two categories of adrenergic receptors: alpha-adrenergic receptors have a higher affinity for NE and beta-adrenergic receptors have a higher affinity for EPI. However, there is cross-reactivity, and both receptors will respond to higher concentrations of both agonists. In the cardiovascular system, the alpha receptors are primarily found on the smooth muscle cells that control the diameter of small blood vessels; NE acts to constrict these vessels. The beta receptors are primarily in the heart and can make it beat faster and harder. Muscle relaxation via adrenergic receptor activation occurs in smooth muscle cells in the gut and the lungs. Some of these functions are discussed at greater length in the next section. Parkinson’s disease is characterized by the loss of dopaminergic neurons; its treatment often includes DOPA, which can partially relieve the symptoms. Drugs that block dopamine receptors have been used to treat schizophrenia; sometimes they induce Parkinson-like tremors. Reserpine, an early tranquilizer, inhibits dopamine transport into vesicles. Cocaine blocks the reuptake of catecholamines, prolonging their actions. Many over-the-counter remedies for nasal congestion, such as neosynephrine, activate catecholamine receptors.

SEROTONIN Serotonin, or 5-hydroxytryptamine (5-HT), is made from tryptophan by hydroxylation and decarboxylation. 5-HT receptors function in the gut in secretion and peristalsis, mediate platelet aggregation and smooth muscle contraction, and are distributed throughout the limbic system of the brain. Serotonin was initially identified as a substance in blood serum that constricted blood vessels, hence the name. Tryptophan hydroxylase is the rate-limiting step of 5-HT synthesis; in the CNS tryptophan hydroxylase is present only in serotonergic neurons. 5-HT is deactivated by reuptake and then broken down by MAO in mitochondria. Most 5-HT receptors are GPCRs; 5-HT3 receptors are ion channels. Selective serotonin reuptake inhibitors such as fluoxetine hydrochloride (Prozac) are commonly prescribed as antidepressants. Lysergic acid diethylamide (LSD) and psilocin, the active metabolite of psilocybin, are hallucinogens that activate 5-HT receptors.

HISTAMINE Most histamine in the body is released from mast cells (part of the immune system) in response to antigens or tissue injury. Histamine also is a regulator of acid secretion in the gut and acts as a neurotransmitter in the central nervous system. Histamine release is associated with allergic reactions; it initiates inflammatory responses, dilates blood vessels and increases capillary permeability, decreases heart rate, and contracts smooth muscles in the lung. Enterochromaffin-like cells in the gastric mucosa also release histamine, which promotes acid production. Histamine is made from histidine, stored in vesicles, and released; it is then broken down by histamine

N-methyl transferase. There are four different histamine receptors, which are all GPCRs.

PURINES ATP is contained in synaptic vesicles and released with NE in sympathetic vasoconstrictor neurons. It induces constriction when applied directly to the smooth muscles. P2X ATP receptors are ion channels that permit the entry of Ca2+, and the cells also have P2Y GPCRs. These receptors are also in the brain, as well as P1 receptors for adenosine.

PEPTIDES Neuropeptides are small polypeptides that are synthesized as larger inactive precursors (propeptides) and then cleaved out by specific endopeptidases. As they are proteins, they are synthesized in the cell body and transported in vesicles to the terminals. There is no reuptake mechanism. Peptides are less concentrated than other neurotransmitters in vesicles but have higher affinity for their receptors, which are GPCRs. Neuropeptides are released from large dense-core vesicles, while other neurotransmitters are secreted from smaller, clearer vesicles. Neuropeptides often act in concert with classic neurotransmitters. Not much is known about the function of most neuropeptides in the CNS except the opiate peptides, endorphin, enkephalin, and dynorphin, which are involved in the regulation of pain perception. Three opiate receptors have been identified, initially as the sites that bind synthetic opiates such as morphine. There are many nonopiod peptides released from neurons. The calcitonin gene–related peptide (CGRP) and substance Y are involved in maintaining blood pressure. Antidiuretic hormone (ADH, also called vasopressin) helps control water reuptake in the kidney. Oxytocin, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) are involved in reproduction. Cholecystokinin (CCK), gastrin, and vasoactive intestinal peptide (VIP) facilitate digestion. All of these and many more have been identified as potential neurotransmitters in the CNS.

SYNAPTIC RELEASE The details of the synaptic release process are currently under active investigation. It is clear that the process is triggered by an increase in cytoplasmic Ca2+ levels. At many synapses, when a presynaptic action potential arrives, the Ca2+ enters the terminal through CaV channels. In some small sensory cells there is no action potential and the sensory generator potential opens the CaV channels. Synaptic vesicles cycle through loading with transmitters, docking at an active zone or release site, fusion with the surface membrane and release of contents, endocytotic recovery,

CHAPTER 7 Synapses

65

Na Dock

Ca

Fuse and release

Recycle

FIGURE 7–6 The channels involved in synaptic release. NaV channels depolarize the ending and CaV channels permit Ca2+ influx to trigger release. There are also KV channels that repolarize the membrane and thereby limit Ca2+ influx. (Modified with permission from Landowne D: Cell Physiology. New York: Lange Medical Books/McGraw-Hill, 2006.)

and then loading again. In Figure 7–6, each step in the vesicular cycle is illustrated by a shift in the position of the vesicle. In reality, however, there is little movement in the attached states. In many synapses, the release site is across from a postsynaptic area containing the channels that are sensitive to the transmitter. In the neuromuscular junction (see Figure 7–9), CaV channels are adjacent to the release site, so that internal Ca2+ need only be elevated locally to cause release.

Docking and fusion involves the SNARE or soluble Nethylmaleimide-sensitive factor attachment protein (SNAP)— receptor proteins that are present on both membranes before fusion and associate into tight core complexes during fusion. Figure 7–7 shows the vesicular v-SNARE synaptobrevin binding the target t-SNARE syntaxin and SNAP-25. Synaptobrevin is the substrate of the endopeptidases contained in botulinum and tetanus toxins.

Synaptotagmin Synaptobrevin v-SNARE Ca

Syntaxin t-SNARE

FIGURE 7–7

A possible mechanism of vesicle fusion. SNARE proteins dock the vesicle and Ca2+ binds to synaptotagmin to cause fusion.

(Modified with permission from Landowne D: Cell Physiology. New York: Lange Medical Books/McGraw-Hill, 2006.)

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Ca-stimulated fusion requires the Ca2+-binding protein synaptotagmin, which is in the vesicular membrane and binds Ca2+. A proposed model suggests that Ca2+ allows the synaptotagmin to bind the surface membrane and pull the two lipid layers together. The recycling process returns the lipids and proteins to the vesicle pool. The vesicle is reformed as a clathrin-coated pit. The clathrin molecules have the shape of a triskelion, or three bent legs. The clathrin forms a closed surface covered with pentagons and pinches the recovered vesicle off the surface.

AXOPLASMIC TRANSPORT All of the proteins in the presynaptic terminal are synthesized in the cell body and transported perhaps 1 m before they are useful. In addition, the neuron has mechanisms that transport some materials in the reverse or retrograde direction back to the cell body. Some of the mechanisms used for this transport are used in other cells to deliver material to the periphery of the cell and also for the movement of chromosomes during mitosis. Axoplasmic transport is distinguished by the direction into orthograde and retrograde. Orthograde transport can be further divided into fast (100–400 mm per day or 1–5 μm/s) and slow (0.5–4 mm per day). Fast transport is for vesicles and mitochondria; slow transport is for soluble enzymes and those that make up the cytoskeleton. Retrograde transport is only of the fast type. Fast axoplasmic transport involves molecular motors that hydrolyze ATP and walk along microtubules, long hollow cylinders 25 nm in diameter. Two different classes of motors are used, kinesins for orthograde transport and dyneins for retrograde. Microtubules are polarized, and these motors can sense the polarity and move by 8-nm steps in the appropriate direction. The motors have two “feet,” or sites of interaction with the microtubules, and exhibit processivity, or the ability to function repetitively without dissociating from their substrate, the microtubule. Accessory molecules are used to attach the payload to the motor (Figure 7–8). Fast orthograde transport delivers the membrane proteins needed in the terminal for both the vesicles and the terminal Orthograde

Kinesin Microtubule Dynein Retrograde

FIGURE 7–8

Axoplasmic transport. Kinesin motors carry vesicles toward the nerve terminals. Dynein motors carry different vesicles toward the cell body. (Modified with permission from Landowne

D: Cell Physiology. New York: Lange Medical Books/McGraw-Hill, 2006.)

membrane. During development, it can also deliver cell adhesion molecules that recognize or induce targets. Retrograde transport can return damaged proteins for the endolytic pathway and bring information about signaling events back to the cell body. Retrograde transport is part of the pathophysiology of several diseases including polio, rabies, tetanus, and herpes simplex. The herpesvirus enters peripheral nerve terminals and then travels back to the cell body, where it replicates or enters latency. It can later return to the nerve ending by orthograde transport and make itself available for contact transmission to another person. The tetanus toxin is transported retrogradely in motoneurons to the dendrites and then transsynaptically to GABA- and glycinereleasing terminals, where it inhibits synaptic release. Axoplasmic transport is important for the regeneration of nerves following injury in the peripheral nervous system. Under usual circumstances, nerves in the CNS do not regenerate, although current researchers are hopeful that this will change in the future. If a peripheral nerve axon is cut or crushed, the distal portion will die and go through a characteristic Wallerian degeneration as the axon is resorbed over a few weeks. Within a few days, the cell body undergoes the axon reaction, often called chromatolysis, because of a change in staining when it is studied histologically. The nucleolus enlarges, the rough endoplasmic reticulum, or ER (Nissl substance), disperses, and the nucleus is displaced. Genes have been activated, RNA transcribed, and proteins synthesized. The longer the distance from the injury to the cell body, the greater the latency, indicating that retrograde transport is involved in the signaling to initiate the axonal reaction. At the site of injury, the end that is coupled to the cell body will reseal in hours and buds or sprouts will appear in a day or two. The cut tip swells with mitochondria and smooth ER. The sprouts grow out as thin fibers. If the regeneration is successful, one of the new fibers finds its way down the sheath of the distal degenerating nerve and reinnervates a postsynaptic target. The fiber will then increase in diameter and become remyelinated. The rate of fiber growth is about 1 mm per day, in the range of slow axonal transport. This is the number to use in estimating recovery times. In addition to the microtubule-based systems, intracellular transport can also occur via myosin motors traveling along actin filaments. The interaction is similar to that described in the section Chapters 8 and 9 except that the actin stays fixed and individual myosin molecules process along it. There are adapter molecules that attach the payload to the myosin.

POSTSYNAPTIC PROCESSES There are several different postsynaptic receptors for each transmitter; they are distinguished by their amino acid sequences and, in some cases, pharmacology. Different regions of the nervous system have characteristic receptors; sometimes an individual postsynaptic cell will have multiple receptor types. The ionotropic receptors are excitatory or inhibitory ac-

CHAPTER 7 Synapses cording to their ionic selectivity. The metabotropic receptors may indirectly cause channels to open or close and may also modulate the activity of the cells in other ways. The PSPs are called excitatory postsynaptic potentials (EPSPs), if their effect is to make the postsynaptic cell more likely to respond with an action potential, or inhibitory postsynaptic potentials (IPSPs), if they make the postsynaptic cell less likely to fire an action potential. Each channel has a selectivity pattern and allows different ions to flow through with differing ease. This means that each channel will have a reversal potential: a potential at which there will be no net flow of ions through the channel. If the membrane potential is more positive than the reversal potential, net current will flow out of the cell, tending to hyperpolarize it. If the membrane is less positive or more negative, current will flow in and tend to depolarize the cell. The current that flows through channels drives the membrane potential toward the reversal potential for that channel. Most neurons in the CNS receive a constantly fluctuating input from a variety of synapses and their membrane potential is always changing. If a synapse opens channels having a reversal potential more positive than the threshold for action potentials, they will produce an EPSP. If the reversal potential is more negative than the threshold, an IPSP will result. If a channel is permeable to a single ion, its reversal potential is the Nernst potential

67

for that ion (equation (4) in Chapter 4). If the channel is permeable to multiple ions, its reversal potential is the weighted average of the Nernst potentials for its ions (equation (6) in Chapter 4). nAChR channels and GluR channels are approximately equally permeable to Na+ and K+, and their reversal potential is about –10 mV; when activated, they make EPSPs. GABAAR and glyR are Cl channels; their reversal potential is about –80 mV. The cardiac mAChR, through a G protein, activates a Kir channel (KACh) that has a reversal potential about –90 mV. Both Cl− channels and K+ channels make IPSPs. If for some reason the cell happens to be more negative than –80 mV, opening Cl channels will depolarize the cell but still work to keep other channels from further depolarizing the cell to threshold.

THE NEUROMUSCULAR JUNCTION—A SPECIALIZED SYNAPSE Because of its easy accessibility, the neuromuscular (or myoneural) junction (Figure 7–9) is the best-studied synapse; it is the source of much of what is known about synapses. This section describes the functioning of this synapse, bringing together

Myelin Axon

Schwann cell

Mitochondria

Synaptic vesicles Synaptic cleft

Presynaptic membrane Postsynaptic membrane

Muscle nucleus

Synaptic fold

Myofibrils

FIGURE 7–9

The neuromuscular junction. A myelinated nerve (gray) ends on a specialized region of a skeletal muscle (colored). (Modified

with permission from Landowne D: Cell Physiology. New York: Lange Medical Books/McGraw-Hill, 2006.)

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SECTION II Cell Physiology

and illustrating many of the ideas introduced more abstractly above. The neuromuscular junction is of considerable clinical interest. Myasthenia gravis is a disease that incapacitates the neuromuscular junction; there are other diseases and several drugs and toxins that target the junction. The neuromuscular junction provides a convenient assay for the anesthesiologist gauging recovery from muscle immobilization after surgery. A single motoneuron controls between 3 and 1,000 muscle cells. Each muscle cell receives input from one motoneuron. The motoneuron and all of its muscle cells function together as a motor unit. In healthy people, an action potential in the motoneuron will produce a large EPSP in all of its muscle cells, large enough to greatly exceed the threshold of the muscle cells and produce action potentials and contraction. The CNS regulates movement by choosing which motor units to activate. Smaller motor units produce finer movements. At the nerve ending, the axon loses its myelin and spreads out to form the motor endplate, named for its anatomic appearance. The nerve terminals contain many mitochondria and many 40-nm-diameter synaptic vesicles that contain ACh. The nerve terminal is separated from the muscle by a 50-nm gap, the synaptic cleft, which contains a basal lamina. The muscle membrane contains AChRs and also AChE. In transmission electron micrographs, both presynaptic and postsynaptic membranes appear thickened, indicating the presence of channels and other proteins. Neuromuscular transmission can be described as a 10-step process: (1) an action potential enters the presynaptic terminal; (2) the nerve terminal is depolarized; (3) depolarization opens CaV channels; (4) Ca2+ enters the cell, moving with its electrochemical gradient; (5) Ca2+ acts on a release site, probably synaptotagmin, causing synaptic vesicles to fuse with the presynaptic membrane; (6) about 200 vesicles release their ACh into the synaptic cleft; (7) the ACh in the cleft either (a) diffuses away out of the cleft, (b) is hydrolyzed by AChE into acetate and choline, or (c) interacts with AChRs on the postsynaptic membrane; (8) the activated AChRs are very permeable to Na+ and K+ and slightly permeable to Ca2+; hence, a net influx of positive charge into the muscle cell depolarizes the muscle membrane in the endplate region; (9) when the muscle membrane is depolarized to threshold, an action potential is elicited, which propagates in both directions to the ends of the muscle cell (the link between muscle excitation and contraction is discussed in the next section); and finally (10) choline is recycled into the nerve terminal, Ca2+ is pumped out of the nerve terminal, and vesicles are recycled and refilled.

RECORDING THE ENDPLATE POTENTIAL If a microelectrode is inserted into a muscle fiber near the neuromuscular junction, a resting potential of about –90 mV will be measured. If the nerve is stimulated and the muscle is prevented from contracting by extreme stretching the membrane potential will be seen to change, as shown in the solid trace on the left in Figure 7–10. If, instead, the electrode is placed sev-

FIGURE 7–10 An endplate potential and action potential at the neuromuscular junction (left) and 2 cm away (right). Dashed lines indicate responses in low Ca2+ (see text). (Modified with permission from Landowne D: Cell Physiology. New York: Lange Medical Books/ McGraw-Hill, 2006.)

eral centimeters away from the neuromuscular junction, the potential shown in the right trace will be seen. If the concentration of Ca2+ in the bath is decreased or the concentration of Mg2+ is increased and the nerve is stimulated again, the potential at the neuromuscular junction will change as shown in the dashed trace. Under these conditions there will be no change in the membrane potential several centimeters away from the junction. The solid trace on the left shows an action potential superimposed on an endplate potential (EPP). There is an initial depolarization due to a net entry of positive charge through AChRs that were activated by the released ACh. When the potential reached about –50 mV, an action potential was initiated. In normal Ca2+ the EPP is two or three times larger than necessary to depolarize the muscle membrane to threshold. The pure action potential is seen in the trace on the right; it can be recorded by stimulating one end of the muscle electrically or by placing the recording electrode a few centimeters away from the endplate. The dashed trace on the left shows an EPP with reduced amplitude. The EPP is not visible a few centimeters away from the endplate (right). A reduction in extracellular Ca2+ reduces the release of ACh and thus reduces the EPP. An increase in Mg2+ reduces transmitter release by reducing Ca2+ entry through CaV channels. These opposing effects of Ca2+ and Mg2+ have been seen on all chemical synapses that have been examined; this is now considered one of the tests for identifying a chemical synapse. Ca2+ and Mg2+ concentrations have different effects on the excitability or the threshold for action potentials on the nerve and muscle cells. The reduction of Ca2+ makes the cells more excitable or have a more negative threshold, or requires a smaller depolarization to reach threshold for an action potential. This is an effect on the NaV channels; in low Ca2+, NaV channels will open at more negative potentials. Ca2+ and Mg2+ have a synergistic action on NaV channels; they have opposing actions on neuromuscular transmission. Clinically, the effects of hypocalcemia are hyperexcitability and spontaneous action potentials in nerve and muscle. These effects are seen when there is still enough Ca2+ to support sufficient ACh release, so that every nerve action potential leads to a muscle action potential.

1 mV

CHAPTER 7 Synapses

10 ms

69

200,000 vesicles are released, which is equal to the number seen by the electron microscope in an unstimulated neuromuscular junction. After BWSV treatment, no vesicles are visible. BWSV paralyzes by depleting the nerve terminals of synaptic vesicles. It can be deadly if the nerve endings controlling breathing are compromised.

TRANSMITTER–RECEPTOR INTERACTION FIGURE 7–11 Some miniature endplate potentials (MEPPs) seen by stimulating a neuromuscular junction bathed in low Ca2+ four times. The second MEPP on the bottom trace was spontaneous. (Modified with permission from Landowne D: Cell Physiology. New York: Lange Medical Books/McGraw-Hill, 2006.)

In this low-Ca2+ and high-Mg2+ case, the EPP is not large enough to reach threshold and elicit an action potential. Action potentials are actively propagated; the EPP spreads passively and will not be visible a few centimeters from the neuromuscular junction. These two potentials are produced by the activity of different channels that have differing pharmacology. Curare will block AChRs and the EPP without affecting the action potential seen following direct electrical stimulation of the muscle. A toxin from a cone snail (μ-conotoxin) will block the muscle action potential but not the EPP. The μ-conotoxin blocks muscle NaV channels but not nerve NaV channels, which are a different gene product. If the Ca2+/Mg2+ ratio is sufficiently low, the response to stimulation will appear as in Figure 7–11. Each trace represents the response to a stimulation that is repeated every 5 seconds. Three of the traces show a small EPP; in the third trial there was no response. The first response is about 1 mV high; the second and fourth responses are about 0.5 mV. When this experiment was repeated many times, the responses were found to be quantized with a unit response of about 0.5 mV. That is, there were many 0.5-, 1-, and 1.5-mV responses but very few with amplitudes in between. In addition, there are sometimes spontaneous 0.5-mV responses without any stimulation; one of these was caught on the fourth trace. These miniature endplate potentials (MEPPs) represent the postsynaptic response to the release of one, two, or three quanta of ACh. Each quantum is the contents of a single vesicle. The exact number of vesicles released on any particular stimulation cannot be known; only the average number or the mean quantal content can be predicted. The EPP in normal Ca2+/Mg2+ conditions is the response to about 200 quanta. The average rate of spontaneous MEPPs is about 1 vesicle/s. In a normal EPP, the 200 vesicles are released within 1 millisecond, which means that stimulation increased the rate of release by 200,000-fold. If BWSV is applied to a neuromuscular junction, the MEPP frequency increases to a few hundred per second for about 30 minutes and then stops. In total about

The nicotinic AChR at the neuromuscular junction has five subunits, each with four TM segments. Two of the subunits are called alpha subunits and bind ACh at the α–γ and α–δ interfaces near the top of the molecule, about 5 nm from the center of the membrane. The channel then undergoes a conformational change that is transmitted through the molecule to open the pore, most likely by causing the M2 TM segments to move out away from the axis of the pore, making it larger. The open pore allows Na+ and K+ and, to a lesser extent, Ca2+ to pass. The pore stays open about 1 millisecond and about 20,000 ions pass at a rate of 2 × 107/s, which is equivalent to about 3 pA. If a single AChR is captured in a patch of membrane and maintained with a –90 mV potential, application of ACh will cause the channel to open and close several times, each opening appearing as a 3-pA current pulse of varying duration averaging about 1 millisecond. A single quantum opens about 2,000 channels; 200 quanta open about 400,000. A neuromuscular junction has many more channels, about 20 million; thus, only a small fraction is used at any one time. The number of open channels is proportional to the concentration of ACh squared and the effective number of receptors. A kinetic scheme for the reaction is shown in Figure 7–12. The receptor can open with one or two ACh molecules bound; it stays open about 10 times longer with two bound. It is the concentration of R • 2ACh that is proportional to the concentration of ACh squared: Number of open channels = k[R][ACh]2

(1)

DESENSITIZATION If a single AChR is exposed to continuous ACh for several minutes, its response will slow and openings will become less frequent. If ACh is added to the bath containing a neuromuscular junction, the muscle membrane potential will

R

R • ACh

R • 2ACh

Closed

R∗ • ACh

R∗ • 2ACh

Open

FIGURE 7–12

A kinetic scheme of the reaction between acetylcholine and the nicotinic acetylcholine receptor. The receptor (R) can bind two ACh molecules. Once ACh is bound the receptors can open (R*) and allow the passage of ions. (Modified with permission from Landowne D: Cell Physiology. New York: Lange Medical Books/McGraw-Hill, 2006.)

70

SECTION II Cell Physiology The Bungarus snake paralyzes its prey with α-bungarotoxin, which binds AChRs irreversibly and prevents their opening. Bungarotoxin has been fluorescently labeled and used experimentally to identify and locate nAChRs.

10 μM ACh

10 mV 1 min

MYASTHENIA GRAVIS FIGURE 7–13 Desensitization of acetylcholine receptors (AChRs). With prolonged ACh exposure the AChRs first open and then enter a desensitized and closed state where they no longer respond to ACh. (Modified with permission from Landowne D: Cell Physiology. New York: Lange Medical Books/McGraw-Hill, 2006.)

depolarize but the response will reach a peak and then decline, as shown in Figure 7–13. This decline is called desensitization; the AChR molecule has entered an inactivated state from which it does not open. This is functionally somewhat similar to the inactivation of NaV channels except that the time course, the agent that causes the inactivation, and the molecular basis in the channels are completely different. Desensitization probably does not occur with normal use of neuromuscular junctions but may become a problem when drugs are used that block AChE. A patient with desensitized AChRs may be paralyzed and unable to breathe due to a lack of functional AChRs.

SOME DRUGS THAT ACT AT THE NEUROMUSCULAR JUNCTION d-Tubocurare is a classic neuromuscular blocking agent, originally discovered as an arrow poison from South America. Curare binds AChRs reversibly and prevents ACh from opening the channels. After application of curare, the EPP becomes smaller; if there is sufficient curare, the EPP becomes so small that it no longer elicits an action potential, similar to the dashed response in Figure 7–10, and the junction is effectively blocked. Higher doses of curare can eliminate the EPP. Curare reduces the EPP by reducing the number of receptors available to respond to ACh. Curare or a related drug is often used during surgery to immobilize muscles; it can also facilitate tracheal intubation and mechanical ventilation. Anticholinesterases such as neostigmine and physostigmine combine with AChE and prevent hydrolysis of ACh, which leads to a larger EPP. Neostigmine is used to speed recovery from the effects of curare and to reduce the symptoms of myasthenia gravis. There are dangers associated with neostigmine; an excess of ACh can lead to desensitization of the remaining receptors. Also, the body uses ACh to slow the heart and release saliva; both of these effects may be enhanced by physostigmine. Botulism is a potentially fatal food poisoning caused by the anaerobic bacterium Clostridium botulinum. Some of the toxins released by this organism are endopeptidases, which are taken up by nerve cells and cleave synaptobrevin, thus preventing transmitter release. The purified toxins are used clinically to prevent unwanted neuromuscular transmission.

Myasthenia gravis is a disease associated with muscle weakness and fatigability on exertion. It is an autoimmune disease that leads to the destruction of AChRs. Patients may have only 10–30% of the number of AChRs found in healthy individuals. Treatment with anticholinesterases increases the amount of available ACh, which makes it more likely that the remaining AChRs will be activated (equation (1)). There is a danger of giving too much anticholinesterase, which can lead to desensitization of the AChRs and further weakness. If this weakness is misinterpreted as insufficient anticholinesterase therapy, a tragic positive feedback loop leading to myasthenic crisis can ensue.

LAMBERT–EATON SYNDROME The Lambert–Eaton syndrome is seen with an autoimmune disease that reduces the number of CaV channels in the presynaptic terminal. With prolonged effort, these patients gain strength, the opposite of myasthenic patients. Prolonging the presynaptic action potentials with drugs that block KV channels, such as diaminopyridine, may alleviate some of the symptoms. The prolonged depolarization opens the remaining CaV channels for a longer time, allowing more Ca2+ entry and therefore more release. If the experiment shown in Figure 7–11 is performed on these neuromuscular junctions, they will be found to have a lower quantal content, that is, they release a lower number of vesicles per stimulus. This is in contrast to myasthenia gravis, which will show the normal quantal content but a smaller MEPP, the depolarization for each quantum.

REPETITIVE STIMULATION The amount of transmitter released by a synapse is not constant from impulse to impulse but depends on the past history of activity. If the nerve leading to a neuromuscular junction is stimulated once every 10 seconds or slower, it will consistently release about 200 vesicles. If the stimulation rate is abruptly changed to 50/s, which is roughly the rate used by the CNS to cause normal muscle contraction, the amount released per impulse will increase in the first half second and then decrease (Figure 7–14). The increase, called facilitation, is related to a buildup in residual calcium in the nerve terminal. The decrease, called depression, is thought to reflect a depletion of vesicles at the release sites. This variation does not affect the functioning of the neuromuscular junction in a healthy individual. Each of those nerve impulses releases sufficient ACh to produce an EPP large enough to fire a muscle action potential. However, the

CHAPTER 7 Synapses

Facilitation X Normal

1

Depression

40

80 Impulses

120

FIGURE 7–14 Facilitation and depression of synaptic transmission at the neuromuscular junction. With repetitive stimulation the amount of transmitter released by each stimulus changes, first increasing and later decreasing. (Modified with permission from Landowne D: Cell Physiology. New York: Lange Medical Books/ McGraw-Hill, 2006.)

myasthenic person may have functional neuromuscular transmission only early in the task and experience weakness as the depression occurs with a prolonged effort and the amount of ACh released falls below what is necessary to trigger a muscle action potential. An anticholinesterase with a short duration of action, edrophonium chloride (Tensilon), is often used as a test for myasthenia gravis in patients who show rapid weakening when asked to perform a sustained contraction.

POSTTETANIC POTENTIATION When the 50/s stimulus is stopped, there is an increase in the amount of transmitter that can be released by a single nerve impulse (Figure 7–15). The nerve was stimulated once every 30 seconds before and after the tetanic stimulation. During the

PTP

x Normal

1

1

2

3

4

Minutes

FIGURE 7–15 Posttetanic potentiation (PTP) of synaptic transmission at the neuromuscular junction. After the end of a period of repetitive stimulation the amount of transmitter released by subsequent infrequent stimuli is increased for several minutes. (Modified with permission from Landowne D: Cell Physiology. New York: Lange Medical Books/McGraw-Hill, 2006.)

71

tetanus, the release increased and decreased, as in Figure 7–14. After the tetanus, as the synapse recovered from depression, a posttetanic potentiation (PTP) was seen that lasted for several minutes. PTP is also related to an increase in residual Ca2+ concentration in the nerve terminal, but it has a slower onset and slower decline than facilitation. PTP is used as a diagnostic procedure following surgical procedures when curare or other neuromuscular blocking agents have been used to prevent unwanted motion. The anesthesiologist will give the patient cholinesterase inhibitors, but she or he wants to know when just enough inhibitor has been given to avoid giving too much and desensitizing the AChRs. The anesthesiologist will repeat the experiment shown in Figure 7–15, stimulating the thenar branch of the patient’s median nerve and feeling the strength of contraction of the thenar muscles. Two shocks are given before the tetanus and then one 30 seconds later. Under deep curare, none of these will produce a palpable contraction. As more ACh is made available by blocking the esterase, the stimulus following the tetanus will give a larger response than the two before the tetanus because it will be the first one with an EPP large enough to excite the muscle. The endpoint is when enough esterase has been given that all three responses are the same because all three EPPs are above threshold for muscle activation.

AUTONOMIC SYNAPSES The autonomic nervous system (ANS) has two divisions, both with two synapses outside the CNS (Figure 7–16). The synapse closer to the CNS is referred to as the ganglionic synapse; the nerves leading into and out of the ganglia are called preganglionic and postganglionic. The sympathetic ganglia lie in a chain adjacent to the spinal column; the parasympathetic ganglia are close to the end organs where the second synapse occurs. The second synapses are onto smooth muscles or cardiac cells or gland cells. Many tissues receive both sympathetic and parasympathetic innervations. The primary transmitter in the ganglionic synapse of both divisions is ACh; the receptors are nicotinic nAChRs that are heteromeric pentamers of related but different gene products than the nAChR of the skeletal muscle. The ganglionic receptors are less sensitive to curare and more easily blocked by hexamethonium. The primary postganglionic transmitter in the sympathetic nervous system is NE, and there are two categories of GPCRs on the postsynaptic cells called alpha- and beta-adrenergic receptors. The primary postganglionic receptor in the parasympathetic division is ACh and the receptors are muscarinic mAChRs, which are also GPCRs but generally with different G proteins than the NE receptors. The ganglionic synapses are usually described as behaving more or less like the neuromuscular junction. However, the situation is more complicated; the postsynaptic neurons have dendrites with more than one presynaptic nerve ending on them. Different subpopulations of presynaptic and postsynaptic cells have been distinguished by looking at the peptide

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SECTION II Cell Physiology

CNS Parasympathetic

ACh

ACh

Preganglionic

ACh

Sympathetic Postganglionic

Target

NE Target

ACh Epinephrine

Motor

ACh

Muscle

FIGURE 7–16

A schematic view of the efferent fibers of the autonomic nervous system and the motoneurons. From top to bottom: parasympathetic, sympathetic, adrenal medulla, motoneuron. (Modified with permission from Landowne D: Cell Physiology. New York: Lange Medical Books/

McGraw-Hill, 2006.)

transmitters that are in these cells along with their classic transmitters. Postganglionic cells also have mAChRs that produce a slow EPSP by closing a K channel. There are also small, intensely fluorescent cells in the ganglia that are innervated by preganglionic fibers and release NE or dopamine. All in all, it seems that some computation must be carried out in the ganglia, more than the simple passthrough circuit seen at the neuromuscular junction. The synapses between the postganglionic cells and the end organs are different from those in the neuromuscular junction. The presynaptic processes are similar, but postganglionic cells make “en passant” synapses on tissue targets over a length of axon. Synaptic vesicles are stored in varicosities of the nerve, which continues on to other varicosities before reaching its terminal. Activation of mAChRs by the ANS increases GI tone and motility, increases urinary bladder tone and motility, increases salivation and sweating, constricts bronchioles, and decreases heart rate and blood pressure. The ANS activates α-, β1-, and β2-adrenergic receptors, and α-adrenergic receptors raise blood pressure. β1-Adrenergic receptors increase heart rate and strength of contraction and blood pressure. β2-Adrenergic receptors dilate bronchioles in the lungs. The mechanism of the effects on cardiac and smooth muscle is discussed in the next section. Many agonist and antagonist drugs have been used to control these processes, some with more specificity than others. Thus, there are specific α agonists and β blockers. Amphetamines and cocaine have an indirect adrenergic effect by stimulating NE release. Some compounds, such as ephedrine, have both direct and indirect adrenergic effects. Atropine is the archetypical mAChR antagonist; its effects are the opposite of those attributed to ACh above. At many sites there is a tonic release of both

ACh and NE from the ANS, so the blocking of one set of receptors may produce effects similar to activating the other.

CENTRAL NERVOUS SYSTEM SYNAPSES The human CNS has billions of neurons with trillions of synapses between them. A single neuron may have thousands of both excitatory and inhibitory inputs; some larger neurons may have over 100,000 endings on them. In order to accommodate this convergence of synaptic inputs, most neurons have a dendritic tree that greatly expands the area available for synaptic contact. The cell body (soma) and the initial region of the axon (axon hillock) integrate the incoming synaptic signals and determine when and how often the neuron will fire action potentials (Figure 7–17). The axon carries the output of the neuron to the next group of neurons or to skeletal muscle cells if it is a motoneuron. Usually only a single axon leaves the cell body, but it later branches to allow the neuron to synapse with many other cells. This divergence of information combined with the convergence of many inputs onto a neuron gives the CNS much of its computational power. Each neuron in the CNS acts as one or more small computers. While each cell performs its computations in milliseconds, millions of times slower than the central processing unit of a modern computer, the billions of neurons operating in parallel make the CNS shine in comparison. The CNS is capable of creating every thought in recorded history while simultaneously regulating both walking and chewing gum. The synapses make this possible. Learning and memory are accomplished by the modification of synapses.

CHAPTER 7 Synapses

73

Axons converge on neuron

Dendrites

Synaptic inputs cover most of the surface of the soma and dendrites

Soma

Axon hillock or initial segment Axon

Synapses diverge

FIGURE 7–17 The convergence and divergence of synapses in the CNS. (Modified with permission from Landowne D: Cell Physiology. New York: Lange Medical Books/McGraw-Hill, 2006.)

There are two general types of synapses in the CNS, electrical and chemical. Electrical synapses operate by direct electrical current flow from the presynaptic neuron into the postsynaptic neuron through gap-junction channels between the membranes of the two cells (Figure 7–18). Neurotransmitters are not involved and electrical synapses can have less synaptic delay than chemical synapses. However, unlike chemical synapses, electrical synapses cannot amplify the signal, nor can they reverse the direction of current flow. Gap junctions, which work as electrical synapses and allow action potentials to flow selectively from one cell to another, also connect cells in the heart and some types of smooth muscle.

There are two general types of chemical synapses in the CNS, excitatory and inhibitory. Excitatory synapses generate EPSPs that depolarize the membrane toward threshold. Inhibitory synapses generate IPSPs that either hyperpolarize the membrane or resist depolarization to threshold. Each of these types can be further divided into chemosensitive ion channels (or ionotropic receptors) and G protein–linked ion channels (or metabotropic receptors). Chemosensitive ion channels typically give rise to fast synaptic events that last a few milliseconds; G protein–linked ion channels may produce effects for hundreds of milliseconds.

INTEGRATION OF SYNAPTIC CURRENTS

FIGURE 7–18

An electrical synapse. Current passes directly from the presynaptic cell to the postsynaptic cell through specialized cell–cell channels. (Modified with permission from Landowne D: Cell Physiology.

New York: Lange Medical Books/McGraw-Hill, 2006.)

Excitatory and inhibitory synapses inject current (positive or negative) into cells. These currents flow into the cell body and are summed. The PSPs passively spread to the spike initiation site or the part of the cell with the lowest threshold because of the cable properties of the cell. More distal synapses will be decremented compared to those near the site. The cell produces the spike initiation site by controlling the local density of NaV channels. Often the spike initiation site is the axon hillock near the start of the axon (see Figure 7–17) or at the first node of Ranvier. Because the PSPs last for several to many milliseconds, they can add together even though they do not occur synchronously; this is called temporal summation. The effects of synapses at different locations on the same postsynaptic cell can also add up; this is called spatial summation. Spatial summation is weighted inversely by the distance from the synapse to the initiation site of the action potential.

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SECTION II Cell Physiology

Synaptic cleft Postsynaptic spine on dendrite

Axon

Presynaptic nerve terminal Synaptic vesicles

Postsynaptic density

FIGURE 7–19

A CNS synapse. These are less elaborate than the synapse at the neuromuscular junction (Figure 6–9). (Modified with

permission from Landowne D: Cell Physiology. New York: Lange Medical Books/ McGraw-Hill, 2006.)

Figure 7–19 is a schematic drawing of a chemical synapse in the CNS. The presynaptic terminal is about 1 μm in diameter and contains mitochondria and synaptic vesicles filled with neurotransmitter. Depolarization of the terminal opens CaV channels, and Ca2+ flows with its electrochemical gradient to act on synaptotagmin and trigger the fusion of a few vesicles with the presynaptic membrane in order to exocytose the neurotransmitter. The membrane is then recycled and the vesicles are refilled. The postsynaptic receptors are often on protrusions from dendrites, called spines, although synapses are also found on the dendritic shaft, the neuronal cell body, and other synaptic endings. CNS synapses share many features with the neuromuscular junction but differ in several important respects. CNS synapses are much smaller and release far fewer vesicles, typically less than 5 per impulse, compared to about 200 at the motor endplate. In the CNS, synaptic clefts are narrower, about 20 nm, and cadherins and other cell adhesion molecules span the gap. ACh is the transmitter at the neuromuscular junction; there is a wide variety of transmitters in the CNS. The EPP is always excitatory and large enough to bring the muscle membrane to threshold; synapses in the CNS are excitatory or inhibitory and threshold is reached by the combination of hundreds of EPSPs. There are some exceptional CNS synapses. In the cerebellum, a climbing fiber axon may make dozens of synapses on a Purkinje cell. In the calyx of Held, in the auditory pathway, the presynaptic ending forms a cap with fingerlike stalks that envelop the postsynaptic neuron, covering about 40% of its soma. At both of these synapses a single presynaptic impulse releases hundreds of quanta, and the resulting EPSP is large enough to trigger a postsynaptic action potential. Glutamate is the principal excitatory neurotransmitter in the CNS. There are several postsynaptic glutamate receptors, both channels and GPCRs. The channels can be grouped into two major types, NMDA and non-NMDA channels, according to their sensitivity to the synthetic agonist N-methyl-daspartate. Both types respond to glutamate. The non-NMDA

channels may be called AMPA, quisqualate, or kainate channels, according to which of these nonphysiologic agonists opens them. Non-NMDA channels typically generate fast EPSPs lasting about 5 milliseconds. When they are activated by glutamate, non-NMDA channels allow Na+ and K+ to flow through their pores. Each ion moves in the direction that will tend to bring the membrane potential to its Nernst equilibrium potential. Because both are moving, the membrane potential tends to approach the average of the two equilibrium potentials, which is about –10 mV. This potential, where the two ionic currents are equal, is called the reversal potential for the channel. When these channels open at potentials more negative than the reversal potential, the tendency for Na+ to enter the cell will dominate and the membrane will depolarize toward the reversal potential. If the starting potential were more positive than the reversal potential, the K+ ions would dominate and the cell would hyperpolarize toward the reversal potential. NMDA receptor channels generate EPSPs lasting hundreds of milliseconds. Open NMDA channels allow Na+ and K+ and also Ca2+ to pass through their pores. In the presence of glutamate, NMDA channels open only if the postsynaptic cell is also depolarized by some other means. This dual control of Ca2+ entry has a key role in learning, as discussed below. GABA is the major inhibitory transmitter in the brain. Glycine is an inhibitory transmitter in the brainstem and spinal cord. GABA opens GABAA channels directly, which allows Cl− ions to pass through their pores. GABA can also cause inhibition through GABAB receptors, which are GPCRs that lead to the opening of K channels. The reversal potential for GABAA channels is at the Nernst potential for Cl−, about –80 mV. If the membrane is more positive than ECl, Cl− will enter the cell and make the membrane potential more negative, which will make it less likely to initiate an action potential. Benzodiazepines such as diazepam (Valium) and barbiturates enhance the open probability of activated GABAARs. Both have been used as sedatives and anticonvulsants. General anesthetics such as ether, chloroform, and halothane increase the duration of IPSPs and decrease the amplitude and duration of EPSPs.

CNS—MODULATORY NEUROTRANSMITTERS In the CNS, ACh, NE, dopamine, and serotonin primarily act as diffuse modulators of activity, acting over timeframes that are long compared to action potentials, as opposed to being involved in specific discrete tasks. Each of these neurotransmitters has its own set of neurons and targets; some of these neurons may influence more than 100,000 postsynaptic neurons. The postsynaptic receptors are metabotropic and alter the responsiveness of the postsynaptic neurons through second messenger pathways. There are also ionotropic nAChRs in the CNS, but there are 10–100 times more mAChRs. The ACh and NE modulatory systems are part of the ascending

CHAPTER 7 Synapses

75

Axon

B A

Neuron C

FIGURE 7–20

Presynaptic inhibition can occur by a synapse (A and B) on another synaptic ending. (Modified with permission from Landowne

D: Cell Physiology. New York: Lange Medical Books/McGraw-Hill, 2006.)

reticular activating system that arouses the forebrain in response to stimuli. In some general ways, the modulatory systems play a role in the CNS similar to the role played by the ANS in the rest of the body.

cellular space by a nonvesicular process. It binds to presynaptic cannabinoid receptors (CB1), which are GPCRs, and can alter the subsequent release of traditional neurotransmitters.

PRESYNAPTIC INHIBITION

REPETITIVE FIRING OF NERVE CELLS

Some CNS synapses act directly on other synaptic endings rather than on dendrites or cell bodies (Figure 7–20). Terminal A releases GABA on to terminal B, activating Cl channels that tend to hyperpolarize terminal B. If an action potential arrives in B while the Cl channels are open, the action potential’s amplitude will be reduced, so that it will open fewer CaV channels and therefore fewer vesicles will be released by terminal B, and it will have a smaller effect on neuron C.

If an axon or a muscle cell is subjected to a maintained depolarization, it will respond with one or perhaps two action potentials and then stop firing because the NaV channels enter the inactivated state and require a brief period near the resting potential to recover. Many CNS cells and the slowly adapting sensory nerve endings will respond to a sustained depolarization with a train of action potentials at about 50/s. This is made possible by CaV channels and Ca-activated K channels. The action potential depolarization opens the CaV channels and the Ca2+ that enters opens the Ca-activated K channels by binding to the intracellular portion of the molecule. The Ca-activated K channel then allows K+ to leave and the membrane potential to approach EK for a long-lasting hyperpolarization, long enough for the NaV channels to recover from inactivation (Figure 7–21). The balance between the sustained stimulus and the rate that Ca2+ is removed from the Ca-activated K channels determines the firing rate.

RETROGRADE FREELY DIFFUSIBLE CHEMICAL TRANSMITTERS In addition to the classic transmitters that are released from vesicles and bind to receptors, there are chemical messengers in the CNS with a different mode of operation. Nitric oxide (NO) is not stored but rather produced when needed. It can freely diffuse across cell membranes from the inside of one cell (typically a postsynaptic cell body) to the inside of other cells (typically presynaptic endings), where it alters some chemical reactions. NO may spread to several presynaptic endings in the vicinity. It is removed from the tissue by binding to hemoglobin. Anandamide, an endogenous cannabinoid, is also produced as needed in postsynaptic cells and reaches the extra-

LEARNING, MEMORY, AND SYNAPTIC PLASTICITY The cellular basis of learning and memory is a functional remodeling of synaptic connections, often called synaptic plasticity. This includes both explicit or declarative memory when

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SECTION II Cell Physiology

+40

mV

0

−60 −70 0

200

400

ms

Sustained excitatory synaptic input

FIGURE 7–21

Repetitive firing of a motoneuron. Unlike axons, many nerve cells respond repetitively to a sustained input. (Modified

with permission from Landowne D: Cell Physiology. New York: Lange Medical Books/ McGraw-Hill, 2006.)

the person can recall and describe some fact or past event and implicit or procedural memory, as in a learned motor skill. Memory is often subdivided into short-term, minutes to hours, and long-term, days to a lifetime. Short-term memory formation involves the modification of existing proteins, often by phosphorylation. Long-term changes involve gene activation, protein synthesis, and membrane rearrangement, including the formation and/or resorption of presynaptic terminals and postsynaptic spines. In a few studies, the volume of cerebral cortex dedicated to a task has been shown to increase with specific training. The most intensively studied cellular learning phenomenon is long-term potentiation (LTP) in hippocampal synapses. The hippocampus is required for the formation of new longterm memories. If both hippocampi are compromised, the person will live continuously in the present with no recollection of events after the damage. In the hippocampus, LTP occurs at glutamate synapses between presynaptic CA3 cells and postsynaptic CA1 cells. LTP and the related long-term depression (LTD) also occur in other locations in the CNS. The classic

experiment is similar to the PTP demonstration shown in Figure 7–15; the synapse is tested infrequently, subjected to high-frequency stimulation, and then tested infrequently again. Unlike PTP, which disappears in a few minutes, with LTP, the potentiation remains for many hours or days (Figure 7–22). Also unlike PTP, LTP is primarily a postsynaptic event. It is not necessary to provide the high-frequency stimulation to the presynaptic terminals; simple depolarization of the postsynaptic cell paired with the presynaptic stimulation will induce LTP. This response to pairs of inputs made LTP a candidate basis for associative learning. There are two types of glutamate receptors on the postsynaptic membranes: AMPA (non-NMDA) and NMDA receptors. During low-frequency unpaired stimulation, only the AMPA receptors are activated; the NMDA receptors are plugged by external Mg2+ ions. The AMPA receptor channels are permeable to Na+ and K+; near the resting potential, Na+ movement into the cell is favored. When the postsynaptic membrane is depolarized, either by high-frequency synaptic input or by injecting current into the postsynaptic cell, the Mg2+ is driven off the NMDA receptors and they respond to glutamate and allow Na+ and Ca2+ to enter the cell. The elevated Ca2+ activates a series of biochemical events that lead to the insertion of more AMPA receptors into the postsynaptic membrane. LTP has been associated with learning in rats using a water maze. Rats with surgically removed hippocampi do not learn the maze, neither do rats that have been treated with a specific antagonist for NMDA receptor channels. There are other examples of synaptic plasticity in other regions of the brain and there may well be additional mechanisms, including retrograde action of NO or anandamide.

CLINICAL CORRELATION About a month before coming to the hospital, a 56-yearold woman noticed she was unable to hold her shopping bag and that her head fell forward when she knelt to tie her shoes. Two weeks later she had to remain in bed and had difficulty sitting up. Her jaw began to droop, she had

5 4

mV

3 2 1 0 10

FIGURE 7–22

20

30 Minutes

40

50

60

Long-term potentiation. A brief conditioning stimulus (blue bar) causes a long-term increase in synaptic efficacy. (Modified

with permission from Landowne D: Cell Physiology. New York: Lange Medical Books/McGraw-Hill, 2006.)

CHAPTER 7 Synapses ■

to hold it up with her hand, and her left eyelid began to droop. Her speech became indistinct when she was excited, swallowing was difficult and fluid sometimes regurgitated through her nose. A few days after admission to the hospital, she developed weakness in the middle and ring fingers of both hands that was increased by excitement and lessened by rest. There was no muscle wasting and tendon reflexes were all present. Her masseter muscles showed a decremental response to tetanic electrical stimulation. In the hospital, she was injected with 1 mg of physostigmine. About 1 hour later, her left eyelid elevated, her arm movements were stronger, her jaw drooped less, swallowing was improved, and she reported feeling “less heavy.” The effect wore off gradually in 2–4 hours. With 1.3 mg the improvement was greater and lasted 4–5 hours. Still greater improvements, lasting 6–7 hours, followed an injection of 1.5 mg but the patient felt faint as if “something were going to happen.” The diagnosis is myasthenia gravis. It is an autoimmune disease that affects about 1 in 5,000 people. The immune system produces antibodies to the nicotinic AChR of the neuromuscular junction and neuromuscular transmission is impaired. With fewer receptors the effects of depression of synaptic transmission lead to a failure of neuromuscular transmission during sustained effort. This fatigability is a characteristic of the disease. Physostigmine is an inhibitor of AChE. In its presence more of the released ACh can interact with the receptor and transmission is more reliable. AChE inhibitors are used to relieve the symptoms of myasthenia gravis. Immunosuppressants, for example, the synthetic corticosteroid prednisone, are used to reduce antibody production. In some cases thymectomy (surgical removal of the thymus) is performed to suppress the immune system. Edrophonium chloride (Tensilon) is a short-acting AChE inhibitor that has been used to assist in diagnosis. Electrical stimulation and testing for circulating antibodies are also used diagnostically.

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77

GABA and glycine are the major inhibitory neurotransmitters in the CNS. Several biogenic amines are important neurotransmitters. NE is released by sympathetic nerves to control the heart and vascular smooth muscle. Neuropeptides are small proteins released as neurotransmitters. Synaptic release involves many proteins and is controlled by CaV channels, which are opened when an action potential invades the presynaptic terminal. Axons have a microtubule-based transport system to move materials from the cell body to the presynaptic terminal (orthograde transport) and in the other direction (retrograde transport). PSPs are excitatory (EPSPs) if they make the postsynaptic cell more likely to initiate an action potential and inhibitory (IPSPs) if they make it less likely. Neuromuscular transmission is a well-studied example of synaptic transmission. Hypocalcemia reduces the number of vesicles released when an action potential invades the presynaptic terminal. At the neuromuscular junction, the number of open channels is proportional to the concentration of ACh squared times the effective number of AChR channels. Several clinically important drugs act at the neuromuscular junction. The number of vesicles released per action potential depends on the rate and pattern of arrival of the action potentials. The ANS has two synapses outside the central nervous system. The first is cholinergic; the second is either adrenergic or cholinergic. In general, CNS synapses are similar to the neuromuscular junction, but they differ in many important ways. In the CNS, several transmitters act through G protein–coupled receptors to modulate the activity of the brain. In order to fire repetitively, nerve cells use Ca-activated K channels to hyperpolarize the cell and allow the NaV channels to recover from their inactivation. Learning and memory involve changes in synaptic efficacy.

STUDY QUESTIONS CHAPTER SUMMARY ■ ■

■

■

Synapses may be chemical or electrical. Chemical synapses may be excitatory or inhibitory. In chemical synapses, the presynaptic terminal packages a neurotransmitter into vesicles. When the synapse is activated, the vesicle’s contents are released and then a recycling process recovers some of the released transmitter and vesicular components. ACh is the neurotransmitter at the neuromuscular junction. It is also an important component of the autonomic and central nervous system synapses. Glutamate is the major excitatory neurotransmitter in the CNS.

1. Ca2+ ions are needed in the extracellular solution for synaptic transmission because A) Ca2+ ions enter the presynaptic nerve terminal with depolarization and trigger synaptic vesicles to release their contents into the synaptic cleft. B) Ca2+ ions are required to activate glycogen metabolism in the presynaptic cell. C) Ca2+ ions must enter the postsynaptic cell to depolarize it. D) Ca2+ ions prevent Mg2+ ions from releasing the transmitter in the absence of nerve impulses. E) Ca2+ ions inhibit the acetylcholine esterase, enabling the released acetylcholine to reach the postsynaptic membrane.

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2. Inhibitory postsynaptic potentials can arise from all of the following except A) increased permeability of the nerve membrane to Cl− ion. B) direct application of GABA to neurons. C) increased permeability of the nerve membrane to K+ ion. D) increased permeability of the cell membrane to Na+ ion. 3. Electrical and chemical synapses differ in that A) electrical synapses have a longer synaptic delay than chemical synapses. B) chemical synapses can amplify a signal while electrical synapses cannot. C) chemical synapses do not have a synaptic cleft while electrical synapses do have a synaptic cleft. D) electrical synapses use agonist-activated channels and chemical synapses do not. E) electrical synapses are found only in invertebrate animals while chemical synapses are found in all animals. 4. Which one of the following does not contribute to the integration of synaptic potentials by neurons? A) convergence of many synaptic inputs on one neuron, allowing spatial summation B) the presence of EPSPs having amplitudes that exceed the threshold for generation of an action potential in the neuron C) temporal summation of synaptic potentials in neurons due to the time constant of the neurons D) the flow of currents from the distal regions of the dendrites to the soma due to the length constants of the dendrites E) inhibitory synaptic inputs

5. Which of the following ions is countertransported to energize neurotransmitter transport into presynaptic vesicles? A) Na+ B) K+ C) H+ D) Cl− E) Ca2+ 6. A branch of a 26-year-old man’s ulnar nerve was crushed in his left forearm, severing axons at a point about about 6 in (15 cm) from the skin on the medial part of the palm, where cutaneous sensation was lost. About how long will it likely take before the patient begins to feel stimuli in that part of the palm? A) 1 day B) 10 days C) 100 days D) 1,000 days E) never, since peripheral axons do not regenerate 7. Treatments for nerve gas poisoning target which of the following proteins? A) acetylcholinesterase (AChE) and choline acetyltransferase (CAT) B) AChE and nicotinic acetylcholine receptors C) muscarinic and nicotinic acetylcholine receptors D) muscarinic acetylcholine receptors and AChE E) CAT and synaptic choline transporters

SECTION III MUSCLE PHYSIOLOGY

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Overview of Muscle Function Kathleen H. McDonough

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Explain the differences in skeletal, cardiac, and smooth muscle with reference to appearance, contractile proteins, calcium-binding proteins, and neural input. Describe how the sarcolemma and the sarcoplasmic reticulum are involved in muscle contraction. Explain the energy source for contraction. Describe the role of the following proteins: actin, myosin, dihydropyridine receptors, ryanodine receptors, calmodulin, and troponin.

GENERAL COMPARISON Muscle is the largest organ system of the body. It consists of three different types based on factors such as morphology, cellular signaling pathways, ways to alter strength of contraction, contraction pattern (cyclic vs. graded), and the role of the nervous system in muscle function. The three types of muscle are skeletal, cardiac, and smooth muscle. Skeletal muscle is, for the most part, attached to bone and represents approximately 40% of the body mass of a typical healthy person. Cardiac muscle is the main component of the heart and contracts in a cyclic fashion for the lifetime of the individual. Smooth muscle is the major component of the organs of the gastrointestinal tract, bladder, uterus, airways, and blood vessels—in general, smooth muscle makes up the walls of hollow structures in the body except the heart. The requirement for calcium to initiate contraction is uniform in all muscle. Mechanisms for increasing calcium for contraction may vary from muscle type to muscle type and removal of calcium for relaxation also varies. However,

Ch08_079-082.indd 79

the overriding unifier is that cytosolic calcium concentrations must increase in order for contraction to occur and cytosolic calcium concentrations must decrease for relaxation to occur. Since, in smooth muscle, there is usually some moderate level of contraction, cytosolic calcium must increase for the strength of the contraction to increase and must decrease for the strength of the contraction to decrease. Thus, the organelles such as the sarcolemma (SL) and the sarcoplasmic reticulum (SR) that contain proteins that effect calcium fluxes are highly organized and efficient in muscle. Calcium levels in resting cardiac muscle, for example, are only 0.1 μM and can increase 100-fold during excitation. Removal of calcium for relaxation to occur is therefore critical. Processes involved in calcium movement are important in the understanding of muscle contraction in all three types of muscle. Muscle contraction is supported by hydrolysis of adenosine triphosphate (ATP). ATP is produced mainly by mitochondrial oxidative phosphorylation from substrates supplied by glycogen or triacylglycerol stores in the tissue or by

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blood-borne substrates such as glucose and fatty acids. Glycolysis also produces ATP but not as efficiently as oxidative phosphorylation. In some types of skeletal muscle, glycogen supplies glucose for glycolysis that provides energy for rapid, short-term contraction. Energy is additionally provided by creatine phosphate (CP), which can rapidly supply a source of high-energy phosphate bonds for resynthesis of ATP from ADP. The ADP is produced by ATPase enzymes located in the muscle cell. CP is not used directly by the ATPase but is used for rapid regeneration of ATP at the site of ATP use. ATP is used for both contraction and relaxation of muscle. The myosin ATPase hydrolyzes ATP to provide the energy for the sliding of the actin filament over the myosin filament; ATP also provides the energy for removal of calcium from the cytosol by calcium ATPases so that relaxation can take place.

DIFFERENCES IN SKELETAL, CARDIAC, AND SMOOTH MUSCLE Skeletal and cardiac muscle are both striated in appearance due to the orderly arrangement of the contractile proteins actin and myosin. In smooth muscle, the contractile proteins actin and myosin are responsible for contraction but they are not arranged in such an organized pattern; therefore, striations do not appear. Skeletal muscle is the only muscle type that is voluntary—you decide when to contract skeletal muscle for the most part and the muscle has to be activated by neurons regulated by the central nervous system. Cardiac muscle is involuntary; it contracts spontaneously. Action potentials are generated by specialized cells within the heart itself; thus, hearts can be transplanted from one person to another and the heart functions adequately even without neural input in the transplanted heart of the recipient. The beating rate of the heart as well as the strength of contraction of the cardiac muscle cells can, however, be modulated by the autonomic nervous system (ANS; see Chapter 19). The sympathetic nervous system (SNS) component of the ANS will increase the heart rate, whereas the parasympathetic nervous system (PNS) will decrease the heart rate. Smooth muscle is also involuntary. It has the potential to contract from many different types of stimuli but does not require neural input for contraction to occur. Even changes in the resting membrane potential and stretch of the muscle can change the strength of contraction. Smooth muscle does not usually exhibit contractions followed by complete relaxation as do skeletal and cardiac muscle but rather demonstrates increased or decreased strength of contraction. For example, if all of the vascular smooth muscle making up the blood vessels to the systemic organs were to relax completely, the individual would go into shock; blood pressure would decrease to dangerously low levels. This occurs under pathological conditions such as severe brain injury causing withdrawal of all neural control of vascular smooth muscle and resulting in neurogenic shock. Blood pressure cannot be maintained if all of the vascu-

lar smooth muscle in the blood vessels is completely relaxed. In smooth muscle, gradations of contraction are regulated and affected by many different influences, depending on the location and function of the smooth muscle.

CALCIUM Although calcium is uniformly required for muscle to contract or increase strength of contraction, the calcium-binding proteins in the three types of muscle differ, as do the sources of calcium. Troponin is the calcium-binding protein that initiates contraction in skeletal and cardiac muscle. Calmodulin binds calcium in smooth muscle and initiates increases in strength of contraction. Actin and myosin form the crossbridges in all three types of muscle. The source of the calcium that initiates contraction is different in the three muscle types. Calcium released from the SR through ryanodine receptors or channels raises the cytosolic calcium concentration and contraction begins in skeletal muscle (see Chapter 9). In cardiac muscle, the calcium that binds to troponin comes from both the SR and the extracellular space through SL voltage-gated calcium channels (dihydropyridine receptors). In addition, it is the calcium entering the cell through the calcium channels that activates the release of calcium from the SR through the ryanodine receptors or channels (see Chapter 10). In smooth muscle, calcium can enter the cytosol from extracellular fluid via the voltage-gated calcium channels in the SL and from the SR via receptors activated by signaling molecules from SL receptor pathways. Smooth muscle also has other receptors on the SL and SR for calcium mobilization that will be discussed in Chapter 11. In all three muscle types, increases in cytosolic calcium initiate cycling of crossbridge attachments between actin and myosin.

CONTRACTION PERIOD The time course of muscle contraction is different in skeletal, cardiac, and smooth muscle. Skeletal muscle contractions take several milliseconds to occur, cardiac muscle contractions take hundreds of milliseconds, while smooth muscle is much slower and can take up to minutes for contractions to occur. This difference in contraction time is mainly due to the rate of ATP hydrolysis occurring in the myosin head. Fast rates of ATP hydrolysis by the myosin ATPase result in more rapid contractions such as in skeletal muscle. Muscles with slower rates of ATP hydrolysis exhibit slower contractions such as in smooth muscle. Signaling pathways that cause increases in calcium in the cytosol can contribute to the delay between the signal and the contraction.

CHANGES IN STRENGTH OF CONTRACTION The strength of muscle contraction can be altered in all three muscle types but by different means. Phosphorylation of

CHAPTER 8 Overview of Muscle Function proteins results in stronger contractions in both cardiac muscle (Chapter 10) and smooth muscle (Chapter 11), whereas skeletal muscle achieves stronger contractions by recruiting more muscle cells or activating muscle cells with a higher frequency of nerve firing (Chapter 9).

SIMILARITIES IN SKELETAL, CARDIAC, AND SMOOTH MUSCLE As stated above, actin and myosin are the contractile proteins involved in crossbridge cycling in all three types of muscle although the anatomic distribution of the actin and myosin is different in smooth muscle compared to skeletal and cardiac muscle (nonstriated vs. striated, respectively). The myosin head contains a binding site for actin. This site is blocked when calcium levels are low but open when calcium binds to troponin (skeletal and cardiac muscle) or calmodulin (smooth muscle). With binding of actin and myosin, the ATPase site located on the myosin head can release energy from the ATP to allow cycling of the crossbridges, that is, actin sliding across myosin. All three types of muscle demonstrate the property of increasing strength of contraction by increasing the precontraction (resting) length of the muscle. This phenomenon is termed the length–tension relationship. Since skeletal muscle is attached to bones by tendons, variations in resting cell length are very limited and the muscle is usually operating at the peak of the length–tension relationship. In the heart, resting muscle cell length is usually not at the optimum length, so there is reserve, that is, stronger contractions can be elicited when the resting length is increased prior to the contraction. Smooth muscle also demonstrates the length–tension relationship but other influences on the muscle can override the effects of increased cell length. For example, in certain types of vascular smooth muscle, when the cell is stretched, the cell responds with an increased level of contraction. This phenomenon is called the myogenic response. In the gastrointestinal tract, this occurs with the presence of food in the stomach and small intestines. Hollow organs with specialized functions such as the bladder and uterus can be “stretched” but contraction is not stimulated due to other influences on muscle function. A comparison of skeletal, cardiac, and smooth muscle is given in Table 8–1. More details on the individual muscle types will be given in the next three chapters.

CHAPTER SUMMARY ■

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There are three types of muscle in the body classified by morphology, function, and cellular mechanisms of contraction—skeletal, cardiac, and smooth. All types of muscle require calcium to initiate contraction. SL and SR have specialized functions that increase cytosolic calcium for contraction and remove calcium for relaxation.

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TABLE 8–1 Comparison of skeletal, cardiac, and smooth muscle. Skeletal

Cardiac

Smooth

Appearance

Striated

Striated

Nonstriated

Sarcoplasmic reticulum

Most

Less

Least

Voluntary

Yes

No

No

Calciumbinding protein

Troponin

Troponin

Calmodulin

Source of calcium

SR

SR and SL

SL and SR

Innervation

Motor neuron

SNS; PNS

SNS; PNS

Contraction length

Milliseconds

100 ms

100 ms – minutes

Strength of contraction

Recruitment

Phosphorylation; length–tension

Phosphorylation; length–tension

Metabolism

Oxidative, glycolytic

Oxidative

Oxidative

Velocity of ATPase reaction

Rapid

Less rapid

Slow

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Muscle can increase strength of contraction by increasing the length of the muscle prior to the contraction—length–tension relationship. The energy for contraction is released from ATP by the myosin ATPase. Skeletal muscle requires neural input from a motor neuron to initiate contraction (voluntary muscle). Cardiac and smooth muscle can contract without neural input but the strength of contraction can be altered by input from the ANS—sympathetic and parasympathetic branches of the ANS (involuntary muscle).

STUDY QUESTIONS 1. Which of the following statements about muscle is true? A) The calcium source for skeletal muscle contraction is solely calcium entering the cell through the dihydropryidine receptors. B) The calcium source for smooth muscle contraction is solely calcium entering the cell through the dihydropyridine receptors. C) The calcium source for cardiac muscle contraction is solely calcium entering the cell through the dihydropryidine receptors. D) The calcium source for skeletal muscle contraction is solely calcium entering the cytosol through the ryanodine receptors. E) The calcium source for cardiac muscle contraction is solely calcium entering the cytosol through the ryanodine receptors.

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2. Which of the following statements about muscle is true? A) Both smooth and cardiac muscle remain partially contracted at all times. B) Both cardiac and skeletal muscle contraction is initiated by calcium binding to troponin. C) Both cardiac and smooth muscle must have action potentials to initiate contraction. D) Both cardiac and smooth muscle initiate contraction by calcium binding to troponin. 3. Which of the following statements about muscle is true? A) Skeletal muscle can increase strength of contraction by recruiting more motor units. B) Cardiac muscle can increase strength of contraction by recruiting more muscle cells. C) Smooth muscle cannot change strength of contraction. D) Cardiac muscle cannot change strength of contraction.

4. Which of the following statements about muscle is true? A) In all three muscle types (cardiac, skeletal, and smooth) all cells contract as a unit. B) All three muscle types are innervated by the autonomic nervous system. C) In all three muscle types, calcium is involved in contraction. D) In all three muscle types, dihydropryidine antagonists or blockers increase strength of contraction.

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Skeletal Muscle Structure and Function Kathleen H. McDonough

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Describe the processes that take place at the neuromuscular junction. Explain excitation–contraction coupling in skeletal muscle. Describe the role of the proteins that are involved in contraction. Describe what happens during an isometric contraction. Describe what happens during an isotonic contraction. How does the load affect shortening and velocity of shortening? Explain how muscle fiber strength of contraction can be increased by summation and tetanus. Explain the length–tension relationship in skeletal muscle. Explain the motor unit. Explain how whole muscle strength of contraction can be increased by recruitment of motor units. Explain the force–velocity relationship in skeletal muscle; explain the basis for the Vmax. Describe the three different types of skeletal muscle fibers and the bases for their differences. State when these fibers are recruited.

STRUCTURE Skeletal muscle is distinctive because of its anatomic structure—striations due to the regular pattern of sarcomeres that are composed of the orderly positioning of the actin and myosin proteins. Figure 9–1 shows sarcomeres composed of parallel alignments of thick filaments (i.e., myosin) and thin filaments (i.e., actin, tropomyosin, and troponin). Myosin makes up the A band. Actin, along with the two other proteins, tropomyosin and troponin, makes up the I band (portion of the sarcomere where actin does not overlap with myosin). Part of the actin filament overlaps with the myosin filament, thus allowing interaction of these two proteins to initiate contraction. The degree of overlap of thick and thin filaments is important in determining the amount of force that skeletal muscle, and cardiac muscle, can generate. The Z lines represent the borders of the sarcomere and, during shortening, the Z lines come closer to each other as the actin filament is pulled

Ch09_083-092.indd 83

over the myosin filament. The A band remains the same length (myosin does not shorten) but the I band becomes smaller as actin is pulled over the myosin. The sliding of the actin over the myosin, with energy provided by the myosin ATPase that is located on the myosin head, is the molecular basis of skeletal muscle contraction (Figure 9–2). Activation of the complex occurs when the calcium concentration in the cytosol increases and binds to the calcium-binding site on the troponin. Troponin has three components designated as TnT that attaches it to tropomyosin, TnI that inhibits interactions between actin and myosin, and TnC that binds the calcium. When calcium binds to TnC, there is a conformational change in the troponin/ tropomyosin position, removing the hindrance by TnI and tropomyosin and allowing the actin and myosin head to interact, thereby hydrolyzing ATP to supply the energy for the contraction—sliding of the actin over the myosin or crossbridge cycling. The cross-bridges will continue to cycle, that is, myosin heads will continue to bind to adjacent sites on actin

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Sarcomere

(a)

I band

A band H zone

(b)

Z line

Z line Titin

Thin filament

M line

Thick filament

FIGURE 9–1 (a) Magnified section of a sarcomere within a skeletal muscle cell showing the pattern of striation due to the orientation of the actin and myosin filaments. (b) Drawing of the components of the sarcomeres from Z band to Z band showing the structural protein titin and the thick filaments (myosin) and the thin filaments (actin, tropomyosin, and troponin). (Reproduced with permission from Widmaier EP, Raff H, Strang KT: Vander’s Human Physiology, 11th ed. McGraw-Hill, 2008.)

Thick filament

Cross-bridge

Thin filament (a) Actin binding sites ATP binding sites

Troponin

Tropomyosin

Light chains Heavy chains

Actin

Myosin

Cross-bridge

(b)

FIGURE 9–2 (a) Drawing of the thick filament with the myosin heads or cross-bridges extending from the thick filament. Also shown is the twisted structure of the thin filaments. (b) Magnification of the myosin and actin showing the three components of the thin filament— actin, tropomyosin, and troponin—and the heavy and light chains of the myosin. Note the actin- and ATP-binding sites on the myosin. The actin-binding sites are blocked by tropomyosin when calcium levels in the cytosol are low. With calcium binding to troponin, tropomyosin is moved away and the binding site for actin is available. The energy for sliding the actin filament across the myosin filament is provided by the ATP hydrolyzed by the myosin ATPase that is located on the myosin head. (Reproduced with permission from Widmaier EP, Raff H, Strang KT: Vander’s Human Physiology, 11th ed. McGraw-Hill, 2008.)

CHAPTER 9 Skeletal Muscle Structure and Function and slide the actin further over the myosin, until the contraction is terminated by removal of calcium. Cross-bridge cycling results in either tension development or shortening or a combination of the two, depending on the load on the muscle. If the load is too great, there will be an isometric contraction in which there is tension development but no shortening of the muscle. If the load is less, there will be an isotonic contraction in which the muscle shortens after developing tension (discussed in more detail in Chapter 10). Other proteins are involved in maintaining the precise structure of the sarcomeres. Titin, a large structural protein in the skeletal muscle cell, extends from the Z line to the center of the sarcomere, stabilizing the structure. Another large protein complex consists of dystrophin and several glycoproteins. This complex is instrumental in attaching the sarcomere, in particular, actin, to the sarcolemma (SL) and the extracellular matrix, again for maintaining structure and stability of the sarcomeres. The gene that codes for the dystrophin complex is large and subject to mutations resulting in disorders of skeletal muscle termed muscular dystrophy. One symptom of this disease is progressive muscle weakness due to the loss of the proper structural integrity of the muscle

1

2

+ –

fibers. Duchenne muscular dystrophy is one type of dystrophy in which there is a complete absence of the dystrophin protein resulting in rapid decline in skeletal muscle function and early death.

NEUROMUSCULAR JUNCTION Skeletal muscle cells or fibers generally extend from one tendon to the other tendon that attaches the muscle to the bones. Skeletal muscle is classified as voluntary muscle since its contraction is mandated by the central nervous system—we can contract muscles at will. Thus, the innervation of skeletal muscle is essential for activation of contraction. Each fiber is activated by one motor neuron, whereas one motor neuron can innervate a number of muscle fibers forming a motor unit. When one motor neuron is activated, all of the fibers innervated by that motor neuron will contract. The motor neurons from the spinal cord or brainstem, in response to action potentials traveling down the axon toward the skeletal muscle cell, release the neurotransmitter acetylcholine as shown in Figure 9–3 at the neuromuscular junction.

Motor neuron action potential

Acetylcholine vesicle

Ca2+ enters voltage-gated channels

8

Propagated action potential in muscle plasma membrane Voltage-gated Na+ channels

Acetylcholine release

3

+ –

+ –

+ +

–

+ – –

9

85

Acetylcholine degradation

4

+

+ –

Acetylcholine binding opens ion channels + + + + – – – –

+ 5

–

Na+ entry + +

+

–

–

–

+

+

+

–

–

–

–

+

7

Acetylcholine receptor Acetylcholinesterase Motor end plate

+

6

Muscle fiber action potential initiation

Local current between depolarized end plate and adjacent muscle plasma membrane

FIGURE 9–3 The neuromuscular junction is the specialized part of the muscle cell—motor end plate—at which the motor neuron releases the neurotransmitter acetylcholine to activate the muscle cell or fiber. Events at the junction are listed in chronological order. Note that each muscle fiber receives impulses from only one motor neuron and all of the fibers receiving input from that motor neuron make up the motor unit and will contract in synchrony. (Reproduced with permission from Widmaier EP, Raff H, Strang KT: Vander’s Human Physiology, 11th ed. McGraw-Hill, 2008.)

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SECTION III Muscle Physiology

The amount of acetylcholine released is proportional to the frequency of action potentials. Acetylcholine diffuses across the synaptic cleft and binds to a cholinergic receptor—the nicotinic receptor—on the muscle cell membrane (SL). The part of the muscle SL that is associated with the neuromuscular junction is called the motor end plate. Within the cleft is the enzyme acetylcholine esterase that can hydrolyze unbound acetylcholine and thereby limit the activation of the muscle cell membrane nicotinic receptors. This receptor is a channel that allows sodium and potassium flux. The predominant ion movement is sodium entering the muscle cell causing partial depolarization of the cell membrane in the synaptic cleft—an end plate potential (see Chapter 7). Since motor neurons cause only depolarization of the postsynaptic membrane and not necessarily an action potential, the change is similar to an excitatory postsynaptic potential (EPSP) occurring in neurons.

EXCITATION–CONTRACTION COUPLING This depolarization is conducted to the SL outside of the neuromuscular junction and if strong enough will induce an action potential. The action potential is transmitted along the SL, into the T-tubules, which are invaginations of the SL that allow the cell membrane to come in close contact with an intracellular membrane system called the sarcoplasmic reticulum (SR; Figure 9–4). In skeletal muscle, the T-tubule makes contact with two components (cisternae or lateral sacs) of the SR forming a triad. Calcium is released from ryanodine receptors located on the cisternae when the T-tubule is depolarized during an action potential. Dihydropyridine (DHP) receptors, also known as calcium channels, on the SL cause a conformational change in the ryanodine receptors causing them to open and allowing calcium to diffuse from the SR into the cytosol. Contraction is initiated when calcium levels in the cytosol reach a critical level and bind to TnC. In skeletal muscle, all of the calcium used for contraction is released from the SR. For relaxation to occur, calcium must be returned to the SR. As seen in Figure 9–4, the SR consists of longitudinal components as well as the cisternal component. The longitudinal portion of the SR contains the calcium ATPase enzyme, referred to as SERCA. SERCA has a high Vmax and, using the energy from ATP, pumps calcium against its concentration gradient into the SR. Proteins such as calsequestrin within the SR bind calcium, providing a storage function in the SR but also maintaining an optimal free calcium concentration so that the calcium gradient for pumping calcium out of cytosol and back into the SR is not excessive. This process in which an action potential leads to increased calcium leading to contraction is termed excitation–contraction coupling. Due to the complexity of the neuromuscular junction, many disease states can occur when there is dysfunction. For example, nerve gases inhibit the acetylcholine esterase, thereby resulting in continuous activation of the nicotinic receptors

Sarcolemma

T tubule

Ca ATPase

Sarcoplasmic reticulum cisterna

Ryanodine receptor, channel

Dihydropyridine receptor

FIGURE 9–4 The connection between the sarcolemmal (SL) T-tubules and the cisternae of the sarcoplasmic reticulum (SR) is the mechanism for the coupling of the action potential traveling along the SL to the release of calcium from the SR. The connection between the calcium channels (dihydropyridine receptors) on the SL and the ryanodine receptors on the SR is altered by the action potential allowing opening of the SR calcium channels and release of calcium into the cytosol. and continuous activation of the skeletal muscle. Eventually the cells can no longer generate action potentials because the cells remain depolarized and sodium ion channels that would normally open and initiate depolarization are inactivated. Muscle weakness ensues and since the diaphragm contains skeletal muscle, respiratory failure leads to death. Autoimmune diseases such as myasthenia gravis can result in production of antibodies to the nicotinic cholinergic receptor. Binding of antibodies to the receptors results in impaired signaling or communication between the motor neuron and the skeletal muscle fibers. Contractions are impaired and with time the entire structure of the motor end plate deteriorates. Degeneration of the motor neuron, which is required to initiate contraction, results in diseases such as amyotrophic lateral sclerosis (ALS or Lou Gehrig’s disease). The motor neuron shrinks and degenerates, leading to denervation of the muscle cells and resulting in impaired ability of skeletal muscle to contract. Eventually the muscle cells atrophy. An early symptom of ALS is muscle weakness.

FUNCTION TYPES OF CONTRACTIONS Contraction can occur in two modalities: isometric and isotonic and combinations thereof. Isometric, as its name implies, refers to contractions in which the length (metric) of the muscle stays the same (iso) but tension or force increases. Figure 9–5 shows the schematic of the apparatus for measuring the output of isometric contractions. A thin skeletal muscle strip is suspended between a force transducer and an immovable bar. Since the muscle is tethered at both ends,

CHAPTER 9 Skeletal Muscle Structure and Function

87

Force transducer

Isometric contractions

Isotonic contractions Muscle

100 75 Stimulator

Muscle length

Stimulator

50 25 0

Force transducer

when the muscle is stimulated, cross-bridge cycling results only in tension (dyne/cm) or force (dyne) development. The length of the muscle does not change during contraction. Isotonic refers to contractions in which the tension (tonic) stays the same but the length changes. Prior to the shortening, however, the muscle must increase tension or force to exceed the load it is lifting or contracting against; thus, the contraction consists of tension development followed by shortening. Figure 9–6 shows the apparatus for measuring isotonic contractions. The change in muscle length (shortening) can be measured after the muscle is stimulated. There are two loads on the muscle: (1) the preload that sets the resting muscle length and (2) the afterload that the muscle does not sense until after the contraction begins. In the protocol, the preload is added to the muscle strip, the passive or resting length is established, and then the horizontal bar is placed under the muscle such that addition of the more weight, the afterload, does not allow the muscle to lengthen anymore. When the stimulator excites the muscle, the bar is removed and the muscle contraction results in the muscle generating force to equal the afterload and then shortening. Figure 9–7 shows a model for skeletal muscle contraction. Muscle consists of the contractile element (CE; the contractile proteins actin and myosin) and a series elastic component. The load can be considered the weight the muscle must lift in an isotonic contraction. Note that prior to shortening, the CE is getting smaller, that is, the cross-bridges are cycling and pulling actin across myosin, but the entire muscle is not shortening— the cross-bridge cycling is generating tension (Figure 9–7, B). When the tension or force matches the load (afterload), the remainder of the cross-bridge cycling (contraction) results in shortening of the muscle (Figure 9–7, C). Note that the afterload determines how much tension the muscle will have to generate

Afterload

FIGURE 9–6 Isolated muscle preparation to study isotonic contractions. The passive tension is set by the preload, and the muscle length is measured. A bar is place under the muscle so that when the afterload is added, the muscle does not lengthen (does not sense the afterload). On stimulation, the bar is removed and the muscle develops tension to just match the afterload. During the remainder of the contraction, the tension remains constant and the muscle shortens. The length of the muscle and the rate of shortening are measured.

B

A

C

Shortening

Isolated muscle preparation to study isometric muscle contractions. The muscle is not allowed to shorten. The passive tension on the muscle as a function of resting muscle length is measured with a force transducer and then the muscle is stimulated to contract.

Tension

FIGURE 9–5

Load (preload)

C CE

CE

CE

SE

Load

SE

SE

L

Time Stimulation

B

L

L L = Load

FIGURE 9–7 A model of skeletal muscle consists of the contractile element (CE) made up of the thick and thin filaments, and the series elastic (SE) component that consists of noncontractile components of the muscle. Phase A is the muscle at rest. Using the model to represent an isotonic contraction, after stimulation, the muscle develops tension (phase B) and stretches the series elastic component, that is, tension is developed (to match the load) but the whole muscle does not shorten. Note the contractile element is shortening, that is, cross-bridges are cycling and actin filament is being pulled over the myosin, but the whole muscle is not shortening. At point C, the tension developed by the contractile element stretching the series elastic component just exceeds the afterload and during the remainder of the contraction, the crossbridge cycling is actually shortening the whole muscle. The load on the muscle determines how much tension the muscle will have to develop in order to shorten and lift the load. (Reproduced with permission from Sonnenblick EH: The Myocardial Cell: Structure, Function and Modification. Briller SA, Conn HL (editors). University of Pennsylvania Press, 1966.)

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SECTION III Muscle Physiology

prior to shortening. A heavier load will require more tension development, and a lighter load will require less tension development. With a heavier load and more tension to develop, the muscle will exhibit less shortening. With a lighter load, and less tension to develop, the muscle will exhibit more shortening. When afterload is plotted on the x-axis and shortening velocity is plotted on the y-axis, an inverse relationship is demonstrated—the force–velocity curve (Figure 9–8). Where the curve intersects with the x-axis, there is no shortening (zero velocity of shortening)—this is an isometric contraction— maximum force is developed but there is no shortening. If afterload is decreased—red circle—less force must be developed and some shortening occurs and therefore the velocity of shortening can be depicted. If the afterload is decreased again, still less force is developed and even more shortening occurs and velocity of shortening increases. At the y-axis intercept, there is the maximum velocity of shortening—Vmax. Note the dashed line connecting the curve to the y-axis—this denotes that the intercept is an extrapolation of the curve—one cannot study a contraction in a muscle with zero load; therefore, Vmax is an estimate of the maximum velocity of shortening. One other fact to note is that shortening and velocity of shortening are changing in the same direction—increases in shortening occur with increases in shortening velocity. The force–velocity

Vmax

Velocity

relationship will also be discussed in Chapter 10 with reference to cardiac muscle contraction.

REGULATION OF CONTRACTION— LENGTH–TENSION The type of contraction, isometric versus isotonic, is determined by the loading conditions on the muscle. If the muscle is not allowed to shorten, tension development is the total outcome of cross-bridge cycling resulting in an isometric contraction. For example, pulling on an immoveable object results in an isometric contraction—the muscle is developing tension but cannot shorten. The amount of force generated during that contraction (twitch) is determined by the amount of calcium released from the SR. Under normal circumstances, the amount of calcium released in response to an action potential is maximal in skeletal muscle fibers. The length (preload) of the muscle prior to the contraction also affects the strength of the contraction. The length of the muscle fibers prior to contraction determines how much overlap there will be between actin and myosin and, thus, how many cross-bridges can be formed. Since the energy for the contraction is released by the myosin ATPase activity, altering the number of cross-bridges that interact alters the amount of myosin ATPase that is activated and thus the amount of ATP that will be hydrolyzed to provide the energy for contraction and relaxation. This has a significant effect on the strength of the contraction. As seen in Figure 9–9, length of the muscle (preload) affects developed tension, passive tension, and total tension. In skeletal muscle, passive tension is low until the Po point at which it begins to increase substantially. Total tension increases as a function of muscle length as does active or developed tension. Active tension is the tension that is developed during contraction by

Total

Po Force or load

FIGURE 9–8 The force–velocity curve is generated from the study of isolated muscle during isotonic contractions. To generate a typical curve, the preload on the muscle is held constant, that is, the resting length is the same for each contraction studied, but the afterload is varied. At the intercept of the x-axis, the greatest afterload, there is no shortening—this represents a maximal isometric contraction (Po). As the load decreases—the red point, less tension must be developed to match the afterload and therefore some shortening can occur. With more shortening there is a greater initial velocity of shortening that is plotted on the y-axis. With a further decrease in afterload to the light red point, there is even less tension developed and even more shortening can occur, so a greater velocity of shortening occurs. The green point represents an even lighter afterload and therefore an even greater velocity of shortening. The curve is extrapolated to the intercept of the y-axis that yields the maximum velocity of shortening (Vmax). This is a theoretical point because the muscle cannot be studied under conditions of zero load.

Active or developed Tension, dynes/cm Passive

Po Length, mm

FIGURE 9–9 The relationship between the length of muscle (set by the preload on the isolated muscle) and the tension that can be measured is shown. The active or developed tension is the difference between the total tension and the passive tension. It is the tension that the muscle produces during the contraction. At Po the muscle is at the optimum length to give the greatest tension— maximum isometric tension.

CHAPTER 9 Skeletal Muscle Structure and Function cross-bridge cycling and is therefore the difference between total tension and passive tension. Passive tension is due to the structural properties of skeletal muscle. Skeletal muscle demonstrates the length–tension relationship but in the body, since most of the skeletal muscle is attached to the bone by tendons, the optimum length is generally set by anatomy.

89

Tetanic contraction Summation A

B

C

D E

REGULATION OF STRENGTH OF CONTRACTION IN SKELETAL MUSCLE— RECRUITMENT, SUMMATION, AND TETANUS The physiological way for intact skeletal muscle to increase tension is via changes in the stimulation pattern by the motor neurons. Spatial recruitment refers to increased numbers of motor neurons firing, and, therefore, more motor units contracting. Temporal recruitment refers to increased number of action potentials in a motor neuron thereby affecting the contraction of the muscle fibers within that motor unit. Within a muscle, usually only a small percent of the muscle cells or fibers will contract at any one time but the contraction of each fiber will be maximal. All of the muscle fibers innervated by the same motor neuron will contract at the same time. The strength of the contraction of the entire muscle increases if more motor neurons are activated and therefore more muscle fibers are stimulated to contract—spatial recruitment. The order of recruitment of motor units will be discussed below with the presentation of muscle fiber types. Temporal recruitment results from increasing the number of action potentials in the motor neuron. In Figure 9–10, curve A shows the contraction or twitch in response to one stimulus. More rapid firing (more action potentials per second) repetitively releases acetylcholine to activate nicotinic receptors giving more action potentials in the muscle membrane. If two stimuli are far enough apart (e.g., 300-millisecond delay as shown for B in Figure 9–10), two separate identical contractions occur. When the two stimuli are approximately 40–50 milliseconds apart, the muscle contraction appears to be one twitch but the strength of the contraction is greater than that generated by a single stimulus (curve D, Figure 9–10). This response is called summation. The mechanism for summation is that the second contraction begins prior to the beginning of relaxation of the first contraction. Therefore, the total contraction is measurable tension development with no energy spent in overcoming the series elastic component or the resistance to contraction by all of the “noncontractile elements” present in the muscle. If the stimuli are more than 40–50 milliseconds apart (curve C), the first contraction begins to wane prior to initiation of the second contraction giving a biphasic appearance to the contractions. The optimum delay between two stimuli may vary in different types of skeletal muscle but the capacity to increase force by summation is present in all skeletal muscle. As the delay between the stimuli becomes smaller and smaller, the contraction becomes weaker and weaker until eventually the “summated” contraction will

Tension Twitch

Single 300 msec stimulus delay

120 msec delay

40–50 60 stimuli 1 msec per sec msec delay delay

FIGURE 9–10 Muscle tension developed during contractions performed under different patterns of stimulation is shown. (A) With a single stimulus, one twitch occurs. (B) With two stimuli that are 300 milliseconds apart, two identical twitches occur. (C) When the second stimulus occurs prior to complete relaxation from the first twitch, the second contraction shows greater tension development. (D) When the two stimuli are approximately 40–50 milliseconds apart, there appears to be only one contraction but the tension is 2–3-fold greater than that with one stimulus. When the muscle is stimulated with a rapid burst of stimuli (60 stimuli/s), tetanus occurs—the greatest amount of tension is developed and there is no relaxation. During this stimulation pattern, the release of calcium with each stimulus outstrips the calcium uptake mechanisms, so cytosolic calcium remains elevated and relaxation does not occur. Depending on the muscle type, tension will remain elevated until the stimulation ends or until fatigue develops and the muscle can no longer maintain tension. (E) When the two stimuli are approximately 1 millisecond apart, the contraction looks identical to the contraction given after one stimulus—the muscle cannot respond to the second stimulus because it is in the refractory period—the muscle cell membrane is not responsive to a normal stimulus. become identical to the single stimulus–initiated contraction—all fibers will have become refractory to the second stimulus—responding only to the first stimulus. This generally occurs with stimuli that are 1–2 milliseconds apart (E). The maximum tension that can be developed occurs during tetanic contractions (Figure 9–10). The basis for this increase in tension is that there are so many action potentials (e.g., 60/s) that the calcium release mechanisms occurring with every action potential outstrip the calcium uptake mechanisms; thus, cytosolic calcium levels remain elevated continuously and the muscle does not relax in between stimuli. The cross-bridges continue to cycle either until stimulation stops and cytosolic calcium concentrations decrease or until the cells fatigue. Both summation and tetanus (tetanic contractions) are examples of temporal recruitment—the same fibers are stimulated to contract by the same motor neurons but the frequency of stimulation by the neuron alters the muscle response. In summary, strength of contraction of an intact

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muscle made up of many different motor units can be increased by: (1) increasing the number of motor neurons activated, thereby increasing the number of motor units contracting; and (2) increasing the frequency of action potentials of the motor neuron, thereby eliciting summation or tetanus of those muscle fibers in the motor unit.

FIBER TYPES As mentioned above, the strength of contraction of skeletal muscle can be increased by spatial recruitment. Spatial recruitment occurs when more motor neurons participate in a contraction, thus “recruiting” more motor units, that is, more muscle fibers to contract. There are three basic types of muscle fibers in skeletal muscle—type I, type IIa, and type IIb (Table 9–1). These were formerly called red and white muscle for the color imbued by the presence of myoglobin and many mitochondria in red muscle and little myoglobin in white muscle. Since the red muscle has many mitochondria, it has the capacity, by oxidative phosphorylation production of ATP, to sustain contractions over long periods of time. The fiber types have different diameters as do the motor neurons that innervate them. The pattern of spatial recruitment is governed by the size of the muscle fibers with smallest fibers being most easily recruited (earliest recruitment), and largest fibers recruited last. The type I fibers have the smallest diameter and are innervated by motor

neurons that are also the smallest in diameter. This makes both the neurons and the fibers easy to activate. These small fibers that are recruited earliest have a high oxidative capacity and can perform work for long periods of time without fatiguing. Adequate blood flow and high concentrations of mitochondria for oxidative metabolism allow these fibers to contract for hours. These fibers have been called slow twitch because their myosin ATPase activity is low. These fibers also contain myoglobin, a heme-containing protein that binds oxygen and can therefore serve as an oxygen store that can be used when oxidative phosphorylation is occurring at elevated rates to support elevated rates of contraction. These type I fibers were classified as “red” fibers in the past because the high concentration of myoglobin gives color to the muscle fibers. Type II fibers have a higher myosin ATPase activity and therefore a faster rate of contraction. There are two subtypes in this group—type IIa are fibers with a fast twitch and both oxidative and glycolytic capacity, and type IIb are fibers with a fast twitch but rely almost entirely on glycolysis for ATP production. The type IIb fibers have high concentrations of the enzymes involved in glycolysis. These fibers have the largest diameter and are recruited last. They are innervated by motor neurons with large diameters that require a greater stimulus in order to generate an action potential, thereby making them the last to be recruited. They are more likely to fatigue than the other types of fibers due to the dependence on glycogen as a substrate for ATP to provide the energy for contraction. The supply of glycogen is limited and since they have a relatively sparse blood supply, glucose may not be as readily available. If

TABLE 9–1 Comparison of skeletal muscle fiber (cell) types. Type I

Type IIa

Type IIb

Metabolism

Oxidative

Oxidative/glycolytic

Glycolytic

Twitch

Slow

Intermediate

Fast

Mitochondria

Abundant

Intermediate

Few

Myoglobin

Abundant

Abundant

Few

Color

Red

Red

White

Glycogen

Little

Intermediate

Abundant

Myosin ATPase rate of hydrolysis of ATP

Lowest

Fastest

Fastest

Speed of contraction

Slowest

Intermediate

Fastest

Blood flow

Great

Intermediate

Low

Fatigue

Not readily

Intermediate

Rapid onset

Force

Least

Intermediate

Greatest

Size of motor neuron

Smallest

Intermediate

Largest

Size of fiber

Smallest

Intermediate

Largest

Recruitment

First

Second

Last

Total tension

Least

Intermediate

Greatest

CHAPTER 9 Skeletal Muscle Structure and Function glycolysis results in lactic acid production because oxygen is not readily available, the cells will fatigue in a matter of minutes and decrease tension development in spite of repeated motor neuron firing. These fibers were formerly classified as “white” fibers because they had lower levels of mitochondria, myoglobin, and blood flow—all of which lend the red color to the type I fibers. The type IIa fibers are of intermediate size and therefore are recruited after the type I slow fibers are activated. Type IIa fibers can use both glycolysis and oxidative phosphorylation for their energy supply and therefore also exhibit an intermediate time course for fatigue to occur. The ATPase activity and therefore speed of contraction is fast as in the type IIb fibers and the time for fatigue to occur is intermediate. The capacity for oxidative phosphorylation to provide some of the ATP for contraction prolongs the time of sustained contraction before fatigue occurs. In general, the diameter of the muscle fiber is indicative of the amount of actin and myosin in the fiber. Therefore, largerdiameter fibers have more actin and myosin, more crossbridges that can form, and can develop more tension. Smaller fibers develop less tension due to lower amounts of actin and myosin but again can contract for prolonged period due to their abundant blood supply and oxidative capacity. Most muscles in the body are made up of combinations of the three muscle fiber types with a predominance of either fast or slow fibers. Muscles involved in maintaining posture must have long-lasting capacity to contract and not to fatigue, so these have more of the type I, slow-twitch fibers. Of course, in maintaining posture, not all muscle fibers will be contracted at any one time but different motor units will take over contraction cyclically. Muscles that are involved in rapid changes such as eye movements are predominantly type IIb fibers—fast contractions that are not sustained for long periods of time. Many muscles have intermediate amounts of the different fiber types. For example, people who do prolonged activities such as endurance running have slower-twitch, oxidative fibers in their muscle responsible for running. Sprinters have more fast-twitch, glycolytic fibers that are best for bursts of activity but not for sustained activity.

(eyelid drooping) occurred with repeated, rapid eye movements. The physician suspects myasthenia gravis and orders tests to confirm the diagnosis. Myasthenia gravis is an autoimmune disease in which the immune system produces antibodies to the nicotinic receptor. Initially small motor units, especially in ocular muscles for eye movement, demonstrate the defect. Rapid motor neuron firing for rapid muscle contractions for eye movement eventually leads to release of less acetylcholine (production lags behind release). In normal individuals, there are adequate receptors to compensate for the decreased amount of acetylcholine released. With myasthenia gravis, antibodies bound to the receptors prevent the acetylcholine binding, thus leading to impaired muscle contractions. Rest can replenish the acetylcholine stores. Antibodies bound to the nicotinic receptor seem to trigger an immune response and degeneration of the muscle motor end plate. Eventually, with more antibody production, more muscle units become involved and can eventually lead to large muscle weakness including impaired respiratory muscle function. Treatments to decrease antibody production, often exacerbated by the thymus gland, include removal of the thymus and treatment with immunosuppressive drugs such as corticosteroids. Cholinesterase inhibitors are also used since they inhibit the enzyme that hydrolyzes acetylcholine at the neuromuscular junction, thereby maintaining higher concentrations of acetylcholine and greater stimulation of the motor end plate.

CHAPTER SUMMARY ■ ■

■

CLINICAL CORRELATION A 45-year-old woman notices that she has been feeling unusually tired after work for the past month. She also notices that her left eyelid begins to droop at the end of the day. Gradually she is noticing that the eyelid begins to droop even by the end of the work day if it has been a particularly stressful day. She is also experiencing more and more severe fatigue but both of these problems are gone after a good night’s sleep. She is concerned and makes an appointment with her physician. On physical examination, her physician notes that all measured variables were in the normal range except for movement of the left eye. Lateral movement was impaired and ptosis

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Skeletal muscle cells are also called fibers. Skeletal muscle cells have a specialized section of SL called the motor end plate where the motor neuron forms a synapse with the muscle. Acetylcholine is the neurotransmitter and nicotinic receptors on the SL bind the acetylcholine and increase sodium influx, causing partial depolarization, and eventually an action potential in the adjacent SL. The action potential travels down the invaginations of the SL (T-tubules) and, via the dihydropyridine receptors, causes the ryanodine receptors to open and release calcium. Troponin binds calcium and begins the contraction process. The motor neuron can innervate more than one skeletal muscle fiber—the motor neuron and the fibers it innervates are called a motor unit. All of these muscle cells contract at the same time. Contraction can be either isometric or isotonic. In isotonic contractions, the load determines how much tension or force the muscle must develop before the shortening phase of the contraction can occur. Skeletal muscle can increase strength of contraction by recruiting more motor units (spatial recruitment). The motor units with the smallest diameter of the neurons and fibers are recruited most readily (first). These are the

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SECTION III Muscle Physiology type I fibers that are highly oxidative and have a low myosin ATPase rate and therefore exhibit a slower contraction time. Type II fibers have a high myosin ATPase rate and therefore a faster contraction time. Type IIa are both glycolytic and oxidative and are recruited second. Type IIb are mainly glycolytic and recruited last (fibers and neurons have the greatest diameter). Type II fibers fatigue more quickly than do type I fibers, with type IIb fibers fatiguing most rapidly—in a few minutes after repeated stimulation. Skeletal muscle can also increase strength of contraction by more rapid firing of the motor neuron—summation and tetanus.

STUDY QUESTIONS 1. Which of the following statements about skeletal muscle contraction is correct? A) Acetylcholine release at the neuromuscular junction initiates an action potential in the motor end plate. B) Acetylcholine binds to a nicotinic receptor on the postsynaptic membrane. C) The depolarization in skeletal muscle results from influx of calcium through voltage-gated calcium channels (dihydropyridine receptors). D) Depolarization of the muscle fiber is not essential for skeletal muscle contraction. E) Norepinephrine activating adrenergic receptors causes increased strength of contraction.

2. Which of the following statements about muscle contraction is true for skeletal muscle? A) All cells have pacemaker potential. B) The strength of contraction is correlated with the degree of phosphorylation of the myosin light chains. C) The strength of contraction is increased by recruiting more motor units. D) All muscle cells have a high oxidative capacity due to the abundant presence of mitochondria and myoglobin. 3. Which of the following statements about muscle contraction is true for skeletal muscle? A) In the body, strength of contraction is altered physiologically by changing the resting cell length from 25% up to 100% of the maximum length. B) Strength of contraction is altered physiologically by altering the frequency of motor neuron firing. C) Tetanus cannot occur because the muscle action potential keeps the cell refractory to stimuli that are closer than 1 second apart. D) Muscle contraction consists only of tension development.

10 C

Cardiac Muscle Structure and Function Kathleen H. McDonough

H A

P

T

E

R

O B J E C T I V E S ■ ■ ■ ■ ■ ■ ■

Explain the process of excitation–contraction coupling in cardiac muscle and how it differs from that of skeletal muscle. Explain the effects of changes in resting cell length on muscle tension development, that is, the length–tension relationship. Describe the sequence of events in isotonic contractions—tension development and shortening. Describe the effects of afterload on isotonic contractions in cardiac muscle. Explain the effects of changes in resting cell length on isotonic contractions at different afterloads, that is, explain the force–velocity curve. Describe the effects of increased contractility on the force–velocity curve. Explain the terms preload, afterload, contractility, force, and tension.

INTRODUCTION Cardiac muscle, like skeletal muscle, is striated due to the orderly structure of the actin and myosin filaments and the accessory proteins that stabilize the sarcomere. Like type I skeletal muscle, cardiac muscle appears to be red in color due to the high content of mitochondria and myoglobin and its blood supply. The heart uses large amounts of ATP in beating 60–100 times/min (during normal resting conditions) for the lifetime of the normal adult and oxidative phosphorylation is the main source of that ATP, thus the high myoglobin concentration and large mitochondrial content. There are estimates that the myocardial ATP pool turns over every 10 seconds. The heart is able to use any substrate provided to it in the blood and uptake is dependent on the concentration of those substrates such as glucose, pyruvate, lactate, free fatty acids, and ketone bodies. Normally fatty acid oxidation provides 60–90% of the ATP used by the adult heart. Like skeletal muscle, calcium is essential for contraction and is provided by excitation–contraction coupling. Although cardiac muscle can contract spontaneously due to pacemaker activity in the sinoatrial (SA) node, the individual muscle cells (myocytes) normally contract only when an action potential is initiated by the conduction system present in the heart and transmitted through cells specialized to conduct action poten-

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tials rapidly. Cardiac muscle cells have gap junctions through which cells communicate information about membrane potential—that is, if one cell depolarizes, the adjacent cells will also depolarize due to communication through the gap junctions. Thus, all cardiac myocytes in the atria contract together and then all of the myocytes in the ventricle contract together (Chapter 23). Because of this unified contraction of the ventricles (or the atria), the heart is said to be a functional syncytium. Since all ventricular muscle cells contract together, there is no type of spatial recruitment in the heart. The heart relies on other mechanisms to increase strength of contraction.

EXCITATION–CONTRACTION COUPLING Cardiac muscle cells contract when calcium levels in the cells increase from approximately 10−7 M (0.1 μM) to 10−6 to 10−5 M (1–10 μM). The level of calcium present in the cytosol to initiate contraction has a profound effect on the strength of the contraction (contractility). Excitation–contraction coupling in cardiac muscle varies somewhat from the process in skeletal muscle. The anatomy of the sarcolemma (SL)–sarcoplasmic reticulum (SR) interaction is different—diads are formed

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rather than triads as in skeletal muscle. There is less SR in cardiac muscle, so the calcium release process relies on entry of calcium into the cardiac cell through the voltage-gated channels (dihydropyridine receptors). These open when the membrane potential reaches approximately −40 mV. These calcium channels are also called “slow” or L-type calcium channels because they open more slowly than sodium channels and remain open longer, generally about 200–300 milliseconds. Therefore, the action potential in cardiac ventricular cells is much longer than the action potential in skeletal muscle in which the calcium channels do not actually open (see Chapter 9). Calcium entry through SL calcium channels is essential for contraction to occur. Absence of calcium in the extracellular fluid would prevent the heart from contracting. The process of excitation–contraction coupling is initiated by the pacemaker cells in the SA node that spontaneously generate action potentials (termed slow action potentials because they lack fast sodium channels and depolarization is due to calcium entry through the slow calcium channels). Action potentials are transmitted through the atrial conduction fibers across the atrioventricular valves and finally to the conduction system in the ventricles. All ventricular muscle cells depolarize at the same time due to the rapid influx of sodium down its electrochemical gradient (higher concentration of sodium outside of the cell and negative membrane potential on the inside of the SL) through SL fast sodium channels. When the membrane potential reaches ~−40 mV, the slow calcium channels open, allowing calcium to diffuse down its concentration gradient into the cytosol. Some of this calcium causes opening of ryanodine channels (receptors) on the SR and calcium diffuses out of the SR down its concentration gradient. Some of the calcium from the SL binds to troponin as does all of the calcium released from the SR. Calcium binding to troponin results in a similar type of interaction of actin and myosin and cross-bridge cycling to that which occurs in skeletal muscle. Relaxation occurs when the calcium concentration in the cytosol is lowered by the calcium ATPase on the longitudinal part of the SR pumping calcium back into the SR. Calsequestrin is also present in cardiac muscle to serve as a “sink” for calcium. When calcium levels decrease, calcium diffuses from the troponin and the cells relax. Two other proteins are involved in removing calcium from the cardiac cell. Since calcium enters the cell with each action potential, there must be mechanisms to remove calcium or the cell calcium content would increase with each heartbeat. The SL contains a calcium ATPase that has a high affinity for calcium and can therefore pump calcium out of the cell probably even during diastole. The other protein is the sodium–calcium exchanger. The exchanger operates on the basis of the sodium ion gradient. The sodium ion concentration is greater outside of the cell than in the cell. Via the exchanger, sodium ion enters the cell and calcium ion is removed from the cell. Three sodium ions enter for every one calcium ion leaving the cell. Manipulation of the sodium gradient can have significant effects on calcium extrusion from the cell and thus affect contraction. Since calcium levels change during each action potential, there is some evidence that increases in heart rate (more action

potentials per minute) can increase calcium availability for contraction, thereby increasing the amount of tension that can be generated. This phenomenon is called the staircase phenomenon or treppe. Physiologically heart rate is altered by autonomic nervous system (ANS) modulation of SA node firing rate and, as will be seen later, the sympathetic nervous system (SNS) component of the ANS not only increases heart rate, but also increases contractility. Therefore, the physiologic role of treppe is difficult to assess independent of SNS modulation of heart rate and contractility. There are two additional variations in contraction that occur in cardiac muscle that do not occur in skeletal muscle. Phosphorylation of contractile proteins alters the strength of contraction in the heart. The heart is very responsive to the SNS— the “fight or flight” component of the ANS. With activation of the SNS, beta-adrenergic receptors on the cardiac muscle cells are activated and an intracellular signaling scheme results in production of cAMP and activation of protein kinase A. Phosphorylation of proteins follows. Several proteins involved in contraction are phosphorylated and their activity is altered. SL calcium channels are phosphorylated and allow more calcium to enter the cell and the strength of contraction is increased (contractility is enhanced). A protein called phospholamban normally inhibits the SR calcium ATPase; when phospholamban is phosphorylated, it exerts less inhibition of the ATPase, so calcium uptake is enhanced. Phosphorylation of the calcium channels does not seem to occur in skeletal muscle in which the maximum amount of calcium is released during each action potential and therefore cannot be increased. Remember that skeletal muscle has two SR cisternae in conjunction with the T-tubule, whereas cardiac muscle has only one cisterna associated with the T-tubule. Skeletal muscle does not seem to have a functional phospholamban, so the calcium ATPase activity is always operating at its maximal capacity. Increasing the amount of calcium entering the cytosol is an important mechanism for increasing strength of contraction (contractility); removing calcium faster for relaxation is an important mechanism when the heart rate increases with SNS stimulation and there is less time during the contraction-relaxation cycle.

CONTRACTION—LENGTH– TENSION, ISOMETRIC CONTRACTIONS The strength of contraction in cardiac muscle can be altered by changes in the initial or resting length of the muscle cells (preload) similar to the phenomenon in skeletal muscle. Cardiac muscle, unlike skeletal muscle, can have physiologic changes in the length of the muscle cells. For example, when the volume in the ventricle at the end of diastole (the relaxation phase of the cardiac cycle) is changed, the muscle cell length is changed in the same direction. Increased ventricular end-diastolic volume results in increased ventricular muscle cell length prior to the

Tension, dynes/cm

CHAPTER 10 Cardiac Muscle Structure and Function

Active or developed

Passive – cardiac muscle Passive – skeletal muscle

Po Length, mm

FIGURE 10–1 The length–tension relationship in cardiac muscle is slightly different from that in skeletal muscle— primarily due to the presence of passive tension at shorter lengths. This is in part due to the anatomic differences in structure of skeletal muscle (all of the fibers in parallel) and cardiac muscle (fibers exist in a basket weave-type pattern) as well as the properties of the noncontractile components in skeletal muscle versus cardiac muscle. Note that in skeletal muscle, the fibers are usually operating at the blue point—resting length is optimum because most skeletal muscle is held in place by the bones and resting length cannot vary greatly. Cardiac muscle normally operates at lower (red point) than optimum length and therefore has reserve capacity to increase tension development, that is, have stronger contractions, when resting length is increased. In the intact heart, cardiac cell resting length is set by the volume in the ventricle at the end of diastole (the relaxed state of cardiac muscle).

onset of contraction. The heart normally operates at lower than maximal cell length or preload (Figure 10–1, red circle), whereas skeletal muscle usually works at maximal preloads (blue circle). Note also that the passive tension properties of the heart differ from those of skeletal muscle. Skeletal muscle does not increase passive tension until the muscle cell length is close to the length that gives the maximum active tension. Cardiac muscle has passive tension even at low cell lengths. These differences are due to the anatomic arrangement of the muscle cells with the noncontractile components in the muscle. Skeletal muscle is more distensible than cardiac muscle. In Figure 10–1, the effects of increases in preload are shown through isometric contractions—that is, greater tension is developed from greater resting cell length. The principle for the length–tension relationship, as in skeletal muscle, is that the change in cell and sarcomere length alters the degree of overlap of the actin and myosin filaments and therefore increases the potential for cross-bridges to form. Changes in the resting length of the whole muscle are associated with proportional changes in the individual sarcomere length. Maximum tension development occurs at sarcomere lengths of 2.2–2.3 μm. At shorter sarcom-

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ere lengths, the opposing thin filaments may overlap with each other and interfere with interaction with myosin. At long sarcomere lengths, overlap may be insufficient for optimal crossbridge formation. More cross-bridge interaction leads to a stronger contraction. Two other factors may contribute to the length–tension phenomenon in cardiac muscle. The second mechanism may result from a length-dependent change in calcium sensitivity of the myofilaments. For a similar cytosolic calcium concentration, a less stretched muscle develops less force than does a more stretched (longer) cardiac muscle preparation. This change in calcium sensitivity occurs immediately after a change in length with no delay. The sensitivity of the contractile proteins, specifically troponin C, seems to increase at greater resting lengths. Finally, there is some evidence that the amount of calcium released from the SR is greater at longer resting lengths. How much these two factors contribute to the greater tension development is open to speculation since studies to demonstrate these two effects of length on calcium dynamics are generally performed in isolated cells or organelles. In summary, the heart usually operates at lower than maximal preloads and therefore has reserve—increasing muscle length can have a profound effect on strength of contraction that allows the heart to meet the demands of increased work such as occurs during exercise.

CONTRACTION— FORCE–VELOCITY, ISOTONIC CONTRACTIONS The effects of altered preload on heart function can also be observed with isotonic contractions that represent a better match to physiologic contractions of the heart as a pump. The left ventricle must develop tension (pressure) to match the afterload (aortic pressure) in order to open the aortic valve and then allow the shortening phase of the contraction to pump blood (stroke volume) into the aorta. Recall from the discussion of skeletal muscle that there is an inverse relationship between afterload and velocity of shortening and therefore between afterload and shortening. Greater afterload results in less shortening. Using isotonic contractions, the effects of increased preload, that is, more cross-bridge cycling, on the force–velocity curve can be analyzed. When shortening and velocity of shortening are measured as a function of afterload, higher afterloads result in less shortening (see Figures 9–8 and 10–2, black curve). If the preload is increased from length 1 (L1) to length 2 (L2) and the same afterloaded contractions are studied from the higher preload, velocity of shortening (and shortening) is greater for each afterload. If more cross-bridges can interact, there is more myosin ATPase activity and therefore more energy from ATP hydrolysis available for the contraction. The cross-bridges develop the greater tension needed to match the greater afterload and more energy is available for more shortening and a greater velocity of shortening to occur (blue curve, labeled L2). Note that the

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maximum isometric tension (x-axis intercept) is increased but the Vmax is not increased compared to the Vmax at L1. Preload shifts only the maximum tension, not the maximum velocity of shortening.

INCREASES IN STRENGTH OF CONTRACTION IN CARDIAC MUSCLE As stated above, cardiac muscle can increase strength of contraction when the preload is increased as demonstrated by the length–tension relationship. Another way that cardiac muscle can increase strength of contraction is by increases in cytosolic calcium resulting in increased contractility. Contractility increases the velocity of cross-bridge cycling; therefore, increasing contractility can alter shortening and the velocity of shortening. In comparing the force–velocity curve during enhanced contractility (red curve in Figure 10–2), one can notice that increasing contractility causes the entire force– velocity curve to shift to the right—both the maximum isometric tension (intercept on the x-axis) and the Vmax

(extrapolated intercept on the y-axis) increase. This increased contractility should be compared to the curve generated at the same preload (L1), the black curve. Generally, increases in contractility result in more rapid contractions such that indexes of speed of tension development or maximum velocity of shortening (Vmax) are used to indicate increases in contractility. The figure demonstrates that there are two ways to increase the velocity of shortening at the same afterload (the three points in the figure), one is by increasing preload (blue curve), and the other is by increasing contractility (red curve). The mechanisms by which the contractions are stronger are, however, different. More optimum overlap of the actin and myosin filaments mediates the preload effect, whereas more cytosolic calcium to induce more rapid cross-bridge cycling mediates the contractility effect. The effects of increasing contractility can also be demonstrated by looking at the length–tension relationship. In Figure 10–3, sympathetic nerve stimulation to the heart results in a shift of the length–tension relationship upward and to the left. This indicates that for any given resting length of cardiac muscle, the tension that can be developed is greater as a result of SNS stimulation. The mechanism is the increase in calcium that results from the activation of beta-adrenergic receptors with the

Vmax

↑Contractility

Velocity

L1

↑Preload or length - L2 L1

Po Force or load

FIGURE 10–2 The force–velocity curve in cardiac muscle can be altered by changes in resting cell length and by changes in contractility. L1 represents the shorter resting cell length and L2 represents a greater resting cell length. In comparing the muscle at the same afterload (black point vs. blue point), the muscle can shorten more if the contraction starts from a greater preload or resting cell length (L2). In both contractions, the tension developed is set by the afterload. Note that the curve for increased preload intercepts the x-axis further to the right—greater resting length allows for greater maximum isometric tension (the length–tension relationship). If the muscle is studied at L1, and a drug that increases contractility is given, the entire force–velocity curve shifts upward and to the right from the black curve to the red curve—both Po and Vmax are increased. More calcium results in stronger contractions and a greater velocity of contraction, that is, a greater velocity of cross-bridge cycling. In comparing the black point to the red point, when contractility is greater, the muscle can develop the same tension to match the load and there is more capacity to shorten and a greater velocity of shortening. Changes in Vmax therefore indicate changes in contractility. Changes in Po can result from changes in preload or from changes in contractility.

CHAPTER 10 Cardiac Muscle Structure and Function

Developed tension

↑SNS

Length

FIGURE 10–3 The effects of changes in contractility on the length–tension relationship are shown. With sympathetic stimulation (SNS) of cardiac muscle, contractility increases and developed tension is greater at each resting cell length. consequent production of cyclic AMP and activation of phosphorylation of the SL calcium channels by protein kinase A. The importance of these two mechanisms will become very obvious in discussions of the cardiovascular system in Section 5.

CHAPTER SUMMARY ■

■

■ ■

■ ■

Excitation–contraction coupling in cardiac muscle is similar to that in skeletal muscle except that calcium must enter the cardiac muscle cell through the voltage-gated calcium channels to cause release of calcium from the SR ryanodine channels. In cardiac muscle, strength of contraction can be altered by changes in resting cell length (length–tension) and by changes in contractility. Indices of contractility, such as the maximum velocity of shortening (Vmax), are increased by beta-adrenergic agonists. Since the heart has cells with pacemaker potential, innervation of the heart is not required for contraction to occur. Ventricular cells contract at the same time (a functional syncytium) due to the conduction system and gap junctions between the cardiac cells. Sympathetic and parasympathetic nerves modulate the intrinsic beating rate. Sympathetic nerves modulate the strength of contraction (contractility) of cardiac cells.

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STUDY QUESTIONS 1. Which of the following statements about cardiac muscle contraction is correct? A) Acetylcholine release at the neuromuscular junction initiates an action potential in the postsynaptic membrane. B) Acetylcholine binds to a nicotinic receptor on the postsynaptic membrane. C) Depolarization of the muscle fiber is not essential for cardiac muscle contraction. D) Norepinephrine activating adrenergic receptors causes increased strength of contraction. 2. Which of the following statements about muscle contraction is true for cardiac muscle? A) All cells in the heart contract at their own rate. B) The strength of contraction is independent of the degree of phosphorylation of cellular proteins. C) The strength of contraction is increased by recruiting more motor units. D) All muscle cells have a high oxidative capacity due to the abundant presence of mitochondria and myoglobin. 3. Which of the following statements about muscle contraction is true for cardiac muscle? A) Strength of contraction is altered physiologically by changing the resting cell length from approximately 25% up to 100% of the maximum length. B) Strength of contraction is altered physiologically by altering the frequency of motor neuron firing. C) Tetanus occurs because the muscle action potential keeps the cell refractory to stimuli that are closer than 1 second apart. D) Muscle contraction consists only of tension development. 4. Which of the following statements about muscle contraction is true for cardiac muscle? A) The Po (maximum isometric tension) is altered by both contractility and the length–tension relationship. B) On the force–velocity curve the Vmax is altered by both contractility and the length–tension relationship. C) Afterload determines how many cross-bridges can interact during a contraction. D) Preload determines the phosphorylation state of the myosin light chain.

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11 C

Smooth Muscle Structure and Function Kathleen H. McDonough

H A

P

T

E

R

O B J E C T I V E S ■ ■ ■ ■ ■

Explain the contraction process in smooth muscle and compare it to those of skeletal and cardiac muscle. Describe how smooth muscle can be activated to induce a contraction or to change the strength of a contraction. Explain the relationship between vascular smooth muscle membrane potential, voltage-gated calcium channels, and strength of contraction. Describe the difference between multiunit and unitary smooth muscle. Explain the following terms and their role in smooth muscle function: calmodulin, myosin light chain kinase, and myosin light chain phosphatase.

INTRODUCTION

CONTRACTION

Smooth muscle makes up the walls of most of the hollow organs of the body except the heart. As such, the function and control of contraction of the smooth muscle will vary depending on the organ in which it is located and the function of that organ or organ system. For example, smooth muscle in the gastrointestinal tract will be activated not only by mechanical stimulation by the presence of food in the GI tract, but also by its neural and hormonal input. Smooth muscle in the uterus will respond differently during development of an embryo/ fetus than during the normal menstrual cycle. Hormones and neural input will even change the morphology of smooth muscle during pregnancy, making the uterus work as a unit rather than as independent muscle cells in the nonpregnant uterus. The myosin ATPase activity in smooth muscle has a much slower rate of hydrolysis of ATP (10–100 times lower than that of skeletal muscle); therefore, contractions are much slower and sometimes the mode of contraction results in increases and decreases in the strength of contraction rather than complete relaxation after a contraction as occurs in skeletal and cardiac muscle.

The general contractile process is uniform in all types of smooth muscle. An increase in calcium in the cytosol results in binding of calcium to a calcium-binding protein, calmodulin (Figure 11–1). This complex will bind to, and activate, myosin light chain kinase (MLCK) that, in turn, phosphorylates the myosin light chain located on the myosin head. In smooth muscle, the myosin light chain must be phosphorylated in order for the actin and myosin to form crossbridges and initiate the crossbridge cycling or contraction. Relaxation or decreased tension development requires dephosphorylation of the myosin light chain by myosin light chain phosphatase. The balance of phosphorylation and dephosphorylation is important in regulating tension development in smooth muscle since the kinase and the phosphatase are always active. Increasing cytosolic calcium tips the balance toward more kinase activity and therefore more tension development. Lower calcium levels tip the balance toward less kinase and therefore more phosphatase activity and less tension development. There are other mechanisms to increase and decrease the activity of the kinase and the phosphatase. For example,

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Smooth muscle cell Contractions

Inactive MLCK

↑Cytosolic Ca2+

Ca calmodulin

Myosin light chain phosphatase

ATP

Active MLCK

~P myosin light chain

Myosin light chain

Cross bridge cycling

Relaxation

FIGURE 11–1 Scheme of steps in smooth muscle contraction. As in other types of muscle, calcium initiates the contraction. Calcium binds to calmodulin that activates the myosin light chain kinase to phosphorylate the myosin light chain. On phosphorylation the myosin can interact with the actin resulting in crossbridge cycling. Phosphatases can dephosphorylate the myosin light chain leading to relaxation or less tension development. The balance of kinase and phosphatase activities determines the level of tension development in smooth muscle. Phosphorylation of both the kinase and the phosphatase leads to a decrease in their activity—one resulting in weaker contraction and one in stronger contraction. phosphorylation of the MLCK enzyme decreases its activity, thereby decreasing phosphorylation of myosin and resulting in more relaxation. This occurs when a specific receptor, the beta2-adrenergic receptor, on the vascular smooth muscle and bronchiolar smooth muscle sarcolemma (SL) is activated and increases intracellular cAMP levels. Subsequent activation of protein kinase A phosphorylates the MLCK and decreases its activity. Nitric oxide causes a similar relaxation of smooth muscle although the kinase that phosphorylates the MLCK is protein kinase G that is activated by cyclic GMP. Regulation of the phosphatase is also important. For example, phosphorylation of the myosin light chain phosphatase decreases its activity, resulting in less dephosphorylation and therefore more phosphorylation of the myosin light chains and more contraction. The Rho kinase pathway leads to phosphorylation of the phosphatase. There are several other types of regulation of the MLC kinase and phosphatase that alter the contraction properties of smooth muscle and are more specific for each organ’s particular function and therefore will be discussed in the organ-specific sections of this book.

would theoretically utilize large amounts of ATP. The latch state seems to occur because the crossbridges do not dissociate very rapidly in spite of the fact that the myosin light chain is dephosphorylated; thereby, energy expenditure is minimized. The exact mechanism by which the latch state occurs is unknown. The physiologic significance, however, is remarkable—maintenance of tension with very little energy expenditure.

ENERGY FOR CONTRACTION AND RELAXATION

TABLE 11-1 Comparison of smooth muscle cell types.

The ATP used in contraction and relaxation in smooth muscle is produced primarily by oxidative phosphorylation. The substrates such as glucose and fatty acids are provided in the blood and mitochondrial oxidative processes produce adequate energy for the slower contractions that occur in smooth muscle due to the lower rate of the myosin ATPase enzyme. An interesting adaptation of smooth muscle ensures that sustained contractions can occur at a lower-than-predicted ATP utilization. Smooth muscle can maintain tension by a phenomenon termed the latch state. This is thought to be important in sphincter muscles where tension development must occur for long periods of time that

VASCULAR VERSUS VISCERAL; MULTIUNIT VERSUS UNITARY Smooth muscle can be divided into visceral and vascular muscle—visceral muscle making up the walls of most of the hollow organs and vascular making up the walls of blood vessels. Vascular smooth muscle and to some extent, visceral smooth muscle, can also be divided into two cell types— multiunit and unitary (Table 11–1). These two types of muscle cells have unique features that contribute to the variety of functions of smooth muscle. Multiunit smooth muscle

Multiunit

Unitary

Functional

Individual units

Syncytium

Innervation

Yes

Little

Gap junctions

Few

Yes

Response to stretch

Little

Yes

Response to SNS

Yes

Little

Control of contraction

Central or neural factors

Local factors

Examples

Airway smooth muscle

Small blood vessels

CHAPTER 11 Smooth Muscle Structure and Function

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Autonomic nerve fiber Varicosity Sheet of cells

Mitochondrion Synaptic vesicles Varicosities

FIGURE 11–2 Pattern of innervation of smooth muscle. Note that the nerve has multiple branches and varicosities on each of the branches. Neurotransmitter is released at the varicosities and diffuses to the smooth muscle. Binding to the appropriate receptor will result in the neural modulation of smooth muscle contraction. (Reproduced with permission from Widmaier EP, Raff H, Strang KT: Vander’s Human Physiology, 11th ed. McGraw-Hill, 2008.)

consists of cells that act as independent units—they are innervated and can respond strongly to nerves of the sympathetic and parasympathetic nervous systems. These types of cells have very few gap junctions and therefore activation of one cell does not necessarily lead to activation of cells in juxtaposition to that activated cell. Other cells receiving the same neural input will respond but only because the nerve is releasing neurotransmitters from varicosities (Figure 11–2) that release neurotransmitter near the muscle cell membrane. Note that the same nerve will release neurotransmitter onto many cells. Released neurotransmitter diffuses to the muscle cell membrane and binds to appropriate receptors—there is no specialized motor end plate on the muscle cell membrane, just the presence of receptors. Both sympathetic and parasympathetic nerves can innervate the same smooth muscle causing opposite effects on the cells as described below. Unitary muscle, on the other hand, has many gap junctions (as described in Chapter 3), so activation of one cell leads rapidly to activation of cells juxtaposed to that cell. Thus, the cells contract as a “unit.” These cells generally have little innervation and exhibit a response to stretch, that is, cells will increase tension in response to stretch, a property that will be discussed in more detail in Sections 5 and 8. Table 11–1 presents a list of the properties of multiunit versus unitary smooth muscle.

METHODS OF STIMULATION Smooth muscle can be stimulated to contract or alter the strength of a contraction by many different stimuli—action potentials, changes in membrane potential that do not achieve

an action potential, activation of receptors that initiate an intracellular signaling network, activation of receptors that are ion channels, and stretch, by itself. The exact stimuli that alter smooth muscle contraction may differ in various organs and even in two different types of muscle—unitary and multiunit. In Figure 11–3, the effects of sympathetic and parasympathetic nerve stimulation on the membrane potential of visceral smooth muscle are shown. Acetylcholine, the neurotransmitter of the parasympathetic nervous system, generally causes the membrane potential to become less negative and for spikes (action potentials) to occur—generating more contractile activity. Sympathetic stimulation generally results in the opposite—more negative membrane potential and resultant decreased contractile activity and relaxation. Note that stretch is also conducive to more action potential spikes, and, subsequently, more contraction; food in the gut induces increased contractile activity of the gut. Many other stimuli lead to activation or relaxation of smooth muscle. Figure 11–4 shows a smooth muscle cell and some of the many mechanisms involved in eliciting contraction and relaxation. Calcium can be provided by both influx of calcium from the extracellular fluid through the L-type voltage-gated calcium channels on the SL and release of calcium from the sarcoplasmic reticulum (SR). The SR, which is less abundant than in skeletal and cardiac muscle, can, nevertheless, release calcium through activation of IP3 receptors. The IP3 receptors are channels similar to the ryanodine receptors in the other two muscle types and when the channel is open, calcium diffuses down its concentration gradient into the cytosol to initiate contraction. IP3 is a product of receptor-mediated activation of phospholipase C (PLC) that hydrolyzes phosphatidylinositol (PIP2). Diacyglycerol, the other product, activates protein

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Acetylcholine, parasympathetic stimulation, cold, stretch

mV

0

−50

Membrane potential

Epinephrine, sympathetic stimulation

FIGURE 11–3 Examples of stimuli such as the SNS and the PNS on smooth muscle membrane potential and action potential generation. At more negative membrane potentials, as with epinephrine or SNS stimulation, there are no action potentials and muscle becomes more relaxed. At less negative action potentials, action potentials occur and the muscle is more likely to have more tension or tone. (Reproduced with permission from Barrett KE, Barman SM, Boitano S, Brooks H: Ganong’s Review of Medical Physiology, 23rd ed. McGraw-Hill Medical, 2009.)

kinase C. There are several different receptors on smooth muscle that are linked to the PLC pathway resulting in stronger contractions. Some of these include alpha-adrenergic receptors that bind norepinephrine, muscarinic receptors that

bind acetylcholine, and specific endothelin receptors that bind endothelin 1. Influx of calcium through the voltage-gated calcium channels can be modulated by the resting membrane potential that is primarily a function of K+ movement. Opening of K channels (by calcium) or closing of K channels (by ATP) alters the membrane potential. Hyperpolarization of the cell (by opening the K channels) results in closure of the voltagegated calcium channels and relaxation or dilation if the cell is a vascular smooth muscle cell. Depolarization of the cell (not necessarily enough to generate an action potential) causes opening of the voltage-gated calcium channels leading to contraction (constriction of smooth muscle if the cell is vascular smooth muscle). Notice also the presence of storageoperated channels (SOC) on the SL. These channels allow entry of calcium into smooth muscle in order to replenish SR calcium stores. The mechanisms sensing decreased SR calcium levels and the communication between the SR and the SL are not clear but do seem to be effective in maintaining adequate calcium stores in the smooth muscle cell. Finally, receptor-operated channels exist on smooth muscle cells. These receptors are literally channels that allow ion movements. Purinergic channels represent this type of control— ATP, which is a purine, opens this type of channel allowing calcium entry into the cell and promoting contraction. In the renal vascular smooth muscle, adenosine, which is normally considered a vasodilator, binds to ROC allowing calcium entry and contraction. Not shown in Figure 11–4 is the modulation of smooth muscle contraction that occurs by products from the other cells associated with smooth muscle. For example, endothelial

Smooth muscle cell

Receptor PLC PIP2

IP3 + DAG

IP3 receptor

SR Ca2+ release ROC

PKC

SOC ~P proteins

Voltage gated calcium channel

ATP (closes K channel)

Ca2+ (opens K channel) Channels

FIGURE 11–4 A smooth muscle cell with some of the many influences on contraction. Contractions can be initiated by action potentials, by receptors that couple to phospholipase C, and by alterations in the open state of the voltage-gated calcium channels that are sensitive to the membrane potential as controlled primarily by potassium movements across the membrane. SOC are the storage-operated channels that open when SR calcium stores are low. ROC are receptor-operated channels—primarily responsive to agents such as adenosine and ATP. Calcium release from the SR or calcium entry through voltage-gated calcium channel leads to the calmodulin binding and ultimately contraction.

CHAPTER 11 Smooth Muscle Structure and Function cells that line the blood vessels release several factors that modulate vascular smooth muscle force development. As stated above, acetylcholine, which activates muscarinic receptors on vascular smooth muscle, can cause contraction by a PLC mechanism. However, acetylcholine binding to muscarinic receptors on endothelial cells causes the production of nitric oxide that diffuses to the vascular smooth muscle cell, and activates guanylate cyclase to produce cGMP. The cGMP activates protein kinase G that phosphorylates MLCK and decreases contraction. Thus, the site at which acetylcholine binds to the receptor (smooth muscle vs. endothelial cell) determines the response. In the body, due to the anatomy of the endothelial cells and the vascular smooth muscle cells and the presence of acetylcholine esterase, acetylcholine from the parasympathetic varicosities would predominantly release acetylcholine that would bind to muscarinic receptors on endothelial cells resulting in relaxation or dilation. Other biological responses of smooth muscle to stimulation are also site specific. For example, visceral smooth muscle in the gastrointestinal tract becomes quiescent with sympathetic nerve stimulation (Figure 11–3), whereas vascular smooth muscle in the blood vessels of the gastrointestinal tract develops stronger contraction when stimulated by sympathetic nerves. This site-specific response is due to the type of receptors on the cells—beta-adrenergic receptors cause relaxation in response to sympathetic stimulation in visceral smooth muscle, whereas alpha-adrenergic receptors cause stronger contraction in response to sympathetic stimulation in vascular smooth muscle. In summary, smooth muscle is the most diverse muscle in the body. Its functions are dependent to a great extent on the tissue in which they are found. Therefore, more specific detail about smooth muscle function will be presented in Sections 5, 7–9.

CHAPTER SUMMARY ■ ■ ■

■ ■

In smooth muscle, the calcium-binding protein is calmodulin rather than troponin as in skeletal and cardiac muscle. The calcium–calmodulin complex activates MLCK. Contraction is dependent on MLCK phosphorylating the myosin light chain allowing for binding of the myosin to the actin. MLC phosphatase removes the phosphate from the myosin light chain resulting in decreased strength of contraction. Many different stimuli can induce contraction or increase the strength of contraction of smooth muscle—voltage-gated calcium channels, voltage-gated potassium channels, receptoroperated channels, SOC, and receptor-mediated pharmacomechanical coupling. Even stretch can activate smooth muscle contraction.

■

■ ■

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The myosin ATPase activity is lowest in smooth muscle, resulting in the slowest contractions or changes in tension development. Multiunit smooth muscle cells are innervated, have few gap junctions, and contract individually. Unitary smooth muscle cells can respond to stretch and have gap junctions that enable them to contract as a “unit.”

STUDY QUESTIONS 1. Which of the following statements about smooth muscle is true? A) Phosphorylation of myosin light chains is required for contraction. B) Inhibition of myosin light chain kinase increases strength of contraction. C) Inhibition of myosin light chain phosphatase decreases contraction. D) Stimulation of the smooth muscle cells by nitric oxide will increase contraction. 2. Which of the following statements about smooth muscle contraction is correct? A) Acetylcholine release at the neuromuscular junction initiates an action potential in the postsynaptic membrane. B) Acetylcholine binds to a nicotinic receptor on the postsynaptic membrane. C) Depolarization of the muscle fiber is not essential for smooth muscle contraction. D) Norepinephrine activating adrenergic receptors always causes increased strength of contraction in all smooth muscle cells. 3. Which of the following statements about muscle contraction is true for smooth muscle? A) All cells have pacemaker potential. B) The strength of contraction is correlated with the degree of phosphorylation of the myosin light chains. C) The strength of contraction is increased by recruiting more motor units. D) All muscle cells have a high myosin ATPase velocity and therefore a rapid contraction. 4. Which of the following statements about muscle contraction is true for smooth muscle? A) Strength of contraction cannot be altered physiologically by changing the resting cell length from 25% up to 100% of the maximum length. B) Strength of contraction is altered physiologically by altering the frequency of motor neuron firing. C) Strength of contraction can be changed by changing the balance of the myosin light chain kinase and phosphatase activities. D) Muscle contraction occurs as contractions followed by complete relaxation of the cell.

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SECTION IV CNS/NEURAL PHYSIOLOGY

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Introduction to the Nervous System Susan M. Barman

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Name the various types of glia and their functions. Name the parts of a neuron and their functions. Describe the role of myelin in nerve conduction. List the types of nerve fibers found in the mammalian nervous system. Describe the general organization of thalamic, cortical, and reticular formation neurons. Describe the function of neurotrophins. Compare peripheral and central nerve regeneration.

INTRODUCTION The nervous system can be divided into two parts: the central nervous system (CNS), which is composed of the brain and spinal cord, and the peripheral nervous system, which is composed of nerves that connect the CNS to muscles, glands, and sense organs. Neurons are the basic building blocks of the nervous system. The human brain contains about 1011 (100 billion) neurons. It also contains 10–50 times this number of glial cells or glia. The CNS is a complex organ; it has been calculated that 40% of the human genes participate, at least to a degree, in its formation.

CELLULAR ELEMENTS IN THE CNS GLIAL CELLS The word glia is Greek for glue; for many years, glia were thought to function merely as connective tissue. However,

Ch12_105-114.indd 105

these cells are now recognized for their role in communication within the CNS in partnership with neurons. Unlike neurons, glial cells continue to undergo cell division in adulthood and their ability to proliferate is particularly noticeable after brain injury. There are two major types of glia, microglia and macroglia. Microglia are scavenger cells that resemble tissue macrophages and remove debris resulting from injury, infection, and disease. Microglia arise from macrophages outside of the CNS and are physiologically and embryologically unrelated to other neural cell types. There are three types of macroglia: oligodendrocytes, Schwann cells, and astrocytes (Figure 12–1). Oligodendrocytes and Schwann cells are involved in myelin formation around axons in the CNS and peripheral nervous system, respectively. Astrocytes, which are found throughout the brain, are of two subtypes. Fibrous astrocytes, which contain many intermediate filaments, are found primarily in white matter. Protoplasmic astrocytes are found in gray

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A Oligodendrocyte Oligodendrocyte in white matter

C Astrocyte

B Schwann cell Perineural oligodendrocytes

Capillary

Nodes of Ranvier

End-foot Neuron

Layers of myelin

Axons Schwann cell

End-foot

Fibrous astrocyte

Nucleus Inner tongue

Axon Neuron

FIGURE 12–1 Principal types of glial cells in the nervous system. A) Oligodendrocytes are small with relatively few processes. Those in the white matter provide myelin, and those in the gray matter support neurons. B) Schwann cells provide myelin to the peripheral nervous system. Each cell forms a segment of myelin sheath about 1 mm long; the sheath assumes its form as the inner tongue of the Schwann cell turns around the axon several times, wrapping in concentric layers. Intervals between segments of myelin are the nodes of Ranvier. C) Astrocytes are the most common glia in the CNS and are characterized by their starlike shape. They contact both capillaries and neurons and are thought to have a nutritive function. They are also involved in forming the blood–brain barrier. (Reproduced with permission from Kandel ER, Schwartz JH, Jessell TM [editors]: Principles of Neural Science, 4th ed. McGraw-Hill, 2000.)

matter and have a granular cytoplasm. Both types of astrocytes send processes to blood vessels, where they induce capillaries to form the tight junctions making up the blood–brain barrier. The blood–brain barrier prevents the diffusion of large or hydrophilic molecules (e.g., proteins) into the cerebrospinal fluid and brain, while allowing diffusion of small molecules. The astrocytes also send processes that envelop synapses and the surface of nerve cells. Protoplasmic astrocytes have a membrane potential that varies with the external K+ concentration but do not generate propagated potentials. They help maintain the appropriate concentration of ions and neurotransmitters by taking up K+ and the neurotransmitters glutamate and γ-aminobutyrate (GABA).

NEURONS Neurons in the mammalian CNS come in many different shapes and sizes. Most have the same parts as the typical spinal motor neuron illustrated in Figure 12–2. The cell body (soma) contains the nucleus and is the metabolic center of the neuron. Dendrites extend outward from the cell body and arborize extensively. Particularly in the cerebral and cerebellar cortex, the dendrites have small knobby projections called dendritic spines. A typical neuron has a long fibrous axon that originates from a thickened area of the cell body, the axon hillock. The first portion of the axon is called the initial segment. The axon divides into presynaptic terminals, each

ending in a number of synaptic knobs that are also called terminal buttons or boutons. They contain granules or vesicles that store the synaptic transmitters secreted by the nerves. Based on the number of processes that emanate from the cell body, neurons can be classified as unipolar, bipolar, and multipolar (Figure 12–3). The axons of many neurons are myelinated, that is, they acquire a sheath of myelin, a protein–lipid complex that is wrapped around the axon (Figure 12–2). In the peripheral nervous system, myelin forms when a Schwann cell wraps its membrane around an axon. This can occur up to 100 times, resulting in many layers of myelin around an axon (Figure 12–1). The myelin is then compacted when the extracellular portions of a membrane protein called protein zero (P0) lock to the extracellular portions of P0 in the apposing membrane. Various mutations in the gene for P0 cause peripheral neuropathies. The myelin sheath envelops the axon except at its ending and at the nodes of Ranvier, periodic 1-μm constrictions that are about 1 mm apart (Figure 12–2). The insulating function of myelin is critical for saltatory conduction of action potentials (see Chapter 6). Some neurons have axons that are unmyelinated, that is, they are simply surrounded by Schwann cells without the wrapping of the Schwann cell membrane that produces myelin around the axon. Within the CNS, the cells that form the myelin are oligodendrocytes (Figure 12–1). Unlike the Schwann cell, which forms the myelin on a single neuron, oligodendrocytes emit multiple processes that form myelin on many neighboring axons. In

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Cell body (soma) Initial segment of axon

Node of Ranvier

Schwann cell

Axon hillock Nucleus

Terminal buttons

Dendrites

FIGURE 12–2 Motor neuron with a myelinated axon. A motor neuron is comprised of a cell body (soma) with a nucleus, several processes called dendrites, and a long fibrous axon that originates from the axon hillock. The first portion of the axon is called the initial segment. A myelin sheath forms from Schwann cells and surrounds the axon except at its ending and at the nodes of Ranvier. Terminal buttons (boutons) are located at the terminal endings. (Reproduced with permission from Barrett KE, Barman SM, Boitano S, Brooks H: Ganong’s Review of Medical Physiology, 23rd ed. McGraw-Hill Medical, 2009.)

multiple sclerosis (MS), a crippling autoimmune disease, patchy destruction of myelin occurs in the CNS. The loss of myelin is associated with delayed or blocked conduction in the demyelinated axons.

PERIPHERAL NERVOUS SYSTEM The peripheral nervous system transmits information from the CNS to the effector organs throughout the body. It contains 12 pairs of cranial nerves and 31 pairs of spinal nerves. The cranial nerves have rather well-defined sensory and motor functions (Table 12–1). Many of these functions are described individually in more detail in later chapters in this section. Spinal nerves are named on the basis of the vertebral level from which the nerve exits (cervical, thoracic, lumbar, sacral, and coccygeal). These nerves include motor and sensory fibers of muscles, skin, and glands throughout the body.

NERVE FIBER TYPES AND FUNCTION Axonal conduction velocity is the speed by which an action potential travels along the axon. In general, there is a direct relationship between the diameter of a given nerve fiber and its speed of conduction. Nerve conduction tests are often used by neurologists in the diagnosis of some diseases. Axonal conduction velocity and other characteristics have led to the classification of nerve fibers as shown in Table 12–2. Mammalian nerve fibers are divided into three major groups (A, B, and C); the A group is further subdivided into α, β, γ, and δ fibers. In Table 12–2, the various fiber types are listed with their diameters, electrical characteristics, and functions. Large axons are concerned primarily with proprioceptive sensation, somatic motor function, conscious touch,

and pressure, while smaller axons subserve pain and temperature sensations and autonomic function. Dorsal root C fibers conduct some impulses generated by touch and other cutaneous receptors in addition to impulses generated by pain and temperature receptors. A numerical system (Ia, Ib, II, III, IV) has also been used to classify sensory fibers. A comparison of the number system and the letter system is shown in Table 12–3. In addition to variations in speed of conduction and fiber diameter, the various classes of fibers in peripheral nerves differ in their sensitivity to hypoxia and anesthetics (Table 12–4). This fact has clinical as well as physiological significance. For example, local anesthetics depress transmission in group C fibers before they affect group A touch fibers. Conversely, pressure on a nerve can cause loss of conduction in large-diameter motor, touch, and pressure fibers while pain sensation remains relatively intact. This is sometimes seen in individuals who sleep with their arms under their heads for long periods, causing compression of the nerves in the arms. Because of the association of deep sleep with alcoholic intoxication, the syndrome is most common on weekends and has acquired the interesting name Saturday night or Sunday morning paralysis.

ORGANIZATION OF THE THALAMUS, CEREBRAL CORTEX, & RETICULAR FORMATION The thalamus is a large collection of neuronal groups within the diencephalon; it participates in sensory, motor, and limbic functions that will be described in later chapters in this section. Virtually all information that reaches the cerebral cortex is first processed by the thalamus, leading to its being called the “gateway” to the cortex.

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A Unipolar cell

B Bipolar cell

C Pseudo-unipolar cell

Dendrites

Peripheral axon to skin and muscle

Dendrite

Cell body Axon Cell body

Single bifurcated process

Axon

Central axon

Cell body

Axon terminals Invertebrate neuron

Bipolar cell of retina

Ganglion cell of dorsal root

D Three types of multipolar cells

Dendrites Apical dendrite Cell body Cell body Basal dendrite Axon

Dendrites

Axon

Motor neuron of spinal cord

Pyramidal cell of hippocampus

Cell body

Axon

Purkinje cell of cerebellum

FIGURE 12–3 Different types of neurons in the mammalian nervous system. A) Unipolar neurons have one process, with different segments serving as receptive surfaces and releasing terminals. B) Bipolar neurons have two specialized processes: a dendrite that carries information to the cell and an axon that transmits information from the cell. C) Some sensory neurons are in a subclass of bipolar cells called pseudounipolar cells. As the cell develops, a single process splits into two, both of which function as axons—one going to skin or muscle and another to the spinal cord. D) Multipolar cells have one axon and many dendrites. Examples include motor neurons, hippocampal pyramidal cells with dendrites in the apex and base, and cerebellar Purkinje cells with an extensive dendritic tree in a single plane. (Adapted from Ramon Y Cajal: Histology. 10th ed. Baltimore: Wood, 1933.)

The thalamus is divided into nuclei that project diffusely to wide regions of the neocortex and nuclei that project to specific portions of the neocortex and limbic system. The nuclei that project to wide regions of the neocortex are the midline and intralaminar nuclei. The nuclei that project to specific areas include the specific sensory relay nuclei and the nuclei concerned with efferent control mechanisms. The specific sensory relay nuclei include the medial and lateral geniculate bodies, which relay auditory and visual impulses to the auditory and visual cortices, and the ventral posterior lateral (VPL) and ventral posteromedial, which relay somatosensory information to the postcentral gyrus. The ventral anterior and ventral lateral nuclei are concerned with motor function; they receive input from the basal ganglia and cerebellum and

project to the motor cortex. The anterior nuclei receive afferents from the mamillary bodies and project to the limbic cortex (memory and emotion). Most thalamic neurons are excitatory and release glutamate. The thalamic reticular nucleus neurons are inhibitory and release GABA; they modulate the responses of other thalamic neurons to input coming from the cortex. The neocortex is arranged in six layers (Figure 12–4). The most common neuronal type is the pyramidal cell with an extensive vertical dendritic tree (Figure 12–5) that may extend to the cortical surface. Their cell bodies can be found in all cortical layers except layer I. The axons of these cells give off recurrent collaterals that turn back and synapse on the superficial portions of the dendritic trees. Afferents from the

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TABLE 12–1 Functions of cranial nerves. Cranial Nerve

Type

Function

I. Olfactory

Sensory

Smell

II. Optic

Sensory

Vision

III. Occulomotor

Motor

Upward, downward, and medial eye movements; pupil diameter; lens shape

IV. Trochlear

Motor

Downward and lateral eye movement

V. Trigeminal

Motor Sensory

Chewing Proprioception from skin and muscle of the face

VI. Abducens

Motor

Lateral eye movements

VII. Facial

Motor Sensory

Facial expression; salivary gland secretions Sensation from skin of external ear canal; taste from anterior two thirds of the tongue

VIII. Vestibulocochlear

Sensory

Hearing; sense of motion

IX. Glossopharyngeal

Motor Sensory

Swallowing; parotid salivary gland secretions Taste from posterior one third of the tongue; baroreceptor and chemoreceptors

X. Vagus

Motor Sensory

Skeletal muscles of larynx and pharynx; smooth muscle and glands in pharynx, larynx, thorax, and abdomen Receptors in thorax and abdomen; taste from posterior tongue and oral cavity

XI. Accessory

Motor

Skeletal muscles in the neck

XII. Hypoglossal

Motor

Skeletal muscle of tongue

specific nuclei of the thalamus terminate primarily in cortical layer IV, and the nonspecific afferents are distributed to layers I–IV. Pyramidal neurons are the only projection neurons of the cortex, and they are excitatory neurons that release glutamate. The other cortical cell types are local circuit neurons (interneurons) that are classified based on their shape, pattern of projection, and neurotransmitter. Inhibitory interneurons

(basket cells and chandelier cells) release GABA. Basket cells account for most inhibitory synapses on the pyramidal soma and dendrites. Chandelier cells are a powerful source of inhibition of pyramidal neurons because they terminate on the initial segment of the pyramidal cell axon. Their terminal boutons form short vertical rows that resemble candlesticks, thus accounting for their name. Spiny stellate cells, excitatory interneurons that release glutamate, are located primarily in

TABLE 12–2 Classification of mammalian nerve fibers.a Fiber Type

Function

Fiber Diameter (μm)

Conduction Velocity (m/s)

Spike Duration (milliseconds)

Absolute Refractory Period (milliseconds)

0.4–0.5

0.4–1

A α

Proprioception; somatic motor

12–20

70–120

β

Touch, pressure

5–12

30–70

γ

Motor to muscle spindles

3–6

15–30

δ

Pain, cold, touch

2–5

12–30

Preganglionic autonomic

<3

3–15

1.2

1.2

Dorsal root

Pain, temperature, some mechanoreception

0.4–1.2

0.5–2

2

2

Sympathetic

Postganglionic sympathetic

0.3–1.3

0.7–2.3

2

2

B C

a

A and B fibers are myelinated; C fibers are unmyelinated.

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TABLE 12–3 Numerical classification sometimes

Pial surface

used for sensory fibers. Number

Origin

Fiber Type

Ia

Muscle spindle, annulospiral ending

Aα

Ib

Golgi tendon organ

Aα

II

Muscle spindle, flower-spray ending; touch, pressure

Aβ

III

Pain and cold receptors; some touch receptors

Aδ

IV

Pain, temperature, and other receptors

Dorsal root C

layer IV and are a major recipient of sensory information arising from the thalamus. In addition to being organized into layers, the cortex is also organized into columns. Neurons within a column have similar response properties, suggesting they comprise a local processing network (e.g., orientation and ocular dominance columns in the visual cortex, as described in Chapter 15). The reticular formation is a complex neural network in the central core of the medulla and midbrain. It is made up of various neural clusters and ascending and descending fibers. It contains the cell bodies and fibers of many of the serotonergic, noradrenergic, adrenergic, and cholinergic systems. Some of the descending fibers in it inhibit transmission in sensory and motor pathways in the spinal cord; various reticular areas and the pathways from them are concerned with spasticity (increased resistance to passive stretch of a muscle) and adjustment of stretch reflexes. The reticular activating system (RAS) is a complex polysynaptic pathway arising from the brain stem reticular formation with projections to the intralaminar and reticular nuclei of the thalamus that, in turn, project diffusely and nonspecifically to wide regions of the cortex (Figure 12–6). Collaterals funnel into it not only from the long ascending sensory tracts, but also from the trigeminal, auditory, visual, and olfactory systems. The complexity of the neural network and the degree of convergence in it abolish modality specificity, and most reticular neurons are activated with equal facility

TABLE 12–4 Relative susceptibility of mammalian A, B, and C nerve fibers to conduction block produced by various agents. Most Susceptible

Intermediate

Least Susceptible

Hypoxia

B

A

C

Pressure

A

B

C

Local anesthetics

C

B

A

Susceptibility To

I

Molecular layer

II

External granule cell layer

III

External pyramidal cell layer

IV

Internal granule cell layer

V

Internal pyramidal cell layer

VI

Multiform layer

Golgi stain

Nissl stain

Weigert stain

White matter

FIGURE 12–4 Structure of the cerebral cortex. The cortical layers are indicated by the numbers. Golgi stain shows neuronal cell bodies and dendrites, Nissl stain shows cell bodies, and Weigert myelin sheath stain shows myelinated nerve fibers. (Modified with permission from Ranson SW, Clark SL: The Anatomy of the Nervous System, 10th ed. Saunders, 1959.)

by different sensory stimuli. The system is therefore nonspecific, whereas the classic sensory pathways are specific in that the fibers in them are activated by only one type of sensory stimulation. The RAS is concerned with consciousness and sleep (see Chapter 20).

NEUROTROPHINS: TROPHIC SUPPORT OF NEURONS Proteins necessary for survival and growth of neurons are called neurotrophins. Many are products of the muscles or other structures that the neurons innervate, but others are produced by astrocytes. These proteins bind to receptors at the endings of a neuron. They are internalized and then transported by retrograde transport to the neuronal cell body, where they foster the production of proteins associated with neuronal development, growth, and survival. Other neurotrophins are produced in neurons and transported in an anterograde

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neurons. It is found in many different tissues. NGF is picked up by neurons and transported in retrograde fashion from the endings of the neurons to their cell bodies. It is also present in the brain and appears to be responsible for the growth and maintenance of cholinergic neurons in the basal forebrain and striatum.

C

A

D

AXONAL DEGENERATION & REGENERATION B

Axon

FIGURE 12–5 Neocortical pyramidal cell, showing the distribution of neurons that terminate on it. A) Nonspecific afferents from the reticular formation and the thalamus; B) recurrent collaterals of pyramidal cell axons; C) commissural fibers from mirror image sites in the contralateral hemisphere; D) specific afferents from thalamic sensory relay nuclei. (Modified with permission from Chow KL, Leiman AL: The structural and functional organization of the neocortex. Neurosci Res Program Bull 1970;8(2):157–220.)

fashion to the nerve ending, where they maintain the integrity of the postsynaptic neuron. The first neurotrophin to be characterized was nerve growth factor (NGF), a protein that is necessary for the growth and maintenance of sympathetic neurons and some sensory

When a motor nerve to skeletal muscle is cut and allowed to degenerate, the muscle will become extremely sensitive to acetylcholine, the transmitter normally released at the nerve ending. This denervation supersensitivity (or hypersensitivity) of the postsynaptic structure to the transmitter previously secreted by the axon endings is largely due to the synthesis or activation of more receptors. This and other reactions triggered by damage to an axon are summarized in Figure 12–7. Orthograde degeneration (Wallerian degeneration) and retrograde degeneration of the axon stump to the nearest collateral (sustaining collateral) occur commonly when a nerve is cut. Also, a series of changes occur in the cell body including a decrease in Nissl substance (chromatolysis). Peripheral nerve damage is often reversible. Although the axon will degenerate distal to the damage, connective elements of the distal stump often survive. Axonal sprouting occurs

Axon branch (sustaining collateral)

Receptor

Retrograde degeneration Cortex

Receptor hypersensitive Site of injury

X Retrograde reaction: chromatolysis

Regenerative sprouting

Orthograde (wallerian) degeneration

Barrett KE, Barman SM, Boitano S, Brooks H: Ganong’s Review of Medical Physiology,

FIGURE 12–7 Summary of changes occurring in a neuron and the structure it innervates when its axon is crushed or cut at the point marked X. Hypersensitivity of the postsynaptic structure to the transmitter previously secreted by the axon occurs largely due to the synthesis or activation of more receptors. There is both orthograde (Wallerian) degeneration from the point of damage to the terminal and retrograde degeneration of the axon stump to the nearest collateral (sustaining collateral). Changes also occur in the cell body, including chromatolysis. The nerve starts to regrow, with multiple small branches projecting along the path the axon previously followed (regenerative sprouting). (Reproduced with permission from Barrett KE, Barman SM, Boitano S,

23rd ed. McGraw-Hill Medical, 2009.)

Brooks H: Ganong’s Review of Medical Physiology, 23rd ed. McGraw-Hill Medical, 2009.)

Intralaminar nuclei of thalamus Midbrain reticular formation

FIGURE 12–6 Diagram showing the ascending reticular system in the human midbrain, its projections to the intralaminar nuclei of the thalamus, and the output from the intralaminar nuclei to many parts of the cerebral cortex. Activation of these areas is shown by PET scans when subjects shift from a relaxed awake state to an attention-demanding task. (Reproduced with permission from

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from the proximal stump, growing toward the nerve ending. This results from growth-promoting factors secreted by Schwann cells that attract axons toward the distal stump. Adhesion molecules of the immunoglobulin superfamily promote axon growth along cell membranes and extracellular matrices. Inhibitory molecules in the perineurium, the connective tissue sheath that covers a nerve bundle, assure that the regenerating axons grow in a correct trajectory. Denervated distal stumps are able to increase the production of neurotrophins that promote growth. Once the regenerated axon reaches its target, a new functional connection is formed. Regeneration allows for considerable, although not full, recovery. For example, fine motor control may be permanently impaired because some motor neurons are guided to an inappropriate muscle fiber. Recovery of peripheral nerves from damage far surpasses that of CNS pathways. The proximal stump of a damaged axon in the CNS will form short sprouts, but distant stump recovery is rare, and the damaged axons are unlikely to form new synapses. This is because CNS neurons do not have the growthpromoting chemicals needed for regeneration. In fact, CNS myelin is a potent inhibitor of axonal growth. Also, following CNS injury, several events—astrocytic proliferation, activation of microglia, scar formation, inflammation, and invasion of immune cells—provide an inappropriate environment for regeneration. Thus, treatment of brain and spinal cord injuries often focuses on rehabilitation rather than reversing the nerve damage. Researchers are trying to identify ways to initiate and maintain axonal growth, to direct regenerating axons to reconnect with their target neurons, and to reconstitute original neuronal circuitry.

CLINICAL CORRELATION A 27-year-old school teacher awakens one morning with rather severe pain in her left eye and blurry vision (optic neuritis). She is out of the country on a summer vacation and decides to wait until she returns home to see her physician. Over the next couple of days, the pain and visual loss worsen. But by the time she returns home 10 days later, the symptoms have abated enough that she decides it is not necessary to see her physician. About 8 months later she develops a sudden onset of weakness in her right leg after a difficult day in the classroom. She decides to relax in a hot bath, but this exacerbates the symptoms. Her problem rapidly progresses to the point where she cannot walk. Three days later, she is seen by her physician and also reports the incident that occurred while on her summer vacation. A brain magnetic resonance imaging (MRI) and a visual evoked potential test are ordered. About 1 week later, she notes significant improvement but she is notified by her physician that the MRI showed multiple periventricular white matter lesions, and the visual evoked potential test showed a delayed response (slowed conduction).

The woman is diagnosed with multiple sclerosis (MS), an autoimmune disease that affects over 3 million people worldwide, usually striking people between the ages of 20 and 50 and affecting women about twice as often as men. In MS, antibodies and white blood cells in the immune system attack myelin, causing inflammation and injury to the sheath and eventually the nerves that it surrounds. Loss of myelin leads to leakage of K+ through voltage-gated channels, hyperpolarization, and failure to conduct action potentials. Deficits may include muscle weakness, fatigue, diminished coordination, slurred speech, blurred or hazy vision, bladder dysfunction, and sensory disturbances. Symptoms are often exacerbated by increased body temperature or ambient temperature. In most cases, transient episodes appear suddenly, last a few weeks or months, and then gradually disappear. Subsequent episodes can appear years later, and eventually full recovery does not occur. Others have a progressive form of the disease in which there are no periods of remission. Diagnoses of MS is generally delayed until there are multiple episodes with deficits separated in time and space. Nerve conduction tests can detect slowed conduction in motor and sensory pathways. Cerebral spinal fluid analysis can detect the presence of oligoclonal bands indicative of an abnormal immune reaction against myelin. The most definitive assessment is MRI to detect multiple scarred (sclerotic) areas in the brain. Although there is no cure for MS, some drugs such as beta-interferon and corticosteroids that suppress the immune response can reduce the severity and slow the progression of the disease.

CHAPTER SUMMARY ■

■

■

■ ■

■

Glia are abundant in the CNS. Microglia are scavenger cells. Macroglia include oligodendrocytes, Schwann cells, and astrocytes. The first two are involved in myelin formation. Astrocytes help maintain the appropriate concentration of ions and neurotransmitters in the CNS. Neurons are composed of a cell body (soma) that is the metabolic center of the neuron, dendrites that extend outward from the cell body and arborize extensively, and a long fibrous axon that originates from a somewhat thickened area of the cell body, the axon hillock. Axons of many neurons acquire a sheath of myelin, a protein– lipid complex that is wrapped around the axon. Myelin is an effective insulator, and depolarization in myelinated axons jumps from one node of Ranvier to the next (saltatory conduction). Nerve fibers are divided into different categories based on their axonal diameter, conduction velocity, and function. Thalamic nuclei that project to wide regions of the neocortex are the midline and intralaminar nuclei and those that project to specific areas include the specific sensory relay nuclei. The neocortex is arranged in six layers; the most common neuronal type is the pyramidal cell whose cell bodies are located in all layers except layer I.

CHAPTER 12 Introduction to the Nervous System ■

■

Neurotrophins are produced by astrocytes and transported by retrograde transport to the neuronal cell body, where they foster the production of proteins associated with neuronal development, growth, and survival. After a peripheral nerve is damaged, Schwann cells secrete a growth-promoting factor that attracts the proximal stump of the axon toward the distal stump, allowing for regeneration. In the CNS, neural regeneration is impaired by factors such as astrocytic proliferation, scar formation, and inflammation.

STUDY QUESTIONS 1. The distance from one stimulating electrode to recording electrode is 4.5 cm. When the axon is stimulated, the latent period is 1.5 milliseconds. What is the conduction velocity of the axon? A) 15 m/s B) 30 m/s C) 40 m/s D) 67.5 m/s E) This cannot be determined from the information given. 2. Which of the following has the slowest conduction velocity? A) Aα fibers B) Aβ fibers C) Aγ fibers D) B fibers E) C fibers

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3. A man falls into a deep sleep with one arm under his head. This arm is paralyzed when he awakens, but it tingles, and pain sensation in it is still intact. The reason for the loss of motor function without loss of pain sensation is that in the nerves to his arm A) A fibers are more susceptible to hypoxia than B fibers. B) A fibers are more sensitive to pressure than C fibers. C) C fibers are more sensitive to pressure than A fibers. D) motor nerves are more affected by sleep than sensory nerves. E) sensory nerves are nearer the bone than motor nerves and hence are less affected by pressure. 4. The thalamus A) is organized into six layers. B) does not relay auditory or visual information to the neocortex. C) is a component of the reticular activating system. D) contains neurons that project diffusely throughout the neocortex. E) is a component of the brain stem. 5. Which of the following is not true about the neocortex? A) It is organized into six layers. B) The most common neuronal type is the pyramidal cell. C) It receives direct input from the thalamus. D) It contains a group of inhibitory interneurons called basket cells. E) It contains a group of excitatory interneurons called chandelier cells.

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General Sensory Systems: Touch, Pain, and Temperature Susan M. Barman

H A

P

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List common senses and their receptors. Explain the terms hyperalgesia and allodynia. Explain sensory coding. Compare the pathway that mediates sensory input from touch, proprioceptive, and vibratory senses to that mediating information from pain and thermoreceptors. Describe mechanisms to modulate transmission in pain pathways.

INTRODUCTION Information about the internal and external environment activates the central nervous system (CNS) via sensory receptors. These receptors are transducers that convert various forms of energy into action potentials in neurons. The characteristics of some of these receptors and the way they generate impulses in afferent neurons were considered in Chapter 5. Cutaneous receptors for touch and pressure are mechanoreceptors. Potentially harmful stimuli such as pain, extreme heat, and extreme cold are mediated by nociceptors. Chemoreceptors are stimulated by a change in the chemical composition of the environment in which they are located. These include receptors for taste and smell as well as visceral receptors such as those sensitive to changes in the plasma level of O2, pH, and osmolality. Photoreceptors are those in the rods and cones in the retina that respond to light. This chapter will focus primarily on cutaneous receptors and transmission in somatosensory pathways mediating touch and proprioception (dorsal column–medial lemniscus pathway) and pain and temperature (spinothalamic tract).

SENSORY RECEPTORS CUTANEOUS MECHANORECEPTORS Sensory receptors can be specialized dendritic endings of afferent nerve fibers and are often associated with nonneural

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cells that surround them, forming a sense organ. Touch and pressure are sensed by four types of mechanoreceptors (Figure 13–1). Meissner’s corpuscles are dendrites encapsulated in connective tissue and respond to changes in texture and slow vibrations. Merkel cells are expanded dendritic endings, and they respond to sustained pressure and touch. Ruffini corpuscles are enlarged dendritic endings with elongated capsules, and they respond to sustained pressure. Pacinian corpuscles consist of unmyelinated dendritic endings of a sensory nerve fiber, encapsulated by concentric lamellae of connective tissue that give the organ the appearance of a cocktail onion. These receptors respond to deep pressure and fast vibration.

NOCICEPTORS AND THERMORECEPTORS Pain and temperature sensations arise from unmyelinated dendrites of sensory neurons located around hair follicles throughout the glabrous and hairy skin, as well as in deep tissue. Impulses from nociceptors (pain) are transmitted via two fiber types. One system comprises thinly myelinated Aδ fibers that conduct at rates of 12–30 m/s. The other is unmyelinated C fibers that conduct at low rates of 0.5–2 m/s. Thermoreceptors also span the following two fiber types: cold receptors are on dendritic endings of Aδ fibers and C fibers, whereas warm receptors are on C fibers. Mechanical nociceptors respond to strong pressure. Thermal nociceptors are activated by skin 115

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A Modality

Touch

Receptors

Meissner’s corpuscle

Merkel cells

Pacinian corpuscle

Ruffini endings

B Location

Receptive field

C Intensity and time course Neural spike train Stimulus

FIGURE 13–1 Sensory systems encode four elementary attributes of stimuli: modality, location (receptive field), intensity, and duration (timing). A) The human hand has four types of mechanoreceptors; their combined activation produces the sensation of contact with an object. Selective activation of Merkel cells and Ruffini endings causes sensation of steady pressure; selective activation of Meissner’s and Pacinian corpuscles causes tingling and vibratory sensation. B) Location of a stimulus is encoded by spatial distribution of the population of receptors activated. A receptor fires only when the skin close to its sensory terminals is touched. These receptive fields of mechanoreceptors (shown as red areas on fingertips) differ in size and response to touch. Merkel cells and Meissner’s corpuscles provide the most precise localization as they have the smallest receptive fields and are most sensitive to pressure applied by a small probe. C) Stimulus intensity is signaled by firing rates of individual receptors; duration of stimulus is signaled by time course of firing. The spike trains indicate action potentials elicited by pressure from a small probe at the center of each receptive field. Meissner’s and Pacinian corpuscles adapt rapidly; the others adapt slowly. (Reproduced with permission from Kandel ER, Schwartz JH, Jessell TM [editors]: Principles of Neural Science, 4th ed. McGraw-Hill, 2000.)

temperatures above 45°C or by severe cold. Chemically sensitive nociceptors respond to various agents such as bradykinin, histamine, high acidity, and environmental irritants. Polymodal nociceptors respond to combinations of these stimuli. Pain is defined by the International Association for the Study of Pain (IASP) as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage….” This is different from nociception, which the IASP defines as the unconscious activity induced by a harmful stimulus applied to sense receptors. Pain can be classified as physiological (or acute) pain and pathological (or chronic) pain, which includes inflammatory pain and neuropathic pain. Acute pain typically has a sudden onset and recedes during the healing process. It can be considered “good pain” because it serves an important protective mechanism. The withdrawal reflex is an example of this protective role of pain (see Chapter 14). Chronic pain can be considered “bad pain” because it persists long after recovery

from an injury and is often refractory to common analgesic agents, including nonsteroidal anti-inflammatory drugs (NSAIDs) and opiates. It can result from nerve injury including diabetic neuropathy, toxin-induced nerve damage, and ischemia. Pain is often accompanied by hyperalgesia, an exaggerated response to a noxious stimulus, and allodynia, a sensation of pain in response to an innocuous stimulus. An example of the latter is the painful sensation from a warm shower when the skin is damaged by sunburn. Hyperalgesia and allodynia signify increased sensitivity of nociceptive afferent fibers. Figure 13–2 shows how chemicals released at the site of injury can further activate nociceptors leading to inflammatory pain. Injured cells release chemicals such as K+ that depolarize nerve terminals, making nociceptors more responsive. Injured cells also release bradykinin and substance P, which can further sensitize nociceptive terminals. Histamine is released from mast cells, serotonin (5-HT)

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Mast cell

CGRP Substance P Histamine

Dorsal root ganglion neuron

Bradykinin Lesion

5-HT Prostaglandin K+ CGRP Substance P Blood vessel Spinal cord

FIGURE 13–2

In response to tissue injury, chemical mediators can sensitize and activate nociceptors. These factors contribute to hyperalgesia and allodynia. Tissue injury releases bradykinin and prostaglandins that sensitize or activate nociceptors, which in turn releases substance P and calcitonin gene-related peptide (CGRP). Substance P acts on mast cells to cause degranulation and release histamine, which activates nociceptors. It causes plasma extravasation and CGRP dilates blood vessels; the resulting edema causes additional release of bradykinin. Serotonin (5-HT) is released from platelets and activates nociceptors. (Reproduced with permission from Kandel ER, Schwartz JH, Jessell TM

[editors]: Principles of Neural Science. McGraw-Hill, 2000.)

from platelets, calcitonin gene-related peptide (CGRP) from nerve terminals, and prostaglandins from cell membranes, all contributing to the inflammatory process and activating or sensitizing the nociceptors. Some released substances act by releasing another one (e.g., bradykinin activates both Aδ and C fibers and increases synthesis and release of prostaglandins). Prostaglandin E2 (a cyclooxygenase metabolite of arachidonic acid) is released from damaged cells and produces hyperalgesia. This is why aspirin and other NSAIDs (inhibitors of cyclooxygenase) alleviate pain.

SENSORY RECEPTORS IN SKELETAL MUSCLES & JOINTS Skeletal muscles contain receptors called muscle spindles and Golgi tendon organs that are important for proprioception. They play major roles in motor control and are described in Chapter 14. Muscles also contain nociceptors that respond to pressure and the release of metabolites during ischemia. Limb joints also contain mechanoreceptors (Pacinian and Ruffini corpuscles) and nociceptors.

SENSORY CODING Converting a receptor stimulus to a recognizable sensation is termed sensory coding. All sensory systems code for four elementary attributes of a stimulus: modality, location, intensity, and duration. These attributes of sensory coding are shown for the modality of touch in Figure 13–1.

Modality is the type of energy transmitted by the stimulus. The particular form of energy to which a receptor is most sensitive is called its adequate stimulus. Location is the site on the body or space where the stimulus originated. A sensory unit is a single sensory axon and all its peripheral branches; the receptive field of a sensory unit is the spatial distribution from which a stimulus produces a response in that unit (Figure 13–1). One of the most important mechanisms that enable localization of a stimulus site is lateral inhibition. Activity arising from sensory neurons whose receptors are at the peripheral edge of the stimulus is inhibited compared to that from the sensory neurons at the center of the stimulus. Thus, lateral inhibition enhances the contrast between the center and periphery of a stimulated area and increases the ability of the brain to localize a sensory input. Lateral inhibition underlies the neurological assessment called the two-point discrimination test, which is used to test the integrity of the dorsal column (medial lemniscus) system, the central pathway for touch and proprioception. In this procedure, the two points on a pair of calipers are simultaneously positioned on the skin and one determines the minimum distance between the two caliper points that can be perceived as separate points of stimulation. This is called the two-point discrimination threshold and is a measure of tactile acuity. If the distance is very small, each caliper point is touching the receptive field of only one sensory neuron. If the distance between stimulation points is less than this threshold, only one point of stimulation can be felt. The magnitude of twopoint discrimination thresholds varies from place to place on the body and is smallest where touch receptors are most abun-

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dant. Stimulus points on the back, for instance, must be separated by at least 65 mm before they can be distinguished as separate, whereas on the fingertips, two stimuli are recognized if they are separated by as little as 2 mm. Intensity is signaled by the response amplitude or frequency of action potential generation. Duration refers to the time from start to end of a response in the receptor. If a stimulus of constant strength is applied to a receptor, the frequency of the action potentials in its sensory nerve declines over time. This phenomenon is known as adaptation or desensitization. The degree to which adaptation occurs varies from one sense to another. Receptors can be classified into rapidly adapting (phasic) receptors and slowly adapting (tonic) receptors. This is illustrated for different types of touch receptors in Figure 13–1.

SOMATOSENSORY PATHWAYS DORSAL HORN

To dorsal columns Mechanoreceptors

Aβ

Mechanoreceptors Nociceptors Cold receptors I II III

Nociceptors Thermoreceptors Mechanoreceptors

Aδ

C

IV V VI VII

FIGURE 13–3 Schematic representation of the terminations of the three types of primary afferent neurons in the various layers of the dorsal horn of the spinal cord. (Reproduced with permission from Barrett KE, Barman SM, Boitano S, Brooks H: Ganong’s Review of Medical Physiology, 23rd ed. McGraw-Hill Medical, 2009.)

The dorsal horn in the spinal cord is divided on the basis of histologic characteristics into laminae I–VII, with I being the most superficial and VII the deepest. Lamina II and part of lamina III make up the substantia gelatinosa, the area near the top of each dorsal horn. Three types of primary afferent fibers (with cell bodies in the dorsal root ganglia) mediate cutaneous sensation: (1) large myelinated Aα and Aβ fibers that transmit impulses generated by mechanical stimuli; (2) small myelinated Aδ fibers that transmit impulses from cold receptors, nociceptors, or mechanoreceptors; and (3) small unmyelinated C fibers that are concerned primarily with pain and temperature. The orderly distribution of these fibers in various layers of the dorsal horn is shown in Figure 13–3.

DORSAL COLUMN PATHWAY The principal direct pathways to the cerebral cortex for touch, vibratory sense, and proprioception (position sense) are shown in Figure 13–4. Fibers mediating these sensations ascend ipsilaterally in the dorsal columns to the medulla, where they synapse in the gracilis and cuneate nuclei. The second-order neurons from these nuclei cross the midline and ascend in the medial lemniscus to end in the contralateral ventral posterior lateral (VPL) nucleus and related specific sensory relay nuclei of the thalamus. This ascending system is called the dorsal column or medial lemniscal system. The fibers within the dorsal column pathway are joined in the brain stem by fibers mediating sensation from the head. Touch and proprioception are relayed mostly via the main sensory and mesencephalic nuclei of the trigeminal nerve. Within the dorsal columns, fibers arising from different levels of the cord are somatotopically organized. Specifically,

fibers from the sacral cord are positioned most medially and those from the cervical cord most laterally. This arrangement continues in the medulla with lower body (e.g., foot) representation in the gracilis nucleus and upper body (e.g., finger) representation in cuneate nucleus. The medial lemniscus is organized dorsal to ventral, representing neck to foot. Somatotopic organization continues through the thalamus and cortex. VPL thalamic neurons carrying sensory information project in a highly specific way to the two somatic sensory areas of the cortex (Figure 13–5): somatic sensory area I (SI) in the postcentral gyrus and somatic sensory area II (SII) in the wall of the Sylvian fissure. In addition, SI projects to SII. SI corresponds to Brodmann’s areas 3, 2, and 1. The arrangement of projections to SI is such that the parts of the body are represented in order along the postcentral gyrus, with the legs on top and the head at the foot of the gyrus (Figure 13–5). Not only is there detailed localization of the fibers from the various parts of the body in the postcentral gyrus, but also the size of the cortical receiving area for impulses from a particular part of the body is proportionate to the use of the part. The relative sizes of the cortical receiving areas are shown dramatically in Figure 13–6, in which the proportions of the homunculus are distorted to correspond to the size of the cortical receiving areas for each. Note that the cortical areas for sensation from the trunk and back are small, whereas very large areas are concerned with impulses from the hand and the parts of the mouth concerned with speech. SII is located in the superior wall of the Sylvian fissure, the fissure that separates the temporal from the frontal and parietal lobes. The head is represented at the inferior end of the postcentral gyrus, and the feet at the bottom of the Sylvian fissure. The representation of the body parts is not as complete or detailed as it is in the postcentral gyrus.

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119

Postcentral gyrus Axons of third-order neurons

Thalamus

Cerebral cortex Medial lemniscal tract (axons of second-order neurons) Medulla oblongata Fasciculus cuneatus (axons of first-order sensory neurons)

Lateral spinothalamic tract (axons of second-order neurons)

Joint stretch receptor (proprioceptor)

Pain receptor

Spinal cord Axons of first-order neurons (not part of spinothalamic tract)

Fasciculus gracilis (axons of first-order sensory neurons)

Touch receptor

(a)

(b)

Temperature receptor

FIGURE 13–4 Ascending tracts carrying sensory information from peripheral receptors to the cerebral cortex. a) Dorsal column pathway mediating touch, vibratory sense, and proprioception. b) Ventrolateral spinothalamic tract mediating pain and temperature. (Reproduced with permission from Fox SI: Human Physiology. McGraw-Hill, 2008.)

Sl 6

8

4

9

3 1 2

Posterior parietal cortex

Trunk Hand Sll

Face Tongue Auditory su Vi

al

FIGURE 13–5 Brain areas concerned with somatic sensation, and some of the cortical receiving areas for other sensory modalities in the human brain. The numbers are those of Brodmann’s cortical areas. The primary auditory area is actually located in the Sylvian fissure on the top of the superior temporal gyrus and is not normally visible in a lateral view of the cortex. (Reproduced with permission from Barrett KE, Barman SM, Boitano S, Brooks H: Ganong’s Review of Medical Physiology, 23rd ed. McGraw-Hill Medical, 2009.)

VENTROLATERAL SPINOTHALAMIC TRACT Fibers from nociceptors and thermoreceptors synapse on neurons in the dorsal horn (Figure 13–3). The axons from these neurons cross the midline and ascend in the ventrolateral quadrant of the spinal cord, where they form the lateral spinothalamic tract (Figure 13–4). Fibers within this tract synapse in the VPL nuclei. Other dorsal horn neurons that receive nociceptive input synapse in the reticular formation of the brain stem (spinoreticular pathway) and then project to the centrolateral nucleus of the thalamus. Positron emission tomographic (PET) and functional magnetic resonance imaging (fMRI) studies in normal humans indicate that pain activates cortical areas SI, SII, and the cingulate gyrus on the side opposite the stimulus. Also, the mediofrontal cortex and insular cortex are activated. These technologies were important in distinguishing two components of pain pathways. From VPL nuclei in the

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Hip Leg

Arm Elbow rm Forea t Wris d Han le Litt g n Ri ddle M i dex b In um Th

E No ye s Fa e ce Upp er li p Lips

Shoulder Head Neck Trunk

afferent terminals that also synapse in the dorsal horn. This is called the gate-control hypothesis.

ot Fo s e To . Gen

Lower lip Teeth, gums, and jaw Tongue Pharynx Intraabdominal

FIGURE 13–6 Sensory homunculus, drawn overlying a coronal section through the postcentral gyrus. Gen., genitalia. (Reproduced with permission from Penfield W, Rasmussen G: The Cerebral Cortex of Man. Macmillan, 1950.)

thalamus, fibers project to SI and SII. This is called the neospinothalamic tract, and it is responsible for the immediate awareness of the painful sensation and the awareness of the location of the noxious stimulus. The pathway that includes synapses in the brain stem reticular formation and centrolateral thalamic nucleus projects to the frontal lobe, limbic system, and insula. This is called the paleospinothalamic tract, and it mediates the emotional response to pain. In the CNS, visceral sensation travels along the same pathways as somatic sensation in the spinothalamic tracts and thalamic radiations, and the cortical receiving areas for visceral sensation are intermixed with the somatic receiving areas. This likely contributes to the phenomenon called referred pain. Irritation of a visceral organ produces pain that is felt not at that site but in a somatic structure. Such pain is said to be referred to the somatic structure. Perhaps the best-known example is referral of cardiac pain to the inner aspect of the left arm.

MODULATION OF PAIN TRANSMISSION Many people have learned from practical experience that touching or shaking an injured area decreases the pain due to the injury. The relief may result from inhibition of pain pathways in the dorsal horn gate by stimulation of large-diameter touch–pressure afferents. Figure 13–3 shows that collaterals from these myelinated afferent fibers synapse in the dorsal horn. These collaterals may modify the input from nociceptive

MORPHINE & ENKEPHALINS One of the most effective analgesic agents is morphine. The receptors that bind morphine and the endogenous morphines, the opioid peptides, are found in the midbrain, brain stem, and spinal cord. There are at least three sites at which opioids can act to produce analgesia: peripherally, at the site of an injury; in the dorsal horn, where nociceptive fibers synapse on dorsal root ganglion cells; and at more rostral sites in the brain stem. Figure 13–7 shows various modes of action of opiates to decrease transmission in pain pathways. Opioid receptors are located on dorsal root ganglion cells and on afferent nerve fibers. In the periphery, inflammation causes the production of opioid peptides by immune cells, and these may act on the receptors in the afferent nerve fibers to reduce the pain that would otherwise be felt. The opioid receptors in the dorsal horn region may act presynaptically to decrease release of substance P. Injections of morphine into the periaqueductal gray matter (PAG) of the midbrain relieve pain by activating descending pathways that produce inhibition of primary afferent transmission in the dorsal horn. This activation may occur via projections from the PAG to the raphe magnus nucleus and descending serotonergic fibers from this nucleus mediate the inhibition. Acupuncture at a location distant from the site of a pain may act by releasing endorphins in the brain; acupuncture at the site of the pain appears to act primarily in the same way as touching or shaking (gate-control mechanism).

NEUROLOGICAL EXAM The sensory component of a neurological exam includes an assessment of various sensory modalities including touch, proprioception, vibratory sense, and pain. The integrity of the pain pathway is assessed by stimulating the skin with a pin and asking the patient if the stimulus is perceived as sharp. To test for proprioception, a physician holds the patient’s finger (toe, hand, or foot) and, with the subject’s eyes closed, asks whether the digit is being moved up or down. Vibratory sensibility is tested by applying a vibrating (128-Hz) tuning fork to the skin on the fingertip, tip of the toe, or bony prominences of the toes. The normal response is a “buzzing” sensation. The sensation is most marked over bones. A pattern of rhythmic pressure stimuli is interpreted as vibration. The impulses responsible for the vibrating sensation are carried in the dorsal columns. Degeneration of this part of the spinal cord occurs in poorly controlled diabetes mellitus, pernicious anemia, and vitamin B12 deficiencies. Elevation of the threshold for vibratory stimuli is an early symptom of this degeneration. Vibratory sensation and proprioception are closely related; when one is diminished, so is the other.

CHAPTER 13 General Sensory Systems: Touch, Pain, and Temperature

A

121

Norepinephrine Serotonin

Nociceptor

ENK

Projection neuron

B1 Sensory input

B2 Sensory input + opiates/opioids Control

Control Opiate Morphine

Nociceptor Glutamate Neuropeptides

Glutamate

Neuropeptides Enkephalin

Enkephalin Morphine

Ca2+

Ca2+

No input

No input + opiates Enkephalin

Sensory input Control

Sensory input + opiates Control Enkephalin

Projection neuron

FIGURE 13–7 Local circuit interneurons in the superficial dorsal horn of the spinal cord integrate descending and afferent pathways. A) Possible interactions of nociceptive afferent fibers, interneurons, and descending fibers in the dorsal horn. Nociceptive fibers terminate on second-order spinothalamic projection neurons. Enkephalin (ENK)-containing interneurons exert both presynaptic and postsynaptic inhibitory actions. Serotonergic and noradrenergic neurons in the brain stem activate opioid interneurons and suppress the activity of spinothalamic projection neurons. B1) Activation of nociceptors releases glutamate and neuropeptides from sensory terminals, depolarizing and activating projection neurons. B2) Opiates decrease Ca2+ influx leading to a decrease in the duration of nociceptor action potentials and a decreased release of transmitter. Also, they hyperpolarize the membrane of dorsal horn neurons by activating K+ conductance and decrease the amplitude of the EPSP (see Chapter 7) produced by stimulation of nociceptors. (Reproduced with permission from Kandel ER, Schwartz JH, Jessell TM [editors]: Principles of Neural Science, 4th ed. McGraw-Hill, 2000.)

Stereognosis is the perception of the form and nature of an object without looking at it. Healthy subjects can readily identify objects such as keys and coins of various denominations. This ability depends on relatively intact touch and pressure sensation and is compromised when the dorsal columns are damaged. The inability to identify an object by touch is called tactile agnosia. Impaired stereognosis is an early sign of damage to the cerebral cortex and sometimes

occurs in the absence of any detectable defect in touch and pressure sensation when there is a lesion in the parietal lobe posterior to the postcentral gyrus. Stereoagnosis can also be expressed by the failure to identify an object by sight (visual agnosia), the inability to identify sounds or words (auditory agnosia) or color (color agnosia), or the inability to identify the location or position of an extremity (position agnosia).

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CLINICAL CORRELATION A 55-year-old female executive at a large corporation developed a burning sensation in the palm of her right hand about 6 months ago. She also noticed tingling and numbness in her right thumb, index finger, and middle finger. These symptoms first developed after spending many long hours at the computer preparing annual report documents for the corporation. Initially, symptoms were most prominent at night, interrupting her sleep. The problem has recently intensified, and she now has pain in her right wrist and difficulty picking up small objects from her desk. She visited her doctor because working on the computer has become increasingly more difficult. Her physician performed several simple diagnostic tests. When the doctor pressed on her median nerve in the wrist, she experienced a shocklike sensation (Tinel’s sign). When the doctor had her hold her forearms upright by pointing the fingers down and pressing the backs of the hands together, within 1 minute she felt tingling and increasing numbness in her fingers (Phalen’s sign). Nerve conduction tests indicated slowed conduction in the median nerve. She was diagnosed with carpal tunnel syndrome, which is due to compression (possibly due to inflammation) of the median nerve that passes through the tunnel. It is more prevalent in women than men and is diagnosed primarily in individuals who use their wrists in repetitive activities (computer operators, cashiers, musicians, painters). About 3% of women and 2% of men are likely to be diagnosed with this syndrome during their lifetime. The median nerve provides sensory information from the thumb, index, and ring fingers, and the nine tendons that flex the fingers. The syndrome is characterized by pain, paresthesia, and weakness in the distribution of the median nerve. Wrist or hand pain or numbness and tingling of the fingers (except the little finger which is not innervated by the median nerve) are often the first symptoms. Patients sometimes report weakness in the hand and a tendency to drop things. Symptoms often first appear at night rather than during activity. Wrist splinting, NSAIDs, or corticosteroids are frequently the therapy of choice. If pain persists following these treatments, surgery may be required.

CHAPTER SUMMARY ■ ■

Sensory receptors are commonly classified as mechanoreceptors, nociceptors, chemoreceptors, or photoreceptors. Touch and pressure are sensed by four types of mechanoreceptors: Meissner’s corpuscles (respond to changes in texture and slow vibrations), Merkel cells (respond to sustained pressure and touch), Ruffini corpuscles (respond to sustained pressure), and Pacinian corpuscles (respond to deep pressure and fast vibrations).

■

■

■

■

■

Nociceptors and thermoreceptors are free nerve endings on unmyelinated or lightly myelinated fibers in hairy and glabrous skin and deep tissues. Hyperalgesia is an exaggerated response to a noxious stimulus; allodynia is a sensation of pain in response to an innocuous stimulus. Converting a receptor stimulus to a recognizable sensation is termed sensory coding. All sensory systems code for four elementary attributes of a stimulus: modality, location, intensity, and duration. Discriminative touch, proprioception, and vibratory sensations are relayed via the dorsal column (medial lemniscus) pathway to SI. Pain and temperature sensations are mediated via the ventrolateral spinothalmic tract to SI. Descending pathways from the mesencephalic PAG inhibit transmission in nociceptive pathways. This descending pathway includes a synapse in the raphe nucleus and the release of endogenous opiates. Morphine is an effective antinociceptive agent that binds to endogenous opiate receptors in the midbrain, brain stem, and spinal cord.

STUDY QUESTIONS 1. Pacinian corpuscles are A) a type of thermoreceptor. B) usually innervated by Aδ nerve fibers. C) rapidly adapting touch receptors. D) slowly adapting touch receptors. E) nociceptors. 2. Adaptation to a sensory stimulus produces A) a diminished sensation when other types of sensory stimuli are withdrawn. B) a more intense sensation when a given stimulus is applied repeatedly. C) a sensation localized to the hand when the nerves of the brachial plexus are stimulated. D) a diminished sensation when a given stimulus is applied repeatedly over time. E) a decreased firing rate in the sensory nerve from the receptor when one’s attention is directed to another matter. 3. Sensory systems code for which of the following attributes of a stimulus? A) modality, location, intensity, and duration B) threshold, receptive field, adaptation, and discrimination C) touch, taste, hearing, and smell D) threshold, laterality, sensation, and duration E) sensitization, discrimination, energy, and projection 4. Thermoreceptors A) are activated only by severe cold or severe heat. B) are located on superficial layers of the skin. C) are a subtype of nociceptor. D) are on dendritic endings of Aδ fibers and C fibers. E) All of the above.

CHAPTER 13 General Sensory Systems: Touch, Pain, and Temperature 5. A 50-year-old woman undergoes a neurological exam that indicates loss of pain and temperature sensitivity, vibratory sense, and proprioception in both legs. These symptoms could be explained by A) a tumor on the medial lemniscal pathway in the sacral spinal cord. B) a peripheral neuropathy. C) a large tumor in the sacral dorsal horn. D) a large tumor affecting the posterior paracentral gyri. E) a large tumor in the ventral posterolateral and posteromedial thalamic nuclei.

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14 C

Spinal Reflexes Susan M. Barman

H A

P

T

E

R

O B J E C T I V E S ■ ■ ■ ■ ■

Describe the components of a reflex arc. Describe the muscle spindles and their role in the stretch reflex. Describe the functions of the Golgi tendon organs as part of a feedback system that maintains muscle force. Define reciprocal innervation, inverse stretch reflex, and clonus. Describe the short- and long-term effects of spinal cord injury on spinal reflexes.

INTRODUCTION The basic unit of integrated reflex activity is the reflex arc. This arc consists of a sense organ, an afferent neuron, synapses within a central integrating station, an efferent neuron, and an effector organ. The afferent neurons enter the central nervous system (CNS) via the spinal dorsal roots or cranial nerves and have their cell bodies in the dorsal root ganglia or in the homologous ganglia for the cranial nerves. The efferent fibers leave the CNS via the spinal ventral roots or corresponding motor cranial nerves. Activity in the reflex arc starts in a sensory receptor with a generator potential whose magnitude is proportional to the strength of the stimulus (Figure 14–1). This generates all-ornone action potentials in the afferent nerve, the number of action potentials being proportional to the size of the generator potential. In the CNS, the responses are again graded in terms of excitatory postsynaptic potentials (EPSPs) and inhibitory postsynaptic potentials (IPSPs) at the synaptic junctions (see Chapter 7). All-or-none responses are generated in the efferent nerve. When these reach the effector organ, they again set up a graded response. When the effector is smooth muscle, responses summate to produce action potentials in the smooth muscle, but when the effector is skeletal muscle, the graded response is adequate to produce action potentials that bring about muscle contraction. Activity within the reflex arc is modified by the multiple inputs converging on the efferent neurons or at any synaptic station within the reflex loop.

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The simplest reflex arc is one with a single synapse between the afferent and efferent neurons. Such arcs are monosynaptic, and reflexes occurring in them are called monosynaptic reflexes. Reflex arcs in which one or more interneuron is interposed between the afferent and efferent neurons are called polysynaptic reflexes. There can be anywhere from two to hundreds of synapses in a polysynaptic reflex arc. As will be evident from the description below, reflex activity is stereotyped and specific in terms of both the stimulus and the response; a particular stimulus elicits a particular response. The fact that reflex responses are stereotyped does not exclude the possibility of their being modified by experience. Reflexes are adaptable and can be modified to perform motor tasks and maintain balance. Descending inputs from higher brain regions play an important role in modulating and adapting spinal reflexes.

MONOSYNAPTIC REFLEX: THE STRETCH REFLEX When a skeletal muscle with an intact nerve supply is stretched, it contracts. This response is called the stretch reflex. The stimulus that initiates the reflex is stretch of the muscle, and the response is contraction of the same muscle. The sense organ (receptor) is a small encapsulated spindlelike or fusiformshaped structure called the muscle spindle, located within the fleshy part of the muscle. The impulses originating from the

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Sense organ

Generator potential

Afferent neuron

Action potentials

Synapse

EPSPs (and IPSPs)

Efferent neuron

Action potentials

Neuromuscular junction

Endplate potentials

Muscle

Action potentials

FIGURE 14–1 Reflex arc. At the receptor and in the CNS a nonpropagated, graded response occurs that is proportionate to the magnitude of the stimulus. The response at the neuromuscular junction is also graded, though under normal conditions it is always large enough to produce a response in skeletal muscle. On the other hand, in the portions of the arc specialized for transmission (afferent and efferent axons, muscle membrane), the responses are all-or-none action potentials. (Reproduced with permission from Barrett KE, Barman SM, Boitano S, Brooks H: Ganong’s Review of Medical Physiology, 23rd ed. McGraw-Hill Medical, 2009.)

spindle are transmitted to the CNS by fast sensory fibers (group Ia) that pass directly to the motor neurons that supply the same muscle. The stretch reflex is the best-known and studied monosynaptic reflex and is typified by the knee-jerk reflex. Tapping the patellar tendon elicits the knee jerk, a stretch reflex of the quadriceps femoris muscle, because the tap on the tendon stretches the muscle. The knee-jerk reflex is an example of a deep tendon reflex in a neurological exam. Absence of the knee jerk can signify an abnormality anywhere within the reflex arc, including the muscle spindle, the Ia afferent nerve fibers, or the motor neurons to the quadriceps muscle. The most common cause is a peripheral neuropathy from such things as diabetes mellitus, alcoholism, and toxins. A hyperactive reflex can signify an interruption of inhibitory corticospinal and other descending pathways that influence the reflex arc.

STRUCTURE OF MUSCLE SPINDLES Figure 14–2A illustrates the composition of a muscle spindle and its innervation. Each muscle spindle has three essential elements: (1) a group of specialized intrafusal muscle fibers with contractile polar ends and a noncontractile center, (2) large-diameter myelinated afferent nerves (types Ia and II) originating in the central portion of the intrafusal fibers, and (3) small-diameter myelinated efferent nerves supplying the polar contractile regions of the intrafusal fibers. It is important to understand the relationship of these elements to each other and to the skeletal muscle itself to appreciate the role of this sense organ in signaling changes in the length of the muscle in which it is located. Changes in muscle length are associated with changes in joint angle; thus, muscle spindles provide information on position (i.e., proprioception). The intrafusal fibers are located in parallel to the extrafusal fibers (the regular contractile units of the muscle) with

the ends of the spindle capsule attached to the tendons at either end of the muscle. They do not contribute to the overall contractile force of the muscle, but rather serve a purely sensory function. There are two types of intrafusal fibers in mammalian muscle spindles. The first type contains many nuclei in a dilated central area and is called a nuclear bag fiber (Figure 14–2B). There are two subtypes of nuclear bag fibers, dynamic and static. Typically, there are two or three nuclear bag fibers per spindle. The second intrafusal fiber type, the nuclear chain fiber, is thinner and shorter and lacks a definite bag. Each spindle has about five nuclear chain fibers. There are two kinds of sensory endings in each spindle, a single primary (group Ia) ending and up to eight secondary (group II) endings. The Ia afferent fiber wraps around the center of the dynamic and static nuclear bag fibers and nuclear chain fibers. Group II sensory fibers are located adjacent to the centers of the static nuclear bag and nuclear chain fibers; these fibers do not innervate the dynamic nuclear bag fibers. Ia afferent fibers are very sensitive to the velocity of the change in muscle length during a stretch (dynamic response); thus, they provide information about the speed of movements and allow for quick corrective movements. The steady-state (tonic) activity of group Ia and II afferent fibers provides information on steady-state length of the muscle (static response). The top trace in Figure 14–2C shows the dynamic and static components of activity in a Ia afferent fiber during muscle stretch. Note that they discharge most rapidly while the muscle is being stretched (shaded area of graphs) and less rapidly during sustained stretch. The spindles have their own efferent motor nerve supply called γ-motor neurons. They are small-diameter (3–6 μm) fibers and constitute about 30% of the fibers in the ventral roots. There are two types of γ-motor neurons: dynamic, which supply the dynamic nuclear bag fibers, and static, which supply the static nuclear bag fibers and the nuclear chain fibers. Activation of dynamic γ-motor neurons increases the dynamic sensitivity of the group Ia afferent endings. Activation of the static γ-motor neurons increases the tonic

CHAPTER 14 Spinal Reflexes

A Muscle spindle

B Intrafusal fibers of the muscle spindle

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C Response of Ia sensory fiber to selective activation of motor neurons 200

Static nuclear bag fiber

Imp/s

Dynamic nuclear bag fiber

Dynamic response Steady-state response

Intrafusal muscle fibers

0

Nuclear chain fiber

Stretch alone

200 II Sensory endings

Ia

Imp/s

Capsule

0

Efferent axons

Stimulate static gamma fiber

200

Dynamic

Imp/s

Afferent axons

Static

0 Stretch

Stimulate dynamic gamma fiber Gamma motor endings

6 0 0.2 s

FIGURE 14–2 Mammalian muscle spindle. A) Diagrammatic representation of the main components of mammalian muscle spindle including intrafusal muscle fibers, afferent sensory fiber endings, and efferent motor fibers (γ-motor neurons). B) Three types of intrafusal muscle fibers: dynamic nuclear bag, static nuclear bag, and nuclear chain fibers. A single Ia afferent fiber innervates all three types of fibers to form a primary sensory ending. A group II sensory fiber innervates nuclear chain and static bag fibers to form a secondary sensory ending. Dynamic γ-motor neurons innervate dynamic bag fibers; static γ-motor neurons innervate combinations of chain and static bag fibers. C) Comparison of discharge pattern of Ia afferent activity during stretch alone and during stimulation of static or dynamic γ-motor neurons. Without γ-stimulation, Ia afferent fibers show a small dynamic response to muscle stretch and a modest increase in steady-state firing. When static γ-motor neurons are activated, the steady-state response increases and the dynamic response decreases. When dynamic γ-motor neurons are activated, the dynamic response is markedly increased but the steady-state response gradually returns to its original level. (Reproduced with permission from Kandel ER, Schwartz JH, Jessell TM [editors]: Principles of Neural Science, 4th ed. McGraw-Hill, 2000.)

level of activity in both group Ia and II afferent endings, decreases the dynamic sensitivity of group Ia afferent fibers, and can prevent silencing of Ia afferent fibers during muscle stretch (Figure 14–2C).

CENTRAL CONNECTIONS OF AFFERENT FIBERS Group Ia afferent fibers end directly on α-motor neurons supplying the extrafusal fibers of the same muscle (Figure 14–3). The time between the application of the stimulus and the response is called the reaction time. In humans, the reaction time for a stretch reflex such as the knee jerk is 19–24 milliseconds. Because the conduction velocities of the afferent and efferent fiber types are known and the distance from the muscle to the spinal cord can be measured, it is possible to calculate how much of the reaction time was taken up by conduction to and from the spinal cord. When this value is subtracted from the reaction time, the remainder, called the central delay,

is the time taken for the reflex activity to traverse the spinal cord. In humans, the central delay for the knee jerk is 0.6–0.9 millisecond. Since the minimal synaptic delay is 0.5 millisecond, only one synapse could have been traversed. Muscle spindles also make connections that cause muscle contraction via polysynaptic pathways, and the afferent fibers involved are probably those from the secondary group II endings.

FUNCTION OF MUSCLE SPINDLES When the muscle spindle is stretched, its sensory endings are distorted and receptor potentials are generated. These in turn set up action potentials in the sensory fibers at a frequency proportional to the degree of stretching. Because the spindle is in parallel with the extrafusal fibers, when the muscle is passively stretched, the spindles are also stretched, referred to as “loading the spindle.” This initiates reflex contraction of the extrafusal fibers in the skeletal muscle. On

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SECTION IV CNS/Neural Physiology Spindle

Dorsal root

Tendon

Extrafusal fiber Sensory nerve

Interneuron releasing inhibitory mediator Impulses in sensory nerve

Motor neuron

Ib fiber from Golgi tendon organ

Muscle at rest

I a fiber from muscle spindle

Ventral root

Motor endplate on extrafusal fiber

FIGURE 14–3 Diagram illustrating the pathways responsible for the stretch reflex and the inverse stretch reflex. Stretch stimulates the muscle spindle, which activates Ia afferent fibers that excite the motor neuron. It also stimulates the Golgi tendon organ, which activates Ib afferent fibers that excite an interneuron that releases the inhibitory mediator glycine. With strong stretch, the resulting hyperpolarization of the motor neuron is so great that it stops discharging. (Reproduced with permission from Barrett KE, Barman SM,

Muscle stretched

Muscle contracted

Boitano S, Brooks H: Ganong’s Review of Medical Physiology, 23rd ed. McGraw-Hill Medical, 2009.)

the other hand, the muscle spindle afferent fibers characteristically stop firing when the muscle is made to contract by electrical stimulation of the α-motor neurons to the extrafusal fibers because the muscle shortens while the spindle is unloaded (Figure 14–4). Thus, the spindle and its reflex connections constitute a feedback device that operates to maintain muscle length; if the muscle is stretched, spindle discharge increases and reflex shortening is produced, whereas if the muscle is shortened without a change in γ-motor neuron discharge, spindle afferent activity decreases and the muscle relaxes. When a stretch reflex occurs, the muscles that antagonize the action of the muscle involved (antagonists) relax. This phenomenon is due to reciprocal innervation. Impulses in the Ia afferent fibers from the muscle spindles of the protagonist muscle cause postsynaptic inhibition of the α-motor neurons to the antagonists. The pathway mediating this effect is bisynaptic. A collateral from each Ia afferent fiber passes in the spinal cord to an inhibitory interneuron that synapses on a motor neuron supplying the antagonist muscles.

EFFECTS OF γ-MOTOR NEURON DISCHARGE Stimulation of γ-motor neurons causes the contractile ends of the intrafusal fibers to shorten and therefore stretches the

Increased γ efferent discharge

Increased γ efferent discharge—muscle stretched

FIGURE 14–4 Effect of various conditions on muscle spindle discharge. When the whole muscle is stretched, the muscle spindle is also stretched and its sensory endings are activated at a frequency proportional to the degree of stretching (“loading the spindle”). Spindle afferent fibers stop firing when the muscle contracts (“unloading the spindle”). Stimulation of γ-motor neurons causes the contractile ends of the intrafusal fibers to shorten. This stretches the nuclear bag region, initiating impulses in sensory fibers. If the whole muscle is stretched during stimulation of the γ-motor neurons, the rate of discharge in sensory fibers is further increased. (Reproduced with permission from Barrett KE, Barman SM, Boitano S, Brooks H: Ganong’s Review of Medical Physiology, 23rd ed. McGraw-Hill Medical, 2009.)

CHAPTER 14 Spinal Reflexes nuclear bag portion of the spindles, deforming the endings and initiating impulses in the Ia afferent fibers (Figure 14–4). This can lead to reflex contraction of the muscle. Thus, skeletal muscle can be made to contract via stimulation of the α-motor neurons that innervate the extrafusal fibers or the γ-motor neurons that initiate contraction indirectly via the stretch reflex. Increased γ-motor neuron activity increases spindle sensitivity during stretch. In response to descending excitatory input to spinal motor circuits, both α- and γ-motor neurons are activated. Because of this “α–γ coactivation,” intrafusal and extrafusal fibers shorten together, and spindle afferent activity can occur throughout the period of muscle contraction. In this way, the spindle remains capable of responding to stretch and adjusting reflexly α-motor neuron discharge. Input from various brain regions to the γ-motor neurons influences the sensitivity of the muscle spindles. Thus, the threshold of the stretch reflexes in various parts of the body can be adjusted and shifted to meet the needs of postural control. Anxiety causes an increased γ-motor neuron discharge, which may explain the appearance of hyperactive tendon reflexes in anxious patients. Also, unexpected movement is associated with a greater discharge.

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tory interneurons that in turn terminate directly on the α-motor neurons (Figure 14–3). They also make excitatory connections with α-motor neurons supplying antagonists to the muscle. Unlike the spindles, the Golgi tendon organs are in series with the muscle fibers. Thus, they are stimulated by both passive stretch and active contraction of the muscle. The threshold of the Golgi tendon organs is low. The degree of stimulation by passive stretch is not great because the more elastic muscle fibers take up much of the stretch, and this is why it takes a strong stretch to produce relaxation. However, discharge is regularly produced by contraction of the muscle, and the Golgi tendon organ thus functions as a transducer in a feedback circuit that regulates muscle force in a fashion analogous to the spindle feedback circuit that regulates muscle length. The importance of the primary endings in the spindles and the Golgi tendon organs in regulating the velocity of the muscle contraction, muscle length, and muscle force is illustrated by the fact that that section of the afferent nerves to an arm causes the limb to hang loosely in a semi-paralyzed state. The organization of the system is shown in Figure 14–6.

MUSCLE TONE INVERSE STRETCH REFLEX Up to a point, the harder a muscle is stretched, the stronger is the reflex contraction. However, when the tension becomes great enough, contraction suddenly ceases and the muscle relaxes. This relaxation in response to strong stretch is called the inverse stretch reflex. The receptor for the inverse stretch reflex is in the Golgi tendon organ (Figure 14–5). This organ consists of a netlike collection of knobby nerve endings among the fascicles of a tendon. There are 3–25 muscle fibers per tendon organ. The sensory fibers from the Golgi tendon organs form the Ib group of myelinated, rapidly conducting nerve fibers. Stimulation of these Ib afferent fibers leads to the production of IPSPs on the α-motor neurons that supply the muscle from which the fibers arise. The Ib afferent fibers end in the spinal cord on inhibi-

Nerve fiber

Organ of Golgi, showing ramification of nerve fibrils

FIGURE 14–5

The resistance of a muscle to stretch is often referred to as its tone. If the motor nerve to a skeletal muscle is cut, the muscle offers very little resistance and is said to be flaccid. A hypertonic (spastic) muscle is one in which the resistance to stretch is high because of hyperactive stretch reflexes. Somewhere between the states of flaccidity and spasticity is the ill-defined area of normal tone. The muscles are generally hypotonic when the rate of γ-motor neuron discharge is low and hypertonic when it is high. When the muscles are hypertonic, the sequence of moderate stretch → muscle contraction, and strong stretch → muscle relaxation is seen. Passive flexion of the elbow, for example, meets immediate resistance as a result of the stretch reflex in the triceps muscle. Further stretch activates the inverse stretch reflex. The resistance to flexion suddenly collapses, and the arm flexes. Continued passive flexion stretches the muscle again, and the sequence may be repeated. This sequence of

Tendon bundles

Muscular fibers

Golgi tendon organ. (Reproduced with permission from Gray H [editor]: Gray’s Anatomy of the Human Body, 29th ed. Lea & Febiger, 1973.)

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Interneuronal control signal Interneurons

α

External forces

Internal disturbances

−

α Control signal +

Tendon organs

Force feedback

Efferent signal

Muscle

+

γ-Dynamic control signal γ-Static control signal

Muscular force

+ −

Load

Muscle length

Length and velocity Length and velocity feedback

Spindles

γd

γs

FIGURE 14–6 Block diagram of peripheral motor control system. Non-neural feedback from muscle (“Length and velocity”) that limits length and velocity via the inherent mechanical properties of muscle. γd, dynamic γ-motor neurons; γs, static γ-motor neurons. (Reproduced with permission from Houk J: Medical Physiology, 13th ed. In: Mountcastle VB (editor). Mosby, 1974.)

resistance followed by give when a limb is moved passively is known as the clasp-knife effect because of its resemblance to the closing of a pocket knife. Clonus is the occurrence of regular, repetitive, rhythmic contractions of a muscle subjected to sudden, maintained stretch. Sustained clonus with five or more beats is considered abnormal. During a neurological exam, ankle clonus can be initiated by brisk, maintained dorsiflexion of the foot, and the response is rhythmic plantar flexion at the ankle. Clonus may also occur after disruption of descending cortical input to a spinal glycinergic inhibitory interneuron called the Renshaw cell. This cell receives excitatory input from α-motor neurons via axon collaterals (and in turn the Renshaw cell inhibits the motor neuron). In addition, cortical fibers activating ankle flexors contact Renshaw cells (as well as inhibitory interneurons activated by Ia afferent fibers) that inhibit the antagonistic ankle extensors. This circuitry prevents reflex stimulation of the extensors when flexors are active. Therefore, when the descending cortical fibers are damaged (upper motor neuron lesion), the inhibition of antagonists is absent. The result is repetitive, sequential contraction of ankle flexors and extensors (clonus). Clonus may be seen in patients with amyotrophic lateral sclerosis, stroke, multiple sclerosis, spinal cord damage, and hepatic encephalopathy.

POLYSYNAPTIC REFLEXES: THE WITHDRAWAL REFLEX The withdrawal reflex is a typical polysynaptic reflex that occurs in response to a painful stimulation of the skin or subcutaneous tissues and muscle. The response is flexor muscle contraction and inhibition of extensor muscles, so that the

body part stimulated is flexed and withdrawn from the stimulus. When a strong stimulus is applied to a limb, the response includes not only flexion and withdrawal of that limb, but also extension of the opposite limb. This crossed extensor response is part of the withdrawal reflex. Flexor responses can be produced by innocuous stimulation of the skin or by stretch of the muscle, but strong flexor responses with withdrawal are initiated only by stimuli that are noxious or at least potentially harmful (nociceptive stimuli). Flexion of the stimulated limb gets it away from the source of irritation, and extension of the other limb supports the body. As the strength of a noxious stimulus is increased, the reaction time is shortened. Spatial and temporal facilitation occurs at synapses in the polysynaptic pathway. Stronger stimuli produce more action potentials per second in the active branches and cause more branches to become active; summation of the EPSPs to the firing level therefore occurs more rapidly. Another characteristic of the withdrawal response is the fact that supramaximal stimulation of any of the sensory nerves from a limb never produces as strong a contraction of the flexor muscles as that elicited by direct electrical stimulation of the muscles themselves. This indicates that the afferent inputs fractionate the α-motor neuron pool, that is, each input goes to only part of the motor neuron pool for the flexors of that particular extremity. On the other hand, if all the sensory inputs are dissected out and stimulated one after the other, the sum of the tension developed by stimulation of each is greater than that produced by direct electrical stimulation of the muscle or stimulation of all inputs at once. This indicates that the various afferent inputs share some of the motor neurons and that occlusion occurs when all inputs are stimulated at once.

CHAPTER 14 Spinal Reflexes

SPINAL INTEGRATION The spinal α-motor neurons that supply the extrafusal fibers in skeletal muscles are the efferent side of many reflex arcs. All neural influences affecting muscular contraction ultimately funnel through them to the muscles, and they are therefore called the final common pathway. The surface of the average α-motor neuron and its dendrites accommodates about 10,000 synaptic knobs, allowing for numerous synaptic inputs. At least five inputs go from the same spinal segment to a typical spinal motor neuron. In addition to these, there are excitatory and inhibitory inputs, generally relayed via interneurons, from other levels of the spinal cord and multiple long-descending tracts from the brain. All of these pathways converge on and determine the activity in the final common pathway.

SPINAL CORD INJURY A key component of neurological exams includes an assessment of the integrity of spinal reflexes. Abnormalities in the reflexes often point to the location of a spinal cord injury (SCI). The deficits after SCI vary, of course, depending on the level and severity of the injury. Transection of the spinal cord is followed by a period of spinal shock during which all spinal reflex responses are profoundly depressed. Subsequently, reflex responses return and become hyperactive. In humans, spinal shock usually lasts for a minimum of 2 weeks. Cessation of tonic bombardment of spinal neurons by excitatory impulses in descending pathways undoubtedly plays a role in spinal shock. The recovery of reflex excitability may be due to the development of denervation hypersensitivity to the mediators released by the remaining spinal excitatory endings (see Chapter 12). Another possibility is the sprouting of collaterals from existing neurons, with the formation of additional excitatory endings on interneurons and motor neurons. The first reflex response to appear as spinal shock wears off is often a slight contraction of the leg flexors and adductors in response to a noxious stimulus. In some patients, the kneejerk reflex recovers first. Once the spinal reflexes begin to reappear after spinal shock, their threshold steadily drops.

ties and the right leg, but he was unable to detect the noxious stimuli applied to the left leg. He also lost the sensation of touch and vibration on his right leg but sensation was normal on his left leg and upper limbs. There was little, if any, spontaneous movement in the right leg, although all other limbs appeared to have normal movement. A magnetic resonance image showed that the right side of his spinal cord was severely damaged at the 10th thoracic level. It has been estimated that the worldwide annual incidence of sustaining SCI is between 10 and 83 per million of the population. Leading causes are vehicle accidents, violence, and sports injuries. Approximately 52% of SCI cases result in quadriplegia and about 42% lead to paraplegia. The mean age of patients who sustain an SCI is 33 years old, and males outnumber females nearly 4 to 1. This patient’s injury led to a hemisection of the spinal cord at the 10th thoracic level. Such an injury causes a characteristic clinical picture that reflects damage to ascending sensory (dorsal column pathway, ventrolateral spinothalamic tract) and descending motor (corticospinal tract) pathways, which is called the Brown-Séquard syndrome. The lesion to fasciculus gracilus or fasciculus cuneatus leads to ipsilateral loss of discriminative touch, vibration, and proprioception below the level of lesion. The loss of the spinothalamic tract leads to contralateral loss of pain and temperature sensation beginning one or two segments below the lesion. Damage to the corticospinal tract produces weakness and spasticity in certain muscle groups on the same side of the body. Although a precise spinal hemisection is rare, the syndrome is fairly common because it can be caused by spinal cord tumor, trauma, degenerative disc disease, and ischemia.

CHAPTER SUMMARY ■

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CLINICAL CORRELATION A 21-year-old male medical student was stabbed in the back during a robbery attempt. A bystander called 911 and, when the paramedics arrived, the student could not move his right leg. He was rushed to the emergency room of the local hospital. In addition to examination and treatment of the injury site, he was given a neurological exam. The muscle spindle reflex was normal in both arms and the left leg but was hyperactive in the right leg. He had normal sensation to pinprick and pinch in upper extremi-

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A reflex arc consists of a sense organ, an afferent neuron, one or more synapses within a central integrating station, an efferent neuron, and an effector response. A muscle spindle is a group of specialized intrafusal muscle fibers with contractile polar ends and a noncontractile center that is located in parallel to the extrafusal muscle fibers and is innervated by types Ia and II afferent fibers and γ-motor neurons. Muscle stretch activates the muscle spindle to initiate reflex contraction of the extrafusal muscle fibers in the same muscle (stretch reflex). A Golgi tendon organ is a netlike collection of knobby nerve endings among the fascicles of a tendon that is located in series with extrafusal muscle fibers and innervated by type Ib afferent fibers. They are stimulated by both passive stretch and active contraction of the muscle to relax the muscle (inverse stretch reflex) and function as a transducer to regulate muscle force. A collateral from an Ia afferent branches to terminate on an inhibitory interneuron that synapses on an antagonistic muscle

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SECTION IV CNS/Neural Physiology (reciprocal innervation) to relax that muscle when the agonist contracts. Clonus is the occurrence of regular, rhythmic contractions of a muscle subjected to sudden, maintained stretch. Spinal cord transection is followed by a period of spinal shock during which all reflexes are profoundly depressed. This is followed by a period of hyperactive reflexes.

STUDY QUESTIONS 1. The inverse stretch reflex A) has a lower threshold than that of the stretch reflex. B) is a monosynaptic reflex. C) is a relaxation of a muscle in response to a strong stretch of the muscle. D) has the muscle spindle as its receptor. E) requires the discharge of central neurons that release acetylcholine. 2. When γ-motor neuron discharge increases at the same time as α-motor neuron discharge to muscle A) prompt inhibition of discharge in spindle Ia afferent fibers takes place. B) contraction of the muscle is prolonged. C) the muscle will not contract. D) the muscle will not relax. E) the number of impulses in spindle Ia afferent fibers is greater than when α discharge alone is increased.

3. Which of the following is not characteristic of a reflex? A) modification by impulses from various parts of the CNS B) may involve simultaneous contraction of some muscles and relaxation of others C) chronically suppressed after spinal cord transection D) always involves transmission across at least one synapse E) frequently occurs without conscious perception 4. Withdrawal reflexes are not A) initiated by nociceptive stimuli. B) an example of a polysynaptic reflex. C) prolonged if the stimulus is strong. D) an example of a flexor reflex. E) accompanied by the same response on both sides of the body.

15 C

Special Senses I: Vision Susan M. Barman

H A

P

T

E

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O B J E C T I V E S ■ ■ ■ ■ ■ ■

Describe the various parts of the eye and list the functions of each. Explain how light rays in the environment are brought to a focus on the retina and the role of accommodation in this process. Define the following terms: hyperopia, myopia, astigmatism, presbyopia, and strabismus. Describe the electrical responses produced by rods and cones and explain how these responses are produced. Trace the neural pathways that transmit visual information from the rods and cones to the visual cortex. Name the four types of eye movements and the function of each.

INTRODUCTION The eyes are complex sense organs. Within its protective casing, each eye has a layer of receptors, a lens system that focuses light on these receptors, and a system of nerves that conducts impulses from the receptors to the brain. The way these components operate to set up conscious visual images is the subject of this chapter.

ANATOMY OF THE EYE The principal structures of the eye are shown in Figure 15–1. The outer protective layer of the eyeball, the sclera, is modified anteriorly to form the transparent cornea, through which light rays enter the eye. Inside the sclera is the choroid, a layer that contains many of the blood vessels that nourish the structures in the eyeball. Lining the posterior two thirds of the choroid is the retina, the neural tissue containing the receptor cells. The crystalline lens is a transparent structure held in place by a circular lens suspensary ligament (zonule) that is attached to the thickened anterior part of the choroid, the ciliary body. The ciliary body contains circular and longitudinal muscle fibers that attach near the corneoscleral

Ch15_133-146.indd 133

junction. In front of the lens is the pigmented and opaque iris, the colored portion of the eye, which contains circular muscle fibers that constrict and radial fibers that dilate the pupil. Variations in the diameter of the pupil can produce up to a 5-fold change in the amount of light reaching the retina. The space between the lens and the retina is filled primarily with a clear gelatinous material called the vitreous humor. Aqueous humor, a clear liquid that nourishes the cornea and lens, is produced in the ciliary body by diffusion and active transport from plasma. It flows through the pupil and fills the anterior chamber of the eye. It is normally reabsorbed through the canal of Schlemm, a venous channel at the junction between the iris and the cornea (anterior chamber angle). Obstruction of this outlet leads to increased intraocular pressure. One cause of increased pressure is decreased permeability through the trabecular meshwork, the tissue around the base of the cornea that drains the aqueous humor from the eye (open-angle glaucoma), and another is forward movement of the iris, obliterating the angle (angle-closure glaucoma). Glaucoma can be treated with β-adrenergic blocking drugs or carbonic anhydrase inhibitors, both of which decrease the production of aqueous humor, or with cholinergic agonists, which increase aqueous outflow.

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Superior rectus muscle

Sclera Choroid

Conjunctiva Ciliary body

Fovea centralis

Posterior chamber Anterior chamber

Central artery

Cornea

Retina

Anterior cavity

Pupil

Central vein

Lens Iris Posterior chamber Optic nerve

Zonular fibers of suspensory ligament Vitreous chamber (posterior cavity) Inferior rectus muscle

FIGURE 15–1

The internal anatomy of the eye. (Reproduced with permission from Fox SI: Human Physiology. McGraw-Hill, 2008.)

The eye is well protected from injury by the bony walls of the orbit. The cornea is moistened and kept clear by tears that course from the lacrimal gland in the upper portion of each orbit across the surface of the eye to empty via the lacrimal duct into the nose. Blinking helps keep the cornea moist.

RETINA The retina extends anteriorly almost to the ciliary body. It is organized into 10 layers and contains rods and cones, which are the visual receptors, plus four types of neurons: bipolar cells, ganglion cells, horizontal cells, and amacrine cells (Figure 15–2). Rods and cones, which are next to the choroid, synapse with bipolar cells, and bipolar cells synapse with ganglion cells. The axons of ganglion cells converge and leave the eye as the optic nerve. Horizontal cells connect receptor cells to the other receptor cells in the outer plexiform layer. Amacrine cells connect ganglion cells to one another in the inner plexiform layer via processes of varying length and patterns. Gap junctions also connect retinal neurons to one another. The receptor layer of the retina rests on the pigment epithelium next to the choroid, so light rays must pass through the ganglion cell and bipolar cell layers to reach the rods and cones. The pigment epithelium absorbs light rays, preventing the reflection of rays back through the retina. Such reflection would produce blurring of the visual images. The optic nerve leaves the eye and the retinal blood vessels enter it at a point 3 mm medial to and slightly above the pos-

terior pole of the globe. This region is visible through the ophthalmoscope as the optic disk. There are no visual receptors over the disk, and consequently it is a blind spot. Near the posterior pole of the eye is a yellowish pigmented spot, the macula lutea. This marks the location of the fovea centralis, a thinned-out, rod-free portion of the retina. In it, the cones are densely packed, and each synapses to a single bipolar cell, which, in turn, synapses on a single ganglion cell, providing a direct pathway to the brain. There are very few overlying cells and no blood vessels; thus, the fovea is the point where visual acuity is greatest. When attention is attracted to or fixed on an object, the eyes are normally moved so that light rays coming from the object fall on the fovea.

VISUAL RECEPTORS IN THE RETINA Rods are responsible for vision in low light (night vision) and provide only black and white vision. Cones are responsible for color vision. Each rod and cone is divided into an outer segment, an inner segment that includes a nuclear region, and a synaptic zone (Figure 15–3). The outer segments are modified cilia and are made up of regular stacks of flattened saccules or disks composed of membrane. These saccules and disks contain the photosensitive compounds that react to light, initiating action potentials in the visual pathways. The inner segments are rich in mitochondria. The rods are named for the thin, rodlike appearance of their outer segments. Cones generally have thick inner segments and conical outer segments, although their morphology varies from place to place in the retina. In cones, the saccules

CHAPTER 15 Special Senses I: Vision

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Pigment epithelium Rod and cone Outer segments

Inner segments

Outer nuclear layer

C

C

C

R

R

R

C

R

R

Outer plexiform layer

H Inner nuclear layer

MB

FB FB

RB

MB

RB A

A

Inner plexiform layer

Ganglion cell layer

MG

DG

MG DG

Optic nerve fibers

FIGURE 15–2 Neural components of the extrafoveal portion of the retina. Direction of light is from the bottom to the top of the figure. C, cone; R, rod; MB, RB, and FB, midget, rod, and flat bipolar cells; DG and MG, diffuse and midget ganglion cells; H, horizontal cells; A, amacrine cells. (Modified with permission from Dowling JE, Boycott BB: Organization of the primate retina: electron microscopy. Proc R Soc Lond B 1966;166:80–111.)

are formed in the outer segments by infoldings of the cell membrane, but in rods the disks are separated from the cell membrane. In the extrafoveal portions of the retina, rods predominate (Figure 15–4), and there is a good deal of convergence. Flat bipolar cells (Figure 15–2) make synaptic contact with several cones, and rod bipolar cells make synaptic contact with several rods. Because there are approximately 6 million cones and 120 million rods in each human eye but only 1.2 million nerve fibers in each optic nerve, the overall convergence of receptors through bipolar cells on ganglion cells is about 105:1. However, there is divergence from this point on. There are twice as many fibers in the geniculocalcarine tracts as in the optic nerves, and

in the visual cortex, the number of neurons concerned with vision is 1,000 times the number of fibers in the optic nerves.

THE IMAGE-FORMING MECHANISM The eyes convert energy in the visible spectrum into action potentials in the optic nerve. The images of objects in the environment are focused on the retina. The light rays striking the retina generate potentials in the rods and cones. Impulses initiated in the retina are conducted to the cerebral cortex, where they produce the sensation of vision.

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Rod

Cone Plasma membrane

30 nm Disks

Outer segment Sacs

at the anterior surface of the cornea (Figure 15–5). The retinal image is inverted. The connections of the retinal receptors are such that from birth any inverted image on the retina is viewed right side up and projected to the visual field on the side opposite to the retinal area stimulated. This perception is present in infants and is innate.

Ciliary neck Mitochondria

Inner segment

Nucleus Synaptic terminal

FIGURE 15–3 Schematic diagram of a rod and a cone. Each rod and cone is divided into an outer segment, an inner segment with a nuclear region, and a synaptic zone. The saccules and disks in the outer segment contain photosensitive compounds that react to light to initiate action potentials in the visual pathways. (Reproduced with permission from Lamb TD: Electrical responses of photoreceptors. In: Recent Advances in Physiology, No.10. Baker PF [editor]. Churchill Livingstone, 1984.)

Light rays are bent when they pass from a medium of one density into a medium of a different density, except when they strike perpendicular to the interface (Figure 15–5). The bending of light rays is called refraction and is the mechanism that allows one to focus an accurate image onto the retina. Parallel light rays striking a biconvex lens are refracted to a point behind the lens. In the eye, light is actually refracted at the anterior surface of the cornea and at the anterior and posterior surfaces of the lens. The process of refraction can be represented diagrammatically by drawing the rays of light as if all refraction occurs

COMMON DEFECTS OF THE IMAGE-FORMING MECHANISM In some individuals, the eyeball is shorter than normal and the parallel rays of light are brought to a focus behind the retina. This abnormality is called hyperopia or farsightedness (Figure 15–6). Sustained accommodation (focusing due to contraction of the ciliary muscle), even when viewing distant objects, can partially compensate for the defect, but the prolonged muscular effort is tiring and may cause headaches and blurring of vision. The defect can be corrected by using glasses with convex lenses, which aid the refractive power of the eye in shortening the focal distance. In myopia (nearsightedness), the anteroposterior diameter of the eyeball is too long (Figure 15–6). The shape of the eye appears to be determined in part by the refraction presented to it. In young adult humans, the extensive close work involved in activities such as studying accelerates the development of myopia. This defect can be corrected by glasses with biconcave lenses, which make parallel light rays diverge slightly before they strike the eye. Astigmatism is a common condition in which the curvature of the cornea is not uniform (Figure 15–6). When the curvature in one meridian is different from that in others, light rays in that meridian are refracted to a different focus, so that part of the retinal image is blurred. Astigmatism can usually be

Cones Rods

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400 0 100°

80° 60° 40° 20° 0° Nasal retina Fovea Distance from the fovea

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FIGURE 15–4 Rod and cone density along the horizontal meridian through the human retina. A plot of the relative acuity of vision in the various parts of the light-adapted eye would parallel the cone density curve; a similar plot of relative acuity of the dark-adapted eye would parallel the rod density curve. (Reproduced with permission from Barrett KE, Barman SM, Boitano S, Brooks H: Ganong’s Review of Medical Physiology, 23rd ed. McGraw-Hill Medical, 2009.)

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(a) Glass

Air

Refraction Point source of light No refraction

Refraction

(b)

b'

a

a'

b

FIGURE 15–5 Focusing point sources of light. a) When diverging light rays enter a dense medium at an angle to its convex surface, refraction bends them inward. b) Refraction of light by the lens system. For simplicity, refraction is shown only at the corneal surface (site of greatest refraction) although it also occurs in the lens and elsewhere. Incoming light from a (above) and b (below) is bent in opposite directions, resulting in b′ being above a′ on the retina. (Reproduced with permission from Widmaier EP, Raff H, Strang KT: Vander’s Human Physiology, 11th ed. McGraw-Hill, 2008.)

corrected with cylindrical lenses placed in such a way that they equalize the refraction in all meridians. Strabismus is a misalignment of the eyes usually due to problems with eye muscles and one of the most common eye problems in children, affecting about 4% of children under 6 years of age. It is characterized by one or both eyes turning inward (crossed-eyes), outward (wall eyes), upward, or downward. Strabismus is also commonly called “wandering eye” or “crossed-eyes.” It occurs when visual images do not fall on corresponding retinal points. When visual images chronically fall on noncorresponding points in the two retinas in young children, one is eventually suppressed (suppression scotoma).

ACCOMMODATION When the ciliary muscle is relaxed, parallel light rays striking the optically normal (emmetropic) eye are brought to a focus on the retina. As long as this relaxation is maintained, rays from objects closer than 6 m from the observer are brought to a focus behind the retina, and consequently the objects appear blurred.

The problem of bringing diverging rays from close objects to a focus on the retina can be solved by increasing the curvature of the lens, a process called accommodation. At rest, the lens is held under tension by the lens ligaments and is pulled into a flattened shape. The ciliary muscle contracts when the gaze is directed at a near object. This decreases the distance between the edges of the ciliary body and relaxes the lens ligaments, so that the lens springs into a more convex shape (Figure 15–7). The degree to which the lens curvature can be increased is limited, and light rays from an object very near the individual cannot be brought to a focus on the retina, even with the greatest of effort. The nearest point to the eye at which an object can be brought into clear focus by accommodation is called the near point of vision. Due to increasing hardness of the lens, the near point recedes throughout life, slowly at first and then rapidly with advancing age, from 9 cm at age 10 to 83 cm at age 60. By the time a healthy individual reaches age 40–45, the loss of accommodation is usually sufficient to make reading and close work difficult. This condition, which is known as presbyopia, can be corrected by wearing glasses with convex lenses.

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(a) Normal sight (faraway object is clear)

Nearsighted (eyeball too long)

Nearsightedness corrected

(b)

FIGURE 15–7 Accommodation. Solid lines represent the shape of the lens, iris, and ciliary body at rest; dashed lines represent the shape during accommodation. Ciliary muscles contract when gaze is directed at a near object, which decreases the distance between the edges of the ciliary body and relaxes the lens ligaments, and the lens becomes more convex. (Reproduced with permission from Barrett KE, Barman SM, Boitano S, Brooks H: Ganong’s Review of Medical Physiology, 23rd ed. McGraw-Hill Medical, 2009.)

Normal sight (near object is clear)

Farsighted (eyeball too short)

Farsightedness corrected

segment maintains ionic equilibrium. Release of synaptic transmitter is steady in the dark. When light strikes the outer segment, the reactions that are initiated close some of the Na+ channels, and the result is a hyperpolarizing receptor potential. The hyperpolarization reduces the release of synaptic transmitter, and this generates a signal in the bipolar cells that ultimately leads to action potentials in ganglion cells. The action potentials are transmitted to the brain.

FIGURE 15–6 Common defects of the optic system of the eye. a and b) In hyperopia (farsightedness), the eyeball is too short and light rays come to a focus behind the retina. A biconvex lens corrects this by adding to the refractive power of the lens of the eye. In myopia (nearsightedness), the eyeball is too long and light rays focus in front of the retina. Placing a biconcave lens in front of the eye causes the light rays to diverge slightly before striking the eye, so that they are brought to a focus on the retina. (Reproduced with permission from Widmaier

Na+

EP, Raff H, Strang KT: Vander’s Human Physiology, 11th ed. McGraw-Hill, 2008.)

K+

THE PHOTORECEPTOR MECHANISM IONIC BASIS OF PHOTORECEPTOR POTENTIALS Na+ channels in the outer segments of the rods and cones are open in the dark, so current flows from the inner to the outer segment (Figure 15–8). Current also flows to the synaptic ending of the photoreceptor. The Na+, K+-ATPase in the inner

K+

Na+ Dark

Na+ Light

FIGURE 15–8 Effect of light on current flow in visual receptors. In the dark, Na+ channels in the outer segment are held open by cGMP. Light leads to increased conversion of cGMP to 5′-GMP, and some of the channels close. This produces hyperpolarization of the synaptic terminal of the photoreceptor. (Reproduced with permission from Barrett KE, Barman SM, Boitano S, Brooks H: Ganong’s Review of Medical Physiology, 23rd ed. McGraw-Hill Medical, 2009.)

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Incident light Structural change in the retinene1 of photopigment Conformational change of photopigment

Outer segment membrane

Rhodopsin

Decreased intracellular cGMP

Closure of

Na+

channels

Hyperpolarization

Transducin

cGMP phosphodiesterase

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GTP

Activation of transducin Activation of phosphodiesterase

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5'-GMP

cGMP Na+

Light cGMP-gated channel

ECF

Rod outer segment

FIGURE 15–10 Initial steps in phototransduction in rods. Light activates rhodopsin, which activates transducin to bind GTP. This activates phosphodiesterase, which catalyzes the conversion of cGMP to 5′-GMP. The resulting decrease in the cytoplasmic cGMP concentration causes cGMP-gated ion channels to close. (Reproduced with permission from Barrett KE, Barman SM, Boitano S, Brooks H: Ganong’s Review of Medical Physiology, 23rd ed. McGraw-Hill Medical, 2009.)

Decreased release of synaptic transmitter Response in bipolar cells and other neural elements

FIGURE 15–9 Sequence of events involved in phototransduction in rods and cones. (Reproduced with permission from Barrett KE, Barman SM, Boitano S, Brooks H: Ganong’s Review of Medical Physiology, 23rd ed. McGraw-Hill Medical, 2009.)

PHOTOSENSITIVE COMPOUNDS The photosensitive compounds in the rods and cones of the eyes are made up of a protein called an opsin and retinal, the aldehyde of vitamin A. The photosensitive pigment in the rods is called rhodopsin, one of the many receptors coupled to G proteins. Its opsin is called scotopsin. Rhodopsin has a peak sensitivity to light at a wavelength of 505 nm. Figure 15–9 summarizes the sequence of events in photoreceptors by which incident light produces a signal in the next succeeding neural unit in the retina. Light activates rhodopsin that then activates the associated heterotrimeric G protein, transducin (Figure 15–10). The G protein exchanges GDP for GTP, and the α-subunit separates. This subunit remains active until its intrinsic GTPase activity hydrolyzes the GTP. The α-subunit activates cGMP phosphodiesterase, which converts cGMP to 5′-GMP. cGMP normally acts directly on Na+ channels to maintain them in the open position, so the decline in the cytoplasmic cGMP concentration causes some Na+ channels to close. This produces the hyperpolarizing potential. This cascade of reactions occurs very rapidly and amplifies the light signal. The amplification helps explain the remarkable sensitivity of rod photoreceptors; these receptors are capable of producing a detectable response to as little as one photon of light.

Cone receptors subserve color vision and respond maximally to light at wavelengths of 440, 535, and 565 nm. The cone opsin resembles rhodopsin. The cell membrane of cones is invaginated to form the saccules, but the cones have no separate intracellular disks like those in rods. The details of the responses of cones to light are similar to those in rods.

PROCESSING OF VISUAL INFORMATION IN THE RETINA A characteristic of the bipolar and ganglion cells is that they respond best to a small, circular stimulus and that, within their receptive field, an annulus of light around the center (surround illumination) inhibits the response to the central spot (Figure 15–11). The center can be excitatory with an inhibitory surround (an “on-center” cell) or inhibitory with an excitatory surround (an “off-center” cell). The inhibition of the center response by the surround is probably due to inhibitory feedback from one photoreceptor to another mediated via horizontal cells. The inhibition of the response to central illumination by an increase in surrounding illumination is an example of lateral inhibition in which activation of a particular neural unit is associated with inhibition of the activity of nearby units. It is a general phenomenon in sensory systems and helps to sharpen the edges of a stimulus and improve discrimination.

VISUAL PATHWAYS The axons of the retinal ganglion cells pass caudally in the optic nerve and optic tract to end in the lateral geniculate body in the thalamus (Figure 15–12). The fibers from each

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On-center field

Off-center field

Light

Light

Central illumination

Surround illumination

FIGURE 15–11 Responses of retinal ganglion cells to light on the portions of their receptive fields indicated in white. Beside each receptive field diagram is a diagram of the ganglion cell response, indicated by extracellularly recorded action potentials. Note that in three of the four situations, there is increased discharge when the light is turned off. (Adapted with permission from Kuffler SW: Discharge patterns and functional organizations of mammalian retina, J Neurophysiol. 1953;16(1):37–68.)

Temporal field

Nasal field

LEFT

RIGHT A

LEFT EYE

RIGHT EYE

B Ganglion cell

B A

C

Optic nerve Optic chiasm

Pretectal region

Optic tract

C

D

Lateral geniculate body Geniculocalcarine tract D

Occipital cortex

FIGURE 15–12 Visual pathways. Transection of the pathways at the locations indicated by the letters causes the visual field defects shown in the diagrams on the right. The fibers from the nasal half of each retina decussate in the optic chiasm, so fibers in the optic tracts are those from the temporal half of one retina and the nasal half of the other. A lesion that interrupts one optic nerve causes blindness in that eye (A). A lesion in one optic tract causes blindness in half of the visual field (C) and is called homonymous (same side of both visual fields) hemianopia (half-blindness). Lesions affecting the optic chiasm destroy fibers from both nasal hemiretinas and produce a heteronymous (opposite sides of the visual fields) hemianopia (B). Occipital lesions may spare the fibers from the macula (as in D) because of the separation in the brain of these fibers from the others subserving vision (see Figure 15–13). (Reproduced with permission from Barrett KE, Barman SM, Boitano S, Brooks H: Ganong’s Review of Medical Physiology, 23rd ed. McGraw-Hill Medical, 2009.)

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Upper peripheral quadrant of retina Upper quadrant of macula Lower quadrant of macula Lower peripheral quadrant of retina

FIGURE 15–13 Medial view of the human right cerebral hemisphere showing projection of the retina on the primary visual cortex (Brodmann’s area 17; also known as V1) in the occipital cortex around the calcarine fissure. The geniculocalcarine fibers from the medial half of the lateral geniculate terminate on the superior lip of the calcarine fissure, and those from the lateral half terminate on the inferior lip. The fibers from the lateral geniculate body that relay macular vision separate from those that relay peripheral vision and end more posteriorly on the lips of the calcarine fissure. (Reproduced with permission from Barrett KE, Barman SM, Boitano S, Brooks H: Ganong’s Review of Medical Physiology, 23rd ed. McGraw-Hill Medical, 2009.)

nasal hemiretina decussate in the optic chiasm. In the geniculate body, the fibers from the nasal half of one retina and the temporal half of the other synapse on the cells whose axons form the geniculocalcarine tract. This tract passes to the occipital lobe of the cerebral cortex. The effects of lesions in these pathways on visual function are discussed below. The primary visual receiving area (primary visual cortex, Brodmann’s area 17; also known as V1) is located principally on the sides of the calcarine fissure (Figure 15–13). The organization of the primary visual cortex is discussed below. The axons of retinal ganglion cells project a detailed spatial representation of the retina on the lateral geniculate body. Each geniculate body contains six well-defined layers (Figure 15–14). Layers 3–6 have small parvocellular cells, and layers 1 and 2 have large magnocellular cells. On each side, layers 1, 4, and 6 receive input from the contralateral eye; layers 2, 3, and 5 receive input from the ipsilateral eye. In each layer, there is a precise point-for-point representation of the retina, and all six layers are in register so that along a line perpendicular to the layers, the receptive fields of the cells in each layer are almost identical. Only 10–20% of the input to the lateral geniculate nucleus comes from the retina; major inputs also come from the visual cortex and other brain regions. The feedback pathway from the visual cortex is involved in visual processing related to the perception of orientation and motion. There are two kinds of retinal ganglion cells: large magno or M cells, which are concerned with movement and stereopsis, and small parvo or P cells, which are concerned with color, texture, and shape. The M and P ganglion cells project to the magnocellular and parvocellular portions of the lateral geniculate, respectively. From the lateral geniculate nucleus, a magnocellular pathway and a parvocellular pathway project to the visual cortex. The magnocellular pathway, from layers 1 and 2,

Optic nerves Optic chiasm

Lateral geniculate nucleus C Dorsal I

Optic tracts

C I I C 5 Ventral 1 2 Magnocellular pathway

3

6

4 Parvocellular pathway

Primary visual cortex (area 17)

FIGURE 15–14 Ganglion cell projections from the right hemiretina of each eye to the right lateral geniculate body and from this nucleus to the right primary visual cortex. Note the six layers of the geniculate. P ganglion cells project to layers 3–6, and M ganglion cells project to layers 1 and 2. The ipsilateral (I) and contralateral (C) eyes project to alternate layers. Not shown are the interlaminar area cells, which project via a separate component of the P pathway to blobs in the visual cortex. (Modified with permission from Kandel ER, Schwartz JH, Jessell TM [editors]: Principles of Neural Science, 4th ed. McGraw-Hill, 2000.)

carries signals for detection of movement, depth, and flicker. The parvocellular pathway, from layers 3–6, carries signals for color vision, texture, shape, and fine detail. Cells in the interlaminar region of the lateral geniculate nucleus also receive input from P ganglion cells, probably via dendrites of interlaminar cells that penetrate the parvocellular layers. They project via a separate component of the P pathway to the “blobs” in the visual cortex. These are clusters of cells about 0.2 mm in diameter that, unlike the neighboring cells, contain a high concentration of the mitochondrial enzyme cytochrome oxidase.

PRIMARY VISUAL CORTEX The lateral geniculate body projects a point-for-point representation on the primary visual cortex (Figure 15–13). Like the rest of the neocortex, the visual cortex has six layers. The axons from the lateral geniculate nucleus that form the magnocellular pathway end in layer 4. Many of the axons that form the parvocellular pathway also end in layer 4; however, the axons from the interlaminar region end in layers 2 and 3.

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Layers 2 and 3 of the cortex contain blobs. They are arranged in a mosaic in the visual cortex and are concerned with color vision. However, the parvocellular pathway also carries coloropponent data to the deep part of layer 4. Like the ganglion cells, the lateral geniculate neurons and the neurons in layer 4 of the visual cortex respond to stimuli in their receptive fields with on-centers and inhibitory surrounds or off-centers and excitatory surrounds. A bar of light covering the center is an effective stimulus for them because it stimulates the entire center and relatively little of the surround. However, the bar has no preferred orientation and, as a stimulus, is equally effective at any angle. The responses of the neurons in other layers of the visual cortex are strikingly different. Simple cells respond to bars of light, lines, or edges, but only when they have a particular orientation. When a bar of light is rotated as little as 10° from the preferred orientation, the firing rate of the simple cell is usually decreased, and if the stimulus is rotated much more, the response disappears. Complex cells, which resemble simple cells in requiring a preferred orientation of a linear stimulus, are less dependent on the location of a stimulus in the visual field than the simple cells and the cells in layer 4. They often respond maximally when a linear stimulus is moved laterally without a change in its orientation. They may receive input from the simple cells. The visual cortex is arranged in vertical columns that are concerned with orientation (orientation columns). Each is about 1 mm in diameter. However, the orientation preferences of neighboring columns differ in a systematic way; as one moves from column to column across the cortex, sequential changes occur in orientation preference of 5°–10°. Thus, it seems likely that for each ganglion cell receptive field in the visual field, there is a collection of columns in a small area of visual cortex representing the possible preferred orientations at small intervals throughout the full 360°. The simple and complex cells have been called feature detectors because they respond to and analyze certain features of the stimulus. Another feature of the visual cortex is the presence of ocular dominance columns. The geniculate cells and the cells in layer 4 receive input from only one eye, and the layer 4 cells alternate with cells receiving input from the other eye. About half the simple and complex cells receive an input from both eyes. The inputs are identical or nearly so in terms of the portion of the visual field involved and the preferred orientation. However, they differ in strength, so that between the cells to which the input comes totally from the ipsilateral or the contralateral eye, there is a spectrum of cells influenced to different degrees by both eyes.

EFFECT OF LESIONS IN THE OPTIC PATHWAYS Lesions along the neural pathways from the eyes to the brain can be localized with a high degree of accuracy by the effects they produce in the visual fields (Figure 15–12). The fibers from the nasal half of each retina decussate in the optic chiasm,

so that the fibers in the optic tracts are those from the temporal half of one retina and the nasal half of the other. Since each optic tract subserves half of the field of vision, a lesion of one optic nerve causes blindness in that eye, but a lesion in one optic tract causes blindness in half of the visual field. This defect is classified as a homonymous (same side of both visual fields) hemianopia (half-blindness). Lesions affecting the optic chiasm (e.g., pituitary tumors) cause disruption of the fibers from both nasal hemiretinas and produce a heteronymous (opposite sides of the visual fields) hemianopia. Because the fibers from the maculas are located posteriorly in the optic chiasm, hemianopic scotomas develop before vision in the two hemiretinas is completely lost. Selective visual field defects are further classified as bitemporal, binasal, and right or left. The optic nerve fibers from the upper retinal quadrants subserving vision in the lower half of the visual field terminate in the medial half of the lateral geniculate body, whereas the fibers from the lower retinal quadrants terminate in the lateral half. The geniculocalcarine fibers from the medial half of the lateral geniculate terminate on the superior lip of the calcarine fissure, and those from the lateral half terminate on the inferior lip. The fibers from the lateral geniculate body that subserve macular vision separate from those that subserve peripheral vision and end more posteriorly on the lips of the calcarine fissure (Figure 15–13). Because of this anatomic arrangement, occipital lobe lesions may produce discrete quadrantic visual field defects (upper and lower quadrants of each half visual field). Macular sparing (i.e., loss of peripheral vision with intact macular vision) is also common with occipital lesions (Figure 15–12) because the macular representation is separate from that of the peripheral fields and very large relative to that of the peripheral fields. Therefore, occipital lesions must extend considerable distances to destroy macular as well as peripheral vision. Bilateral destruction of the occipital cortex in humans causes subjective blindness.

COLOR VISION Colors have three attributes: hue, intensity, and saturation (degree of freedom from dilution with white). For any color there is a complementary color that, when properly mixed with it, produces a sensation of white. Black is the sensation produced by the absence of light, but it is probably a positive sensation because the blind eye does not “see black;” rather, it “sees nothing.” The sensation of white, any spectral color, and even the extraspectral color, purple, can be produced by mixing various proportions of red light (wavelength 723–647 nm), green light (575–492 nm), and blue light (492–450 nm). Red, green, and blue are therefore called the primary colors. Also, the color perceived depends in part on the color of other objects in the visual field. Thus, for example, a red object is seen as red if the field is illuminated with green or blue light, but as pale pink or white if the field is illuminated with red light. Color is mediated by ganglion cells that subtract or add input from one type of cone to input from another type. Processing in

CHAPTER 15 Special Senses I: Vision the ganglion cells and the lateral geniculate nucleus produces impulses that pass along three types of neural pathways that project to V1: a red-green pathway that signals differences between L- and M-cone responses, a blue-yellow pathway that signals differences between S-cone and the sum of L- and M-cone responses, and a luminance pathway that signals the sum of L- and M-cone responses. These pathways project to the blobs and the deep portion of layer 4 of V1. From the blobs and layer 4, color information is projected to V8. However, it is not known how V8 converts color input into the sensation of color. Color blindness is most often an inherited condition in which individuals are unable to distinguish certain colors. The most common type is a red-green color vision deficit, a genetically sex-linked condition that occurs in about 8% of males and 0.4% of females. Blue-yellow color vision deficits are less common and show no gender selectivity. Color blindness is usually due to an inherited absence of cones for specific colors. It can also occur in individuals with lesions of area V8 of the visual cortex.

PUPILLARY LIGHT REFLEX When light is directed into one eye, the pupil constricts (pupillary light reflex). The optic nerve fibers that carry the impulses initiating these pupillary responses leave the optic nerves near the lateral geniculate bodies. On each side, they enter the midbrain via the brachium of the superior colliculus and terminate in the pretectal nucleus. From this nucleus, the

second-order neurons project to the ipsilateral and contralateral Edinger–Westphal nucleus. The third-order neurons pass from this nucleus to the ciliary ganglion in the oculomotor nerve, and the fourth-order neurons pass from this ganglion to the ciliary body.

EYE MOVEMENTS The eye is moved within the orbit by six ocular muscles (Figure 15–15). These are innervated by the oculomotor, trochlear, and abducens (cranial) nerves. Because the oblique muscles pull medially, their actions vary with the position of the eye. When the eye is turned nasally, the inferior oblique elevates it and the superior oblique depresses it. When it is turned laterally, the superior rectus elevates it and the inferior rectus depresses it. Because much of the visual field is binocular, a very high order of coordination of the movements of the two eyes is necessary if visual images are to fall at all times on corresponding points in the two retinas and diplopia (double vision) is to be avoided. There are four types of eye movements, each controlled by a different neural system but sharing the same final common path, the motor neurons that supply the external ocular muscles. Saccades, sudden jerky movements, occur as the gaze shifts from one object to another. They bring new objects of interest onto the fovea and reduce adaptation in the visual

FIGURE 15–15 Extraocular muscles subserving six cardinal positions of gaze. The eye is adducted by the medial rectus and abducted by the lateral rectus. The adducted eye is elevated by the inferior oblique and depressed by the superior oblique; the abducted eye is elevated by the superior rectus and depressed by the inferior rectus. (Reproduced with permission from Squire LR, et al [editors]: Fundamental Neuroscience, 3rd ed. Academic Press, 2008.)

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pathway that would occur if gaze were fixed on a single object for long periods. Smooth pursuit movements are tracking movements of the eyes as they follow moving objects. Vestibular movements, adjustments that occur in response to stimuli initiated in the semicircular canals, maintain visual fixation as the head moves. Convergence movements bring the visual axes toward each other as attention is focused on objects near the observer. The similarity to a human-made tracking system on an unstable platform such as a ship is apparent: saccadic movements seek out visual targets, pursuit movements follow them as they move about, and vestibular movements stabilize the tracking device as the platform on which the device is mounted (i.e., the head) moves about. Saccades are programmed in the frontal cortex and the superior colliculi and pursuit movements in the cerebellum.

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CLINICAL CORRELATION A 33-year-old salesman was driving his car in a rural area and did not notice the bicyclist riding on the sidewalk to the right of his car. He made a right-hand turn at the corner and accidentally hit the young woman. Luckily she was not hurt, but he recalled that a few days ago as he was walking along a sidewalk, he did not notice a dog approaching him from the left. He was now aware that he has reduced peripheral vision. He made an appointment with an ophthalmologist for a visual field exam. The results showed that he had reduced vision on the temporal half of the visual field of both eyes. When asked whether he had noticed an increase incidence of headaches recently, he responded positively. He had thought the headaches were due to recent stress of his job. The results of the visual field exam indicated bitemporal hemianopia (a type of heteronymous hemianopia). This signifies damage to the optic chiasm that carries axons of ganglion cells from the nasal halves of the retina that transmits visual information from the temporal visual fields. A common cause for this defect is a pituitary tumor such as a pituitary adenoma. The pituitary gland is located ventral to the optic chiasm. When the tumor grows, it presses on the optic chiasm. Headaches and decreased libido often occur as a result of the tumor that is typically benign. A magnetic resonance image of the pituitary gland in this patient revealed a tumor pressing on the optic chiasm. Medical treatment caused the tumor to shrink and his visual fields were restored to normal. (See Chapter 62 for more details about tumors of the anterior pituitary.)

CHAPTER SUMMARY ■

The major parts of the eye are the sclera (protective covering), cornea (transfer light rays), choroids (nourishment), retina (receptor cells), lens, and iris.

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The bending of light rays (refraction) allows one to focus an accurate image onto the retina. Light is refracted at the anterior surface of the cornea and at the anterior and posterior surfaces of the lens. To bring diverging rays from close objects to a focus on the retina, the curvature of the lens is increased, a process called accommodation. In hyperopia (farsightedness), the eyeball is too short and light rays come to a focus behind the retina. In myopia (nearsightedness), the anteroposterior diameter of the eyeball is too long. Astigmatism is a common condition in which the curvature of the cornea is not uniform. Presbyopia is the loss of accommodation for near vision. Strabismus is a misalignment of the eyes usually due to problems with eye muscles. Na+ channels in the outer segments of the rods and cones are open in the dark, so current flows from the inner to the outer segment. When light strikes the outer segment, some of the Na+ channels are closed and the cells are hyperpolarized. Neurons in layer 4 of the visual cortex respond to stimuli in their receptive fields with on-centers and inhibitory surrounds or off-centers and excitatory surrounds. Neurons in other layers are called simple cells if they respond to bars of light, lines, or edges, but only when they have a particular orientation. Complex cells also require a preferred orientation of a linear stimulus but are less dependent on the location of a stimulus in the visual field. The visual pathway is from the rods and cones to bipolar cells to ganglion cells, and then via the optic tract to the thalamic lateral geniculate body to the occipital lobe of the cerebral cortex. The fibers from each nasal hemiretina decussate in the optic chiasm; the fibers from the nasal half of one retina and the temporal half of the other synapse on the cells whose axons form the geniculocalcarine tract. Saccades (sudden jerky movements) occur as the gaze shifts from one object to another, and they reduce adaptation in the visual pathway that would occur if gaze were fixed on a single object for long periods. Smooth pursuit movements are tracking movements of the eyes as they follow moving objects. Vestibular movements occur in response to stimuli in the semicircular canals to maintain visual fixation as the head moves. Convergence movements bring the visual axes toward each other as attention is focused on objects near the observer.

STUDY QUESTIONS 1. A visual exam in an 80-year-old man shows he has a reduced ability to see objects in the upper and lower quadrants of the left visual fields of both eyes but some vision remains in the central regions of the visual field. The diagnosis is A) central scotoma. B) heteronymous hemianopia with macular sparing. C) lesion of the optic chiasm. D) homonymous hemianopia with macular sparing. E) retinopathy. 2. Visual accommodation involves A) increased tension on the lens ligaments. B) a decrease in the curvature of the lens. C) relaxation of the sphincter muscle of the iris. D) contraction of the ciliary muscle. E) increased intraocular pressure.

CHAPTER 15 Special Senses I: Vision 3. The fovea of the eye A) has the lowest light threshold. B) is the region of highest visual acuity. C) contains only cones. D) contains only rods. E) is situated over the head of the optic nerve. 4. Which of the following parts of the eye has the greatest concentration of rods? A) ciliary body B) iris C) optic disk D) fovea E) extrafoveal region 5. The correct sequence of events involved in phototransduction in rods and cones in response to light is A) activation of transducin, decreased release of glutamate, structural changes in rhodopsin, closure of Na+ channels, and decrease in intracellular cGMP. B) decreased release of glutamate, activation of transducin, closure of Na+ channels, decrease in intracellular cGMP, and structural changes in rhodopsin. C) structural changes in rhodopsin, decrease in intracellular cGMP, decreased release of glutamate, closure of Na+ channels, and activation of transducin. D) structural changes in rhodopsin, activation of transducin, decrease in intracellular cGMP, closure of Na+ channels, and decreased release of glutamate. E) activation of transducin, structural changes in rhodopsin, closure of Na+ channels, decrease in intracellular cGMP, and decreased release of glutamate.

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6. Vitamin A is a precursor for the synthesis of A) transducin. B) retinals. C) the pigment of the iris. D) scotopsin. E) aqueous humor. 7. Which of the following is not involved in color vision? A) activation of a pathway that signals differences between S-cone responses and the sum of L- and M-cone responses B) geniculate layers 3–6 C) P pathway D) area V3A of visual cortex E) area V8 of visual cortex

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16 C

Special Senses II: Hearing and Equilibrium Susan M. Barman

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Describe the components and functions of the external, middle, and inner ear. Describe the way that movements of molecules in the air are converted into impulses generated in hair cells in the cochlea. Trace the path of auditory impulses in the neural pathways from the cochlear hair cells to the auditory cortex, and discuss the function of the auditory cortex. Explain how pitch and loudness are coded in the auditory pathways. Describe the various forms of deafness and tests for their diagnosis. Explain how the receptors in the semicircular canals detect rotational acceleration and how the receptors in the saccule and utricle detect linear acceleration. List the major sensory inputs that provide the information synthesized in the brain into the sense of position in space.

INTRODUCTION Receptors for hearing and equilibrium are housed in the ear. The external ear, middle ear, and cochlea of the inner ear are concerned with hearing. The semicircular canals, utricle, and saccule of the inner ear are concerned with equilibrium. Receptors in the semicircular canals (hair cells) detect rotational acceleration, receptors in the utricle detect linear acceleration in the horizontal direction, and receptors in the saccule detect linear acceleration in the vertical direction.

ANATOMY OF THE EAR EXTERNAL AND MIDDLE EAR The external ear funnels sound waves to the external auditory meatus (Figure 16–1). Sound waves pass inward to the tympanic membrane (eardrum). The middle ear is an

Ch16_147-158.indd 147

air-filled cavity in the temporal bone that opens via the auditory (Eustachian) tube into the nasopharynx and through the nasopharynx to the exterior. The tube is usually closed, but during swallowing, chewing, and yawning it opens, equalizing air pressure on the two sides of the eardrum. The three auditory ossicles (malleus, incus, and stapes) are in the middle ear (Figure 16–2). The manubrium (handle of the malleus) is attached to the back of the tympanic membrane. Its head is attached to the wall of the middle ear, and its short process is attached to the incus, which articulates with the head of the stapes. The foot plate of the stapes is attached by an annular ligament to the walls of the oval window. Two small skeletal muscles (tensor tympani and stapedius) are located in the middle ear. Contraction of the former pulls the manubrium of the malleus medially and decreases the vibrations of the tympanic membrane; contraction of the latter pulls the foot plate of the stapes out of the oval window.

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FIGURE 16–1 Structures of the outer, middle, and inner portions of the human ear. For clarity, the cochlea has been turned slightly and the middle ear muscles have been omitted. (Reproduced with permission from Fox SI: Human Physiology. McGraw-Hill, 2008.)

FIGURE 16–2

The medial view of the middle ear. The locations of auditory muscles attached to the middle ear ossicles are indicated.

(Reproduced with permission from Fox SI: Human Physiology. McGraw-Hill, 2008.)

CHAPTER 16 Special Senses II: Hearing and Equilibrium

INNER EAR AND COCHLEA The inner ear (labyrinth) is made up of two parts, one within the other. The bony labyrinth is a series of channels in the temporal bone. Inside these channels, surrounded by a fluid (perilymph) is the membranous labyrinth (Figure 16–3) that is filled with a K+-rich fluid (endolymph). There is no communication between the spaces filled with endolymph and those filled with perilymph. The cochlear portion of the labyrinth is a coiled tube that, in humans, is 35-mm long and makes approximately 2.75 turns. The basilar membrane and Reissner’s membrane divide it into three chambers or scalae (Figure 16–4). The upper scala vestibuli and the lower scala tympani contain perilymph and communicate with each other at the apex of the cochlea via a small opening (helicotrema). At the base of the cochlea, the scala vestibuli ends at the oval window, which is closed by the footplate of the stapes. The scala tympani end at the round window, a foramen on the medial wall of the middle ear that is closed by the flexible secondary tympanic membrane.

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The scala media is continuous with the membranous labyrinth and does not communicate with the other two scalae. The organ of Corti contains the auditory receptors (hair cells) whose processes pierce the reticular lamina that is supported by the pillar cells or rods of Corti (Figure 16–4). The hair cells are arranged in four rows: three rows of outer hair cells lateral to the tunnel formed by the rods of Corti, and one row of inner hair cells medial to the tunnel. Covering the rows of hair cells is the tectorial membrane in which the tips of the hairs of the outer cells are embedded. The cell bodies of the sensory neurons are located in the spiral ganglion within the modiolus; ~95% of these sensory neurons innervate inner hair cells, ~5% innervate outer hair cells, and each sensory neuron innervates several outer hair cells. By contrast, most efferent fibers in the auditory nerve terminate on the outer hair cells. The axons of afferent neurons that innervate hair cells form the auditory (cochlear) division of the eighth cranial nerve. The semicircular canals are oriented in the three planes. Inside the bony canals, the membranous canals are suspended

Cupula

Semicircular canal VIII

Tectorial membrane Basilar membrane

Otolithic membrane

Cochlea

Sacculus

FIGURE 16–3 Schematic of the human inner ear showing the membranous labyrinth with enlargements of the structures in which hair cells are embedded. The membranous labyrinth is suspended in perilymph and filled with K+-rich endolymph that bathes the receptors. Hair cells (darkened for emphasis) are in different arrays characteristic of the receptor organs. The semicircular canals are sensitive to angular acceleration that deflects the gelatinous cupula and associated hair cells. In the cochlea, hair cells spiral along the basilar membrane in the organ of Corti. Airborne sounds set the eardrum in motion, which is conveyed to the cochlea by bones of the middle ear. This flexes the membrane up and down. Hair cells in the organ of Corti are stimulated by shearing motion. The otolithic organs (saccule and utricle) are sensitive to linear acceleration in vertical and horizontal planes. Hair cells are attached to the otolithic membrane. VIII, eighth cranial nerve, with auditory and vestibular divisions. (Adapted with permission from Hudspeth AJ. How the ear’s works work. Nature. 1989;341:397. Copyright 1989 by Macmillan Magazines.)

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Stria vascularis

Scala vestibuli Reissner’s membrane Tectorial membrane

Spiral ligament Scala media

Limbus

Spiral prominence Spiral ganglion

Scala tympani

Spiral ligament

Modiolus Spiral lamina

Organ of Corti

Reticular lamina

Basilar membrane

Outer hair cells

DCs

Tectorial membrane Inner hair cell IPC

Nerve fibers

AUDITORY RECEPTORS: HAIR CELLS The hair cells in the organ of Corti signal hearing, the hair cells in the utricle signal horizontal acceleration, the hair cells in the saccule signal vertical acceleration, and a patch in each of the three semicircular canals signals rotational acceleration. These hair cells have a common structure (Figure 16–5). Each is embedded in an epithelium made up of supporting cells, with the basal end in close contact with afferent neurons. Projecting from the apical end are 30–150 rod-shaped processes or hairs. Except in the cochlea, one of these, the kinocilium, is a true but nonmotile cilium with nine pairs of microtubules around its circumference and a central pair of microtubules. It is one of the largest processes and has a clubbed end. The kinocilium is lost from the hair cells of the cochlea in adults; however, the other processes (stereocilia) are found in all hair cells. They have cores composed of parallel filaments of actin that is coated with isoforms of myosin. Within the clump of processes on each cell there is an orderly structure. Along an axis toward the kinocilium, the stereocilia increase progressively in height; along the perpendicular axis, all stereocilia are the same height.

Arch Tunnel

Habenula perforata

ELECTRICAL RESPONSES Pillar cell (rod of Corti)

Basilar membrane

Spiral lamina

FIGURE 16–4 Top: Cross-section of the cochlea, showing the organ of Corti and the three scalae of the cochlea. Bottom: Structure of the organ of Corti, as it appears in the basal turn of the cochlea. DC, outer phalangeal cells (Deiters’ cells) supporting outer hair cells; IPC, inner phalangeal cell supporting inner hair cell. (Reproduced with permission from Pickels JO: An Introduction to the Physiology of Hearing, 2nd ed. Academic Press, 1988.)

in perilymph. A receptor structure (crista ampullaris) is located in the expanded end (ampulla) of each of the membranous canals. Each crista consists of hair cells and supporting (sustentacular) cells surmounted by a gelatinous partition (cupula) that closes off the ampulla (Figure 16–3). The processes of the hair cells are embedded in the cupula, and the bases of the hair cells contact the afferent fibers of the vestibular division of the eighth cranial nerve. Within each membranous labyrinth is an otolithic organ (macula). Another macula is located on the wall of the saccule in a semivertical position. The maculae contain supporting cells and hair cells, surmounted by an otolithic membrane in which are embedded crystals of calcium carbonate, the otoliths (Figure 16–3), which are also called otoconia or ear dust. The processes of the hair cells are embedded in the membrane. The nerve fibers from the hair cells join those from the cristae in the vestibular division of the eighth cranial nerve.

The resting membrane potential of the hair cells is about –60 mV. When the stereocilia are pushed toward the kinocilium, the membrane potential is decreased to about –50 mV. The hair processes provide a mechanism to generate changes in membrane potential proportional to the direction and distance the hair moves. When the bundle of processes is pushed in the opposite direction, the cell is hyperpolarized. Displacing the processes in a direction perpendicular to this axis provides no change in membrane potential, and displacing the processes in directions that are intermediate between these two directions produces depolarization or hyperpolarization that is proportionate to the degree to which the direction is toward or away from the kinocilium.

GENESIS OF ACTION POTENTIALS IN AFFERENT NERVE FIBERS Very fine processes called tip links (Figure 16–6) tie the tip of each stereocilium to the side of its higher neighbor, and at the junction are mechanosensitive cation channels. If shorter stereocilia are pushed toward higher ones, the open time of the channels increases. K+ and Ca2+ enter via the channel and produce depolarization. A molecular motor in the higher neighbor then may move the channel toward the base, releasing tension in the tip link. This causes the channel to close and permits restoration of the resting state. Depolarization of hair cells causes them to release a neurotransmitter that initiates depolarization of neighboring afferent neurons.

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151

OM

OM OL K

S

RC

A

SC

E

FIGURE 16–5 Structure of a hair cell in the saccule. Left: Hair cells in the membranous labyrinth of the ear have a common structure, and each is within an epithelium of supporting cells (SC) surmounted by an otolithic membrane (OM) embedded with the otoliths (OL). Projecting from the apical end are rod-shaped processes, or hair cells (RC), in contact with afferent (A) and efferent (E) nerve fibers. Except in the cochlea, one of these, kinocilium (K), is a true but nonmotile cilium with nine pairs of microtubules around its circumference and a central pair of microtubules. The other processes, stereocilia (S), are found in all hair cells; they have cores of actin filaments coated with isoforms of myosin. There is an orderly structure within the clump of processes on each cell. Along an axis toward the kinocilium, the stereocilia increase progressively in height; along the perpendicular axis, all stereocilia are the same height. (Reproduced with permission from Hillman DE: Morphology of peripheral and central vestibular systems. In: Frog Neurobiology. Llinas R, Precht W (editors). Springer, 1976.) Right: Scanning electron photomicrograph of processes on a hair cell in the saccule. The otolithic membrane has been removed. The small projections around the hair cell are microvilli on supporting cells. (Courtesy of A.J. Hudspeth.)

Myosin Ca2+

K+

Tip link

FIGURE 16–6 Schematic representation of the role of tip links in the responses of hair cells. When a stereocilium is pushed toward a taller stereocilium, the tip link is stretched and opens an ion channel in its taller neighbor. The channel next is moved down the taller stereocilium by a molecular motor, so the tension on the tip link is released. When hairs return to their resting position, the motor moves back up the stereocilium. (Modified with permission from Kandel ER, Schwartz JH, Jessel TM [editors]: Principles of Neuroscience, 4th ed. McGraw-Hill, 2000.)

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SL and SV

Scala vestibuli Na+ 150 K+ 5 Cl− 125

Na+ 1 K+ 150 − Cl 130

Na+ 150 K+ 3 Cl− 125

Organ of Corti

chain saw, lawn mower) is extremely high, 60–80 dB (e.g., alarm clock, busy traffic, dishwasher, conversation) is very loud, 40–50 dB (e.g., moderate rainfall, normal room noise) is moderate, and 30 dB (e.g., whisper, library) is faint. The sound frequencies audible to humans range from about 20 to 20,000 cycles per second (cps, Hz). The range decreases with age, especially difficulty detecting higher frequency sounds. The threshold of the human ear varies with the pitch of the sound; the greatest sensitivity is in the 1,000–4,000-Hz range. The pitch of the average male and female voice in conversation is 120 and 250 Hz, respectively. The number of pitches that can be distinguished by an average individual is about 2,000, but trained musicians can improve on this figure considerably.

Scala tympani

FIGURE 16–7

Ionic composition (mmol/L) of perilymph in the scala vestibuli, endolymph in the scala media, and perilymph in the scala tympani. SL, spiral ligament; SV, stria vascularis. The dashed arrow indicates the path by which K+ recycles from the hair cells to the supporting cells to the spiral ligament and is then secreted back into the endolymph by cells in the stria vascularis. (Reproduced with permission from Barrett KE, Barman SM, Boitano S, Brooks H: Ganong’s Review of Medical Physiology, 23rd ed. McGraw-Hill Medical, 2009.)

The K+ that enters hair cells via the mechanosensitive cation channels is recycled (Figure 16–7). It enters supporting cells and then passes on to other supporting cells via tight junctions. In the cochlea, it eventually reaches the stria vascularis and is secreted back into the endolymph, completing the cycle. The processes of the hair cells project into the endolymph and the bases are bathed in perilymph. The perilymph is formed mainly from plasma; endolymph is formed in the scala media by the stria vascularis and has a high concentration of K+ and a low concentration of Na+. Cells in the stria vascularis have a high concentration of Na+,K+-ATPase.

HEARING SOUND WAVES Sound is the sensation produced when vibrations of molecules in the external environment strike the tympanic membrane. The loudness of a sound is typically correlated with the amplitude of a sound wave and its pitch with its frequency (number of waves per unit of time). The amplitude of a sound wave is expressed on a relative scale, called a decibel scale. The intensity of a sound in bels is the logarithm of the ratio of the intensity of that sound to a standard sound. A value of 0 dB does not mean the absence of sound; rather, it is a sound level whose intensity is equal to that of a standard. The 0–160-dB range from threshold pressure to a pressure that is potentially damaging to the organ of Corti actually represents a 107-fold variation in sound pressure. A range of 120–160 dB (e.g., firearms, jackhammer, jet plane on takeoff) is painful, 90–110 dB (e.g., subway, bass drum,

SOUND TRANSMISSION The ear converts sound waves in the environment into action potentials in the auditory nerves. The waves are transformed by the eardrum and auditory ossicles into movements of the foot plate of the stapes. These movements set up waves in the fluid of the inner ear. The action of the waves on the organ of Corti generates action potentials in the nerve. The tympanic membrane moves in and out in response to the pressure changes produced by sound waves on its external surface. Thus, the membrane functions as a resonator that reproduces the vibrations of the sound source. It stops vibrating almost immediately when the sound wave stops. The motions of the tympanic membrane are imparted to the manubrium. The malleus rocks on an axis through the junction of its long and short processes, so that the short process transmits the vibrations of the manubrium to the incus. The incus moves in such a way that the vibrations are transmitted to the head of the stapes. Movements of the head of the stapes swing its foot plate to and fro like a door hinged at the posterior edge of the oval window. The auditory ossicles function as a lever system that converts the resonant vibrations of the tympanic membrane into movements of the stapes against the perilymphfilled scala vestibuli of the cochlea (Figure 16–8). This system increases the sound pressure that arrives at the oval window, because the lever action of the malleus and incus multiplies the force 1.3 times and the area of the tympanic membrane is much greater than the area of the foot plate of the stapes. When the middle ear muscles (tensor tympani and stapedius) contract, the manubrium of the malleus pulls inward and the foot plate of the stapes pushes outward (Figure 16–2), decreasing sound transmission. Loud sounds initiate the tympanic reflex, which contracts the middle ear muscles to prevent strong sound waves from causing excessive stimulation of the auditory receptors.

BONE AND AIR CONDUCTION Ossicular conduction is the normal conduction of sound waves to the fluid of the inner ear via the tympanic

CHAPTER 16 Special Senses II: Hearing and Equilibrium

ACTION POTENTIALS IN AUDITORY NERVE FIBERS

Malleus Incus

Pivot

Stapes Oval window

Reissner's membrane

Organ of Corti Round window Auditory tube

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Basilar membrane

FIGURE 16–8 Schematic representation of the auditory ossicles and the way their movement translates movements of the tympanic membrane into a wave in the fluid of the inner ear. The wave is dissipated at the round window. The movements of the ossicles, the membranous labyrinth, and the round window are indicated by dashed lines. (Reproduced with permission from Barrett KE, Barman SM, Boitano S, Brooks H: Ganong’s Review of Medical Physiology, 23rd ed.

Inner hair cells are the primary sensory cells that generate action potentials in auditory nerves and are stimulated by the fluid movements noted above. Outer hair cells respond to sound, but depolarization makes them short and hyperpolarization makes them lengthy. They do this over a very flexible part of the basal membrane, and this action increases the amplitude and clarity of sounds. The frequency of the action potentials in auditory nerve fibers is proportional to the loudness of the sound stimuli. The major determinant of the pitch perceived when a sound wave strikes the ear is the place in the organ of Corti that is maximally stimulated. The traveling wave set up by a tone produces peak depression of the basilar membrane, and consequently maximal receptor stimulation, at one point. The distance between this point and the stapes is inversely related to the pitch of the sound, with low tones producing maximal stimulation at the apex of the cochlea and high tones producing maximal stimulation at the base.

McGraw-Hill Medical, 2009.)

CENTRAL PATHWAY membrane and the auditory ossicles. Sound waves also initiate vibrations of the secondary tympanic membrane that closes the round window; this process, unimportant in normal hearing, is called air conduction. Bone conduction is the transmission of vibrations of the bones of the skull to the fluid of the inner ear; this plays a role in transmission of extremely loud sounds. Considerable bone conduction also occurs when a vibrating tuning fork is applied directly to the skull.

TRAVELING WAVES The movements of the foot plate of the stapes set up a series of traveling waves in the perilymph of the scala vestibuli. The bony walls of the scala vestibuli are rigid, but Reissner’s membrane is flexible. The basilar membrane is not under tension, and it also is readily depressed into the scala tympani by the peaks of waves in the scala vestibuli. Displacements of the fluid in the scala tympani are dissipated into air at the round window. Sound distorts the basilar membrane, and the site at which this distortion is maximal is determined by the frequency of the sound wave. The tops of the hair cells in the organ of Corti are held rigid by the reticular lamina, and the processes of the outer hair cells are embedded in the tectorial membrane (Figure 16–4). When the stapes moves, both membranes move in the same direction, but they are hinged on different axes, so a shearing motion bends the hairs. The processes of the inner hair cells are not attached to the tectorial membrane, but they are bent by fluid moving between the membrane and the underlying hair cells.

The afferent fibers in the auditory division of the eighth cranial nerve end in dorsal and ventral cochlear nuclei (Figure 16–9). From there, auditory impulses pass by various routes to the inferior colliculi, the centers for auditory reflexes, and via the medial geniculate body in the thalamus to the auditory cortex. Other impulses enter the reticular formation. Information from both ears converges on each superior olive, and beyond this, most of the neurons respond to inputs from both sides. The primary auditory cortex is Brodmann’s area 41. Low tones are represented anterolaterally and high tones posteromedially in the auditory cortex. In the primary auditory cortex, most neurons respond to inputs from both ears, but strips of cells are stimulated by input from the contralateral ear and inhibited by input from the ipsilateral ear. There are several additional auditory receiving areas, just as there are several receiving areas for cutaneous sensation. The auditory association areas adjacent to the primary auditory receiving areas are widespread. The olivocochlear bundle is a prominent bundle of efferent fibers in each auditory nerve that arises from both ipsilateral and contralateral superior olivary complexes and ends primarily around the bases of the outer hair cells of the organ of Corti.

SOUND LOCALIZATION Determination of the direction from which a sound emanates in the horizontal plane depends on detecting the difference in time between the arrival of the stimulus in the two ears and the consequent difference in phase of the sound

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waves on the two sides; it also depends on the fact that the sound is louder on the side closest to the source. The detectable time difference, which can be as little as 20 microseconds, is the most important factor at frequencies below 3,000 Hz and the loudness difference the most important factor at frequencies above 3,000 Hz. Neurons in the auditory cortex that receive input from both ears respond maximally or minimally when the time of arrival of a stimulus at one ear is delayed by a fixed period relative to the time of arrival at the other ear. This fixed period varies from neuron to neuron. Sounds coming from directly in front of the individual differ in quality from those coming from behind because each pinna (the visible portion of the exterior ear) is turned slightly forward. Also, reflections of sound waves from the pinnal surface change as sounds move up or down; the change in the sound waves is the primary factor in locating sounds in the vertical plane. Lesions of the auditory cortex disrupt sound localization.

eighth cranial nerve or within central auditory pathways. It can impair the ability to hear certain pitches while others are unaffected. Aminoglycoside antibiotics such as streptomycin and gentamicin obstruct the mechanosensitive channels in the stereocilia of hair cells and can cause the cells to degenerate, producing sensorineural hearing loss and abnormal vestibular function. Damage to the outer hair cells by prolonged exposure to noise is associated with hearing loss. Other causes include tumors of the eighth cranial nerve and cerebellopontine angle and vascular damage in the medulla. Conduction and sensorineural deafness can be differentiated by simple tests with a tuning fork. Three of these tests, named for the individuals who developed them, are outlined in Table 16–1. The Weber and Schwabach tests demonstrate the important masking effect of environmental noise on the auditory threshold.

VESTIBULAR SYSTEM DEAFNESS Hearing loss is the most common sensory defect in humans. Presbycusis, the gradual hearing loss associated with aging, affects more than one third of those over 75 and is probably due to gradual cumulative loss of hair cells and neurons. In most cases, hearing loss is a multifactorial disorder caused by both genetic and environmental factors. Conductive deafness refers to impaired sound transmission in the external or middle ear and impacts all sound frequencies. Causes of conduction deafness include plugging of the external auditory canals with wax (cerumen) or foreign bodies, fluid accumulation due to otitis externa (inflammation of the outer ear, “swimmer’s ear”) or otitis media (inflammation of the middle ear), perforation of the eardrum, and osteosclerosis in which bone is resorbed and replaced with sclerotic bone that grows over the oval window. Sensorineural deafness is usually due to the loss of cochlear hair cells but can also be due to problems with the

The vestibular system is divided into the vestibular apparatus and central vestibular nuclei. The vestibular apparatus within the inner ear detects head motion and position and transduces this information into a neural signal. The vestibular nuclei are concerned with maintaining the position of the head in space; the tracts that descend from these nuclei mediate head-onneck and head-on-body adjustments. The vestibular ganglia contain the cell bodies of the neurons supplying the cristae and maculae. Each vestibular nerve terminates in the ipsilateral vestibular nucleus and in the flocculonodular lobe of the cerebellum (Figure 16–9). Fibers from the semicircular canals end in the superior and medial divisions of the vestibular nucleus and project mainly to nuclei controlling eye movement. Fibers from the utricle and saccule end in Deiters’ nucleus, which projects to the spinal cord. The vestibular nuclei also project to the thalamus and from there to the primary somatosensory cortex. The ascending connections to cranial nerve nuclei are concerned with eye movements.

TABLE 16–1 Common tests with a tuning fork to distinguish between sensorineural and conduction deafness. Weber

Rinne

Schwabach

Method

Base of vibrating tuning fork placed on vertex of skull

Base of vibrating tuning fork placed on mastoid process until subject no longer hears it, and then held in air next to ear

Bone conduction of patient compared with that of healthy subject

Normal

Hears equally on both sides

Hears vibration in air after bone conduction is over

Conduction deafness (one ear)

Sound louder in diseased ear because masking effect of environmental noise is absent on diseased side

Vibrations in air not heard after bone conduction is over

Bone conduction better than normal (conduction defect excludes masking noise)

Sensorineural deafness (one ear)

Sound louder in normal ear

Vibration heard in air after bone conduction is over, as long as nerve deafness is partial

Bone conduction worse than normal

CHAPTER 16 Special Senses II: Hearing and Equilibrium

155

To somatosensory cortex To cortex (superior temporal gyrus) Thalamus Thalamus

Medial geniculate body

III IV To cerebellum

Pineal Inferior colliculus Reticular formation

VI

Medial longitudinal fasciculus

IV ventricle

Dorsal and ventral cochlear nuclei

Vestibular ganglion

Spiral ganglion

Medulla Superior olives

Vestibular nuclei: superior, lateral (Deiters’), medial, spinal

Lateral vestibulospinal tract

Anterior vestibulospinal tracts

From utricle, semicircular canals

From cochlea AUDITORY

VESTIBULAR

FIGURE 16–9 Simplified diagram of main auditory (left) and vestibular (right) pathways superimposed on a dorsal view of the brain stem. Cerebellum and cerebral cortex have been removed. III, IV, and VI are the 3rd, 4th, and 6th cranial nerves. (Reproduced with permission from Barrett KE, Barman SM, Boitano S, Brooks H: Ganong’s Review of Medical Physiology, 23rd ed. McGraw-Hill Medical, 2009.)

RESPONSES TO ROTATIONAL ACCELERATION Rotational acceleration in the plane of a given semicircular canal stimulates its crista. The endolymph is displaced in a direction opposite to the rotation, and the fluid pushes on the cupula, deforming it. This bends the processes of the hair cells (Figure 16–3). When a constant speed of rotation is reached, the fluid spins at the same rate as the body and the cupula swings back into the upright position. When rotation is stopped, deceleration produces displacement of the endolymph in the direction of the rotation, and the cupula is deformed in a direction opposite to that during acceleration. It returns to mid position in 25–30 seconds. Movement of the cupula in one direction increases the activity of nerves from the crista, and movement in the opposite direction inhibits neural activity. Rotation causes maximal stimulation of the semicircular canals in the plane of rotation. Because the canals on one side of the head are a mirror image of those on the other side, the endolymph is displaced toward the ampulla on one side and away from it on the other. The pattern of stimulation reaching the brain varies with the direction and the plane of rotation.

Nystagmus is the characteristic jerky movement of the eye observed at the start and end of a period of rotation. It is a reflex that maintains visual fixation on stationary points while the body rotates. When rotation starts, the eyes move slowly in a direction opposite to the direction of rotation, maintaining visual fixation (vestibulo-ocular reflex). At the end of this movement, the eyes quickly snap back to a new fixation point and then again move slowly in the other direction. The slow component is initiated by impulses from the vestibular labyrinths; the quick component is triggered by a center in the brain stem. By convention, the direction of eye movement in nystagmus is identified by the direction of the quick component. The direction of the quick component is the same as that of the rotation; postrotatory nystagmus, which is due to displacement of the cupula, is in the opposite direction. Nystagmus can be observed at rest in patients with lesions of the brain stem. Caloric stimulation can be used to test the function of the vestibular labyrinth. The semicircular canals are stimulated by instilling warm (40°C) or cold (30°C) water into the ear. The temperature difference sets up convection currents in the endolymph, with consequent motion of the cupula. In normal subjects, warm water causes nystagmus that bears toward the stimulus, and cold water induces nystagmus that bears toward the opposite ear.

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RESPONSES TO LINEAR ACCELERATION The utricular and saccular maculae respond to horizontal and vertical acceleration, respectively. The otoliths are denser than the endolymph, and acceleration in any direction causes them to be displaced in the opposite direction, distorting the hair cell processes and generating neural activity. The maculae also discharge tonically in the absence of head movement, because of the pull of gravity on the otoliths. The labyrinth righting reflexes are a series of responses integrated in midbrain nuclei in response to head tilt. The response is a compensatory contraction of neck muscles to keep the head level. These reflexes stabilize the head and keep the eyes fixed on visual targets despite movements of the body. Vestibular impulses that reach the cerebral cortex are likely responsible for conscious perception of motion and supply part of the information necessary for orientation in space. Vertigo is the sensation of rotation in the absence of actual rotation and is a prominent symptom when one labyrinth is inflamed.

SPATIAL ORIENTATION Orientation in space depends on input from the vestibular receptors as well as visual cues, information from proprioceptors in joint capsules, and cutaneous touch and pressure receptors. These four inputs are synthesized at a cortical level into a continuous picture of the individual’s orientation in the environment.

ear causing vertigo or severe dizziness, tinnitus, fluctuating hearing loss, and the sensation of pressure or pain in the affected ear lasting for several hours. Symptoms can occur suddenly and recur daily or very rarely. The hearing loss is initially transient but can become permanent. The pathophysiology may involve an immune reaction. An inflammatory response can increase fluid volume within the membranous labyrinth, causing it to rupture and allowing the endolymph and perilymph to mix together. There is no cure for Ménière disease but the symptoms can be controlled by reducing the fluid retention through dietary changes (low-salt or salt-free diet, no caffeine, no alcohol) or medication.

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CLINICAL CORRELATION A 26-year-old woman came to her primary care physician’s office because of a recent series of episodes in which she has experienced severe dizziness, tinnitus (ringing in the ears), and nausea and vomiting. During her latest episode, she realized that she could barely hear her daughter calling for her in the next room. When queried by the physician’s assistant, she recalled that similar, although less severe, incidences of these symptoms had occurred while she was in college. In particular, she experienced tinnitus, vertigo, and nausea on various occasions. Because the symptoms occurred only sporadically and lasted for only hours or a day, she did not seek medical advice. The latest episodes have her fearful that something serious is wrong with her. A hearing test detected reduced hearing in one ear. Based on the symptoms, her physician suspected that she had Ménière disease. She was later seen by an otolaryngologist and a neurologist to rule out other causes of her symptoms. Ménière disease is an abnormality of the inner

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The external ear funnels sound waves to the external auditory meatus and tympanic membrane. From there, sound waves pass through three auditory ossicles (malleus, incus, and stapes) in the middle ear. The inner ear, or labyrinth, contains the cochlea and organ of Corti. The hair cells in the organ of Corti signal hearing. The stereocilia provide a mechanism for generating changes in membrane potential proportional to the direction and distance the hair moves. Sound is the sensation produced when longitudinal vibrations of air molecules strike the tympanic membrane. The activity within the auditory pathway passes from the eighth cranial nerve afferent fibers to the dorsal and ventral cochlear nuclei to the inferior colliculi to the thalamic medial geniculate body and then to the auditory cortex. Loudness is correlated with the amplitude of a sound wave and pitch with the frequency. Conductive deafness is due to impaired sound transmission in the external or middle ear and impacts all sound frequencies. Sensorineural deafness is due to loss of cochlear hair cells or to damage to the eighth cranial nerve or central auditory pathways. Rotational acceleration stimulates the crista in the semicircular canal, displacing the endolymph in a direction opposite to the direction of rotation, deforming the cupula and bending the hair cell. The utricle responds to horizontal acceleration and the saccule to vertical acceleration. Acceleration in any direction displaces the otoliths, distorting the hair cell processes and generating neural activity. Spatial orientation is dependent on input from vestibular receptors, visual cues, proprioceptors in joint capsules, and cutaneous touch and pressure receptors.

STUDY QUESTIONS 1. A 40-year-old male, employed as a road construction worker for nearly 20 years, went to his physician to report that he has been having difficulty hearing during normal conversations. A Weber test showed that sound from a vibrating tuning fork was localized to the right ear. A Schwabach test showed that bone conduction was below normal. A Rinne test showed that both air and bone

CHAPTER 16 Special Senses II: Hearing and Equilibrium conduction were abnormal, but air conduction lasted longer than bone conduction. The diagnosis was A) sensorial deafness in both ears. B) conduction deafness in the right ear. C) sensorial deafness in the right ear. D) conduction deafness in the left ear. E) sensorineural deafness in the left ear. 2. What would the diagnosis be if a patient had the following test results? Weber test showed that sound from a vibrating tuning fork was louder than normal; Schwabach test showed that bone conduction was better than normal; and Rinne test showed that air conduction did not outlast bone conduction. A) sensorial deafness in both ears B) conduction deafness in both ears C) normal hearing D) both sensorial and conduction deafness E) a possible tumor on the eighth cranial nerve 3. Postrotational nystagmus is caused by continued movement of A) aqueous humor over the ciliary body in the eye. B) cerebrospinal fluid over the vestibular nuclei. C) endolymph in the semicircular canals, with consequent bending of the cupula and stimulation of hair cells. D) endolymph toward the helicotrema. E) perilymph over hair cells with processes embedded in the tectorial membrane.

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4. Some diseases damage the hair cells in the ear. When the damage to the outer hair cells is greater than the damage to the inner hair cells A) perception of vertical acceleration is disrupted. B) K+ concentration in endolymph is decreased. C) K+ concentration in perilymph is decreased. D) there is severe hearing loss. E) affected hair cells fail to shorten when exposed to sound. 5. Which of the following are incorrectly paired? A) tympanic membrane:manubrium of malleus B) helicotrema:apex of cochlea C) foot plate of stapes:oval window D) otoliths:semicircular canals E) basilar membrane:organ of Corti 6. The direction of nystagmus is vertical when a subject is rotated A) after warm water is put in one ear. B) with the head tipped backward. C) after cold water is put in both ears. D) with the head tipped sideways. E) after section of one vestibular nerve. 7. In the utricle, tip links in hair cells are involved in A) formation of perilymph. B) depolarization of the stria vascularis. C) movements of the basement membrane. D) perception of sound. E) regulation of mechanosensitive ion channels.

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17 C

Special Senses III: Smell and Taste Susan M. Barman

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Describe the basic features of the olfactory epithelium and olfactory bulb. Explain signal transduction in odorant receptors. Outline the pathway by which impulses generated in the olfactory epithelium reach the olfactory cortex. Describe the location and cellular composition of taste buds. Name the five major taste receptors and their signal transduction mechanisms. Outline the pathways by which impulses generated in taste receptors reach the insular cortex.

INTRODUCTION Smell and taste are classified as visceral senses because of their close association with gastrointestinal function. Physiologically, they are related to each other; the flavors of various foods are in large part a combination of their taste and smell. This explains why food may taste “different” if one has a cold that depresses the sense of smell. Both smell and taste receptors are chemoreceptors that are stimulated by molecules in solution in mucus in the nose and saliva in the mouth.

SMELL OLFACTORY EPITHELIUM AND OLFACTORY BULBS A specialized portion of the nasal mucosa, the yellowish, pigmented olfactory epithelium (Figure 17–1), contains 10–20 million bipolar olfactory sensory neurons interspersed with glia-like supporting (sustentacular) cells and basal stem cells. The olfactory epithelium is the place in the body where the nervous system is closest to the external world. Each neuron has a short, thick dendrite that projects into the nasal cavity where it terminates in a knob containing 10–20 cilia (Figure 17–2). The cilia are unmyelinated processes that contain odorant recep-

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tors. The axons of the olfactory sensory neurons pass through the cribriform plate of the ethmoid bone and enter the olfactory bulbs (Figure 17–1). New olfactory sensory neurons are generated by basal stem cells as needed to replace those damaged by exposure to the environment. In the olfactory bulbs, the axons of the olfactory sensory neurons (first cranial nerve) contact the primary dendrites of the mitral cells and tufted cells (Figure 17–3) to form anatomically discrete synaptic units called olfactory glomeruli. Both types of neurons send axons into the olfactory cortex. The olfactory bulbs also contain periglomerular cells, which are inhibitory neurons connecting one glomerulus to another, and granule cells, which have no axons and make reciprocal synapses with the lateral dendrites of the mitral and tufted cells. At these synapses, the mitral or tufted cell excites the granule cell by releasing glutamate, and the granule cell in turn inhibits the mitral or tufted cell by releasing γ-Aminobutyric acid (GABA).

OLFACTORY CORTEX The axons of the mitral and tufted cells pass posteriorly through the lateral olfactory stria to terminate on apical dendrites of pyramidal cells in five regions of the olfactory cortex: anterior olfactory nucleus, olfactory tubercle, piriform cortex, amygdala, and entorhinal cortex (Figure 17–4). 159

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Olfactory bulb

Olfactory bulb

Cribriform plate Olfactory epithelium

Olfactory sensory neurons

FIGURE 17–1 Olfactory sensory neurons embedded within the olfactory epithelium in the dorsal posterior recess of the nasal cavity. These neurons project axons to the olfactory bulb of the brain, a small ovoid structure that rests on the cribriform plate of the ethmoid bone. (Reproduced with permission from Kandel ER, Schwartz JH, Jessell TM [editors]: Principles of Neural Science, 4th ed. McGraw-Hill, 2000.) From these regions, information travels directly to the frontal cortex or via the thalamus to the orbitofrontal cortex. Conscious discrimination of odors relies on the pathway to the orbitofrontal cortex. The orbitofrontal activation is generally greater on the right side than the left; thus, cortical representation of olfaction is asymmetric. The pathway to the amygdala

is involved with the emotional responses to olfactory stimuli, and the pathway to the entorhinal cortex is concerned with olfactory memories.

To olfactory bulb

Basal cells

Axon

Olfactory sensory neuron

Dendrite Supporting cell

Mucus

Cilia

FIGURE 17–2 Structure of the olfactory epithelium. There are three cell types: olfactory sensory neurons, supporting cells, and basal stem cells at the base of the epithelium. Each sensory neuron has a dendrite that projects to the epithelial surface. Numerous cilia protrude into the mucosal layer lining the nasal lumen. A single axon projects from each neuron to the olfactory bulb. Odorants bind to specific odorant receptors on the cilia and initiate a cascade of events leading to generation of action potentials in the sensory axon.

FIGURE 17–3 Basic neural circuits in the olfactory bulb. Note that olfactory receptor cells with one type of odorant receptor project to one olfactory glomerulus (OG) and olfactory receptor cells with another type of receptor project to a different olfactory glomerulus. CP, cribriform plate; PG, periglomerular cell; M, mitral cell; T, tufted cell; Gr, granule cell. White arrows, excitatory synapses; black arrows, inhibitory synapses.

(Modified with permission from Kandel ER, Schwartz JH, Jessell TM [editors]:

(Adapted with permission from Mori K, Nagao H, Yoshihara Y. The olfactory bulb: Coding

Principles of Neural Science, 4th ed. McGraw-Hill, 2000.)

and processing of odor molecular information. Science. 1999;286(5440):711–715.)

CHAPTER 17 Special Senses III: Smell and Taste

Mitral cell

Accessory olfactory bulb

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Lateral olfactory tract

Mitral cell Tufted cell Olfactory bulb Vomeronasal organ

Anterior olfactory nucleus

Olfactory tubercle

Piriform cortex

Amygdala

Entorhinal cortex

Olfactory epithelium Hypothalamus Contralateral olfactory bulb Hippocampus

Thalamus

Orbitofrontal cortex

Frontal cortex

FIGURE 17–4 Diagram of the olfactory pathway. Information is transmitted from the olfactory bulb by axons of mitral and tufted relay neurons in the lateral olfactory tract. Mitral cells project to five regions of the olfactory cortex: anterior olfactory nucleus, olfactory tubercle, piriform cortex, and parts of the amygdala and entorhinal cortex. Tufted cells project to anterior olfactory nucleus and olfactory tubercle; mitral cells in the accessory olfactory bulb project only to the amygdala. Conscious discrimination of odor depends on the neocortex (orbitofrontal and frontal cortices). Emotive aspects of olfaction derive from limbic projections (amygdala and hypothalamus). In rodents and some mammals, a well-developed vomeronasal organ is concerned with perception of odors that act as pheromones; its receptors project to the accessory olfactory bulb. (Reproduced with permission from Kandel ER, Schwartz JH, Jessell TM [editors]: Principles of Neural Science, 4th ed. McGraw-Hill, 2000.)

OLFACTORY DISCRIMINATION AND SIGNAL TRANSDUCTION The olfactory epithelium is covered by a thin layer of mucus secreted by the supporting cells and Bowman glands that lie beneath the epithelium. The mucus bathes the odorant receptors on the cilia and provides the appropriate molecular and ionic environment for odor detection. Odor-producing molecules are usually small, containing from 3 to 20 carbon atoms, and molecules with the same number of carbon atoms but different structural configurations have different odors. Relatively high water and lipid solubility are characteristic of substances with strong odors. Anosmia (inability to smell) and hyposmia or hypesthesia (diminished olfactory sensitivity) can result from simple nasal congestion or from damage to the olfactory nerves due to fractures of the cribriform plate, neuroblastomas or meningiomas, or infections (such as abscesses). Aging is also associated with abnormalities in smell sensation; more than 75% of humans over the age of 80 have an impaired ability to identify odors. The genes that code for about 1,000 different types of odorant receptors make up the largest gene family so far described in mammals. The amino acid sequences of odorant receptors are diverse, but all the odorant receptors are coupled to heterotrimeric G proteins. When an odorant molecule binds to its receptor, the G protein subunits (α, β, γ) dissociate (Figure 17–5). The α-subunit activates adenylate cyclase to

catalyze the production of cAMP, which acts as a second messenger to open cation channels, causing an inward-directed Ca2+ current. This produces the graded receptor potential, which then leads to an action potential in the olfactory nerve. Although there are millions of olfactory sensory neurons, each expresses only 1 of the 1,000 different odorant receptors. Each neuron projects to one or two glomeruli (Figure 17–3). This provides a distinct two-dimensional map in the olfactory bulb that is unique to the odorant. The mitral cells with their glomeruli project to different parts of the olfactory cortex. The olfactory glomeruli demonstrate lateral inhibition mediated by periglomerular and granule cells. This sharpens and focuses olfactory signals. In addition, the extracellular field potential in each glomerulus oscillates, and the granule cells can regulate the frequency of the oscillation. The exact function of the oscillation is unknown, but it may also help to focus the olfactory signals reaching the cortex.

TASTE TASTE BUDS The specialized sense organ for taste (gustation) consists of approximately 10,000 taste buds. There are four morphologically distinct types of cells within each taste bud: basal cells,

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Odorant

Na+/Ca2+ channel

Adenylate cyclase

Odorant receptor

G-proteins (a)

Odorant

Odorant receptor

Adenylate cyclase

Na+

Na+/Ca2+ channel

cAMP

FIGURE 17–5

Signal transduction in an odorant receptor. Olfactory receptors are G protein–coupled receptors that dissociate on binding to the odorant. The α-subunit of G proteins activates adenylate cyclase to catalyze production of cAMP. cAMP acts as a second messenger to open cation channels. Inward diffusion of Na+ and Ca2+ produces depolarization. (Reproduced with

Ca2+

ATP cAMP (b)

permission from Fox SI: Human Physiology. McGraw-Hill, 2008.)

dark cells, light cells, and intermediate cells (Figure 17–6). The latter three cell types are referred to as Type I, II, and III taste cells. They are the sensory neurons that respond to taste stimuli. The apical ends of taste cells have microvilli that project into the taste pore, a small opening on the dorsal surface of the tongue where taste cells are exposed to the oral contents. Each taste bud is innervated by about 50 nerve fibers, and conversely, each nerve fiber receives input from an average of five taste buds. The basal cells arise from the epithelial cells surrounding the taste bud. They differentiate into new taste cells, and the old cells are replaced with a half-time of about 10 days. If the sensory nerve is cut, the taste buds it innervates degenerate and eventually disappear. The taste buds are located in the mucosa of the epiglottis, palate, and pharynx and in the walls of papillae of the tongue (Figure 17–6). The fungiform papillae are rounded structures most numerous near the tip of the tongue; the circumvallate papillae are prominent structures arranged in a V on the back of the tongue; the foliate papillae are on the posterior edge of the tongue. Each fungiform papilla has up to 5 taste buds, mostly located at the top of the papilla; each vallate and foliate papilla contains up to 100 taste buds, mostly located along the sides of the papillae.

TASTE PATHWAYS The sensory nerve fibers from the taste buds on the anterior two thirds of the tongue travel in the chorda tympani branch of the facial nerve, and those from the posterior third of the

tongue reach the brain stem via the glossopharyngeal nerve (Figure 17–7). The fibers from areas other than the tongue (e.g., pharynx) reach the brain stem via the vagus nerve. On each side, the myelinated but relatively slowly conducting taste fibers in these three nerves unite in the gustatory portion of the nucleus of the tractus solitarius (NTS) in the medulla oblongata (Figure 17–7). From there, axons of second-order neurons ascend in the ipsilateral medial lemniscus to pass directly to the ventral posteromedial nucleus of the thalamus, from which fibers project to the anterior insula and frontal operculum in the ipsilateral cerebral cortex. This region is rostral to the face area of the postcentral gyrus, which may be the area that mediates conscious perception of taste and taste discrimination.

TASTE MODALITIES, RECEPTORS, AND TRANSDUCTION A 30% change in the concentration of the substance being tasted is necessary before an intensity difference can be detected. A protein that binds taste-producing molecules is produced by the Ebner gland that secretes mucus into the cleft around vallate papillae. Ageusia (absence of the sense of taste) and hypogeusia (diminished taste sensitivity) can be caused by damage to the lingual or glossopharyngeal nerve. Neurological disorders such as vestibular schwannoma, Bell’s palsy, familial dysautonomia, multiple sclerosis, and certain infections (e.g., primary amoeboid meningoencephalopathy) can also cause problems with taste sensitivity.

CHAPTER 17 Special Senses III: Smell and Taste

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Taste pore Saliva

Glossopharyngeal nerve (IX)

Epithelial cell

Circumvallate

Taste cell Basal cell Gustatory afferent nerve

Serous gland

A

To sensory ganglion Foliate

C

Taste bud

B

Fungiform

FIGURE 17–6 Taste buds located in papillae of the human tongue. A) Taste buds on the anterior two thirds of the tongue are innervated by the chorda tympani branch of the facial nerve; those on the posterior one third of the tongue are innervated by the lingual branch of the glossopharyngeal nerve. B) The three major types of papillae (circumvallate, foliate, and fungiform) are located on specific parts of the tongue. C) Taste buds are composed of basal stem cells and three types of taste cells (dark, light, and intermediate). Taste cells extend from the base of the taste bud to the taste pore, where microvilli contact tastants dissolved in saliva and mucus. (Modified with permission from Kandel ER, Schwartz JH, Jessell TM [editors]: Principles of Neural Science, 4th ed. McGraw-Hill, 2000.)

Ageusia can also be an adverse side effect of various drugs or vitamin B3 or zinc deficiencies. Aging and tobacco abuse also contribute to diminished taste. Dysgeusia or parageusia (unpleasant perception of taste) causes a metallic, salty, foul, or rancid taste. Humans have five established basic tastes: sweet, sour, bitter, salt, and umami. All tastants are sensed from all parts of the tongue and adjacent structures. Afferent nerves to the NTS contain fibers from all types of taste receptors, without any clear localization of types. A fifth taste sense, umami, has been added to the four classic tastes. This taste is triggered by glutamate and particularly by the monosodium glutamate (MSG) used very extensively in Asian cooking. The taste is pleasant and sweet but differs from the standard sweet taste. Figure 17–8 illustrates signal transduction in taste receptors. The salty taste is triggered by NaCl. Salt-sensitive taste is mediated by a Na+-selective channel known as ENaC, the amiloride-sensitive epithelial sodium channel. The entry of Na+ into the salt receptors depolarizes the membrane, generating the receptor potential. In humans, the amiloride sensitivity of salt taste is less pronounced than in some species, suggesting that there are additional mechanisms to activate salt-sensitive receptors. The sour taste is triggered by protons (H+ ions). ENaCs permit the entry of protons and may contribute to the sensation of sour taste. The H+ ions can also bind to and block a K+sensitive channel. The decrease in K+ permeability can depolarize the membrane. A hyperpolarization-activated cyclic

nucleotide–gated cation channel, and other mechanisms may contribute to sour transduction. Substances that taste sweet also act via the G protein gustducin. The T1R3 family of G protein–coupled receptors is expressed by about 20% of taste cells, some of which also express gustducin. Sugars taste sweet, but so do compounds such as saccharin that have an entirely different structure. Natural sugars such as sucrose and synthetic sweeteners may act via different receptors on gustducin. Like the bitter-responsive receptors, sweet-responsive receptors act via cyclic nucleotides and inositol phosphate metabolism. Bitter taste is produced by a variety of unrelated compounds. Many of these are poisons, and bitter taste serves as a warning to avoid them. Some bitter compounds bind to and block K+-selective channels. Many G protein–linked receptors in the human genome are taste receptors (T2R family) and are stimulated by bitter substances such as strychnine. In some cases, these receptors couple to the heterotrimeric G protein, gustducin. Gustducin decreases cAMP and increases the formation of inositol phosphates that could lead to depolarization. Some bitter compounds are membrane permeable and may not involve G proteins; quinine is an example. Umami taste is due to activation of a truncated metabotropic glutamate receptor, mGluR4, in the taste buds. The way activation of the receptor produces depolarization is unsettled. Glutamate in food may also activate ionotropic glutamate receptors to depolarize umami receptors.

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Gustatory cortex (anterior insulafrontal operculum)

Ventral posterior medial nucleus of thalamus Geniculate ganglion

Chorda tympani

N. VII Tongue Glossopharyngeal

Nucleus of solitary tract

N. IX

Petrosal ganglion

N. X

Gustatory area

Nodose ganglion

Pharynx

FIGURE 17–7 Diagram of taste pathways. Signals from the taste buds travel via different nerves to gustatory areas of the nucleus of the tractus solitarius that relays information to the thalamus; the thalamus projects to the gustatory cortex N. VII, N. IX, and N. X are the 7th, 9th, and 10th cranial nerves, respectively. (Modified with permission from Kandel ER, Schwartz JH, Jessell TM [editors]: Principles of Neural Science, 4th ed. McGraw-Hill, 2000.)

Salty α

Sour

Predicted sweet receptor

γ

Bitter

Umami (L-glutamate)

N

X N

N

N C

C

ENaC, others

N

N C

C

ENaC, HCN, others

C T1R3 (sac locus)

C T2R family, others

C Taste mGluR4

FIGURE 17–8 Signal transduction in taste receptors. Salt-sensitive taste is mediated by a Na -selective channel (ENaC); sour taste is mediated by H+ ions permeable to ENaCs; umami taste is mediated by glutamate acting on a metabotropic receptor, mGluR4; bitter taste is mediated by the T2R family of G protein–coupled receptors; sweet taste may be dependent on the T1R3 family of G protein–coupled receptors that couple to the G protein gustducin. (Adapted with permission from Lindemann B. Receptors and transduction in taste. Nature. 2001;413:219.) +

CHAPTER 17 Special Senses III: Smell and Taste

CLINICAL CORRELATION A 10-year-old boy was riding in the front passenger seat of an automobile being driven by his father. He dropped his MP3 player and released his seat belt to retrieve it. At that moment, the car was hit from the rear by a speeding motorist. He received a sharp blow to his nose when he struck the dashboard. He was taken to the emergency room of a nearby hospital. An x-ray showed that he had broken his ethmoid bone that separates the nasal cavity from the brain. Following this accident, he lost the sense of smell (anosmia), and his sense of taste was also diminished. The olfactory nerve runs through the ethmoid bone. The nerve can be damaged when the bone is broken, resulting in the loss of the ability to smell. Because of the close relationship between taste and smell, anosmia is associated with a reduction in taste sensitivity (hypogeusia). Major causes of anosmia include upper respiratory tract infection, nasal polyps, head trauma, tumors of the frontal lobe, toxins, and prolonged use of nasal decongestants. Anosmia is generally permanent in cases in which the olfactory nerve or other neural elements in the olfactory neural pathway are damaged. In addition to not being able to experience the enjoyment of pleasant aromas and full spectrum of tastes, individuals with anosmia are at risk because they are not being able to detect the odor from such dangers as gas leaks, fire, and spoiled food

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Olfactory sensory neurons, supporting (sustentacular) cells, and basal stem cells are located in the olfactory epithelium within the upper portion of the nasal cavity. The cilia located on the dendritic knob of the olfactory sensory neuron contain odorant receptors that are coupled to heterotrimeric G proteins. Axons of olfactory sensory neurons contact the dendrites of mitral and tufted cells in the olfactory bulbs to form olfactory glomeruli. Information from the olfactory bulb travels via the lateral olfactory stria directly to the olfactory cortex, including the anterior olfactory nucleus, olfactory tubercle, piriform cortex, amygdala, and entorhinal cortex. Taste buds are the specialized sense organs for taste and are composed of basal stem cells and Type I, II, and III taste cells that may represent various stages of differentiation of developing taste cells. They are located in the mucosa of the epiglottis, palate, and pharynx and in the walls of papillae of the tongue. There are taste receptors for sweet, sour, bitter, salt, and umami tastes. Signal transduction mechanisms include passage through ion channels, binding to and blocking ion channels, and second messenger systems. The afferents from taste buds in the tongue travel via the 7th, 9th, and 10th cranial nerves to synapse in the NTS. From there, axons ascend via the ipsilateral medial lemniscus to the ventral

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posteromedial nucleus of the thalamus, and on to the anterior insula and frontal operculum in the ipsilateral cerebral cortex.

STUDY QUESTIONS 1. Odorant receptors are A) located in the olfactory bulb. B) located on dendrites of mitral and tufted cells. C) located on neurons that project directly to the olfactory cortex. D) located on neurons in the olfactory epithelium that project to mitral cells and from there directly to the olfactory cortex. E) located on sustentacular cells that project to the olfactory bulb. 2. Taste receptors A) for sweet, sour, bitter, salt, and umami tastes are spatially separated on the surface of the tongue. B) are synonymous with taste buds. C) are a type of chemoreceptor. D) are innervated by afferents in the facial, trigeminal, and glossopharyngeal nerves. E) All of the above are correct. 3. Which of the following does not increase the ability to discriminate many different odors? A) many different receptors B) pattern of olfactory receptors activated by a given odorant C) projection of different mitral cell axons to different parts of the brain D) neural processing in the amygdala E) lateral inhibition 4. Which of the following are incorrectly paired? A) ENaC:sour B) α-gustducin:bitter taste C) nucleus tractus solitarius:taste D) fungiform papillae:smell E) Ebner glands:taste acuity 5. Which of the following is true about olfactory transmission? A) An olfactory sensory neuron expresses a wide range of odorant receptors. B) Lateral inhibition within the olfactory glomeruli reduces the ability to distinguish between different types of odorant receptors. C) Conscious discrimination of odors is dependent on the pathway to the orbitofrontal cortex. D) Olfaction is closely related to gustation because odorant and gustatory receptors use the same central pathways. E) All of the above are correct. 6. Which of the following is not true about gustatory sensation? A) The sensory nerve fibers from the taste buds on the anterior two thirds of the tongue travel in the chorda tympani branch of the facial nerve. B) The sensory nerve fibers from the taste buds on the posterior third of the tongue travel in the petrosal branch of the glossopharyngeal nerve. C) The pathway from taste buds on the left side of the tongue is transmitted ipsilaterally to the cerebral cortex. D) Sustentacular cells in the taste buds serve as stem cells to permit growth of new taste buds. E) The pathway from taste receptors includes synapses in the nucleus of the tractus solitarius in the brain stem and ventral posterior medial nucleus in the thalamus.

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Control of Posture and Movement Susan M. Barman

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Describe how skilled movements are planned and carried out. Describe the posture-regulating parts of the central nervous system. Describe decerebrate and decorticate rigidity. Describe the function of the basal ganglia in control of movement. Describe the symptoms of Parkinson’s disease. Discuss the functions of the cerebellum and the neurological abnormalities produced by diseases of this part of the brain.

INTRODUCTION Somatic motor activity ultimately depends on the pattern and rate of discharge of the spinal motor neurons and homologous neurons in the motor nuclei of the cranial nerves. These neurons, the final common pathway to skeletal muscle, receive input from an array of descending pathways, other spinal neurons, and peripheral afferents. The integration of these multiple inputs regulates the posture of the body and makes coordinated movement possible. The inputs bring about voluntary activity, adjust body posture to provide a stable background for movement, and coordinate the action of the various muscles to make movements smooth and precise. As shown by the scheme in Figure 18–1, voluntary movement is planned in the cortex, basal ganglia, and lateral cerebellum. The basal ganglia and cerebellum funnel information to the premotor and motor cortex via the thalamus. Posture is continually adjusted both before and during movement by descending brain stem pathways and peripheral afferents. Movement is smoothed and coordinated by the connections of medial and intermediate portions of the cerebellum. The basal ganglia and lateral cerebellum are part of a feedback circuit to the premotor and motor cortex that is concerned with planning and organizing voluntary movement.

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CONTROL OF AXIAL AND DISTAL MUSCLES Within the brain stem and spinal cord, pathways and neurons that control skeletal muscles of the trunk and proximal portions of the limbs are located medially or ventrally. Pathways and neurons that are concerned with the control of skeletal muscles in the distal portions of the limbs are located laterally. The axial muscles are concerned with postural adjustments and gross movements; the distal limb muscles mediate fine, skilled movements. For example, neurons in the medial portion of the ventral horn innervate proximal limb muscles, particularly the flexors, and lateral ventral horn neurons innervate distal limb muscles. Similarly, the ventral corticospinal tract and medial descending brain stem pathways (rubrospinal, reticulospinal, tectospinal, and vestibulospinal tracts) are concerned with adjustments of proximal muscles and posture, and the lateral corticospinal and rubrospinal tracts are concerned with distal limb muscles and, particularly in the case of the corticospinal tract, with skilled voluntary movements.

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Basal ganglia

Idea

Cortical association areas

Premotor and motor cortex Lateral cerebellum

Movement

Intermediate cerebellum

FIGURE 18–1 Control of voluntary movement. Commands for voluntary movement originate in cortical association areas. The cortex, basal ganglia, and cerebellum work cooperatively to plan movements. Movement executed by the cortex is relayed via the corticospinal tracts and corticobulbar tracts to motor neurons. The cerebellum provides feedback to adjust and smooth movement. (Reproduced with permission from Barrett KE, Barman SM, Boitano S, Brooks H: Ganong’s Review of Medical Physiology, 23rd ed. McGraw-Hill Medical, 2009.)

CORTICOSPINAL AND CORTICOBULBAR TRACTS The axons of neurons from the motor cortex that project to spinal motor neurons form the corticospinal tracts, a large bundle of about 1 million fibers. About 80% of these fibers cross the midline in the medullary pyramids to form the lateral corticospinal tract (Figure 18–2). The other 20% form the ventral corticospinal tract, which does not cross the midline until it reaches the level of the spinal cord at which it terminates. Lateral corticospinal tract neurons make monosynaptic connections to motor neurons, especially those concerned with skilled movements, and on spinal interneurons. The trajectory from the cortex to the spinal cord passes through the corona radiata to the posterior limb of the internal capsule. Within the midbrain corticospinal tract fibers traverse the cerebral peduncle and the basilar pons until they reach the medullary pyramids on their way to the spinal cord. The corticobulbar tract is composed of the fibers that pass from the motor cortex to motor neurons in the trigeminal, facial, and hypoglossal nuclei. Corticobulbar neurons end either directly on the cranial nerve nuclei or on their antecedent interneurons within the brain stem. Their axons traverse through the genu of the internal capsule, the cerebral peduncle (medial to corticospinal tract neurons), to descend with corticospinal tract fibers in the pons and medulla. The motor system can be divided into lower and upper motor neurons. Lower motor neurons refer to the spinal and cranial motor neurons that directly innervate skeletal muscles. Upper motor neurons are those in the cortex and brain stem that activate the lower motor neurons. The pathophysiologic responses to damage to lower and upper motor neurons are very distinctive. Damage to lower motor neurons is associated with flaccid paralysis, muscular atrophy, fasciculations (visible muscle twitches that appear as flickers under the skin), hypotonia (decreased muscle tone), and hyporeflexia or areflexia. Damage to upper motor neurons initially causes muscles to become weak and flaccid but eventually leads to spasticity,

Precentral gyrus (area 4, etc)

Corticospinal tract

Internal capsule Decussation of the pyramids Pyramids

Ventral corticospinal tract (20% of fibers)

Interneuron

Lateral corticospinal tract (80% of fibers) Anterior horn cell Spinal nerve

Distal muscle Proximal muscle

FIGURE 18–2 Corticospinal tracts. This tract originates in the precentral gyrus and passes through the internal capsule. Most fibers decussate in the pyramids and descend in the lateral white matter of the spinal cord to form the lateral division of the tract that can make monosynaptic connections with spinal motor neurons. The ventral division of the tract remains uncrossed until reaching the spinal cord where axons terminate on spinal interneurons antecedent to motor neurons. (Reproduced with permission from Barrett KE, Barman SM, Boitano S, Brooks H: Ganong’s Review of Medical Physiology, 23rd ed. McGraw-Hill Medical, 2009.)

d Eye

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Motor cortex Primary somatic sensory cortex Posterior parietal cortex 4 3,1,2

7

5

7

Prefrontal cortex

FIGURE 18–3 A view of the human cerebral cortex, showing the motor cortex (Brodmann’s area 4) and other areas concerned with control of voluntary movement, along with the numbers assigned to the regions by Brodmann. (Reproduced with permission from Kandel ER, Schwartz JH, Jessell TM [editors]: Principles of Neural Science, 4th ed. McGraw-Hill, 2000.)

SA LIVA TIO

Corticospinal and corticobulbar tract neurons are pyramidal shaped and located in layer V of the cerebral cortex (see Chapter 12). Figure 18–3 shows the major cortical regions involved in motor control. About 31% of the corticospinal tract neurons are from the primary motor cortex (M1; Brodmann’s area 4) in the precentral gyrus of the frontal lobe, extending into the central sulcus. The premotor cortex and supplementary motor cortex (Brodmann’s area 6) account for 29% of the corticospinal tract neurons. The premotor area is anterior to the precentral gyrus, on the lateral and medial cortical surface, and the supplementary motor area is on and above the superior bank of the cingulate sulcus on the medial side of the hemisphere. The other 40% of corticospinal tract neurons originate in the parietal lobe (Brodmann’s area 5, 7) and primary somatosensory area (Brodmann’s area 3, 1, 2) in the postcentral gyrus. The various parts of the body are represented in M1, with the feet at the top of the gyrus and the face at the bottom (Figure 18–4). The facial area is represented bilaterally, but the rest of the representation is unilateral, with the cortical motor area controlling

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hypertonia (increased resistance to passive movement), hyperactive stretch reflexes, and abnormal plantar extensor reflex (Babinski sign). The Babinski sign is dorsiflexion of the great toe and fanning of the other toes when the lateral aspect of the sole of the foot is scratched. In adults, the normal response to this stimulation is plantar flexion in all the toes. It is of value in the localization of disease processes, but its physiologic significance is unknown.

Shoulder Elbow Wrist

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ST MA

FIGURE 18–4 Motor homunculus. The figure represents, on a coronal section of the precentral gyrus, the location of the cortical representation of the various parts. The size of the various parts is proportionate to the cortical area devoted to them. Compare with Figure 13–6. (Reproduced with permission from Penfield W, Rasmussen G: The Cerebral Cortex of Man. Macmillan, 1950.)

the musculature on the opposite side of the body. The size of the cortical representation of each body part is proportional to the number of corticospinal neurons supplying the musculature of that region of the body and its role in fine, voluntary movement. Thus, the areas involved in speech and hand movements are especially large. A somatotopic organization continues throughout the corticospinal and corticobulbar pathways. The cells in the cortical motor areas are arranged in columns. Neurons in several cortical columns project to the same muscle; also, the cells in each column receive extensive sensory input from the peripheral area in which they produce movement, providing the basis for feedback control of movement. The supplementary motor area (Figure 18–3), which projects to M1, also contains a map of the body, but it is less precise than in M1. It is involved in organizing or planning motor sequences, while M1 executes the movements. When human subjects count to themselves without speaking, the motor cortex is quiescent, but when they speak the numbers aloud, blood flow increases in M1 and the supplementary motor area. Thus, both M1 and the supplementary motor area are involved in voluntary movement when the movements being performed are complex and involve planning. The premotor cortex (Figure 18–3), which also contains a somatotopic map, receives input from sensory regions of the parietal cortex and projects to M1, the spinal cord, and the brain stem reticular formation. This region is concerned with setting posture at the start of a planned movement and with getting the individual prepared to move. It is most involved in control of proximal limb muscles needed to orient the body for movement.

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In addition to providing fibers that run in the corticospinal and corticobulbar tracts, the somatic sensory area and portions of the posterior parietal lobe project to the premotor area. Some of the neurons in area 5 (Figure 18–3) are concerned with aiming the hands toward an object and manipulating it, whereas some of the neurons in area 7 are concerned with hand–eye coordination.

MEDIAL AND LATERAL BRAIN STEM PATHWAYS: POSTURE AND VOLUNTARY MOVEMENT As mentioned above, spinal motor neurons are organized such that those innervating the most proximal muscles are located most medially and those innervating the more distal muscles are located more laterally. This organization is also reflected in descending brain stem pathways (Figure 18–5). The medial brain stem pathways, which work in concert with the ventral corticospinal tract, are the pontine and med-

A Medial brain stem pathways

ullary reticulospinal, vestibulospinal, and tectospinal tracts. These pathways descend in the ipsilateral ventral columns of the spinal cord and terminate predominantly on interneurons in the ventromedial part of the ventral horn to control axial and proximal muscles. A few medial pathway neurons synapse directly on motor neurons controlling axial muscles. The medial and lateral vestibulospinal tracts were briefly described in Chapter 16. The medial tract originates in the medial and inferior vestibular nuclei and projects bilaterally to cervical spinal motor neurons that control neck musculature. The lateral tract originates in the lateral vestibular nuclei and projects ipsilaterally to neurons at all spinal levels. It activates motor neurons to antigravity muscles (e.g., proximal limb extensors) to control posture and balance. The pontine and medullary reticulospinal tracts project to all spinal levels. They are involved in the maintenance of posture and in modulating muscle tone, especially via an input to γ-motor neurons. Pontine reticulospinal neurons are primarily excitatory and medullary reticulospinal neurons are primarily inhibitory. The tectospinal tract originates in the superior colliculus of the midbrain. It projects to the contralateral cervical spinal cord to control head and eye movements.

B Lateral brain stem pathways

Tectum

Red nucleus (magnocellular part)

Medial reticular formation

Lateral and medial vestibular nuclei

Tectospinal tract

Reticulospinal tract Vestibulospinal tracts Rubrospinal tract

FIGURE 18–5 Medial and lateral descending brain stem pathways involved in motor control. A) Medial pathways (reticulospinal, vestibulospinal, and tectospinal) terminate in ventromedial area of spinal gray matter and control axial and proximal muscles. B) Lateral pathway (rubrospinal) terminates in dorsolateral area of spinal gray matter and controls distal muscles. (Reproduced with permission from Kandel ER, Schwartz JH, Jessell TM [editors]: Principles of Neural Science, 4th ed. McGraw-Hill, 2000.)

CHAPTER 18 Control of Posture and Movement The main control of distal muscles is from the lateral corticospinal tract, but neurons within the red nucleus of the midbrain cross the midline and project to interneurons in the dorsolateral part of the spinal ventral horn to also influence motor neurons that control distal limb muscles. This rubrospinal tract excites flexor motor neurons and inhibits extensor motor neurons.

DECEREBRATION AND DECORTICATION A complete transection of the brain stem between the superior and inferior colliculi permits the brain stem pathways to function independent of their input from higher brain structures. This is called a midcollicular decerebration and is diagramed in Figure 18–6 by the dashed line labeled A. This lesion interrupts all input from the cortex and red nucleus to distal muscles of the extremities. The excitatory and inhibitory reticulospinal pathways (primarily to postural extensor muscles) remain intact. The dominance of drive from ascending sensory pathways to the excitatory reticulospinal pathway leads to decerebrate rigidity, which is characterized by hyperactivity in extensor muscles in all four extremities. This resembles what ensues after uncal herniation resulting from a supratentorial lesion as seen in patients with large tumors or a hemorrhage in the cerebral hemisphere. After decerebration, section of dorsal roots to a limb (dashed line labeled B in Figure 18–6) eliminates the hyperactivity of extensor muscles, suggesting that decerebrate rigidity is spasticity due to facilitation of the myotatic stretch reflex. The excitatory input from the reticulospinal pathway activates γ-motor neurons that indirectly activate α-motor neurons (via Ia spindle afferent activity; see Chapter 14). This is called the gamma loop. Decerebrate rigidity may also lead to direct activation of α-motor neurons. If the anterior lobe of the cerebellum is removed in a decerebrate animal (dashed line labeled C in Figure 18–6), extensor muscle hyperactivity is exaggerated (decerebellate rigidity). This cut eliminates cortical inhibition of the cerebellar fastigial nucleus and secondarily increases excitation to vestibular nuclei. This rigidity is not reversed by cutting the dorsal roots. Removal of the cerebral cortex (decortication; dashed line labeled D in Figure 18–6) produces decorticate rigidity that is characterized by flexion of the upper extremities at the elbow and extensor hyperactivity in the lower extremities. The flexion can be explained by rubrospinal excitation of flexor muscles in the upper extremities; the hyperextension of lower extremities is due to the same changes that occur after midcollicular decerebration. Decorticate rigidity is seen on the hemiplegic side in humans after hemorrhages or thromboses in the internal capsule. Sixty percent of intracerebral hemorrhages occur in the internal capsule, and 10% each in the cerebral cortex, pons, thalamus, and cerebellum.

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BASAL GANGLIA The basal ganglia are comprised of the caudate nucleus, putamen, globus pallidus, and the functionally related subthalamic nucleus and substantia nigra (Figure 18–7). The globus pallidus is divided into external and internal segments (GPe and GPi). The substantia nigra is divided into pars compacta and pars reticulata. The caudate nucleus and putamen are collectively called the striatum; the putamen and globus pallidus form the lenticular nucleus. The main inputs to the basal ganglia terminate in the striatum (Figure 18–8). They include the excitatory corticostriate pathway from M1 and premotor cortex. There is also a projection from intralaminar nuclei of the thalamus to the striatum (thalamostriatal pathway). The connections between the parts of the basal ganglia include a dopaminergic nigrostriatal projection from the substantia nigra pars compacta to the striatum and a corresponding GABAergic projection from the striatum to substantia nigra pars reticulata. The striatum projects to both GPe and GPi. GPe projects to the subthalamic nucleus, which in turn projects to both GPe and GPi. The principal output from the basal ganglia is from GPi via the thalamic fasciculus to the ventral lateral, ventral anterior, and centromedian nuclei of the thalamus. From the thalamic nuclei, fibers project to the prefrontal and premotor cortex. The substantia nigra also projects to the thalamus. The main feature of the connections of the basal ganglia is that the cerebral cortex projects to the striatum, the striatum to GPi, GPi to the thalamus, and the thalamus back to the cortex, completing a loop. The output from GPi to the thalamus is inhibitory, whereas the output from the thalamus to the cerebral cortex is excitatory.

FUNCTION The basal ganglia are involved in the planning and programming of voluntary movement (Figure 18–1). They influence the motor cortex via the thalamus. Also, GPi projects to brain stem nuclei and from there to motor neurons in the brain stem and spinal cord. Three biochemical pathways in the basal ganglia normally operate in a balanced fashion (Figure 18–8): (1) the nigrostriatal dopaminergic system, (2) the intrastriatal cholinergic system, and (3) the GABAergic system, which projects from the striatum to the globus pallidus and substantia nigra. When one or more of these pathways become dysfunctional, characteristic motor abnormalities occur. Diseases of the basal ganglia lead to two general types of disorders: hyperkinetic and hypokinetic. The hyperkinetic conditions are those in which movement is excessive and abnormal, including tremor, chorea, athetosis, and ballism. Hypokinetic abnormalities include akinesia and bradykinesia. Chorea is characterized by rapid, involuntary “dancing” movements. Athetosis is characterized by continuous, slow

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FIGURE 18–6 A circuit drawing representing lesions produced in experimental animals to replicate decerebrate and decorticate deficits seen in humans. Bilateral transections are indicated by dashed lines A–D. Decerebration is at a midcollicular level (A), decortication is rostral to the superior colliculus, dorsal roots sectioned for one extremity (B), and removal of anterior lobe of cerebellum (C). The objective was to identify anatomic substrates responsible for decerebrate or decorticate rigidity/posturing seen in humans with lesions that either isolate the forebrain from the brain stem or separate rostral from caudal brain stem and spinal cord. (Reproduced with permission from Haines DE [editor]: Fundamental Neuroscience for Basic and Clinical Applications, 3rd ed. Elsevier, 2006.)

writhing movements. Choreiform and athetotic movements have been likened to the start of voluntary movements occurring in an involuntary, disorganized way. In ballism, involuntary flailing, intense, and violent movements occur. Akinesia is difficulty in initiating movement and decreased spontaneous movement. Bradykinesia is slowness of movement.

PARKINSON’S DISEASE Parkinson’s disease has both hypokinetic and hyperkinetic features. It was the first disease identified as being due to a deficiency in a specific neurotransmitter; it is due to the degeneration of dopaminergic neurons in the substantia nigra pars

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Caudate nucleus Thalamus Thalamus Internal capsule Lateral ventricle

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Caudate nucleus

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l ca

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Tail of caudate nucleus

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FIGURE 18–7 Basal ganglia. The basal ganglia are composed of the caudate nucleus, putamen, and globus pallidus and the functionally related subthalamic nucleus and substantia nigra. The frontal (coronal) section shows the location of the basal ganglia in relation to surrounding structures. (Reproduced with permission from Barrett KE, Barman SM, Boitano S, Brooks H: Ganong’s Review of Medical Physiology, 23rd ed. McGraw-Hill Medical, 2009.) compacta. It is one of the most common neurodegenerative diseases; it is estimated to occur in 1–2% of individuals over age 65. Symptoms appear when 60–80% of the nigrostriatal dopaminergic neurons degenerate. The hypokinetic features of Parkinson’s disease are akinesia and bradykinesia, and the hyperkinetic features are

Cerebral cortex Glu Globus pallidus, ES GABA

GABA

Glu

GABA

Subthalamic Glu nucleus Brain stem and spinal cord

Striatum (acetylcholine) GABA

Globus pallidus, IS

GABA PPN

GABA

SNPR

DA SNPC

GABA

Thalamus

FIGURE 18–8 Diagrammatic representation of the principal connections of the basal ganglia. Solid lines indicate excitatory pathways, dashed lines inhibitory pathways. The transmitters are indicated in the pathways, where they are known. Glu, glutamate; DA, dopamine. Acetylcholine is the transmitter produced by interneurons in the striatum. SNPR, substantia nigra pars reticulata; SNPC, substantia nigra pars compacta; ES, external segment; IS, internal segment; PPN, pedunculopontine nuclei. The subthalamic nucleus also projects to the pars compacta of the substantia nigra; this pathway has been omitted for clarity. (Reproduced with permission from Barrett KE, Barman SM, Boitano S, Brooks H: Ganong’s Review of Medical Physiology, 23rd ed. McGraw-Hill Medical, 2009.)

cogwheel rigidity and tremor at rest. The absence of motor activity and the difficulty in initiating voluntary movements are striking. Normal, unconscious movements such as swinging of the arms during walking, facial expressions, and fidgeting are absent in Parkinson’s disease. The rigidity is different from spasticity because motor neuron discharge increases to both the agonist and antagonist muscles. Passive motion of an extremity meets with a plastic, dead-feeling resistance that has been likened to bending a lead pipe and is therefore called lead pipe rigidity. Sometimes a series of “catches” takes place during passive motion (cogwheel rigidity), but the sudden loss of resistance seen in a spastic extremity is absent. The tremor, which is present at rest and disappears with activity, is due to regular, alternating contractions of antagonistic muscles. A common treatment for Parkinson’s disease is the administration of l-DOPA (levodopa). Unlike dopamine, this dopamine precursor crosses the blood–brain barrier and helps repair the dopamine deficiency. However, the degeneration of these neurons continues and in 5–7 years, the beneficial effects of l-DOPA usually disappear.

CEREBELLUM The cerebellum sits astride the main sensory and motor systems in the brain stem and is connected to the brain stem by the superior, middle, and inferior peduncles. From a functional point of view, the cerebellum is divided into three parts (Figure 18–9). The vestibulocerebellum has vestibular connections and is concerned with equilibrium and eye

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Spinocerebellum

To medial descending systems To lateral descending systems

ning and programming movements. The medial portion of the cerebellum is called the vermis and it projects to the brain stem area concerned with control of axial and proximal limb muscles (medial brain stem pathways). The area just lateral to the vermis projects to the brain stem areas concerned with control of distal limb muscles (lateral brain stem pathways).

Motor execution

To motor Motor and premotor planning cortices Balance To vestibular and eye movements nuclei

Cerebrocerebellum

CELLULAR ORGANIZATION OF THE CEREBELLUM

Vestibulocerebellum

FIGURE 18–9 Functional divisions of the cerebellum. (Modified with permission from Kandel ER, Schwartz JH, Jessell TM [editors]: Principles of Neural Science, 4th ed. McGraw-Hill, 2000.)

movements. The spinocerebellum receives proprioceptive input from the body as well as a copy of the “motor plan” from the motor cortex. It functions to smooth out and coordinate ongoing movements. The cerebrocerebellum in the lateral hemisphere interacts with the motor cortex in plan-

The cerebellar cortex contains five types of neurons: Purkinje, granule, basket, stellate, and Golgi cells (Figure 18–10). The Purkinje cells are among the biggest neurons in the CNS, with extensive dendritic arbors. They are the only output neurons of the cerebellar cortex, and their synaptic actions are inhibitory via GABA release. The granule cells innervate the Purkinje cells; their axons bifurcate to form a T. The branches of the T are straight and run long distances; thus, they are called parallel fibers. The parallel fibers make synaptic contact with the dendrites of many Purkinje cells and release glutamate (an excitatory neurotransmitter). The other three types of neurons in the cerebellar cortex are inhibitory interneurons that release GABA. Basket cells

5 Stellate cell

Parallel fibers: Axons of granule cells Axon 1 Purkinje cell

Molecular layer

1

Purkinje layer Axon

Granular layer 4 Granule cell

2

5 4 3

2 Golgi cell

3 Basket cell Axons

FIGURE 18–10 Location and structure of five neuronal types in the cerebellar cortex. Drawings are based on Golgi-stained preparations. Purkinje cells (1) have processes aligned in one plane; their axons are the only output from the cerebellum. Axons of granule cells (4) traverse and make connections with Purkinje cell processes in molecular layer. Golgi (2), basket (3), and stellate (5) cells have characteristic positions, shapes, branching patterns, and synaptic connections. (Reproduced with permission from Kuffler SW, Nicholls JG, Martin AR: From Neuron to Brain, 2nd ed. Sinauer, 1984.)

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modulating or timing the excitatory output of the deep cerebellar nuclei to the brain stem and thalamus.

Parallel fiber Cerebellar cortex

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FIGURE 18–11 Diagram of neural connections in the cerebellum. Plus (+) and minus (–) signs indicate whether endings are excitatory or inhibitory. BC, basket cell; GC, Golgi cell; GR, granule cell; NC, cell in deep nucleus; PC, Purkinje cell. Note that PCs and BCs are inhibitory. The connections of the stellate cells, which are not shown, are similar to those of the basket cells, except that they end for the most part on Purkinje cell dendrites. (Reproduced with permission from Barrett KE, Barman SM, Boitano S, Brooks H: Ganong’s Review of Medical Physiology, 23rd ed. McGraw-Hill Medical, 2009.)

receive input from the parallel fibers, and each projects to many Purkinje cells (Figure 18–10). Their axons form a basket around the cell body and axon hillock of each Purkinje cell they innervate. Stellate cells are similar to the basket cells but more superficial in location. The dendrites of Golgi cells receive input from the parallel fibers. Their cell bodies receive input from the mossy fibers, and their axons project to the dendrites of the granule cells. The primary afferent inputs to the cerebellum are the mossy and climbing fibers, both of which are excitatory (Figure 18–11). The climbing fibers relay proprioceptive input from a single source, the inferior olivary nuclei. The mossy fibers provide proprioceptive input as well as input from the cerebral cortex via the pontine nuclei. The fundamental circuits of the cerebellar cortex are relatively simple (Figure 18–11). Climbing fiber inputs exert a strong excitatory effect on a single Purkinje cell, and mossy fiber inputs exert a weak excitatory effect on many Purkinje cells via the granule cells. The basket and stellate cells are also excited by granule cells via the parallel fibers, and their output inhibits Purkinje cell discharge (feed-forward inhibition). Golgi cells are excited by the mossy fiber collaterals, Purkinje cell collaterals, and parallel fibers, and they inhibit transmission from mossy fibers to granule cells. The output of Purkinje cells is inhibitory to the deep cerebellar nuclei. These nuclei also receive excitatory inputs via collaterals from the mossy and climbing fibers. Thus, almost all the cerebellar circuitry seems to be concerned solely with

Damage to the cerebellum leads to several characteristic abnormalities, including hypotonia, ataxia, and intention tremor. Most abnormalities are apparent during movement. The marked ataxia is characterized as incoordination due to errors in the rate, range, force, and direction of movement. Ataxia is manifest not only in the wide-based, unsteady, “drunken” gait of patients, but also in defects of the skilled movements involved in the production of speech. The individual pauses between words and syllables, a phenomenon referred to as scanning speech. Voluntary movements are also highly abnormal. As an example, if one attempts to touch an object with a finger, there is an overshoot to one side or the other. This dysmetria promptly initiates a gross corrective action, but the correction overshoots to the other side. Consequently, the finger oscillates back and forth. This oscillation is the intention tremor of cerebellar disease. Another characteristic of cerebellar disease is the inability to stop movement promptly. Normally, for example, flexion of the forearm against resistance is quickly checked when the resistance force is suddenly broken off. The patient with cerebellar disease cannot stop the movement of the limb, and the forearm flies backward in a wide arc (rebound phenomenon). This is one of the reasons these patients show dysdiadochokinesia, the inability to perform rapidly alternating opposite movements such as repeated pronation and supination of the hands. Finally, patients with cerebellar disease have difficulty performing actions that involve simultaneous motion at more than one joint. They dissect such movements and carry them out one joint at a time (decomposition of movement). Motor abnormalities associated with cerebellar damage vary depending on the region involved. The major dysfunctions seen after damage to the vestibulocerebellum are ataxia, dysequilibrium, and nystagmus. Damage to the vermis and fastigial nucleus (part of the spinocerebellum) leads to disturbances in control of axial and trunk muscles during attempted antigravity postures and scanning speech. Degeneration of this portion of the cerebellum can result from thiamine deficiency in alcoholics or malnourished individuals. The major dysfunctions seen after damage to the cerebrocerebellum are delays in initiating movements and decomposition of movement.

CLINICAL CORRELATION About 2 years ago at the age of 34, a man developed progressive weakness in his right leg and eventually his whole right side weakened. He was unable to continue his work as an electrician. He experienced cramps in his right calf muscle and muscle twitches in his arm and leg. A neurological examination revealed muscular atrophy,

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fasciculations (muscle twitches that appear as flickers under the skin), and hypotonia of muscles in the arm and leg. He also had marked hyporeflexia. Sensory and cognitive function tests were normal. All signs were indicative of a lower motor neuron disease affecting multiple spinal cord levels. He was eventually diagnosed with amyotrophic lateral sclerosis (ALS). Over the course of the next year, the disease progressed to the point where he had difficulty swallowing (dysphagia), so he had to be fed via a gastric tube. About 6 months ago, he developed difficulty breathing and was placed on a ventilator. One week ago, he died of pneumonia. ALS is a selective, progressive degeneration of α-motor neurons. “Amyotrophic” means “no muscle nourishment” and describes the atrophy that muscles undergo because of disuse. “Sclerosis” refers to the hardness felt when a pathologist examines the spinal cord on autopsy; the hardness is due to proliferation of astrocytes and scarring of the lateral columns of the spinal cord. This fatal disease is also known as Lou Gehrig’s disease in recognition of a famous American baseball player who died of it. The worldwide annual incidence of ALS is estimated to be 0.5–3 cases per 100,000 people. Most cases are sporadic, but 5–10% of the cases are familial. Forty percent of the familial cases have a mutation in the gene for Cu/Zn superoxide dismutase (SOD-1) on chromosome 21. SOD is a free radical scavenger that reduces oxidative stress. A defective SOD-1 gene permits free radicals to accumulate and kill neurons. The disease has no racial, socioeconomic, or ethnic boundaries. The life expectancy of ALS patients is usually 3–5 years after diagnosis. ALS is most commonly diagnosed in middle age and affects men more often than women. The causes of ALS are unclear, but may include viruses, neurotoxins, heavy metals, DNA defects (especially in familial ALS), immune system abnormalities, and enzyme abnormalities. There is no cure for ALS; treatments (e.g., physical and occupational therapy) focus on relieving symptoms and maintaining the quality of life.

CHAPTER SUMMARY ■

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The ventral corticospinal tract and medial descending brain stem pathways (tectospinal, reticulospinal, and vestibulospinal tracts) regulate proximal muscles and posture. The lateral corticospinal and rubrospinal tracts control distal limb muscles and skilled voluntary movements. Decerebrate rigidity leads to hyperactivity in extensor muscles in all four extremities; it is actually spasticity due to facilitation of the myotatic stretch reflex. Decorticate posturing or decorticate rigidity is flexion of the upper extremities at the elbow and extensor hyperactivity in the lower extremities. The basal ganglia include the caudate nucleus, putamen, globus pallidus, subthalamic nucleus, and substantia nigra. The connections between the parts of the basal ganglia include a dopaminergic nigrostriatal projection from the substantia nigra

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to the striatum and a GABAergic projection from the striatum to substantia nigra. Parkinson’s disease is due to degeneration of the nigrostriatal dopaminergic neurons and is characterized by akinesia, bradykinesia, cogwheel rigidity, and tremor at rest. The cerebellar cortex contains five types of neurons: Purkinje, granule, basket, stellate, and Golgi cells. The two main inputs to the cerebellar cortex are climbing fibers and mossy fibers. Purkinje cells are the only output from the cerebellar cortex and they generally project to the deep nuclei. Damage to the cerebellum leads to several characteristic abnormalities, including hypotonia, ataxia, and intention tremor.

STUDY QUESTIONS 1. A primary function of the basal ganglia is A) sensory integration. B) short-term memory. C) planning voluntary movement. D) neuroendocrine control. E) slow-wave sleep. 2. The therapeutic effect of l-DOPA in patients with Parkinson’s disease eventually wears off because A) antibodies to dopamine receptors develop. B) inhibitory pathways grow into the basal ganglia from the frontal lobe. C) cholinergic neurons in the striatum degenerate. D) the normal action of nerve growth factor (NGF) is disrupted. E) the dopaminergic neurons in the substantia nigra continue to degenerate. 3. Increased neural activity before a skilled voluntary movement is first seen in the A) spinal motor neurons. B) precentral motor cortex. C) midbrain. D) cerebellum. E) cortical association areas. 4. After falling down a flight of stairs, a young woman is found to have partial loss of voluntary movement on the right side of her body and loss of pain and temperature sensation on the left side below the midthoracic region. It is probable that she has a lesion A) transecting the left half of the spinal cord in the lumbar region. B) transecting the left half of the spinal cord in the upper thoracic region. C) transecting sensory and motor pathways on the right side of the pons. D) transecting the right half of the spinal cord in the upper thoracic region. E) transecting the dorsal half of the spinal cord in the upper thoracic region. 5. Which of the following are not correctly paired? A) medial brain stem pathways:axial and proximal muscle control B) lateral brain stem pathway:rubrospinal tract C) upper motor neuron disease:hypotonia D) cerebellar disease:intention tremor E) decerebrate rigidity:hyperactivity of extensor muscles

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Autonomic Nervous System Susan M. Barman

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Describe the location of the cell bodies and axonal trajectories of preganglionic sympathetic and parasympathetic neurons. Describe the location and trajectories of postganglionic sympathetic and parasympathetic neurons. Name the neurotransmitters that are released by preganglionic and postganglionic autonomic neurons. List the major functions of the autonomic nervous system. Identify some of the neural inputs to sympathetic and parasympathetic neurons.

INTRODUCTION The autonomic nervous system (ANS) is one of the control systems responsible for homeostasis and is the source of innervation of organs other than skeletal muscle. Nerve terminals are located in smooth muscle (e.g., blood vessels, gut wall, urinary bladder), cardiac muscle, and glands (e.g., sweat glands, salivary glands). Although survival is possible without an ANS, the ability to adapt to environmental stressors and other challenges is severely compromised in diseases that affect this component of the nervous system. The ANS has two major divisions: sympathetic and parasympathetic nervous systems. It is classically defined by the preganglionic and postganglionic neurons within the sympathetic and parasympathetic divisions. A more modern definition of the ANS takes into account the descending pathways from several forebrain and brain stem regions as well as visceral afferent pathways that set the level of activity in sympathetic and parasympathetic nerves.

ANATOMIC ORGANIZATION OF AUTONOMIC OUTFLOW Figure 19–1 compares some fundamental characteristics of the innervation of skeletal muscle and innervation of smooth muscle, cardiac muscle, and glands. As described in Chapter 14,

Ch19_177-184.indd 177

α-motor neurons serve as the final common pathway linking the central nervous system (CNS) to skeletal muscles. Similarly, sympathetic and parasympathetic neurons serve as the final common pathway from the CNS to visceral targets. However, the peripheral portion of the ANS is composed of two neurons: preganglionic and postganglionic neurons. The cell bodies of the preganglionic neurons are located in the intermediolateral column (IML) of the spinal cord and in motor nuclei of some cranial nerves. In contrast to the large-diameter and rapidly conducting α-motor neurons, preganglionic axons are small-diameter and relatively slowly conducting B fibers. A preganglionic axon diverges to an average of about nine postganglionic neurons, making autonomic output diffuse. The axons of the postganglionic neurons are mostly unmyelinated C fibers and terminate on the visceral effectors.

SYMPATHETIC DIVISION In contrast to α-motor neurons that are located at all spinal segments, sympathetic preganglionic neurons are located in the IML of only the first thoracic to the third or fourth lumbar segments. This is why the sympathetic nervous system is sometimes called the thoracolumbar division of the ANS. The axons of sympathetic preganglionic neurons leave the spinal cord at the level at which their cell bodies are located and exit via the ventral root along with axons of α- and

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Somatic nervous system

CNS

Effector organ ACh Autonomic nervous system: Parasympathetic division

CNS

Effector organ Ganglion

ACh

Autonomic nervous system: Sympathetic division

CNS

Effector organ ACh

Ganglion

ACh

(via bloodstream) Adrenal medulla

NE Effector organ

Epi (also NE, DA, peptides)

FIGURE 19–1 Comparison of peripheral organization and transmitters released by somatomotor and autonomic nervous systems (NS). ACh, acetylcholine; DA, dopamine; NE, norepinephrine; Epi, epinephrine. (Reproduced with permission from Widmaier EP, Raff H, Strang KT: Vander’s Human Physiology. McGraw-Hill, 2008.)

γ-motor neurons (Figure 19–2). They then separate from the ventral root via the white rami communicans and project to the adjacent sympathetic paravertebral ganglion, where some of them end on the cell bodies of postganglionic neurons. Paravertebral ganglia are located adjacent to each thoracic and upper lumbar segment; in addition, there are a few ganglia adjacent to the cervical and sacral spinal segments. Paravertebral ganglia form the sympathetic chain (or sympathetic trunk) bilaterally. The ganglia are connected to each other via the axons of preganglionic neurons that travel rostrally or caudally to terminate on postganglionic neurons located at some distance. This arrangement is shown in Figures 19–2 and 19–3. Some preganglionic neurons pass through the sympathetic chain and end on postganglionic neurons located in prevertebral (or collateral) ganglia close to the viscera, including the celiac, superior mesenteric, and inferior mesenteric ganglia (Figure 19–3). There are also preganglionic neurons whose axons terminate directly on an effector organ, the medulla of the adrenal gland. The axons of some of the postganglionic neurons leave the chain ganglia and reenter the spinal nerves via the gray rami communicans and are distributed to autonomic effectors in the areas supplied by these spinal nerves (Figure 19–2). These postganglionic sympathetic nerves terminate on smooth muscle of blood vessels and hair follicles and on sweat glands in the limbs. Other postganglionic fibers leave the chain ganglia to enter the thoracic cavity to terminate in visceral organs. Postganglionic fibers from prevertebral ganglia also terminate in visceral targets.

PARASYMPATHETIC DIVISION The parasympathetic nervous system is sometimes called the craniosacral division of the ANS because of the location of its preganglionic neurons (Figure 19–3). The parasympathetic nerves supply the visceral structures in the head via the oculomotor, facial, and glossopharyngeal nerves, and those in the thorax and upper abdomen via the vagus nerves. The sacral outflow supplies the pelvic viscera via branches of the second to fourth sacral spinal nerves. Parasympathetic preganglionic fibers synapse on ganglia cells clustered within the walls of visceral organs; thus, these parasympathetic postganglionic fibers are very short.

CHEMICAL TRANSMISSION AT AUTONOMIC JUNCTIONS ACETYLCHOLINE AND NOREPINEPHRINE The principal transmitter agents released by autonomic nerves are acetylcholine and norepinephrine (Figure 19–1). The neurons that are cholinergic (i.e., release acetylcholine) include (1) all preganglionic neurons, (2) all parasympathetic postganglionic neurons, (3) sympathetic postganglionic neurons that innervate sweat glands, and (4) sympathetic postganglionic neurons that end on blood vessels in some skeletal muscles and produce vasodilation when stimulated

CHAPTER 19 Autonomic Nervous System

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FIGURE 19–2 Projection of sympathetic preganglionic and postganglionic fibers. The drawing shows the thoracic spinal cord, paravertebral, and prevertebral ganglia. Preganglionic neurons are shown in red, postganglionic neurons in dark blue, afferent sensory pathways in blue, and interneurons in black. (Reproduced with permission from Boron WF, Boulpaep EL: Medical Physiology. Elsevier, 2005.)

(sympathetic vasodilator nerves). The remaining sympathetic postganglionic neurons are noradrenergic (i.e., release norepinephrine). The adrenal medulla is essentially a sympathetic ganglion in which the postganglionic cells have lost their axons and secrete norepinephrine and epinephrine directly into the bloodstream. Transmission in autonomic ganglia is mediated primarily by N2 nicotinic cholinergic receptors that are blocked by hexamethonium, whereas transmission at the neuromuscular junction is via N1 nicotinic cholinergic receptors that are blocked by D-tubocurare. The release of acetylcholine from postganglionic fibers acts on muscarinic receptors, which are blocked by atropine. The release of norepinephrine from sympathetic postganglionic fibers acts on α1-, α2-, β1-, or β2-adrenoreceptors, depending on the target organ. Table 19–1 shows the types of receptors at various junctions within the ANS. In addition to these “classical” neurotransmitters, some autonomic fibers also release neuropeptides. The small granulated vesicles in postganglionic noradrenergic neurons contain ATP and norepinephrine, and the large granulated vesicles

contain neuropeptide Y. Low-frequency stimulation may promote release of ATP, whereas high-frequency stimulation may cause release of neuropeptide Y. The viscera contain purinergic receptors, and ATP may be a mediator in the ANS along with norepinephrine.

RESPONSES OF EFFECTOR ORGANS TO AUTONOMIC NERVE IMPULSES The effects of stimulation of the noradrenergic and cholinergic postganglionic nerve fibers are indicated in Figure 19–3 and Table 19–1. Release of acetylcholine onto smooth muscle of some organs leads to contraction (e.g., walls of the gastrointestinal tract), and release onto other organs leads to relaxation (e.g., sphincters in the gastrointestinal tract). For some targets innervated by the ANS, one can shift from contraction to relaxation by switching from activation of the parasympathetic nervous system to activation of the

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FIGURE 19–3 Organization of sympathetic (left) and parasympathetic (right) nervous systems. Preganglionic sympathetic and parasympathetic neurons are shown in red and orange, respectively; postganglionic sympathetic and parasympathetic neurons in blue and green, respectively. (Reproduced with permission from Boron WF, Boulpaep EL: Medical Physiology. Elsevier, 2005.)

CHAPTER 19 Autonomic Nervous System

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TABLE 19–1 Responses of some effector organs to autonomic nerve activity. Sympathetic Nervous System Effector Organs

Parasympathetic Nervous System

Receptor Type

Response

Radial muscle of iris

—

α1

Contraction (mydriasis)

Sphincter muscle of iris

Contraction (miosis)

—

Ciliary muscle

Contraction for near vision

—

Eyes a

Heart SA node

Decreases heart rate

β1

Increases heart rate

Atria and ventricle

Decreases contractility

β 1 , β2

Increases contractility

AV node and Purkinje

Decreases conduction velocity

β 1 , β2

Increases conduction velocity

—

α1, α2

Constriction

β2

Dilation

Arterioles Coronary

Skin

—

α1, α2

Constriction

Skeletal muscle

—

α1

Constriction

β2, Muscarinic

Dilation

Abdominal viscera

—

α1

Constriction

Salivary glands

Dilation

α1, α2

Constriction

Renal

—

α1

Constriction

—

α1, α2

Constriction

β2

Dilation

Systemic veins

Lungs Bronchial muscle

Contraction

β2

Relaxation

Bronchial glands

Stimulation

α1

Inhibition

β2

Stimulation

Stomach Motility and tone

Increases

α1, α2, β2

Decreases

Sphincters

Relaxation

α1

Contraction

Secretion

Stimulation

Unknown

Inhibition

Motility and tone

Increases

α1, α2, β1, β2

Decreases

Sphincters

Relaxation

α1

Contraction (usually)

Secretion

Stimulation

α2

Inhibition

Gall bladder

Contraction

β2

Relaxation

Detrusor

Contraction

β2

Relaxation

Sphincter

Relaxation

α1

Contraction

Intestine

Urinary bladder

(Continued)

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TABLE 19–1 Responses of some effector organs to autonomic nerve activity. (Continued) Sympathetic Nervous System Effector Organs

Parasympathetic Nervous System

Receptor Type

Response

Uterus

Variable

α1

Contraction (pregnant)

β2

Relaxation

Erection

α1

Ejaculation

—

α1

Contraction

α1

Slight, localized secretionb

Muscarinic

Generalized abundant, dilute secretion

—

α1, β2

Glycogenolysis

Exocrine glands

Increases secretion

α

Decreases secretion

Endocrine glands

—

α2

Inhibits secretion

Profuse, watery secretion

α1

Thick, viscous secretion

β

Amylase secretion

Male sex organs Skin Pilomotor muscles Sweat glands

Liver Pancreas

Salivary glands

Lacrimal glands

Secretion

Adipose tissue

—

— α2, β3

Lipolysis

a

A dash means these cells are not innervated by this division of the autonomic nervous system.

b

On palms of hands and in some other locations (“adrenergic sweating”).

Modified with permission from Hardman JG, Limbird LE, Gilman AG [editors]: Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 10th ed. McGraw-Hill, 2001.

sympathetic nervous system. This is the case for the many organs that receive dual innervation with antagonistic effects, including the digestive tract, airways, and urinary bladder. The heart is another example of an organ with dual antagonistic control. Stimulation of sympathetic nerves increases heart rate, and stimulation of parasympathetic nerves decreases heart rate. In other cases, the effects of sympathetic and parasympathetic activation are complementary. An example is the innervation of salivary glands. Parasympathetic activation causes release of watery saliva, while sympathetic activation causes the production of thick, viscous saliva. The two divisions of the ANS act in a synergistic or cooperative manner in the control of some functions. One example is the control of pupil diameter in the eye. Both sympathetic and parasympathetic innervations are excitatory, but the former contracts the radial muscle to dilate the pupil (mydriasis) and the latter contracts the sphincter muscle to constrict the pupil (miosis). Another example is the synergistic actions of these nerves on sexual function. Activation of parasympathetic nerves to the penis increases blood flow and leads to erection while activation of sympathetic nerves to the male genitalia causes ejaculation.

There are also several organs that are innervated by only one division of the ANS. The adrenal medulla, most blood vessels, the pilomotor muscles in the skin (hair follicles), and sweat glands are innervated exclusively by sympathetic nerves. The lacrimal muscle (tear gland), ciliary muscle (for accommodation for near vision), and the sublingual salivary gland are innervated exclusively by parasympathetic nerves. The parasympathetic nervous system is largely concerned with the vegetative aspects of day-to-day living and is sometimes called the anabolic nervous system. For example, parasympathetic action favors digestion and absorption of food by increasing the activity of the intestinal musculature, increasing gastric secretion, and relaxing the pyloric sphincter. The sympathetic nervous system can prepare an individual to cope with an emergency and can be called the catabolic nervous system. Sympathetic activity dilates the pupils (letting more light into the eyes), accelerates the heartbeat and raises blood pressure (providing better perfusion of the vital organs and muscles), and constricts blood vessels in the skin (which limits bleeding from wounds). Sympathetic discharge also leads to elevated plasma glucose and free fatty acid levels (supplying more energy).

CHAPTER 19 Autonomic Nervous System

REFLEX AND CENTRAL CONTROL OF AUTONOMIC ACTIVITY As is the case for α-motor neurons, the activity of autonomic nerves depends on reflexes (e.g., baroreceptor and chemoreceptor reflexes) and on descending excitatory and inhibitory inputs from several brain regions. For example, preganglionic sympathetic neurons in the IML receive excitatory input from the rostral ventrolateral medulla and the paraventricular nucleus of the hypothalamus and inhibitory input from medullary raphe neurons. In addition to these direct pathways to the IML, there are many brain regions that feed into these pathways to regulate autonomic nerve activity. These include the caudal ventrolateral medulla, nucleus of the tractus solitarius, and locus ceruleus. This is analogous to the control of somatomotor function by areas such as the basal ganglia and cerebellum. Chapters 29 and 30 describe reflex and central mechanisms that regulate autonomic nerves as related to the control of the cardiovascular system in health and disease. The hypothalamus is often regarded as a major central autonomic control area. Indeed, many of the complex autonomic mechanisms that maintain homeostasis are integrated in the hypothalamus. The hypothalamus also functions with the limbic system as a unit that regulates emotional and instinctual behavior. It interconnects with nuclei in the midbrain, pons, and medulla to regulate autonomic activity. The autonomic responses triggered by activation of the hypothalamus are part of complex phenomena such as eating, emotions such as rage, and responses to stress.

CLINICAL CORRELATION A 67-year-old retired biology professor suddenly collapsed at his home when he stood up from a reclining position. His wife called for an ambulance and reported he was pale but never lost consciousness. He was taken to a local hospital. His blood pressure was normal in a reclining position but decreased to hypotensive levels when he stood. On questioning, he reported that he began to experience erectile dysfunction about 6 months ago. He also has noticed difficulty adapting to altered environmental temperatures. Episodes of urinary incontinence have also been experienced. The physician detected a mild degree of ataxia (staggering gait) and tremor. After a series of neurological exams, he was diagnosed with Shy–Drager syndrome that is a subtype of multiple system atrophy (MSA) in which autonomic failure dominates. MSA is a neurodegenerative disorder associated with autonomic failure due to loss of preganglionic autonomic neurons in the spinal cord and brain stem. In the

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absence of an ANS, it is difficult to regulate body temperature, fluid and electrolyte balance, and blood pressure. MSA can also present with cerebellar, basal ganglia, locus ceruleus, inferior olivary nucleus, and pyramidal tract deficits. It is defined as a sporadic, progressive, adultonset disorder characterized by autonomic dysfunction, parkinsonism, and cerebellar ataxia in any combination. The pathological hallmark of MSA is cytoplasmic and nuclear inclusions in oligodendrocytes and neurons in central motor and autonomic areas. There is also depletion of monoaminergic, cholinergic, and peptidergic markers in several brain regions and in the cerebrospinal fluid. Basal levels of sympathetic activity and plasma norepinephrine levels are normal in MSA patients, but they fail to increase in response to standing up or other stimuli and lead to severe orthostatic hypotension (low blood pressure upon standing). In addition to the decrease in blood pressure, orthostatic hypotension can lead to dizziness, dimness of vision, and fainting because of insufficient perfusion of the brain. MSA is also accompanied by parasympathetic dysfunction, including urinary and sexual dysfunction. MSA is most often diagnosed in individuals between 50 and 70 years of age; it affects more men than women. Erectile dysfunction is often the first symptom of the disease. There are also abnormalities in baroreceptor reflex and respiratory control mechanisms. Although autonomic abnormalities are often the first symptoms, 75% of patients with MSA also experience motor disturbances. There is no cure for MSA. Treatment is directed toward assuring patient comfort and maintaining bodily functions as long as possible.

CHAPTER SUMMARY ■

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■

■

Preganglionic sympathetic neurons are located in the IML of the thoracolumbar spinal cord and project to postganglionic neurons in the paravertebral or prevertebral ganglia or the adrenal medulla. Preganglionic parasympathetic neurons are located in motor nuclei of cranial nerves III, VII, IX, and X and the sacral IML. Nerve terminals of postganglionic neurons are located in smooth muscle (e.g., blood vessels, gut wall, urinary bladder), cardiac muscle, and glands (e.g., sweat gland, salivary glands). Acetylcholine is released at nerve terminals of preganglionic neurons, postganglionic parasympathetic neurons, and a few postganglionic sympathetic neurons (sweat glands, sympathetic vasodilator fibers). The remaining sympathetic postganglionic neurons release norepinephrine. Sympathetic activity can prepare the individual to cope with an emergency by accelerating the heartbeat, raising blood pressure (perfusion of the vital organs), and constricting the blood vessels of the skin (limits bleeding from wounds). Parasympathetic activity is concerned with the vegetative aspects of

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SECTION IV CNS/Neural Physiology day-to-day living and favors digestion and absorption of food by increasing the activity of the intestinal musculature, increasing gastric secretion, and relaxing the pyloric sphincter. The activity of autonomic nerves is dependent on both reflexes (e.g., baroreceptor and chemoreceptor reflexes) and descending excitatory and inhibitory inputs from several brain regions including the hypothalamus and brain stem.

STUDY QUESTIONS 1. Administration of a β-adrenergic receptor antagonist would not be expected to A) decrease the conduction velocity in the Purkinje fibers of the heart. B) decrease the heart rate. C) decrease the force of cardiac contraction. D) relax the detrusor muscle of the bladder. E) contract bronchial smooth muscle. 2. Sympathetic nerve activity A) is essential for survival. B) causes contraction of some smooth muscles and relaxation of others. C) causes relaxation of the radial muscle of the eye to dilate the pupil. D) relaxes smooth muscle of the gastrointestinal wall and gastrointestinal sphincter. E) all of the above

3. Parasympathetic nerve activity A) relaxes most vascular smooth muscle. B) affects only smooth muscles and glands. C) causes contraction of the radial muscle of the eye to allow accommodation for near vision. D) contracts smooth muscle of the gastrointestinal wall and relaxes the gastrointestinal sphincter. E) all of the above 4. Which of the following are correctly paired? A) sinoatrial (SA) node:nicotinic cholinergic receptors B) autonomic ganglia:muscarinic cholinergic receptors C) pilomotor smooth muscle:β2-adrenergic receptors D) vasculature of some skeletal muscles:muscarinic cholinergic receptors E) sweat glands:α2-adrenergic receptors

20 C

Electrical Activity of the Brain, Sleep–Wake States, and Circadian Rhythms Susan M. Barman

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List the main clinical uses of the electroencephalogram. Describe the primary types of brain rhythms. Summarize the behavioral and electrophysiological characteristics of each of the stages of nonrapid eye movement and rapid eye movement sleep. Describe the pattern of normal nighttime sleep in adults and the variations in this pattern from birth to old age. Discuss the circadian rhythm and the role of the suprachiasmatic nuclei in its regulation. Describe the diurnal regulation of synthesis of melatonin from serotonin in the pineal gland and its secretion into the bloodstream.

INTRODUCTION The spectrum of behavioral states ranges from deep sleep to light sleep, rapid eye movement (REM) sleep, and the two awake states: relaxed awareness and awareness with concentrated attention. Specific patterns of brain electrical activity correlate with each of these states. Some disease processes lead to changes in these activity patterns. Arousal can be produced by sensory stimulation and by impulses ascending in the reticular core of the midbrain. Many of these activities have rhythmic fluctuations that are approximately 24 hours in length (circadian rhythm).

ELECTROENCEPHALOGRAM EPILEPSY The electroencephalogram (EEG) recorded from the scalp is a measure of the summation of dendritic postsynaptic potentials in underlying cortical neurons. The EEG is of value in localizing pathologic processes in the brain. Epilepsy is a syndrome with multiple causes and is characterized by both behavioral and EEG changes. In some forms, characteristic EEG patterns occur during seizures; between attacks, abnor-

Ch20_185-190.indd 185

malities are often difficult to demonstrate. Seizures are divided into partial (focal) seizures and generalized seizures. Partial seizures originate in a small group of neurons and can result from head injury, brain infection, stroke, or tumor. Symptoms depend on the seizure focus and are subdivided into simple (without loss of consciousness) and complex partial seizures (with altered consciousness). An example of a partial seizure is localized jerking movements in one hand progressing to clonic movements of the entire arm. Auras typically precede the onset of a partial seizure and include abnormal sensations. The time after the seizure until normal neurological function returns is called the postictal period. Generalized seizures are associated with widespread electrical activity and involve both hemispheres simultaneously and are subdivided into convulsive and nonconvulsive categories depending on whether tonic or clonic movements occur. Absence seizures (formerly called petit mal seizures) are one of the forms of nonconvulsive generalized seizures characterized by a momentary loss of consciousness. The most common convulsive generalized seizure is tonic– clonic seizure (formerly called grand mal seizure). This is associated with sudden onset of contraction of limb muscles (tonic phase) lasting about 30 seconds, followed by a phase with symmetric jerking of the limbs as a result of alternating contraction and relaxation (clonic phase) lasting 1–2 minutes.

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(a)

Alpha rhythm (relaxed with eyes closed)

(b)

Beta rhythm (alert)

beta rhythm (Figure 20–1). This phenomenon is called alpha block (or arousal or alerting response) and can be produced by any form of sensory stimulation or mental concentration (e.g., solving arithmetic problems). It has also been called desynchronization, because it represents breaking up of the highly synchronized neural activity. However, the rapid EEG activity seen in the alert state is also synchronized, but at a higher rate. Therefore, the term desynchronization is misleading. Gamma oscillations at 30–80 Hz are often observed when an individual is aroused and focuses attention on something. This can be replaced by irregular fast activity when the individual initiates motor activity in response to the stimulus.

Time

FIGURE 20–1 EEG records showing the alpha and beta rhythms. a and b) When attention is focused on something, the 8–13-Hz alpha rhythm is replaced by an irregular 13–30-Hz low-voltage activity, the beta rhythm. (Reproduced with permission from Widmaier EP, Raff H, Strang KT: Vander’s Human Physiology, 11th ed. McGraw-Hill, 2008.)

There is fast EEG activity during the tonic phase. Slow waves, each preceded by a spike, occur at the time of each clonic jerk. For a while after the attack, slow waves are present.

BRAIN RHYTHMS IN WAKEFULNESS AND SLEEP In adult humans who are awake but at rest with the mind wandering and the eyes closed, the most prominent component of the EEG is a fairly regular pattern of waves at a frequency of 8–13 Hz and amplitude of 50–100 μV when recorded from the scalp. This pattern is the alpha rhythm (Figure 20–1). It is most marked in the parietal and occipital lobes and is associated with decreased levels of attention. When attention is focused on something, the alpha rhythm is replaced by an irregular 13–30-Hz low-voltage activity, the

Awake

Sleep stage 1

SLEEP STAGES There are two kinds of sleep: REM sleep and non-REM (NREM) or slow-wave sleep. REM sleep is so named because of the characteristic eye movements that occur during this stage of sleep. NREM sleep is divided into four stages (Figure 20–2). A person falling asleep enters stage 1 sleep, and the EEG shows a lowvoltage, mixed frequency pattern. A theta rhythm (4–7 Hz) can be seen at this early stage of slow-wave sleep. Throughout NREM sleep, there is some activity of skeletal muscle but no eye movements. Stage 2 is marked by the appearance of sleep spindles (12–14 Hz) and occasional high-voltage biphasic K complexes. In stage 3, a high-amplitude delta rhythm (0.5–4 Hz) dominates the EEG waves. Maximum slowing with large waves is seen in stage 4. Thus, the characteristic of deep sleep is a pattern of rhythmic slow waves, indicating marked synchronization, and it is referred to as slow-wave sleep. Whereas theta and delta rhythms are normal during sleep, their appearance during wakefulness is a sign of brain dysfunction. The high-amplitude slow waves seen in the EEG during sleep are periodically replaced by rapid, low-voltage EEG activity, which resembles that seen in the awake, aroused state (Figure 20–2). However, sleep is not interrupted; indeed, the threshold for arousal by sensory stimuli is elevated. Rapid,

2

3

4

REM

EOG

EMG

EEG 50 V 1s

FIGURE 20–2 EEG and muscle activity during various stages of the sleep–wake cycle. NREM sleep has four stages. Stage 1 is characterized by a slight slowing of the EEG. Stage 2 has high-amplitude K complexes and spindles. Stages 3 and 4 have slow, high-amplitude delta waves. REM sleep is characterized by eye movements, loss of muscle tone, and a low-amplitude, high-frequency activity pattern. The higher voltage activity in the EOG tracings during stages 2 and 3 reflects high-amplitude EEG activity in the prefrontal areas rather than eye movements. EOG, electrooculogram registering eye movements; EMG, electromyogram registering skeletal muscle activity. (Reproduced with permission from Kandel ER, Schwartz JH, Jessell TM [editors]: Principles of Neural Science, 4th ed. McGraw-Hill, 2000.)

CHAPTER 20 Electrical Activity of the Brain, Sleep–Wake States, and Circadian Rhythms

DISTRIBUTION OF SLEEP STAGES In a typical night of sleep, a young adult first enters NREM sleep, passes through stages 1 and 2, and spends 70–100 minutes in stages 3 and 4. Sleep then lightens, and a REM period follows. This cycle is repeated at intervals of about 90 minutes throughout the night (Figure 20–3). The cycles are similar, though there is less stage 3 and 4 sleep and more REM sleep toward morning. Four to six REM periods occur per night. If humans are awakened every time they show REM sleep and then permitted to sleep without interruption, they show a great deal more than the normal amount of REM sleep for a few subsequent nights. Various studies imply that sleep is needed to maintain metabolic–caloric balance, thermal equilibrium, and immune competence.

SLEEP DISORDERS Narcolepsy is a chronic neurological disorder caused by the brain’s inability to regulate sleep–wake cycles normally. There is a sudden loss of voluntary muscle tone (cataplexy), an eventual irresistible urge to sleep during daytime, and sometimes brief episodes of total paralysis at the beginning or end of sleep. Narcolepsy is characterized by a sudden onset of REM sleep, unlike normal sleep that begins with NREM, slow-wave sleep. Brains from humans with narcolepsy often contain fewer hypocretin (orexin)-producing neurons in the hypothalamus. An immune attack on these neurons can lead to their degeneration. Obstructive sleep apnea (OSA) is a common sleep disorder that involves periodic cessation of air flow during sleep and causes abnormal sleep architecture and daytime hypersomnolence. Central sleep apnea is a rare sleep disorder that occurs when the brain temporarily stops sending signals to the phrenic motor neurons controlling the diaphragm.

Sleep stages

Awake

Children

REM 1 2 3 4 1

Sleep stages

Awake

2

3

4

5

6

7

3

4

5

6

7

3 4 5 Hours of sleep

6

7

Young Adults

REM 1 2 3 4 1

Awake Sleep stages

roving movements of the eyes occur during this sleep stage, accounting for its name. Another characteristic of REM sleep is the occurrence of large phasic potentials that originate in the cholinergic neurons in the pons and pass rapidly to the lateral geniculate body and from there to the occipital cortex. They are called pontogeniculooccipital (PGO) spikes. The tone of the skeletal muscles in the neck is markedly reduced during REM sleep. Humans aroused during REM sleep often report that they were dreaming, whereas individuals awakened from slowwave sleep do not. Thus, REM sleep and dreaming are closely associated. Positron emission tomography (PET) scans of humans in REM sleep show increased activity in the pontine area, amygdala, and anterior cingulate gyrus, but decreased activity in the prefrontal and parietal cortex. Activity in visual association areas is increased, but there is a decrease in the primary visual cortex. This is consistent with increased emotion and operation of a closed neural system cut off from the areas that relate brain activity to the external world.

187

2

Elderly

REM 1 2 3 4 1

2

FIGURE 20–3 Normal sleep cycles at various ages. REM sleep is indicated by the darker-colored areas. (Reproduced with permission from Kales AM, Kales JD. Sleep disorders. Recent findings in the diagnosis and treatment of disturbed sleep. N Engl J Med. 1974; 290:487.)

Sleepwalking (somnambulism), bed-wetting (nocturnal enuresis), and night terrors are referred to as parasomnias, which are sleep disorders associated with arousal from NREM and REM sleep. Episodes of sleepwalking are more common in children than in adults, occur predominantly in males, and may last several minutes. Somnambulists walk with their eyes open and avoid obstacles, but when awakened, they cannot recall the episodes.

CIRCADIAN RHYTHMS AND THE SLEEP–WAKE CYCLE Most, if not all, living cells in plants and animals have rhythmic fluctuations in their function on a circadian cycle. Normally, they become entrained (synchronized) to the day– night light cycle in the environment. If they are not entrained, the cycles become progressively more out of phase with the light–dark cycle because they are longer or shorter than 24 hours. The entrainment process in most cases is dependent

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CH3O

Melatonin H H H O C C N C CH3 H H N H Pineal gland

Day

Inhibition Sympathetic neurons Night

Stimulation

Retinohypothalamic tract Suprachiasmatic nucleus (the "biological clock")

Superior cervical ganglion

FIGURE 20–4 Secretion of melatonin. Retinohypothalamic fibers synapse in the suprachiasmatic nuclei (SCN), and there are connections from the SCN to sympathetic preganglionic neurons in the spinal cord that project to the superior cervical ganglion. Postganglionic neurons project from this ganglion to the pineal gland that secretes melatonin. The cyclic activity of SCN sets up a circadian rhythm for melatonin release. This rhythm is entrained to light/dark cycles by neurons in the retina. (Reproduced with permission from Fox SI: Human Physiology. McGraw-Hill, 2008.)

on the suprachiasmatic nuclei (SCN) that are located above the optic chiasm (Figure 20–4). The SCN receives information about the light–dark cycle via a special neural pathway, the retinohypothalamic tract. Efferents from the SCN initiate neural and humoral signals that entrain a wide variety of circadian rhythms including the sleep–wake cycle and the secretion of the pineal hormone melatonin. The exposure to bright light can advance, delay, or have no effect on the sleep–wake cycle depending on the time of day when it is experienced. During the usual daytime it has no effect, but just after dark it delays the onset of the sleep period, and just before dawn it accelerates the onset of the next sleep period. Injections of melatonin have similar effects.

NEUROCHEMICAL MECHANISMS PROMOTING SLEEP AND AROUSAL Transitions between sleep and wakefulness manifest a circadian rhythm consisting of an average of 8 hours of sleep and 16 hours of wakefulness. Nuclei in both the brain stem and hypothalamus are critical for the transitions between these states of consciousness. The brain stem reticular activating

system (RAS) is composed of several groups of neurons that release norepinephrine, serotonin, or acetylcholine. In the case of the forebrain neurons involved in control of the sleep–wake cycles, preoptic neurons in the hypothalamus release GABA and posterior hypothalamic neurons release histamine. One theory regarding the basis for transitions from sleep to wakefulness involves alternating reciprocal activity of different groups of RAS neurons. In this model (Figure 20–5), wakefulness and REM sleep are at opposite extremes. When the activity of norepinephrine- and serotonin-containing neurons (locus ceruleus and raphe nuclei) is dominant, there is a reduced level of activity in acetylcholine-containing neurons in the pontine reticular formation. This pattern of activity contributes to the appearance of the awake state. The reverse of this pattern leads to REM sleep. When there is a more even balance in the activity of the aminergic and cholinergic neurons, NREM sleep occurs. In addition, an increased release of GABA and reduced release of histamine increase the likelihood of NREM sleep via deactivation of the thalamus and cortex. Wakefulness occurs when GABA release is reduced and histamine release is increased.

CHAPTER 20 Electrical Activity of the Brain, Sleep–Wake States, and Circadian Rhythms

Brainstem nuclei that are part of the reticular activating system

Norepinephrine and serotonin

Norepinephrine and serotonin

Acetylcholine

Acetylcholine

Waking

Activation of the thalamus and cortex

NREM sleep

REM sleep

Activation of the thalamus and cortex

Histamine

Histamine

GABA

GABA

Hypothalamus with circadian and homeostatic centers

FIGURE 20–5 A model of how alternating activity of brain stem and hypothalamic neurons may influence the different states of consciousness. (Reproduced with permission from Widmaier EP, Raff H, Strang KT: Vander’s Human Physiology, 11th ed. McGraw-Hill, 2008.)

MELATONIN AND THE SLEEP–WAKE STATE Melatonin release from the richly vascularized pineal gland also plays a role in sleep mechanisms (Figure 20–4). The pineal arises from the roof of the third ventricle in the diencephalon and is encapsulated by the meninges. The pineal stroma contains glia and pinealocytes with features suggesting that they have a secretory function. Like other endocrine glands, it has highly permeable fenestrated capillaries. In infants, the pineal is large and the cells tend to be arranged in alveoli. It begins to involute before puberty and small concretions of calcium phosphate and carbonate (pineal sand) appear in the tissue. Because the concretions are radiopaque, the pineal is often visible on x-ray films of the skull in adults. Displacement of a calcified pineal from its normal position indicates the presence of a space-occupying lesion such as a tumor in the brain. Melatonin is synthesized by pinealocytes and secreted into the blood and the cerebrospinal fluid. The diurnal change in

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melatonin secretion may function as a timing signal to coordinate events with the light–dark cycle in the environment. Melatonin synthesis and secretion are increased during the dark period of the day and maintained at a low level during daylight hours. This diurnal variation in secretion is brought about by norepinephrine secreted by the postganglionic sympathetic nerves that innervate the pineal gland (Figure 20–4). Norepinephrine acts via β-adrenergic receptors to increase intracellular cAMP, and the cAMP in turn produces a marked increase in N-acetyltransferase activity. This results in increased melatonin synthesis and secretion. Circulating melatonin is rapidly metabolized in the liver by 6-hydroxylation followed by conjugation, and over 90% of the melatonin that appears in the urine is in the form of 6-hydroxy conjugates and 6-sulfatoxymelatonin. The mechanism by which the brain metabolizes melatonin may involve cleavage of the indole nucleus. The discharge of the sympathetic nerves to the pineal is entrained to the light–dark cycle in the environment via the retinohypothalamic nerve fibers to the SCN. From the hypothalamus, descending pathways converge onto preganglionic sympathetic neurons that in turn innervate the superior cervical ganglion, the site of origin of the postganglionic neurons to the pineal gland.

CLINICAL CORRELATION A 47-year-old male research scientist at a biotechnology institute has always been liked for his positive attitude and high energy level. Recently, his colleagues have noticed that he becomes agitated if things do not go well in the laboratory, and he appears to be tired all of the time. His wife has also been concerned about his being more grumpy than normal. She accompanies him to his physician’s office for his annual physical. When the doctor questions him about his sleep pattern, he insists there has been no change. But his wife mentions that he has been waking up suddenly at night and making very loud noises, sounding somewhat like gasping. He is referred to a sleep clinic where he undergoes a polysomnogram (PSG) that records brain activity, eye movements, body movements, breathing and heart rate, and blood oxygen saturation over the course of a sleep cycle. The results of PSG confirmed the doctor’s suspicion that the scientist has obstructive sleep apnea OSA. OSA is the most common cause of daytime sleepiness (hypersomnolence) due to fragmented sleep at night and affects about 24% of middle-aged men and 9% of women in the United States. Breathing ceases for more than 10 seconds during frequent episodes of obstruction of the upper airway (especially the pharynx) due to reduction in upper airway muscle tone despite continued activity of the inspiratory muscles. The apnea causes brief arousals from sleep in order to reestablish upper airway tone. Snoring is

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a common patient complaint, and OSA is often associated with obesity. There is actually not a reduction in total sleep time, but individuals with OSA experience a much greater time in stage 1 NREM sleep (from an average of 10% of total sleep to 30–50%) and a marked reduction in slowwave sleep (stage 3 and 4 NREM sleep). The pathophysiology of OSA includes both a reduction in neuromuscular tone at the onset of sleep and a change in the central respiratory drive. A common treatment of OSA is the use of a continuous positive airway pressure (CPAP) mask during sleep to prevent airway occlusions.

CHAPTER SUMMARY ■ ■

■

■ ■

■

■ ■

The EEG is of some value in localizing pathologic processes, and it is useful in characterizing different types of epilepsy. The major rhythms in the EEG are alpha (8–13 Hz), beta (13–30 Hz), theta (4–7 Hz), delta (0.5–4 Hz), and gamma (30–80 Hz) oscillations. Throughout NREM sleep, there is some activity of skeletal muscle. A theta rhythm can be seen during stage 1 of sleep. Stage 2 is marked by the appearance of sleep spindles and occasional K complexes. In stage 3, a delta rhythm is dominant. Maximum slowing with large slow waves is seen in stage 4. REM sleep is characterized by low-voltage, high-frequency EEG activity and rapid, roving movements of the eyes. A young adult typically passes through stages 1 and 2, and spends 70–100 minutes in stages 3 and 4. Sleep then lightens, and a REM period follows. This cycle repeats at 90-minute intervals throughout the night. Transitions from sleep to wakefulness may involve alternating reciprocal activity of different groups of RAS neurons. When the activity of norepinephrine- and serotonin-containing neurons is dominant, the activity in acetylcholine-containing neurons is reduced, leading to the appearance of wakefulness. The reverse of this pattern leads to REM sleep. Also, wakefulness occurs when GABA release is reduced and histamine release is increased. The entrainment of biological processes to the light–dark cycle is regulated by the SCN. The diurnal change in melatonin secretion from serotonin in the pineal gland may function as a timing signal to coordinate events with the light–dark cycle, including the sleep–wake cycle.

STUDY QUESTIONS 1. In a healthy, alert adult sitting with the eyes closed, the dominant EEG rhythm observed with electrodes over the occipital lobes is A) delta (0.5–4 Hz). B) theta (4–7 Hz). C) alpha (8–13 Hz). D) beta (18–30 Hz). E) fast, irregular low-voltage activity.

2. Which of the following pattern of changes in central neurotransmitters or neuromodulators is associated with the transition from NREM to wakefulness? A) decrease in norepinephrine, increase in serotonin, increase in acetylcholine, decrease in histamine, and decrease in GABA B) decrease in norepinephrine, increase in serotonin, increase in acetylcholine, decrease in histamine, and increase in GABA C) decrease in norepinephrine, decrease in serotonin, increase in acetylcholine, increase in histamine, and increase in GABA D) increase in norepinephrine, increase in serotonin, decrease in acetylcholine, increase in histamine, and decrease in GABA E) increase in norepinephrine, decrease in serotonin, decrease in acetylcholine, increase in histamine, and decrease in GABA 3. A gamma rhythm (30–80 Hz) A) is characteristic of seizure activity. B) is seen in an individual who is awake but not focused. C) may be a mechanism to bind together sensory information into a single percept and action. D) is also called an alerting response. E) is characteristic of obstructive sleep apnea. 4. Melatonin secretion would probably not be increased by A) stimulation of the superior cervical ganglia. B) a reduction in sunlight. C) intravenous infusion of norepinephrine. D) stimulation of the optic nerve. E) an increase in N-acetyltransferase activity. 5. Absence seizures are a form of A) nonconvulsive generalized seizures accompanied by momentary loss of consciousness. B) complex partial seizures accompanied by momentary loss of consciousness. C) nonconvulsive generalized seizures without loss of consciousness. D) simple partial seizures without loss of consciousness. E) convulsive generalized seizures accompanied by momentary loss of consciousness. 6. Narcolepsy is triggered by abnormalities in the A) skeletal muscles. B) medulla oblongata. C) hypothalamus. D) olfactory bulb. E) neocortex.

21 C

Learning, Memory, Language, and Speech Susan M. Barman

H A

P

T

E

R

O B J E C T I V E S ■ ■ ■ ■ ■ ■

Describe the various types of long-term memory. Define synaptic plasticity, long-term potentiation, long-term depression, habituation, and sensitization, and their roles in learning and memory. List the parts of the brain that are involved in memory and their role in memory processing and storage. Describe the abnormalities of brain structure and function found in Alzheimer disease. Define the terms categorical hemisphere and representational hemisphere. Explain the differences between fluent and nonfluent aphasia.

INTRODUCTION A revolution in our understanding of brain function has been brought about by the development and widespread availability of positron emission tomography (PET), functional magnetic resonance imaging (fMRI), and related techniques. PET is often used to measure local glucose metabolism, which is proportionate to neural activity, and fMRI is used to measure local amounts of oxygenated blood. These techniques make it possible to determine the activity in various parts of the brain in healthy subjects and in those with various diseases. They have been used to study not only simple responses, but also complex aspects of learning, memory, and perception. An example of the use of PET scans to study the functions of the cerebral cortex in processing words is shown in Figure 21–1. Different portions of the cortex are activated when a person is hearing, seeing, speaking, or generating words.

From a physiologic point of view, memory is divided into explicit and implicit forms (Figure 21–2). Explicit or declarative memory is associated with consciousness (or at least awareness) and is dependent on the hippocampus and other parts of the medial temporal lobes of the brain for its retention. Implicit or nondeclarative memory does not involve awareness, and its retention does not usually involve processing in the hippocampus.

LEARNING AND MEMORY Learning is acquisition of information that makes it possible to alter behavior on the basis of experience, and memory is the retention and storage of that information. The two are obviously closely related and should be considered together.

Ch21_191-198.indd 191

FIGURE 21–1 Images of active areas of the brain in a male (left) and female (right) during a language task. Note that males use only one side of the brain whereas females use both sides of the brain when language is being processed. (Reproduced with permission from Widmaier EP, Raff H, Strang KT: Vander’s Human Physiology. McGraw-Hill, 2008.)

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Two forms of long term memory

Explicit (declarative)

Facts (Semantic)

FIGURE 21–2

Events (Episodic)

Implicit (nondeclarative)

Priming

Procedural (skills and habits)

Forms of long-term

Associative learning: classical and operant conditioning

Emotional responses

Skeletal musculature

Amygdala

Cerebellum

Nonassociative learning: habituation and sensitization

memory. (Modified with permission from Kandel ER, Schwartz JH, Jessell TM [editors]: Principles of Neural Science, 4th ed. McGraw-Hill, 2000.)

Medial temporal lobe Hippocampus

Explicit memory is divided into episodic memory for events and semantic memory for facts (e.g., words, rules, and language). Explicit memories initially required for activities such as riding a bicycle can become implicit once the task is thoroughly learned. Implicit memory is subdivided into four types. Procedural memory includes skills and habits, which, once acquired, become unconscious and automatic. Priming is facilitation of recognition of words or objects by prior exposure to them. An example is improved recall of a word when presented with the first few letters of it. In nonassociative learning, one learns about a single stimulus. In associative learning, one learns about the relation of one stimulus to another. Explicit memory and many forms of implicit memory involve (1) short-term memory, which lasts seconds to hours, during which processing in the hippocampus and elsewhere leads to long-term changes in synaptic strength; and (2) longterm memory, which stores memories for years. During shortterm memory, the memory traces are subject to disruption by trauma and various drugs, whereas long-term memory traces are remarkably resistant to disruption. Working memory is a form of short-term memory that keeps information available, usually for very short periods, while the individual plans action based on it.

SYNAPTIC PLASTICITY AND LEARNING The key to memory is alteration in the strength of selected synaptic connections. In all but the simplest of cases, the alteration involves activation of genes and protein synthesis. This occurs during the change from short-term working memory to long-term memory. If an intervention occurs too soon after a training session, acquisition of long-term memory is impaired. This is exemplified by the loss of memory for the events immediately preceding brain concussion or electroshock therapy (retrograde amnesia). Short- and long-term changes in synaptic function can occur as a result of the history of discharge at a synapse, that is,

Neocortex

Striatum

Reflex pathways

synaptic conduction can be strengthened or weakened on the basis of past experience. These changes, which can be presynaptic or postsynaptic, are of great interest because they represent forms of learning and memory. One form of plastic change is post-tetanic potentiation, the production of enhanced postsynaptic potentials in response to stimulation. This enhancement lasts up to 60 seconds and occurs after a brief (tetanizing) train of stimuli in a presynaptic neuron. The stimulation causes Ca2+ to accumulate in the presynaptic neuron to such a degree that the intracellular binding sites that keep cytoplasmic Ca2+ low are overwhelmed. Habituation is a simple form of learning in which a neutral stimulus is repeated many times. The first time it is applied it is novel and evokes a reaction (the “what is it?” response); however, it evokes less and less electrical response as it is repeated. Eventually, the subject becomes habituated to the stimulus and ignores it. This is associated with decreased release of neurotransmitter from the presynaptic terminal because of decreased intracellular Ca2+. The decrease in intracellular Ca2+ is due to a gradual inactivation of Ca2+ channels. It can be short-term, or it can be prolonged if exposure to the benign stimulus is repeated many times. Habituation is a classic example of nonassociative learning. Sensitization is the prolonged occurrence of augmented postsynaptic responses after a stimulus to which one has become habituated is paired once or several times with a noxious stimulus. It is due to presynaptic facilitation and may occur as a transient response. If it is reinforced by additional pairings of the noxious stimulus and the initial stimulus, it can exhibit features of short- or long-term memory. The shortterm prolongation of sensitization is due to a Ca2+-mediated change in adenylyl cyclase that increases production of cAMP. The long-term potentiation (LTP) involves protein synthesis and growth of the presynaptic and postsynaptic neurons and their connections. LTP is a rapidly developing persistent enhancement of the postsynaptic potential response to presynaptic stimulation

CHAPTER 21 Learning, Memory, Language, and Speech after a brief period of rapidly repeated stimulation of the presynaptic neuron. It resembles post-tetanic potentiation but is much more prolonged and can last for days. Unlike post-tetanic potentiation, it is initiated by an increase in intracellular Ca2+ in the postsynaptic rather than the presynaptic neuron. It occurs in many parts of the CNS but has been studied in greatest detail in the hippocampus where there are two forms: mossy fiber LTP, which is presynaptic and independent of N-methyld-aspartate (NMDA) receptors, and Schaffer collateral LTP, which is postsynaptic and NMDA receptor-dependent. The hypothetical basis of the latter form is summarized in Figure 21–3. The basis of mossy fiber LTP appears to include cAMP and Ih, a hyperpolarization-activated cation channel. Long-term depression (LTD) is found throughout the brain in the same fibers as LTP. It is characterized by a decrease in synaptic strength. It is produced by slower stimulation of presynaptic neurons and is associated with a smaller rise in intracellular Ca2+ than occurs in LTP.

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Prefrontal cortex

Parahippocampal cortex

Hippocampus

FIGURE 21–4 Areas concerned with encoding explicit memories. The prefrontal cortex and the parahippocampal cortex of the brain are active during the encoding of memories. (Adapted with permission from Rugg Russ MD. Memories are made of this. Science. 1998;281(5380):1151–1152.)

WORKING MEMORY

Mg2+

Ca2+

Na+

Glu

PS NMDA

AMPA P

Ca2+ AMPA CaM

CaM kII

FIGURE 21–3 Production of long-term potentiation (LTP) in Schaffer collaterals in the hippocampus. Glutamate (Glu) released from the presynaptic neuron binds to α-amino-3-hydroxyl-5methyl-4-isoxazole-propionate (AMPA) and N-methyl-d-aspartate (NMDA) receptors in the membrane of the postsynaptic neuron. The depolarization triggered by activation of the AMPA receptors relieves the Mg2+ block in the NMDA receptor channel, and Ca2+ enters the neuron with Na+. The increase in cytoplasmic Ca2+ activates calmodulin (CaM), which in turn activates Ca2+/calmodulin kinase II (CaM kII). The kinase phosphorylates the AMPA receptors (P), increasing their conductance, and moves more AMPA receptors into the synaptic cell membrane from cytoplasmic storage sites. In addition, a chemical signal (PS) may pass to the presynaptic neuron, producing a long-term increase in the quantal release of glutamate. (Courtesy of R. Nicoll)

Working memory areas are connected to the hippocampus and the adjacent parahippocampal portions of the medial temporal cortex (Figure 21–4). Bilateral destruction of the ventral hippocampus, or Alzheimer disease (described below) and similar disease processes that destroy its CA1 neurons, causes striking defects in short-term memory. Individuals with such destruction have intact working memory and remote memory. Their implicit memory processes are generally intact. They perform adequately in terms of conscious memory as long as they concentrate on what they are doing. However, if they are distracted for even a very short period, all memory of what they were doing and what they proposed to do is lost. They are thus capable of new learning and retain old prelesion memories, but they cannot form new long-term memories. The hippocampus is closely associated with the overlying parahippocampal cortex in the medial frontal lobe (Figure 21–4). When subjects recall words, activity in their left frontal lobe and their left parahippocampal cortex increases, but when they recall pictures or scenes, activity takes place in their right frontal lobe and the parahippocampal cortex on both sides. The connections of the hippocampus to the diencephalon are also involved in memory. Some people with alcoholismrelated brain damage develop impairment of recent memory, and the memory loss correlates well with the presence of pathologic changes in the mamillary bodies, which have extensive efferent connections to the hippocampus via the fornix. The mamillary bodies project to the anterior thalamus via the mamillothalamic tract. From the thalamus, the fibers concerned with memory project to the prefrontal cortex and from there to the basal forebrain. From the basal forebrain, a diffuse cholinergic projection goes to all of the neocortex, the amygdala, and the hippocampus from the nucleus

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basalis of Meynert. Severe loss of these fibers occurs in Alzheimer disease. The amygdala is closely associated with the hippocampus and is concerned with encoding and recalling emotionally charged memories. During retrieval of fearful memories, the theta rhythms of the amygdala and the hippocampus become synchronized. In healthy subjects, events associated with strong emotions are remembered better than events without an emotional charge, but in patients with bilateral lesions of the amygdala, this difference is absent.

LONG-TERM MEMORY While the encoding process for short-term explicit memory involves the hippocampus, long-term memories are stored in various parts of the neocortex. Various parts of the memories—visual, olfactory, auditory, etc.—are located in the cortical regions concerned with these functions, and the pieces are tied together by long-term changes in the strength of transmission at relevant synaptic junctions so that all the components are brought to consciousness when the memory is recalled. Once long-term memories have been established, they can be recalled or accessed by many different associations. For example, the memory of a vivid scene can be evoked not only by a similar scene, but also by a sound or smell associated with the scene. Thus, each stored memory must have multiple routes, and many memories have an emotional component.

ALZHEIMER DISEASE AND SENILE DEMENTIA Alzheimer disease is the most common age-related neurodegenerative disorder. Memory decline initially manifests as a loss of episodic memory, which impedes recollection of recent events. Loss of short-term memory is followed by general loss of cognitive and other brain functions, the need for constant care, and, eventually, death. The cytopathologic hallmarks of the disease are intracellular neurofibrillary tangles, made up in part of hyperphosphorylated forms of the tau protein that normally binds to microtubules, and extracellular senile plaques, which have a core of β-amyloid peptides (Aβ) surrounded by altered nerve fibers and reactive glial cells. Figure 21–5 compares a normal nerve cell to one showing abnormalities associated with Alzheimer disease. The Aβ peptides are products of a normal protein, amyloid precursor protein (APP), a transmembrane protein that projects into the extracellular fluid (ECF) from all nerve cells. This protein is hydrolyzed at three different sites by α-, β-, and γ-secretase, respectively. When APP is hydrolyzed by α-secretase, nontoxic peptide products are produced. However, when it is hydrolyzed by β- and γ-secretase, polypeptides with 40–42 amino acids are produced; the actual length varies because of variation in the site at which γ-secretase cuts the protein chain. These polypeptides are toxic, the most toxic being Aβσ1–42. The polypeptides form extracellular aggregates, which can stick to α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) receptors and Ca2+ ion channels, increasing Ca2+ influx.

A Normal

Nerve terminals

B Alzheimer disease

Aβ (fibrillar)

Neuropil threads Neurofibrillary tangles

Paired helical filaments

Abnormal membranous organelles

Neurites

Senile plaque

FIGURE 21–5

Comparison of a normal neuron (A) and one with abnormalities associated with Alzheimer disease (B). (Reproduced with

permission from Kandel ER, Schwartz JH, Jessell TM [editors]: Principles of Neural Science, 4th ed. McGraw-Hill, 2000.)

CHAPTER 21 Learning, Memory, Language, and Speech

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They also initiate an inflammatory response, with production of intracellular tangles. The damaged cells eventually die. An interesting finding that may have broad physiologic implications is that frequent effortful mental activities, such as doing difficult crossword puzzles and playing board games, slow the onset of cognitive dementia due to Alzheimer disease and vascular disease. The explanation for this “use it or lose it” phenomenon is as yet unknown, but it certainly suggests that the hippocampus and its connections have plasticity like other parts of the brain.

normally thicker than the left, and the left occipital lobe is wider and protrudes across the midline. In patients with schizophrenia, a disorder characterized by a distorted sense of reality, MRI studies show reduced volumes of gray matter on the left side in the anterior hippocampus, amygdala, parahippocampal gyrus, and posterior superior temporal gyrus. The degree of reduction in the left superior temporal gyrus correlates with the degree of disordered thinking in the disease. There are also apparent abnormalities of dopaminergic systems and cerebral blood flow in this disease.

LANGUAGE AND SPEECH

PHYSIOLOGY OF LANGUAGE

Memory and learning are functions of large parts of the brain, but the centers controlling some of the other “higher functions of the nervous system,” particularly the mechanisms related to language, are more or less localized to the neocortex. Human language functions depend more on one cerebral hemisphere than on the other. This is called the dominant hemisphere and is concerned with categorization and symbolization. The other hemisphere is not less developed or “nondominant”; instead, it is specialized in the area of spatiotemporal relations. It is this hemisphere that is concerned, for example, with the identification of objects by their form and plays a primary role in the recognition of faces. This contributes to the concept of complementary specialization of the hemispheres, one for sequential-analytic processes (the categorical hemisphere) and one for visuospatial relations (the representational hemisphere). The categorical hemisphere is concerned with language functions. Lesions in the categorical hemisphere produce language disorders. In contrast, lesions in the representational hemisphere lead to astereognosis, the inability to identify objects by feeling them. Hemispheric specialization is related to handedness. In 96% of right-handed individuals, who constitute 91% of the human population, the left hemisphere is the dominant or categorical hemisphere, and in the other 4%, the right hemisphere is dominant. In 70% of left-handers, the left hemisphere is also the categorical hemisphere; in 15%, the right hemisphere is the categorical hemisphere; and in 15%, there is no clear lateralization. Learning disabilities such as dyslexia (an impaired ability to learn to read) are 12 times as common in left-handers as they are in right-handers, possibly because some fundamental abnormality in the left hemisphere led to a switch in handedness early in development. The spatial talents of lefthanders may be well above average as a disproportionately large number of artists, musicians, and mathematicians are left-handed. Some anatomic differences between the two hemispheres may correlate with the functional differences. The planum temporale, an area of the superior temporal gyrus that is involved in language-related auditory processing, is regularly larger on the left side than the right. Imaging studies show that other portions of the upper surface of the left temporal lobe are larger in right-handed individuals, the right frontal lobe is

The primary brain areas concerned with language are located along and near the Sylvian fissure (lateral cerebral sulcus) of the categorical hemisphere. A region at the posterior end of the superior temporal gyrus called Wernicke’s area (Figure 21–6) is concerned with comprehension of auditory and visual information. It projects via the arcuate fasciculus to Broca’s area (area 44) in the frontal lobe immediately in front of the inferior end of the motor cortex. Broca’s area processes the information received from Wernicke’s area into a detailed and coordinated pattern for vocalization and then projects the pattern via a speech articulation area in the insula to the motor cortex, which initiates the appropriate movements of the lips, tongue, and larynx to produce speech. The probable sequence of events that occurs when a subject names a visual object is shown in Figure 21–7. The angular gyrus behind Wernicke’s area processes information from words that are read in such a way that they can be converted into the auditory forms of the words in Wernicke’s area. In individuals who learn a second language in adulthood, fMRI reveals that the portion of Broca’s area concerned with it is adjacent to but separate from the area concerned with the native language. However, in children who learn two languages early in life, only a single area is involved with both. It is well known, of course, that children acquire fluency in a second language more easily than adults.

Arcuate fasciculus

Broca’s area

Angular gyrus Wernicke’s area

FIGURE 21–6 Location of some of the areas in the categorical hemisphere that are concerned with language functions. (Reproduced with permission from Barrett KE, Barman SM, Boitano S, Brooks H: Ganong’s Review of Medical Physiology, 23rd ed. McGraw-Hill Medical, 2009.)

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Left

Right

Broca’s area Facial area of motor cortex (area 4)

6

Wernicke’s area (area 22)

Arcuate fasciculus

5 From lateral geniculate nucleus 4

Angular gyrus (area 39) Higher order visual cortical areas (area 18)

1 3

RECOGNITION OF FACES An important part of the visual input goes to the inferior temporal lobe, where representations of objects, particularly faces, are stored. Faces are particularly important in distinguishing friends from foes and the emotional state of those seen. Storage and recognition of faces is more strongly represented in the right inferior temporal lobe in right-handed individuals. Lesions in this area cause prosopagnosia, the inability to recognize faces. Patients with this abnormality can recognize forms and reproduce them. They can recognize people by their voices, and many of them show autonomic responses when they see familiar as opposed to unfamiliar faces. However, they cannot identify the familiar faces they see.

2

Primary visual cortex (area 17)

FIGURE 21–7

Path taken by impulses when a subject names a visual object projected on a horizontal section of the human brain. (Reproduced with permission from Barrett KE, Barman SM, Boitano S, Brooks H: Ganong’s Review of Medical Physiology, 23rd ed. McGraw-Hill Medical, 2009.)

LANGUAGE DISORDERS Aphasias are abnormalities of language functions that are not due to defects of vision or hearing or to motor paralysis. They are caused by lesions in the categorical hemisphere. The most common cause is embolism or thrombosis of a cerebral blood vessel. A convenient classification divides them into fluent, nonfluent, and anomic aphasias. In one form of fluent aphasia, the lesion is in Wernicke’s area. Speech itself is normal, and sometimes the patients talk excessively; however, what they say is full of jargon and neologisms that make little sense. The patient also fails to comprehend the meaning of spoken or written words, so other aspects of the use of language are compromised. Another form of fluent aphasia is a condition in which patients can speak relatively well and have good auditory comprehension but cannot put parts of words together or conjure up words. It appears to be due to lesions in and around the auditory cortex (Brodmann’s areas 40, 41, and 42). In nonfluent aphasia, the lesion is in Broca’s area. Speech is slow, and words are hard to come by. Patients with severe damage to this area are limited to two or three words with which to express the whole range of meaning and emotion. Sometimes the words retained are those that were being spoken at the time of the injury or vascular accident that caused the aphasia. When a lesion damages the angular gyrus in the categorical hemisphere without affecting Wernicke’s or Broca’s area, there is no difficulty with speech or the understanding of auditory information; instead, there is trouble understanding written language or pictures, because visual information is not processed and transmitted to Wernicke’s area. The result is a condition called anomic aphasia.

CLINICAL CORRELATION A 9-year-old boy began to have epileptic seizures following a bicycle accident. An electroencephalogram (EEG) showed that the seizures originated in the temporal lobes bilaterally. He had numerous partial seizures and several tonic–clonic seizures by the age of 16. The frequent occurrence of seizures and lapses in consciousness made completing high school very difficult, despite his intellectual abilities. He was also unable to hold down a job as an assembly worker. At the age of 27, he underwent experimental brain surgery to remove the amygdala, large portions of the hippocampal formation, and portions of the association area of the temporal cortex. The seizures were better controlled after surgery, reduced to only about one major seizure a year. However, the surgery led to devastating memory deficits. He has maintained long-term memory for events that occurred before surgery, but he suffers from anterograde amnesia. His short-term memory is intact, but he is unable to commit new events to longterm memory. He has normal procedural memory, and he can learn new puzzles and motor tasks. This is an actual patient who underwent the experimental brain surgery in 1953. This case has been studied by many scientists and has led to a greater understanding of the link between the temporal lobe and declarative memory. His case is the first to bring attention to the critical role of temporal lobes in formation of long-term memories and to implicate this region in the conversion of short- to long-term memories. Later work showed that the hippocampus is the primary structure within the temporal lobe involved in this conversion. Because he retained memories from before surgery, his case also shows that the hippocampus is not involved in the storage of declarative memory. A fascinating audio recording by National Public Radio from the 1990s of the patient talking to scientists was released in 2007 and is available at http:// www.npr.org/templates/story/story.php?storyId=7584970.

CHAPTER 21 Learning, Memory, Language, and Speech

CHAPTER SUMMARY ■

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Long-term memory is divided into explicit (declarative) and implicit (nondeclarative). Explicit is further subdivided into semantic and episodic. Implicit is further subdivided into priming, procedural, associative learning, and nonassociative learning. Synaptic plasticity is the ability of neural tissue to change as reflected by LTP (an increased effectiveness of synaptic activity) or LTD (a reduced effectiveness of synaptic activity) after continued use. Hippocampal and other temporal lobe structures and association cortex are involved in declarative memory. Alzheimer disease is characterized by progressive loss of short-term memory followed by general loss of cognitive function. The cytopathologic hallmarks of Alzheimer disease are intracellular neurofibrillary tangles and extracellular senile plaques. Categorical and representational hemispheres are for sequential-analytic processes and visuospatial relations, respectively. Lesions in the categorical hemisphere produce language disorders, whereas lesions in the representational hemisphere produce astereognosis. Aphasias are abnormalities of language functions and are caused by lesions in the categorical hemisphere. They are classified as fluent (Wernicke’s area; auditory cortex), nonfluent (Broca’s area), and anomic (angular gyrus) based on the location of brain lesions.

STUDY QUESTIONS 1. The representational hemisphere A) is the right cerebral hemisphere in most right-handed individuals. B) is the left cerebral hemisphere in most left-handed individuals. C) includes the part of the brain concerned with language functions. D) is the site of lesions in most patients with aphasia. E) is morphologically identical to the opposite nonrepresentational hemisphere.

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2. The effects of bilateral loss of hippocampal function include A) disappearance of remote memories. B) loss of working memory. C) loss of the ability to encode events of the recent past in long-term memory. D) loss of the ability to recall faces and forms but not the ability to recall printed or spoken words. E) production of inappropriate emotional responses when recalling events of the recent past. 3. Which of the following are incorrectly paired? A) lesion of the parietal lobe of the representational hemisphere:unilateral inattention and neglect B) loss of cholinergic neurons in the nucleus basalis of Meynert and related areas of the forebrain:loss of recent memory C) lesions of mamillary bodies:loss of recent memory D) lesion of the angular gyrus in the categorical hemisphere:nonfluent aphasia E) lesion of Broca’s area in the categorical hemisphere:slow speech 4. The representational hemisphere is better than the categorical hemisphere at A) language functions. B) recognition of objects by their form. C) understanding printed words. D) understanding spoken words. E) mathematical calculations. 5. A lesion of Wernicke’s area (the posterior end of the superior temporal gyrus) in the categorical hemisphere causes patients to A) lose short-term memory. B) speak in a slow, halting voice. C) experience déjà vu. D) talk rapidly but make little sense. E) lose the ability to recognize faces. 6. Which of the following is most likely not to be involved in production of LTP? A) cAMP B) Ca2+ C) NMDA receptors D) membrane hyperpolarization E) membrane depolarization

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SECTION V CARDIOVASCULAR PHYSIOLOGY

22 C

Overview of the Cardiovascular System Lois Jane Heller and David E. Mohrman

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Define the role of the cardiovascular system in overall body homeostasis. Identify the major body fluid compartments and state the approximate volume of each. Diagram the blood flow pathways between the heart and other major body organs. State the relationship among blood flow, blood pressure, and vascular resistance. Predict the relative changes in flow through a tube caused by changes in tube length, tube radius, fluid viscosity, and pressure difference. Identify the chambers and valves of the heart and describe the pathway of blood flow through the heart. Define cardiac output. Describe the pathway of action potential propagation in the heart. List five factors essential to proper ventricular pumping action. State the relationship between ventricular filling and cardiac output (Starling’s law of the heart) and describe its importance in the control of cardiac output. Identify the distribution of sympathetic and parasympathetic nerves in the heart and list the basic effects of these nerves on the cardiac function. List the major different types of vessels in a vascular bed and describe the morphological differences among them. Describe the basic anatomical features and functions of the different vessel types. Identify the major mechanisms in vascular control and blood flow distribution. Describe the basic composition of the fluid and cellular portions of blood and list the events associated with blood clotting.

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HOMEOSTATIC ROLE OF THE CARDIOVASCULAR SYSTEM Three compartments of watery fluids, known collectively as the total body water, account for about 60% of body weight. This water is distributed among the intracellular, interstitial, and plasma compartments, as indicated in Figure 22-1. Note that about two thirds of our body water is contained within cells and communicates with the interstitial fluid across the plasma membranes of cells. Of the fluid that is outside cells (i.e., extracellular fluid), only a small amount, the plasma volume, circulates within the cardiovascular system. Blood is composed of plasma and roughly an equal volume of formed elements (primarily red cells). The circulating plasma fluid communicates with the interstitial fluid across the walls of small capillary vessels within organs. The interstitial fluid is the immediate environment of individual cells. The cells must draw their nutrients from and release their products into the interstitial fluid. The interstitial fluid cannot, however, be considered a large reservoir for nutrients or a large sink for metabolic products since its volume is less than half that of the cells that it serves.

The well-being of individual cells therefore depends heavily on the homeostatic mechanisms that regulate the composition of the interstitial fluid. This task is accomplished by continuously exposing the interstitial fluid to “fresh” circulating plasma fluid. As blood passes through capillaries, solutes exchange between plasma and interstitial fluid by the process of diffusion. The net result of transcapillary diffusion is always that interstitial fluid tends to take on the composition of the incoming blood. If, for example, potassium ion concentration in the interstitium of a particular skeletal muscle were higher than that in the plasma entering the muscle, potassium would diffuse into the blood as it passed through the muscle’s capillaries. Since this removes potassium from the interstitial fluid, interstitial potassium ion concentration would decrease. It would stop decreasing when net movement of potassium into capillaries no longer occurred, that is, when interstitial concentration reached that of incoming plasma. Three conditions are essential for this circulatory mechanism to effectively control the composition of interstitial fluid: (1) there must be adequate blood flow through the tissue capillaries, (2) the chemical composition of the incoming (or arterial) blood must be controlled to be that which is

LUNGS

RIGHT HEART

LEFT HEART BODY ORGANS

CAPILLARIES

CELLS Circulating plasma compartment ≈3 L

Interstitial compartment (internal environment) ≈12 L

Intracellular compartment ≈30 L

FIGURE 22–1 Major body fluid compartments with average volumes indicated for a 70-kg human. Total body water is about 60% of body weight. (Modified with permission from Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.)

CHAPTER 22 Overview of the Cardiovascular System

100%

201

LUNGS

RIGHT HEART PUMP

LEFT HEART PUMP 100%

100%

HEART MUSCLE

BRAIN

SKELETAL MUSCLE

BONE

3%

14%

15%

5%

VEINS

ARTERIES GASTROINTESTINAL SYSTEM, SPLEEN

LIVER

KIDNEY

21%

6%

22%

6%

SKIN

OTHER

8%

FIGURE 22–2 Cardiovascular circuitry indicating the percentage distribution of cardiac output to various organ systems in a resting individual. (Modified with permission from Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.)

optimal in the interstitial fluid, and (3) diffusion distances must be short. Figure 22–1 shows how the cardiovascular transport system operates to accomplish these tasks. As discussed above, substances are transported between cells and plasma in capillary vessels within organs by the process of diffusion. This transport occurs over extremely small distances because almost no cell in the body is located farther than about 10 μm from a capillary. Over such microscopic distances, diffusion is a very rapid process; however, it is a very poor mechanism by which to move substances from the capillaries of one organ, such as the lungs, to the capillaries of another organ that may be 1 m or more distant. Consequently, substances are transported between organs by the process of convection, by which the substances move along with blood flow simply because they are dissolved or otherwise contained within blood. The relative distances involved in cardiovascular transport are not well illustrated in Figure 22–1. If the figure were drawn to scale with 1 inch representing the distance from capillaries to cells within a calf muscle, the capillaries in the lungs would have to be located about 1.5 miles away!

The overall functional arrangement of the cardiovascular system is illustrated in Figure 22–2. Since a functional rather than an anatomical viewpoint is expressed in this figure, the heart appears in three places: as the right heart pump, as the left heart pump, and as the heart muscle tissue. It is common practice to view the cardiovascular system as (1) the pulmonary circulation, composed of the right heart pump and the lungs, and (2) the systemic circulation, in which the left heart pump supplies blood to the systemic organs (all structures except the gas exchange portion of the lungs). The pulmonary and systemic circulations are arranged in series, that is, one after the other. Consequently, the right and left hearts must each pump the same volume of blood each minute. This amount is called the cardiac output. A cardiac output of 5–6 L/min is normal for a resting individual. As indicated in Figure 22–2, the systemic organs are generally arranged in parallel (i.e., side by side) within the cardiovascular system. There are two important consequences of this parallel arrangement. First, nearly all systemic organs receive blood of identical composition—that which has just left the lungs and is known as arterial blood. Second, the

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flow through any one of the systemic organs can be controlled independently of the flow through the other organs. Thus, for example, the cardiovascular response to whole body exercise can involve increased blood flow through some organs, but decreased or unchanged blood flow through others. Many of the organs in the body help perform the task of continuously reconditioning the blood circulating in the cardiovascular system. Organs that communicate with the external environment, such as the lungs, play key roles. As is evident from the arrangement shown in Figure 22–2, blood that has just passed through a systemic organ returns to the right heart and is pumped through the lungs, where oxygen and carbon dioxide are exchanged. Thus, the blood’s gas composition is always reconditioned immediately after leaving a systemic organ. Like the lungs, many of the systemic organs also serve to recondition the composition of blood, although the flow circuitry precludes their doing so each time the blood completes one circuit. The kidneys, for example, adjust the electrolyte composition of the blood passing through them. Because the blood conditioned by the kidneys mixes freely with all the circulating blood and because electrolytes and water freely pass through most capillary walls, the kidneys control the electrolyte balance of the entire internal environment. To achieve this, it is necessary that a given unit of blood pass often through the kidneys. In fact, the kidneys (under resting conditions) normally receive about one fifth of the cardiac output. This greatly exceeds the amount of flow that is necessary to supply the nutrient needs of the renal tissue. This situation is common to organs that have a blood-conditioning function. Blood-conditioning organs can also withstand, at least temporarily, severe reductions of blood flow. Skin, for example, can easily tolerate a large reduction in blood flow when it is necessary to conserve body heat (see Chapter 70). Most of the large abdominal organs also fall into this category. The reason is simply that because of their blood-conditioning functions, their normal blood flow is far in excess of that necessary to maintain their basal metabolic needs. The brain, heart muscle, and skeletal muscles typify organs in which blood flows primarily to supply the metabolic needs of the tissue. They do not recondition blood for the benefit of any other organ. Flow to brain and heart muscle is normally

only slightly greater than that required for their metabolism, and they do not tolerate blood flow interruptions well. Unconsciousness can occur within a few seconds after stoppage of cerebral flow, and permanent brain damage can occur in as little as 4 minutes without flow. Similarly, the heart muscle (myocardium) normally consumes about 75% of the oxygen supplied to it, and the heart’s pumping ability begins to deteriorate within beats of a coronary flow interruption. As we shall see later, the task of providing adequate blood flow to the brain and the heart muscle receives a high priority in the overall operation of the cardiovascular system.

THE BASIC PHYSICS OF BLOOD FLOW As outlined above, the task of maintaining interstitial homeostasis requires that an adequate quantity of blood flow continuously through the millions of capillaries in the body. In a resting individual, this adds up to a cardiac output of about 5 L/min (about 80 gal/h). As people go about their daily lives, the metabolic rates and therefore the blood flow requirements in different organs and regions throughout the body change from moment to moment. Thus, the cardiovascular system must continuously adjust both the magnitude of cardiac output and how that cardiac output is distributed to different parts of the body. One of the most important keys to comprehending how the cardiovascular system operates is a thorough understanding of the relationship among the physical factors that determine the rate of fluid flow through a tube. The tube depicted in Figure 22–3 might represent a segment of any blood vessel in the body. It has a certain length (L) and a certain internal radius (r) through which blood flows. Fluid flows through the tube only when the pressures in the fluid at the inlet and outlet ends (Pi and Po) are unequal, that is, when there is a pressure difference (ΔP) between the ends. Pressure differences supply the driving force for flow. Because friction develops between moving fluid and the stationary walls of a tube, vessels tend to resist fluid movement through them. This vascular resistance is a measure of how difficult it is to make fluid flow through the tube, that is, how much of a pressure Length (L)

Radius (r ) P0

Pi · Flow (Q )

Inlet pressure

FIGURE 22–3

ΔP = Pi − P0

Outlet pressure

Factors influencing fluid flow through a tube. (Modified with permission from Mohrman DE, Heller LJ: Cardiovascular Physiology,

6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.)

CHAPTER 22 Overview of the Cardiovascular System difference it takes to cause a certain flow. The all-important relation among flow, pressure difference, and resistance is described by the basic flow equation as follows: difference ______________ Flow = Pressure Resistance

(1)

ΔP Q· = ___ R

where Q· is the flow (volume/time), ΔP the pressure difference (mm Hg), and R the resistance to flow (mm Hg × time/volume). The basic flow equation may be applied not only to a single tube, but also to complex networks of tubes, for example, to the vascular bed of an organ or to the entire systemic circulation. The blood flow through the brain, for example, is determined by the difference in pressure between cerebral arteries and veins divided by the overall resistance to flow through the vessels in the cerebral vascular bed. It should be evident from the basic flow equation that there are only two ways in which blood flow through any organ can be changed: (1) by changing the pressure difference across its vascular bed or (2) by changing its vascular resistance. Most often, it is the change in an organ’s vascular resistance that causes the flow through the organ to change. The resistance to flow through a cylindrical tube depends on several factors, including the radius and length of the tube and the viscosity of the fluid flowing through it. These factors influence resistance to flow as follows: 8 Lη

R = ____ πr4

(2)

where r is the inside radius of the tube, L the tube length, and η the fluid viscosity. Note that resistance is inversely proportional to the internal radius of the tube to the fourth power. Thus, even small changes in the internal radius of a tube have a very large influence on its resistance to flow. For example, halving the inside radius of a tube will increase its resistance to flow by 16-fold. Equations (1) and (2) may be combined into one expression known as the Poiseuille equation (equation (3)), which includes all the terms that influence flow through a cylindrical vessel: π r4 Q· = ΔP ____ 8 Lη

(3)

Again note that flow occurs only when a pressure difference exists. It is not surprising then that arterial blood pressure is an extremely important and carefully regulated cardiovascular variable. Also note once again that, for any given pressure difference, tube radius has a very large influence on the flow through a tube. It is logical, therefore, that organ blood flows are regulated primarily through changes in the radius of blood vessels within organs. Whereas vessel length and blood viscosity are factors that influence vascular resistance, they are not variables that can be easily manipulated for the purpose of moment-to-moment control of blood flow. In regard to the overall cardiovascular system as depicted in Figures 22–1 and 22–2, one can conclude that blood flows

203

through the vessels within an organ only because a pressure difference exists between the blood in the arteries supplying the organ and the veins draining it. The primary job of the heart pump is to keep the pressure within arteries higher than that within veins. Normally, the average pressure in systemic arteries is approximately 100 mm Hg, and the average pressure in systemic veins approaches 0 mm Hg. Therefore, because the pressure difference (ΔP) is identical across all systemic organs, cardiac output is distributed among the various systemic organs solely on the basis of their individual resistances to flow. Because blood flows along the path of least resistance, organs with relatively low resistance receive relatively high flow.

THE HEART PUMPING ACTION The heart lies in the center of the thoracic cavity suspended by its attachments to the great vessels within a thin fibrous sac called the pericardium. A small amount of fluid in the sac lubricates the surface of the heart and allows it to move freely during contraction and relaxation. Blood flow through all organs is passive and occurs only because arterial pressure is kept higher than venous pressure by the pumping action of the heart. The right heart pump provides the energy necessary to move blood through the pulmonary vessels, and the left heart pump provides the energy to move blood through the systemic organs. The amount of blood from each ventricle pumped per minute (the cardiac output, CO) depends on the volume of blood ejected per beat (the stroke volume, SV) and the number of heart beats per minute (the heart rate, HR) as follows: CO[volume/minute] = SV[volume/beat] × HR[beats/min] (4) It should be evident from the above relationship that all influences on cardiac output must act by changing either the heart rate or the stroke volume. These influences will be described in detail in subsequent chapters. The pathway of blood flow through the chambers of the heart is indicated in Figure 22–4. Venous blood returns from the systemic organs to the right atrium via the superior and inferior venae cavae. It passes through the tricuspid valve into the right ventricle and from there is pumped through the pulmonic valve into the pulmonary circulation via the pulmonary arteries. Oxygenated pulmonary venous blood flows in pulmonary veins to the left atrium and passes through the mitral valve into the left ventricle. From there it is pumped through the aortic valve into the aorta to be distributed to the systemic organs. Although the gross anatomy of the right heart pump is somewhat different than the left heart pump, the pumping principles are identical. Each pump consists of a ventricle, which is a closed chamber surrounded by a muscular wall, as

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Superior vena cava

Aorta

Pulmonary artery Right atrium

Pulmonary veins

Pulmonic valve

Left atrium Aortic valve Mitral valve

Tricuspid valve

Left ventricle

Inferior vena cava Right ventricle

FIGURE 22–4

Pathway of blood flow through the heart.

(Modified with permission from Mohrman DE, Heller LJ: Cardiovascular Physiology,

by rhythmic and synchronized contraction and relaxation of the individual cardiac muscle cells that lie in a circumferential orientation within the ventricular wall. When the ventricular muscle cells are contracting, they generate a circumferential tension in the ventricular walls that causes the pressure within the chamber to increase. As soon as the ventricular pressure exceeds the pressure in the pulmonary artery (right pump) or aorta (left pump), blood is forced out of the chamber through the outlet valve (pulmonic or aortic) as shown in Figure 22–5. This phase of the cardiac cycle during which the ventricular muscle cells are contracting is called systole. Because the pressure is higher in the ventricle than in the atrium during systole, the inlet or atrioventricular (AV) valve (tricuspid or mitral) is closed. When the ventricular muscle cells relax, the pressure in the ventricle decreases below that in the atrium, the AV valve opens, and the ventricle refills with blood as shown on the right of Figure 22–5. This portion of the cardiac cycle is called diastole. The outlet valve is closed during diastole because arterial pressure is greater than intraventricular pressure. After the period of diastolic filling, the systolic phase of a new cardiac cycle is initiated.

EXCITATION

6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.)

illustrated in Figure 22–5. The valves are structurally designed to allow flow in only one direction and passively open and close in response to the direction of the pressure differences across them. Ventricular pumping action occurs because the volume of the intraventricular chamber is cyclically changed

Efficient pumping action of the heart requires a precise coordination of the contraction of millions of individual cardiac muscle cells. Contraction of each cell is triggered when an electrical excitatory impulse (action potential) sweeps over its membrane. Proper coordination of the contractile activity of the individual cardiac muscle cells is achieved primarily by the conduction of action potentials from one cell to the next via

VENTRICULAR SYSTOLE

Atrium

VENTRICULAR DIASTOLE

Outlet valve

Inlet valve

Ventricular wall

FIGURE 22–5

Intraventricular chamber

Ventricular pumping action. (Modified with permission from Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange

Medical Books/McGraw-Hill, 2006.)

CHAPTER 22 Overview of the Cardiovascular System

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3. The valves must not leak (not insufficient or regurgitant). 4. The muscle contractions must be forceful (not failing). 5. The ventricles must fill adequately during diastole. In the subsequent chapters, we will study in detail how the above-mentioned requirements are met in the normal heart.

Sinoatrial node Atrioventricular node Atrial muscle

CONTROL OF THE HEART AND CARDIAC OUTPUT

Cartilage

Diastolic Filling Bundle of His Left bundle branch Right bundle branch Ventricular muscle

FIGURE 22–6

Electrical conduction system of the heart.

As cardiac filling increases during diastole, the volume ejected during systole also increases. As a consequence, and as illustrated in Figure 22–7, with other factors equal, stroke volume increases as cardiac end-diastolic volume increases. This phenomenon (Starling’s law of the heart) is an intrinsic property of the cardiac muscle and is one of the primary regulators of cardiac output. The mechanisms responsible for this phenomenon depend largely on the cardiac muscle cell’s length–tension relationship and will be described in detail in subsequent chapters.

(Modified with permission from Mohrman DE, Heller LJ: Cardiovascular Physiology,

gap junctions that connect all cells of the heart into a functional syncytium (i.e., acting as one synchronous unit). In addition, muscle cells in certain areas of the heart are specifically adapted to control the frequency of cardiac excitation, the pathway of conduction, and the rate of the impulse propagation through various regions of the heart. The major components of this specialized excitation and conduction system are shown in Figure 22–6. They include the sinoatrial node (SA node), the atrioventricular (AV) node, the bundle of His, and the right and left bundle branches made up of specialized cells called Purkinje fibers. The SA node contains specialized cells that normally function as the heart’s pacemaker and initiate the action potential that is conducted through the heart. The AV node contains slowly conducting cells that normally function to create a slight delay between atrial contraction and ventricular contraction. The Purkinje fibers are specialized for rapid conduction and assure that all ventricular cells contract at nearly the same instant.

REQUIREMENTS FOR EFFECTIVE OPERATION

Autonomic Neural Influences While the heart can inherently beat on its own, cardiac function can be influenced profoundly by neural inputs from both the sympathetic and parasympathetic divisions of the autonomic nervous system. These inputs allow us to modify cardiac pumping as appropriate to meet changing homeostatic needs of the body. All portions of the heart are richly innervated by adrenergic sympathetic fibers. When active, these sympathetic nerves release norepinephrine (noradrenalin) on cardiac cells. Norepinephrine interacts with β1-adrenergic receptors on cardiac muscle cells to increase heart rate, increase action potential conduction velocity, and increase force of con-

Stroke volume

6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.)

For effective efficient ventricular pumping action, the heart must be functioning properly in five basic respects: 1. The contractions of individual cardiac muscle cells must occur at regular intervals and be synchronized (not arrhythmic). 2. The valves must open fully (not stenotic).

Ventricular end-diastolic volume

FIGURE 22–7

Starling’s law of the heart. (Reproduced with

permission from Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.)

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traction and rates of contraction and relaxation. Overall, sympathetic activation acts to increase cardiac pumping. Cholinergic parasympathetic nerve fibers travel to the heart via the vagus nerve and innervate the SA node, the AV node, and atrial muscle. When active, these parasympathetic nerves release acetylcholine on cardiac muscle cells. Acetylcholine interacts with muscarinic receptors on cardiac muscle cells to decrease heart rate (SA node) and decrease action potential conduction velocity (AV node). Parasympathetic nerves may also act to decrease the force of contraction of atrial (not ventricular) muscle cells. Overall, parasympathetic activation acts to decrease cardiac pumping. Usually an increase in parasympathetic nerve activity is accompanied by a decrease in sympathetic nerve activity, and vice versa.

THE VASCULATURE Blood that is ejected into the aorta by the left heart passes consecutively through many different types of vessels before it returns to the right heart. As diagrammed in Figure 22–8, the major vessel classifications are arteries, arterioles, capillaries, venules, and veins. These consecutive vascular segments are

ARTERIES

distinguished from one another by differences in physical dimensions, morphological characteristics, and function. One thing that blood vessels have in common is that they are lined with a contiguous single layer of endothelial cells. In fact, this is true for the entire circulatory system including the heart chambers and even the valve leaflets. Some representative physical characteristics are shown in Figure 22–8 for each of the major vessel types. It should be realized, however, that the vascular bed is a continuum and that the transition from one type of vascular segment to another does not occur abruptly. The total cross-sectional area through which blood flows at any particular level in the vascular system is equal to the sum of the cross-sectional areas of all the individual vessels arranged in parallel at that level. The number and total cross-sectional area values presented in Figure 22–8 are estimates for the entire systemic circulation. Arteries are thick-walled vessels that contain, in addition to some smooth muscle, a large component of elastin and collagen fibers. Primarily because of the elastin fibers, which can stretch to twice their unloaded length, arteries can expand to accept and temporarily store some of the blood ejected by the heart during systole and then, by passive recoil, supply this blood to the organs downstream during diastole. The aorta is

ARTERIOLES CAPILLARIES VENULES

VEINS

One-way valves

Venae cavae

Aorta

FIGURE 22–8

Internal diameter

2.5 cm

0.4 cm

30 mm

5 mm

70 mm

0.5 cm

Wall thickness

2 mm

1 mm

20 mm

1 mm

7 mm

0.5 mm 1.5 mm

Number

1

160

5 = 107

1010

108

200

2

Total crosssectional area

4.5 cm2

20 cm2

400 cm2

4500 cm2

4000 cm2

40 cm2

18 cm2

3 cm

Structural characteristics of the peripheral vascular system. (Modified with permission from Mohrman DE, Heller LJ: Cardiovascular

Physiology, 6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.)

CHAPTER 22 Overview of the Cardiovascular System the largest artery and has an inside (luminal) diameter of about 25 mm. Arterial diameter decreases with each consecutive branching, and the smallest arteries have diameters of approximately 0.1 mm. The consecutive arterial branching pattern causes an exponential increase in arterial numbers. Thus, while individual vessels get progressively smaller, the total cross-sectional area available for blood flow within the arterial system increases to several-fold that in the aorta. Arteries are often referred to as conduit vessels because they have relatively low and unchanging resistance to flow. Arterioles are smaller and structured differently than arteries. In proportion to lumen size, arterioles have much thicker walls with more smooth muscle and less elastic material than arteries. Because arterioles are so muscular, their diameters can be actively changed to regulate the blood flow through peripheral organs. Despite their minute size, arterioles are so numerous that in parallel their collective cross-sectional area is much larger than that at any level in arteries. Arterioles are often referred to as resistance vessels because of their high and changeable resistance, which regulates peripheral blood flow through individual organs. Capillaries are the smallest vessels in the vasculature. In fact, red blood cells with diameters of about 7 μm must deform to pass through them. The capillary wall consists of a single layer of endothelial cells, which separate the blood from the interstitial fluid by only about 1 μm. Capillaries contain no smooth muscle and thus lack the ability to change their diameters actively. They are so numerous that the total collective cross-sectional area of all the capillaries in systemic organs is more than 1,000 times that of the root of the aorta. Given that capillaries are about 0.5 mm in length, the total surface area available for exchange of material between blood and interstitial fluid can be calculated; it exceeds 100 m2. For obvious reasons, capillaries are viewed as the exchange vessels of the cardiovascular system. In addition to the transcapillary diffusion of solutes that occurs across these vessel walls, there can sometimes be net movements of fluid (volume) into and/or out of capillaries. For example, tissue swelling (edema) is a result of net fluid movement from plasma into the interstitial space. After leaving capillaries, blood is collected in venules and veins and returned to the heart. Venous vessels have very thin walls in proportion to their diameters. Their walls contain smooth muscle and the diameters of venous vessels can actively change. Because of their thin walls, venous vessels are quite distensible. Therefore, their diameters change passively in response to small changes in transmural distending pressure (i.e., the difference between the internal and external pressures across the vessel wall). Venous vessels, especially the larger ones, also have one-way valves that prevent reverse flow. As will be discussed later, these valves are especially important in the cardiovascular system’s operation during standing and during exercise. It turns out that peripheral venules and veins normally contain more than 50% of the total blood volume. Consequently, they are commonly thought of as the capacitance vessels. More importantly, changes in venous volume

207

greatly influence cardiac filling and therefore cardiac pumping. Thus, peripheral veins actually play an extremely important role in controlling cardiac output.

CONTROL OF BLOOD VESSELS Blood flow through individual vascular beds is profoundly influenced by changes in activity of sympathetic nerves innervating arterioles. These nerves release norepinephrine from their endings that interacts with α-adrenergic receptors on the smooth muscle cells to cause contraction and thus arteriolar constriction. The reduction in arteriolar diameter increases vascular resistance and decreases blood flow. These neural fibers provide the most important means of reflex control of vascular resistance and organ blood flow. Arteriolar smooth muscle is also very responsive to changes in the local chemical conditions within an organ that accompany changes in the metabolic rate of the organ. For reasons to be discussed later, increased tissue metabolic rate leads to arteriolar dilation and increased tissue blood flow. Venules and veins are also richly innervated by sympathetic nerves and constrict when these nerves are activated. The mechanism is the same as that involved with arterioles. Thus, increased sympathetic nerve activity is accompanied by decreased venous volume. The importance of this phenomenon is that venous constriction tends to increase cardiac filling and therefore cardiac output via Starling’s law of the heart. There is no important neural or local metabolic control of either the arterial or capillary vessels.

BLOOD Blood is a complex fluid that serves as the medium for transporting substances between the tissues of the body and it performs a host of other functions as well. Normally about 40% of the volume of whole blood is occupied by blood cells that are suspended in the plasma, which accounts for the rest of the volume. The fraction of blood volume occupied by cells is a clinically important parameter termed the hematocrit: cell volume Hematocrit = ______________ total blood volume

(5)

BLOOD CELLS Blood contains three general types of “formed elements”: red cells, white cells, and platelets (Table 22–1). All are formed in bone marrow from a common stem cell. Red cells (erythrocytes) are by far the most abundant. They are specialized to carry oxygen from the lungs to other tissues by binding oxygen to hemoglobin, an iron-containing heme protein concentrated within red blood cells. Because of the presence of hemoglobin, blood can transport 50–60 times the

208

SECTION V Cardiovascular Physiology

TABLE 22–1 Normal values of erythrocytes, leukocytes, and platelets in adult human blood.a Erythrocytes

4.0–5.5 million/μL of blood

Platelets

130,000–400,000/μL of blood

Leukocytes

4,000–10,000/μL of blood

Type of Leukocyte

Percent Total Leukocytes

Primary Role

Neutrophils

50–70

Phagocytosis

Eosinophils

1–4

Allergic hypersensitivity reactions

Basophils

0–0.75

Allergic hypersensitivity reaction

Monocytes

2–8

Phagocytosis and antibody production

Lymphocytes

15–40

Antibody production and cellmediated immunity

Polymorphonuclear granulocytes

a

Normal reference ranges vary somewhat with age, gender, and race. They also may vary from laboratory to laboratory. To confuse the issue further, various unit measurements are used to report blood values, so caution must be used in interpreting data.

amount of oxygen that plasma alone could carry. In addition, the hydrogen ion buffering capacity of hemoglobin is vitally important to the blood’s capacity to transport carbon dioxide. A small but important fraction of the cells in blood is white cells or leukocytes. Leukocytes are involved in immune processes and have specific roles as indicated in Table 22–1. Platelets are small cell fragments that are important in the blood clotting process.

PLASMA Plasma is the liquid component of blood and, as indicated in Table 22–2, is a complex solution of electrolytes and proteins. Serum is the fluid obtained from a blood sample after it has been allowed to clot. For all practical purposes, the composition of serum is very similar to that of plasma except that it contains none of the clotting proteins. Inorganic electrolytes (ions such as sodium, potassium, chloride, and bicarbonate) are the most concentrated solutes in plasma. Of these, sodium and chloride are by far the most abundant and, therefore, are primarily responsible for plasma’s normal osmolarity of about 300 mOsm/L. To a first approximation, plasma is a 150-mM solution of sodium chloride. Such a solution is called isotonic saline and has many clinical uses as a fluid that is compatible with cells. Plasma normally contains many different proteins. Most plasma proteins can be classified as albumins, globulins, or fibrinogen on the basis of different physical and chemical characteristics used to separate them. More than 100 distinct plasma proteins have been identified and each presumably serves some specific function. Many plasma proteins are involved in blood clotting or immune/defense reactions. Many others are important carrier proteins for a variety of substances including fatty acids, iron, copper, and certain hormones.

Proteins do not readily cross capillary walls and, in general, their plasma concentrations are much greater than their concentrations in the interstitial fluid. As will be discussed, plasma proteins play an important osmotic role in transcapillary fluid movement and thus the distribution of extracellular volume between the plasma and interstitial compartments. Albumin plays an especially important role in this regard simply because it is by far the most abundant of the plasma proteins. Plasma also serves as the vehicle for transporting nutrients and waste products. Thus, a plasma sample contains many small organic molecules such as glucose, amino acids, urea, creatinine, and uric acid whose measured values are useful in clinical diagnosis.

HEMOSTASIS Whenever damage occurs to a blood vessel, a variety of processes are initiated that are aimed at preventing or stopping blood from exiting the vascular space. The three primary processes are summarized in the following outlines: 1. Platelet aggregation and plug formation: occur as a result of the following steps: A. vessel injury with endothelial damage and collagen exposure; B. platelet adherence to collagen (mediated by von Willebrand factor); C. platelet shape change (from disks to spiny spheres); D. platelet degranulation with release of the following: (i) adenosine diphosphate, which causes platelet aggregation to “plug” the hole, (ii) thromboxane, causing vasoconstriction, and platelet adhesion and aggregation.

CHAPTER 22 Overview of the Cardiovascular System

209

TABLE 22–2 Normal constituents of adult human plasma. Class Cations

Constituent

Normal Concentration Range

+

Sodium (Na )

136–145 mEq/L

+

Potassium (K )

3.5–5.0 mEq/L

2+

Calcium (Ca )

4.3–5.2 mEq/L 2+

Magnesium (Mg )

1.2–1.8 mEq/L

3+

Iron (Fe )

60–160 μg/dL +

Hydrogen (H ) Anions

35–45 nmol/L (pH 7.35–7.45)

–

Chloride (Cl )

98–106 mEq/L –

Bicarbonate (HCO3 )

23–28 mEq/L

Lactate

0.67–1.8 mEq/L 2–

Proteins

Phosphate (HPO4 mostly)

3.0–4.5 mg/dL

Total (7% of plasma weight)

6–8 g/dL

Albumin

3.4–5.0 g/dL

Globulins

2.2–4.0 g/dL

Fibrinogen

0.3 g/dL

(Note: Aspirin and other cyclooxygenase inhibitors are anticoagulants because they prevent the formation of thromboxane.) 2. Local vasoconstriction: mediated largely by thromboxane but also may be induced by local release of other chemical signals that constrict local vessels and reduce blood flow. 3. Blood clotting: the formation of a solid gel made up of the protein, fibrin, platelets, and trapped blood cells. The critical step in blood clotting is the formation of thrombin from prothrombin, which then catalyzes the conversion of fibrinogen to fibrin. The final clot is stabilized by covalent cross-linkages between fibrin strands catalyzed by factor XIIIa (the formation of which is catalyzed by thrombin). The cascade of reactions that leads from vessel injury to the formation of thrombin is as follows: (1) Vessel injury or tissue damage with blood exposure to subendothelial cells that release thromboplastin (“tissue factor”). (2) The plasma protein factor VII binds to the tissue factor, which converts it to an activated form, factor VIIa. (3) VIIa catalyzes conversion of both factors IX and X to activated forms, IXa and Xa, respectively. (4) IXa also helps convert factor X to Xa (Stuart factor). (5) Xa converts prothrombin to thrombin. (6) Thrombin: (a) activates platelets (makes them sticky, induces degranulation, promotes attachment of various factors that participate in clotting);

(b) converts fibrinogen to fibrin; (c) recruits the “intrinsic pathway,” which amplifies further formation of factor Xa and facilitates the conversion of prothrombin to thrombin by promoting the following reactions: (i) conversion of factor XI to its activated form, XIa, which then converts factor IX to IXa, which then attaches to activated platelets and converts factor X to Xa, (ii) conversion of factor VIII (missing in people with hemophilia) to its activated form, VIIIa, which attaches to activated platelets and accelerates conversion of factor X to Xa, (iii) conversion of factor V to its activated form, Va, which attaches to activated platelets and accelerates conversion of prothrombin to thrombin. Several agents clinically used as anticoagulants interfere with various steps in this clotting process. Dicoumarol and coumadin block the activity of vitamin K, which is necessary for synthesis of many of the clotting factors by the liver. Heparin activates a plasma protein called antithrombin III, which, in turn, inactivates thrombin and several of the other clotting factors. Because calcium is an important clotting cofactor, calcium chelators such as EDTA, oxalate, and citrate are used to prevent stored blood from clotting. Various thrombolytic agents modeled after the endogenous tissue plasminogen activator (tPA) are also available that promote dissolution of the fibrin clot after it is formed. These agents promote the formation of plasmin from plasminogen that enzymatically attacks the clot, turning it into soluble peptides.

210

SECTION V Cardiovascular Physiology ■

CLINICAL CORRELATION A 45-year-old investment banker passed out at the mall. He was conscious by the time the paramedics arrived a few minutes later but was brought to the emergency room for evaluation. He reported that he had been very busy and somewhat stressed lately but otherwise was healthy. He looked pale and felt somewhat nauseated and dizzy just before the episode, but did not remember falling or anything else until the paramedic was leaning over him on the floor. Physical findings included: weight = 90 kg, height = 5΄10˝, arterial blood pressure = 130/85 mm Hg, heart rate = 85 b/min, normal heart and breath sounds, normal reflexes, and normal cognition. An electrocardiogram was obtained and found to be normal. Blood samples were obtained for markers of myocardial infarction and heart failure, and also found to be normal. He was admitted to the hospital and ECG was monitored overnight with no significant findings. Unexplained syncopal (fainting) episodes may be a result of either a neural problem (seizure) or a significant decrease in blood flow to the brain. The latter may be caused by either a failure of the heart to maintain sufficient cardiac output (due to an arrhythmia, valve failure, or infarction affecting significant myocardial mass) or a failure within the systemic vasculature either to maintain sufficient contractile activity (due to a withdrawal of sympathetic neural influences as in vasovagal syncope) or to provide sufficient arterial blood supply to the brain (due to severe, often transient, carotid artery occlusions provoking a transient ischemic attack [TIA]). Diagnostic testing was performed to evaluate these possibilities. The man was outfitted with a Holter monitor that recorded his ECG for a 24-hour period, and found to be normal. By process of elimination, he was given the diagnosis of vasovagal syncope that is usually due to an increase in efferent vagal (parasympathetic) input to the heart that will be discussed in Chapters 23 and 29. In most cases of vasovagal syncope, no treatment is necessary.

CHAPTER SUMMARY ■ ■

■

■

The primary role of the cardiovascular system is to maintain homeostasis of the interstitial fluid. The physical law that governs cardiovascular operation is that flow through any segment is equal to pressure difference across · that segment divided by its resistance to flow, that is, Q = ΔP/R. The heart pumps blood by rhythmically filling with and ejecting blood from the ventricular chambers that are served by passive one-way inlet and outlet valves. Changes in heart rate and stroke volume (and therefore cardiac output) can be accomplished by alterations in ventricular filling and by alterations in autonomic nerve activity to the heart.

■

■

■

Blood flow through individual organs is regulated by changes in the diameters of their arterioles. Changes in arteriolar diameter can be accomplished by alterations in sympathetic nerve activity and by variations in local conditions. Blood is a complex suspension of red cells, white cells, and platelets in plasma that is ideally suited to carry gases, salts, nutrients, and waste molecules throughout the system. Hemostasis involves platelet aggregation, local vasoconstriction, and blood clotting.

STUDY QUESTIONS 1. You need to determine the correct dose of an i.v. drug that distributes only within the extracellular space. Which of the following values would be the closest estimate of the extracellular fluid volume of a healthy young adult male weighing 100 kg (220 lb)? A) 3 L B) 5 L C) 8 L D) 10 L E) 20 L 2. You have transfused a liter of blood into your dehydrated patient. At any instant, most of this blood will be found in which segment of the systemic vascular bed? A) arteries B) arterioles C) capillaries D) veins E) right atrium 3. Which of the following will produce the greatest increase in blood flow through exercising muscles? A) halve the length of the capillaries B) halve the viscosity of the blood C) double the radius of the venules D) double the blood pressure difference across the bed E) double the radius of the arterioles 4. An individual has had the “flu” for 3 days with severe vomiting and diarrhea without increasing his fluid intake. How is this likely to influence his hematocrit? A) no effect B) higher than normal C) lower than normal D) cannot predict E) eliminate it 5. Calculate the cardiac output from the following data: pulmonary arterial pressure = 20 mm Hg; left atrial pressure = 5 mm Hg; pulmonary vascular resistance = 3 mm Hg per L/min. A) 3 L/min B) 5 L/min C) 4 L/min D) 15 L/min E) 60 mm Hg

23 C

Cardiac Muscle Cells Lois Jane Heller and David E. Mohrman

H A

P

T

E

R

O B J E C T I V E S ■ ■ ■

■ ■ ■ ■ ■

■ ■ ■ ■ ■ ■ ■ ■ ■

■ ■

Ch23_211-222.indd 211

Describe the characteristics of cardiac resting potentials and “fast” and “slow” response cardiac action potentials. Identify the refractory periods of the cardiac cell electrical cycle. Define threshold potential and describe the interaction between ion channel conditions and membrane potential during the depolarization phase of the action potential. Define pacemaker potential and describe the basis for rhythmic electrical activity of cardiac cells. List the phases of the cardiac cell electrical cycle and state the membrane permeability alterations responsible for each phase. Describe gap junctions and their role in cardiac excitation. Describe the normal pathway of action potential conduction through the heart. Indicate the timing of electrical excitation of various areas of the heart and identify the characteristic action potential shapes and conduction velocities in each major part of the conduction system. State the relationship between electrical events of cardiac excitation and the P, QRS, and T waves, the PR interval, and the ST segment of the electrocardiogram. State how diastolic potentials of pacemaker cells can be altered to produce changes in heart rate. Describe how cardiac sympathetic and parasympathetic nerves alter heart rate and conduction of cardiac action potentials. Define the terms chronotropic and dromotropic. Define and describe the excitation–contraction process in cardiac muscle. Define isometric, isotonic, and afterloaded contractions of cardiac muscle. Identify the influence of altered preload on the tension-producing and shortening capabilities of cardiac muscle. Describe the influence of altered afterload on the shortening capabilities of cardiac muscle. Define the terms contractility and inotropic state and describe the influence of altered contractility on the tension-producing and shortening capabilities of cardiac muscle. Describe the effect of altered sympathetic neural activity on cardiac inotropic state. State the relationships between ventricular volume and muscle length, and between intraventricular pressure and muscle tension; explain the law of Laplace.

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11/26/10 10:00:01 AM

212

SECTION V Cardiovascular Physiology

CHARACTERISTICS OF CARDIAC MUSCLE CELLS Coordination of the activity of cardiac muscle cells (myocytes) depends on an electrical stimulus that is regularly initiated at an appropriate rate and reliably conducted through the entire heart. Mechanical pumping action depends on a robust contraction of the muscle cells that results in repeating cycles of tension development, shortening, and relaxation. In addition, mechanisms to adjust the excitation and contraction characteristics must be available to meet changing demands on the circulatory system.

ELECTRICAL PROPERTIES Contraction of cardiac myocytes is triggered by action potentials that occur on the cell membrane. Cardiac action potentials differ sharply from those of skeletal muscle in three important ways that promote synchronous rhythmic excitation of the heart: (1) they can be self-generating; (2) they can be conducted directly from cell to cell; and (3) they have long durations, which preclude fusion of individual twitch contractions. To understand these special electrical properties of cardiac muscle and how cardiac function depends on them, the basic electrical properties of excitable cell membranes described in Chapters 3 and 6 should be carefully reviewed.

SUMMARY OF CARDIAC CELL MEMBRANE POTENTIALS At rest, cardiac cell membranes are more permeable to potassium than to any other ion. Because the potassium concentration inside the cells is significantly higher than that of the interstitial fluid (150 mM vs. 4 mM, respectively), the outward diffusion of potassium down its concentration gradient is balanced by the generation of a membrane potential (i.e., the potassium equilibrium potential). Both the electrical and the concentration gradients favor Na+ and Ca2+ entry into the resting cells. However, the very low permeability of the resting membrane to Na+ and Ca2+, in combination with an energyrequiring sodium pump that extrudes Na+ from the cell, prevents Na+ and Ca2+ from gradually accumulating inside the resting cell. The steep sodium gradient promotes Ca2+ removal from the cytoplasm via the sodium/calcium exchanger. Action potentials of cells from different regions of the heart are not identical but have varying characteristics that depend on differences in the patterns of changes in their ion permeabilities. Some cardiac cells have the ability to act as pacemakers and to spontaneously initiate action potentials, whereas ordinary cardiac muscle cells do not (except under unusual conditions). Basic membrane electrical features of an ordinary cardiac muscle cell and a cardiac pacemaker-type cell are shown in Figure 23–1. Action potentials from these cell types are referred to as “fast response” and “slow response” action

potentials, respectively. As shown in panel A of this figure, fast response action potentials are characterized by a rapid depolarization (phase 0) with a substantial overshoot (positive inside voltage), a rapid reversal of the overshoot potential (phase 1), a long plateau (phase 2), and a repolarization (phase 3) to a stable, high (i.e., large negative) resting membrane potential (phase 4). In comparison, the slow response action potentials are characterized by a slower initial depolarization phase (phase 0), a lower amplitude overshoot, a shorter and less stable plateau phase (phase 2), and a repolarization (phase 3) to an unstable, slowly depolarizing “resting” potential (phase 4) (Figure 23–1B). The unstable resting potential seen in pacemaker cells with slow response action potentials is variously referred to as the phase 4 depolarization, diastolic depolarization, or pacemaker potential. Such cells are usually found in the sinoatrial (SA) and atrioventricular (AV) nodes. As indicated at the bottom of Figure 23–1A, cells are in an absolute refractory state during most of the action potential (i.e., they cannot be stimulated to fire another action potential). Near the end of the action potential, the membrane is relatively refractory and can be re-excited only by a largerthan-normal stimulus. Immediately after the action potential, the membrane is transiently hyperexcitable and is said to be in a “vulnerable” or “supranormal” period. Similar alterations in membrane excitability occur during slow action potentials but at present are not well characterized. Recall that the membrane potential of any cell at any given instant depends on the relative permeability of the cell membrane to specific ions. As in all excitable cells, cardiac cell action potentials are the result of transient changes in the ionic permeability of the cell membrane that are triggered by an initial depolarization. Panels C and D of Figure 23–1 indicate the changes in membrane permeabilities to K+, Na+, and Ca2+ that produce the various phases of the fast and slow response action potentials. Note that during the resting phase, the membranes of both types of cells are dominated by a higher permeability to K+ than to Na+ or Ca2+. Therefore, the membrane potentials are closer to the potassium equilibrium potential during this period than to the equilibrium potential of any other ion. In the pacemaker-type cells, at least three mechanisms are thought to contribute to the slow depolarization of the membrane observed during the diastolic interval: (1) there is a progressive slow decrease in the membrane permeability to K+, (2) there is a slow increase in permeability to Na+, and (3) there is a slight increase in the permeability of the membrane to calcium ions. When the membrane potential depolarizes to the threshold potential in either type of cell, major rapid alterations in the permeability of the membrane to specific ions are triggered. Once initiated, these permeability changes cannot be stopped and they proceed to completion. The characteristic rapid rising phase of the fast response action potential is a result of a sudden increase in Na+ permeability. As indicated in panel C of Figure 23–1, this

CHAPTER 23 Cardiac Muscle Cells

B

Fast-response action potentials

Phase

2

Phase 0

0

e3

–50

Slow-response action potentials

Phas

Transmembrane potential (mV)

A

213

se 4

Pha

Phase 4

–100 Absolute refractory period Relative refractory period Supranormal period

Relative membrane permeability

C

D 10.0

Na+ Ca2+

Ca2+

K+

K+

1.0

Na+ 0.1 0

0.15 Time (s)

0.30

0

0.15 Time (s)

0.30

FIGURE 23–1 Time course of membrane potential and ion permeability changes that occur during “fast response” (A and C) and “slow response” (B and D) action potentials. (Modified with permission from Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.)

period of very high sodium permeability (phase 0) is shortlived and is followed by a very brief increase in potassium permeability (not shown in Figure 23–1C). This brief current accounts for the very early repolarization that immediately follows the initial rising phase of the action potential (phase 1). Development and maintenance of a depolarized plateau state (phase 2) depends on: (1) a sustained reduction in K+ permeability, (2) a slowly developed and sustained increase in the membrane permeability to Ca2+, and (3) electrogenic action of an Na+/Ca2+ exchanger in which three Na+ ions move into the cell in exchange for a single Ca2+ moving out of the cell. In cells with the slow response action potential, the initial fast inward current is small (or even absent). The slow rising phase of these action potentials is therefore primarily a result of an inward movement of Ca2+ ions. In both types of cells, the membrane is repolarized (phase 3) to its original resting potential as the K+ permeability increases and the Ca2+ and Na+ permeabilities return to their low resting values. Recall that the smoothly graded permeability changes that produce action potentials are the net result of alterations in each of the many individual ion channels within the plasma

membrane of a single cell as discussed in Chapter 6. Table 23–1 summarizes some of the major currents and channel types (both voltage- and ligand-gated) involved in cardiac cell electrical activity. Some of the voltage-gated channels respond to a suddenonset, sustained change in membrane potential with only a brief period of activation. However, changes in membrane potential of slower onset but the same magnitude may fail to activate these channels at all. To explain such behavior, it is postulated that these channels have two independently operating “gates”—an activation gate and an inactivation gate—both of which must be open for the channel as a whole to be open. Both of these gates respond to changes in membrane potential but do so with different voltage sensitivities and time courses. With an abrupt depolarization to threshold, sodium channel activation gates open and within a few milliseconds their inactivation gates close. In pacemaker cells with slow diastolic depolarization, the inactivation gates of the sodium channels are closed before the activation gates have a chance to open. When threshold is reached, only the calcium channel is available to open, thus accounting for the initial

214

SECTION V Cardiovascular Physiology

TABLE 23–1 Characteristics of important cardiac ion channels in order of their participation in an action potential. Current

Channel

Gating Mechanism

Functional Role

iK1

Kir+ channel (inward rectifier)

Voltage

Maintains high K+ permeability during phase 4 Its decay contributes to diastolic depolarization Its suppression during phases 0–2 contributes to plateau

iNa

+

Na channel (fast)

Voltage

Accounts for phase 0 of action potential Inactivation may contribute to phase 1 of action potential

Ito iCa

+

K channel (transient outward) 2+

Ca channel (slow inward, L channels)

Voltage

Contributes to phase 1 of action potential

Both

Contributes to phase 2 of action potential Inactivation may contribute to phase 3 of action potential Is enhanced by sympathetic stimulation and β-adrenergic agents

iK

+

K channel (delayed rectifier)

Voltage

Causes phase 3 of action potential Is enhanced by increased intracellular Ca2+

iKATP

K+ channel (ATP-sensitive)

Ligand

Increases K+ permeability when [ATP] is low

iKACh

K+ channel (acetylcholine-activated)

Ligand

Responsible for effects of vagal stimulation Decreases diastolic depolarization (and heart rate) Hyperpolarizes resting membrane potential Shortens phase 2 of the action potential

if (“funny”)

+

Nạ (pacemaker current)

Both

Is activated by hyperpolarization and contributes to the diastolic depolarization Is enhanced by sympathetic stimulation and β-adrenergic agents Is suppressed by vagal stimulation

slow rising phase of the action potentials in pacemaker cells. Calcium channel inactivation gate closing is delayed for more than 100 milliseconds until near the end of the plateau phase. Inactivation gates on the sodium and calcium channels remain closed until the membrane repolarizes. This accounts for the long cardiac muscle cell refractory period. Multiple factors influence the operation of K+ channels, some of which are summarized in Table 23–1. For example, high intracellular Ca2+ concentration contributes to activation of some K+ channels during repolarization. Although cells in certain areas of the heart typically have fast-type action potentials and cells in other areas normally have slow-type action potentials, it is important to recognize that all cardiac cells are potentially capable of having either type of action potential depending on their resting membrane potentials and how fast they depolarize to the threshold potential. Rapid depolarization to the threshold potential is usually an event forced on a cell by the occurrence of an action potential in an adjacent cell. Slow depolarization to threshold occurs when a cell itself spontaneously and gradually loses its resting polarization, which normally happens only in the SA node. A chronic moderate depolarization of the resting membrane (caused, e.g., by moderately high extracellular K+ concentration) can inactivate the fast sodium channels (i.e., prevent them from opening) without inactivating the slow calcium channels. Under these conditions, all cardiac cell action potentials will be of the slow type. Large sustained depolarizations,

however, can inactivate both the fast and slow channels and thus make the cardiac muscle cells completely unexcitable.

CONDUCTION OF CARDIAC ACTION POTENTIALS Action potentials are conducted over the surface of individual cells because active depolarization in any one area of the membrane produces local currents in the intracellular and extracellular fluids that passively depolarize immediately adjacent areas of the membrane to their voltage threshold for active depolarization. In the heart, cardiac muscle cells are connected end-to-end by structures called intercalated disks. These disks contain the following: (1) firm mechanical attachments between adjacent cell membranes by proteins called adherins in structures called desmosomes and (2) low-resistance electrical connections between adjacent cells through channels formed by a protein called connexin in structures called gap junctions. Figure 23–2 shows schematically how these gap junctions allow action potential propagation from cell to cell. Cells B, C, and D are shown in the resting phase with more negative charges on the inside than the outside. Cell A is shown in the plateau phase of an action potential and has more positive charges inside than out. Because of the gap junctions, electrostatic attraction can cause a local current flow (ion movement)

CHAPTER 23 Cardiac Muscle Cells

Resting cell B – – – + + + – +

+ + + + – – – –

–

– – – – – – – – + + + + + + + + Cell A with action potential + + + + + + + + – – – – – – – –

+ + + + – – + + – – – –

– –+ ++ – –

– – – + + +

+ + – –

+ –

215

+ + + – – –

Resting cell C – – – + + + + + + + + – – – – – – – –+ + Resting cell D – – – – – – + + + – – – – + + + +

– – + + + + – –

– – + +

– – + + + + – –

Gap junction (nexus)

FIGURE 23–2

Local currents and cell-to-cell conduction of cardiac muscle cell action potentials. (Modified with permission from Mohrman

DE, Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.)

between the depolarized membrane of active cell A and the polarized membrane of resting cell B, as indicated by the arrows in the figure. This ion movement depolarizes the membrane of cell B. Once the local currents from active cell A depolarize the membrane of cell B near the gap junction to the threshold level, an action potential will be triggered at that site and will be conducted over cell B. Because cell B branches (a common morphological characteristic of cardiac muscle fibers), its action potential will evoke action potentials on cells C and D. This process is continued through the entire myocardium. Thus, an action potential initiated at any site in the myocardium will be conducted from cell to cell throughout the entire myocardium. The speed at which an action potential propagates through a region of cardiac tissue is called the conduction velocity. The conduction velocity varies considerably in different areas in the heart and is determined by three variables: 1. Conduction velocity is directly dependent on the diameter of the muscle fiber involved. Thus, conduction over

small-diameter cells in the AV node is significantly slower than conduction over large-diameter cells in the ventricular Purkinje system. 2. Conduction velocity is also directly dependent on the intensity of the local depolarizing currents, which are in turn directly determined by the rate of rise of the action potential. Rapid depolarization favors rapid conduction. 3. Conduction velocity is dependent on the capacitive and/ or resistive properties of the cell membranes, gap junctions, and cytoplasm. Electrical characteristics of gap junctions can be influenced by external conditions that promote phosphorylation/dephosphorylation of the connexin proteins. Details of the overall consequences of the cardiac conduction system are shown in Figure 23–3. As noted earlier, the specific electrical adaptations of various cells in the heart are reflected in the characteristic shape of their action potentials that are shown in the right half of Figure 23–3. Note that the

–100 Atrial muscle

mV

SA node

A B

Atrial muscle

C

AV node

D

Purkinje fiber

E

Ventricular muscle Ventricular muscle

F G R P wave

T wave

ECG Q S PR Interval ST segment QT Interval

1.0 second

FIGURE 23–3

Electrical activity of the heart: single-cell voltage recordings (traces A–G) and lead II electrocardiogram. (Modified with

permission from Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.)

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action potentials shown in Figure 23–3 have been positioned to indicate the time at which the electrical impulse that originates in the SA node reaches other areas of the heart. Cells of the SA node act as the heart’s normal pacemaker and determine the heart rate. This is because the spontaneous diastolic depolarization of the resting membrane is most rapid in SA nodal cells, and they reach their threshold potential before cells elsewhere in the heart. The action potential initiated by an SA nodal cell first spreads progressively through the atrial wall. Action potentials from cells in two different regions of the atria are shown in Figure 23–3: one close to the SA node and one more distant from the SA node. Both cells have similarly shaped action potentials, but their temporal displacement reflects the fact that it takes some time for the impulse to spread over the atria. Action potential conduction is greatly slowed as it passes through the AV node. This is because of the small size of the AV nodal cells and the slow rate of rise of their action potentials. Since the AV node delays the transfer of the cardiac excitation from the atria to the ventricles, atrial contraction can contribute to ventricular filling just before the ventricles contract. Note also that AV nodal cells have a faster spontaneous depolarization during the resting period than other cells of the heart except those of the SA node. The AV node is sometimes referred to as a latent pacemaker, and in many pathological situations it (rather than the SA node) controls the heart rhythm. Because of sharply rising action potentials and other factors, such as large cell diameters, electrical conduction is extremely rapid in Purkinje fibers. This allows the Purkinje system to transfer the cardiac impulse to cells in many areas of the ventricle nearly in unison. Action potentials from muscle cells in two areas of the ventricle are shown in Figure 23–3. Because of the high conduction velocity in ventricular tissue, there is only a small discrepancy in their time of onset. Note that the ventricular cells that are the last to depolarize have shorter-duration action potentials and thus are the first to repolarize. The physiological importance of this unexpected behavior is not clear but it does have an influence on the electrocardiograms that will be discussed in Chapter 25.

ELECTROCARDIOGRAMS Fields of electrical potential caused by the electrical activity of the heart extend through the extracellular fluid of the body and can be measured with electrodes placed on the body surface. Electrocardiography provides a record of how the voltage difference between two points on the body surface changes with time as a result of the electrical events of the cardiac cycle. At any instant of the cardiac cycle, the electrocardiogram indicates the net electrical field that is the summation of many weak electrical fields being produced by voltage changes occurring on individual cardiac cells. When a large number of cells are simultaneously depolarizing or repolarizing, large voltages are observed on the electrocardiogram. Since the electrical impulse spreads through the heart tissue in a consis-

tent pathway, the temporal pattern of voltage change recorded between two points on the body surface is also consistent and will repeat itself with each heart cycle. The lower trace of Figure 23–3 represents a typical recording of the voltage changes normally measured between the right arm and the left leg as the heart goes through two cycles of electrical excitation; this record is called a lead II electrocardiogram. The major features of an electrocardiogram are the P wave, the QRS complex, and the T wave. The P wave corresponds to atrial depolarization, the QRS complex to ventricular depolarization, and the T wave to ventricular repolarization.

CONTROL OF HEART RATE Normal rhythmic contractions of the heart occur because of spontaneous electrical pacemaker activity (automaticity) of cells in the SA node. The interval between heartbeats (and thus the heart rate) is determined by how long it takes the membranes of these pacemaker cells to spontaneously depolarize to the threshold level. The SA nodal cells fire at a spontaneous or intrinsic rate (≈100 beats/min) in the absence of any outside influences. The two most important outside influences on automaticity of SA nodal cells come from the autonomic nervous system (see Chapter 19). Fibers from both the sympathetic and parasympathetic divisions of the autonomic system terminate on cells in the SA node and these fibers can modify the intrinsic heart rate. Activation of the cardiac sympathetic nerves (increasing cardiac sympathetic tone) increases the heart rate. Increasing cardiac parasympathetic tone decreases the heart rate. As shown in Figure 23–4, the parasympathetic and sympathetic nerves both influence heart rate by altering the course of spontaneous depolarization of the resting potential in SA pacemaker cells. Cardiac parasympathetic fibers, which travel to the heart through the vagus nerves, release the transmitter substance acetylcholine on SA nodal cells. Acetylcholine increases the permeability of the resting membrane to K+ and decreases the diastolic permeability to Na+. The signaling process involves acetylcholine interaction with muscarinic receptors on the SA nodal cell membrane that in turn are linked to inhibitory G proteins, Gi. The activation of Gi has two effects: (1) an increase in K+ permeability resulting from an increased opening of the KAch channels and (2) a suppression of adenylate cyclase leading to a decrease in intracellular cyclic adenosine monophosphate (cAMP) concentration that reduces the inward-going pacemaker current carried by Na+ (if). As indicated in Figure 23–4, these permeability changes have two effects on the resting potential of cardiac pacemaker cells: (1) they cause an initial hyperpolarization of the resting membrane potential by bringing it closer to the K+ equilibrium potential and (2) they slow the rate of spontaneous depolarization of the resting membrane. Both of these effects increase the time between beats by prolonging the time required for

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Parasym pathetic tone

–30

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decreases conduction velocity (has a negative dromotropic effect). These effects are most notable at the AV node and can influence the time between the P and R waves (the PR interval).

Intrinsic

Membrane potential (mV)

–10

Sympathetic tone

CHAPTER 23 Cardiac Muscle Cells

–70 Threshold potential –90 Time

FIGURE 23–4 Effect of sympathetic and parasympathetic tones on pacemaker potential. (Modified with permission from Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/ McGraw-Hill, 2006.)

the resting membrane to depolarize to the threshold level. Since there is normally some continuous tonic activity of cardiac parasympathetic nerves, the normal resting heart rate is approximately 70 beats/min. Sympathetic nerves release the transmitter substance norepinephrine on cardiac cells. In addition to other effects discussed later, norepinephrine increases the inward currents carried by Na+ (if ) and by Ca2+ during the diastolic interval. The signaling process involves norepinephrine interaction with β1-adrenergic receptors on the SA nodal cell membrane that in turn are linked to stimulatory G proteins, Gs. The activation of Gs increases adenylate cyclase, leading to an increase in intracellular cyclic AMP that increases the open-state probability of the pacemaker Na+ current channel (if ). These changes increase heart rate by increasing the rate of diastolic depolarization as shown in Figure 23–4. In addition to sympathetic and parasympathetic nerves, there are many (usually less important) factors that can alter heart rate. These include a number of ions and circulating hormones, as well as physical influences such as temperature and atrial wall stretch. All act by altering the time required for the resting membrane to depolarize to the threshold potential. An abnormally high concentration of Ca2+ in the extracellular fluid, for example, tends to decrease heart rate by shifting the threshold potential. Factors that increase heart rate are said to have a positive chronotropic effect. Those that decrease heart rate have a negative chronotropic effect. An increase in sympathetic activity also increases action potential conduction velocity (has a positive dromotropic effect), whereas an increase in parasympathetic activity

MECHANICAL PROPERTIES Contraction of the cardiac muscle cell is initiated by the action potential acting on intracellular organelles to evoke tension generation and/or shortening of the cell. The reader is encouraged to carefully review the materials presented in Chapters 9 and 10 for specific cellular details describing contraction of skeletal and cardiac muscle.

EXCITATION–CONTRACTION COUPLING The major event in excitation–contraction coupling in cardiac muscle is a dramatic rise in the intracellular free Ca2+ concentration from less than 0.1 μM to as much as 100 μM. When the wave of depolarization passes over the muscle cell membrane, Ca2+ is released from the sarcoplasmic reticulum (SR) into the intracellular fluid. The specific trigger is a small localized increase in calcium concentration triggering a massive release of calcium from the SR. Although the amount of Ca2+ that enters the cell during a single action potential is quite small compared with that released from the SR, it is not only essential for triggering the SR calcium release, but also essential for maintaining adequate levels of Ca2+ in the intracellular stores over the long run. The contractile process initiated by the increase in intracellular calcium concentration has been described in Chapters 9 and 10. Recall that excitation–contraction coupling in cardiac muscle differs from that in skeletal muscle in that it may be modulated; different intensities of actin–myosin interaction (contraction) can result from a single action potential trigger in cardiac muscle. The mechanism for this is largely dependent on variations in the amount of Ca2+ reaching the myofilaments and therefore the number of cross-bridges activated during the twitch. This ability of cardiac muscle to vary its contractile strength—that is, change its contractility—is extremely important to cardiac function, as will be discussed later in this chapter.

RELAXATION The processes that participate in the reduction of intracellular Ca2+ that terminates the contraction include (1) active uptake of ~80% of the calcium back into the SR by the action of Ca2+-ATPase pumps, (2) active extrusion of ~5% of the calcium from the cell via sarcolemmal Ca2+-ATPase pumps, and (3) passive exchange of ~15% of the calcium with extracellular sodium via the Na+–Ca2+ exchanger located in the sarcolemma. The Na+–Ca2+ exchanger is powered by the sodium gradient

SECTION V Cardiovascular Physiology

CARDIAC MUSCLE CELL MECHANICS

across the sarcolemma that in turn is maintained by the Na+/ K+-ATPase. This exchanger is electrogenic in that three Na+ ions move into the cell in exchange for each Ca2+ ion that moves out. This net inward movement of positive charge may contribute to the maintenance of the plateau phase of the action potential. The cardiac glycoside, digitalis, slows down the Na+/K+ pump and thus reduces the sodium gradient, resulting in an increase in intracellular Ca2+ that gets sequestered into the SR. This mechanism contributes importantly to the positive effect of cardiac glycosides on the contractile force of the failing heart. The duration of the cardiac muscle cell contraction is approximately the same as that of its action potential. Therefore, the electrical refractory period of a cardiac muscle cell is not over until the mechanical response is completed. Mechanical relaxation accompanies electrical repolarization. As a consequence, heart muscle cells cannot be activated rapidly enough to cause a fused (tetanic) state of prolonged contraction. This is fortunate because intermittent contraction and relaxation are essential for the heart’s pumping action.

As has been described in Chapters 9 and 10, the cross-bridge interaction that occurs after a muscle is activated to contract gives the muscle the potential to develop force and/or shorten. Whether it does one, the other, or some combination of the two depends primarily on what is allowed to happen by the external constraints placed on the muscle during the contraction. Muscle cells in the ventricular wall operate under different constraints during different phases of each cardiac cycle and undergo both isometric and isotonic contractions.

ISOMETRIC CONTRACTIONS: LENGTH–TENSION RELATIONSHIPS Recall that the cardiac muscle maximum isometric contractile force is strongly influenced by the initial length of the muscle as is indicated in Figure 23–5. The top panel shows the

2

1

sarcomere

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3

4 5

Resting Contracting

6

Resting Contracting Resting Contracting 6

Muscle tension

4

2

Active tension 5

5 1

1

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3 Resting tension

Stimulus Time

FIGURE 23–5

Muscle tension

6

Peak isometric tension

5 Active tension

2

Isometric contractions and the effect of muscle length on resting tension and active tension development. (Modified with permission from Mohrman DE, Heller LJ: Cardiovascular

4

Resting tension 3 1

Lmax

Physiology, 6th ed. New York: Lange Medical Books/ McGraw-Hill, 2006.)

Muscle length

CHAPTER 23 Cardiac Muscle Cells experimental arrangement for measuring muscle force at rest and during contraction at three different lengths. The middle panel shows time records of muscle tensions recorded at each of the three lengths in response to an external stimulus, and the bottom panel shows a graph of the resting and peak tension results plotted against muscle length. The length-dependent influence on the resting tension of cardiac muscle is represented by the lower curve in the graph in Figure 23–5. When a muscle is stimulated to contract while its length is held constant (i.e., isometric contraction), it develops active tension. The total tension exerted by a muscle during contraction is the sum of the active and resting tensions and is represented by the upper curve in Figure 23–5. Active tension development is shown to be maximal at some intermediate length referred to as Lmax. Normally, cardiac muscle operates at lengths well below Lmax, so that increasing muscle length increases the tension developed during an isometric contraction. The mechanisms involved in the relationship between cardiac muscle length and developed tension are discussed in Chapter 10. The important point is that the dependence of active tension development and shortening on muscle length is a fundamental property of cardiac muscle that has extremely powerful effects on heart function.

ISOTONIC & AFTERLOADED CONTRACTIONS During an isotonic (“fixed load”) contraction, muscle shortens against a constant load as shown in Figure 23–6. When a 1-g weight is suspended from a resting muscle, it will result in some specific resting muscle length, which is determined by the muscle’s resting length–tension curve. If the muscle were to contract isometrically at this length, it would be capable of generating a certain amount of tension, for example, 4.5 g as indicated by the dashed line in the graph of Figure 23–6. However, a contractile tension of 4.5 g will not be generated when lifting a 1-g weight. When a muscle has contractile potential in excess of the tension it is actually developing, it shortens. Thus, in an isotonic contraction, muscle length decreases at constant tension, as illustrated by the horizontal arrow from point 1 to point 3 in Figure 23–6. As the muscle shortens, however, its contractile potential inherently decreases, as indicated by the downward slope of the peak isometric tension curve in Figure 23–6. There exists some short length at which the muscle is capable of generating only 1 g of tension, and when this length is reached, shortening must cease. Thus, the curve on the cardiac muscle length–tension diagram that indicates how much

Isotonic contraction

Afterloaded contraction

Isometric

Isotonic

3 2 1

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Muscle length

FIGURE 23–6

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Relationship of isotonic and afterloaded contractions to the cardiac muscle length–tension diagram. (Modified with

permission from Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.)

SECTION V Cardiovascular Physiology

CARDIAC MUSCLE CONTRACTILITY A number of factors in addition to initial muscle length can affect the tension-generating potential of cardiac muscle. Any intervention that increases the peak isometric tension that a muscle can develop at a fixed length is said to increase cardiac muscle contractility. Such an agent is said to have a positive inotropic effect on the heart. The most important physiological regulator of cardiac muscle contractility is norepinephrine. When norepinephrine is released on cardiac muscle cells from sympathetic nerves, it has not only the chronotropic effect on heart rate discussed earlier, but also a pronounced positive inotropic effect that causes cardiac muscle cells to contract more rapidly and forcefully. The positive effect of norepinephrine on the isometric tension-generating potential is illustrated in Figure 23–7A. When norepinephrine is present, cardiac muscle will, at every length, develop more isometric tension, thus raising the peak isometric tension curve on the cardiac muscle length–tension graph. Norepinephrine increases cardiac muscle contractility because

A

Isometric contraction

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Peak isometric tension

N E

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NE

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ith

NE

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ut ho t i or w

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Afterloaded contraction

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ith W

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ou ith

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isometric tension a muscle can develop at various lengths also establishes the limit on how far muscle shortening can proceed with different loads. Figure 23–6 also shows an afterloaded isotonic contraction, in which the load on the muscle at rest (the preload) and the load on the muscle during contraction (the total load) are different. In the example of Figure 23–6, the preload is equal to 1 g, and because an additional 2-g weight (the afterload) is engaged during contraction, the total load equals 3 g. Since preload determines the resting muscle length, both isotonic contractions shown in Figure 23–6 begin from the same length. Because of the different loading arrangement, however, the afterloaded muscle must increase its total tension to 3 g before it can shorten. This initial tension will be developed isometrically and can be represented as going from point 1 to point 4 on the length–tension diagram. Once the muscle generates enough tension to equal the total load, its tension output is fixed at 3 g and it will now shorten isotonically because its contractile potential still exceeds its tension output. This isotonic shortening is represented as a horizontal movement on the length–tension diagram along the line from point 4 to point 5. As in any isotonic contraction, shortening must cease when the muscle’s tension-producing potential is decreased sufficiently by the length change to be equal to the load on the muscle. Note that the afterloaded muscle shortens less than the non-afterloaded muscle even though both muscles began contracting at the same initial length. Increases in afterload will further decrease the shortening of the muscle. The factors that affect the extent of cardiac muscle shortening during an afterloaded contraction are of special interest because stroke volume is determined by how far cardiac muscle shortens under these conditions.

Muscle tension (g)

220

2 1

Resting tension

N ut ho t i or w With Muscle length

FIGURE 23–7 Effect of norepinephrine (NE) on isometric (A) and afterloaded (B) contractions of cardiac muscle. (Modified with permission from Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.)

it enhances the forcefulness of muscle contraction even when length is constant. Changes in contractility and initial length can occur simultaneously, but by definition, a change in contractility must involve a shift from one peak isometric length– tension curve to another. Figure 23–7B shows how raising the peak isometric length– tension curve with norepinephrine increases the amount of shortening in afterloaded contractions of cardiac muscle. With preload and total load constant, more shortening occurs in the presence of norepinephrine than in its absence. This is because when contractility is increased, the tension-generating potential is equal to the total load at a shorter muscle length. Note that norepinephrine has no effect on the resting length–tension relationship of cardiac muscle. Thus, norepinephrine causes increased shortening by changing the final but not the initial muscle length associated with afterloaded contractions. The cellular mechanism of the norepinephrine effect on contractility is mediated by its interaction with a β1-adrenergic receptor. The signaling pathway involves an activation of the Gs protein–cAMP–protein kinase A, which then phosphorylates the Ca2+ channel, increasing the inward calcium current during the plateau of the action potential. This increase in

CHAPTER 23 Cardiac Muscle Cells calcium influx not only contributes to the magnitude of the increase in intracellular Ca2+ for a given beat, but also loads the internal calcium stores, which allows more to be released during subsequent depolarizations. This increase in free Ca2+ during activation allows more cross-bridges to be formed, increases the speed of cross-bridge turnover, and allows greater tension to be developed at a faster rate. Because norepinephrine also causes phosphorylation of the regulatory protein, phospholamban, on the sarcoplasmic reticular Ca2+-ATPase pump, the rate of calcium retrapping into the SR is enhanced and the rate of relaxation is also increased. This is called a positive lusitropic effect. In addition to more rapid calcium retrapping by the SR, there is also a norepinephrine-induced decrease in the action potential duration. This effect is achieved by a potassium channel alteration, occurring in response to the elevated intracellular [Ca2+] that increases potassium permeability, terminates the plateau phase of the action potential, and contributes to the early relaxation. (Such shortening of the systolic interval is helpful in the presence of elevated heart rates that might otherwise significantly compromise diastolic filling time.) Enhanced parasympathetic activity has been shown to have a small negative inotropic effect on the heart. In the atria, where this effect is most pronounced, the negative inotropic effect is thought to be due to a decrease in the duration of the action potential and a decrease in the amount of Ca2+ that enters the cell during the action potential. Changes in heart rate also influence cardiac contractility. Recall that a small amount of extracellular Ca2+ enters the cell during the plateau phase of each action potential. As the heart rate increases, more Ca2+ enters the cells per minute. There is a buildup of intracellular Ca2+ and a greater amount of Ca2+ is released into the sarcoplasm with each action potential. Thus, a sudden increase in beating rate is followed by a progressive increase in contractile force to a higher plateau (the force– frequency relationship).

RELATING CARDIAC MUSCLE CELL MECHANICS TO VENTRICULAR FUNCTION Certain geometric factors dictate how the length–tension relationships of cardiac muscle fibers in the ventricular wall determine the volume and pressure relationships of the ventricular chamber. The actual relationships are complex because the shape of the ventricle is complex. The ventricle is often modeled as either a cylinder or a sphere, although its actual shape lies somewhere between the two. Because cardiac muscle cells are oriented circumferentially in the ventricular wall, either model can be used to illustrate three important functional points: 1. An increase in ventricular volume causes an increase in ventricular circumference and therefore an increase in

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the length of the individual cardiac muscle cells. Thus, the extent of diastolic filling of the ventricle determines the “preload.” 2. At any given ventricular volume, an increase in the tension of individual cardiac muscle cells in the wall causes an increase in intraventricular pressure. 3. As ventricular volume decreases (i.e., as the ventricular radius decreases), a lesser total (collective) force is required by the muscle cells in the ventricular walls to produce any given intraventricular pressure. The last point is a reflection of the law of Laplace that states the physical relationship that must exist between total wall tension and internal pressure in any hollow vessel with circular containing walls. Regardless of whether the ventricle is envisioned as a hollow cylinder or a hollow sphere, the law of Laplace says that the total wall tension (T) depends on both intraventricular pressure (P) and its internal radius (r) as follows: T = P × r. One implication of the law of Laplace is that the muscle cells in the ventricular wall have a somewhat easier job of producing internal pressure at the end of systole (when the radius is small) than at the beginning of systole (when the radius is large). More importantly, the law of Laplace has significant clinical relevance in some pathological situations.

CLINICAL CORRELATION An elderly man is brought to the emergency room by his daughter. She reports that he has recently complained of severe weakness, fatigue, some dizziness, and seems to be a bit confused. This condition appeared only a few days ago and does not seem to be getting better or worse. He has been healthy otherwise and usually likes to square dance. The patient is alert and responsive but very weak and pale. His blood pressure on admission is 100/60 mm Hg and his heart rate is 41 beats/min. An electrocardiogram taken at the time of admission verifies the bradycardia (slow heart rate) with a ventricular rate of 41 beats/min and atrial rate at 95 beats/min. There are no ECG signs of cardiac ischemia or infarction but the occurrence of P waves is very rapid and not correlated with slow occurrence of QRS waves. This patient has a third degree (total) AV nodal heart block in which the normal conduction of action potentials originating in the SA node is not conducted through the AV node to the ventricles. The ventricles are being driven at an "escape" rhythm established by a pacemaker located below the AV node firing at a rate that is significantly slower than that of SA nodal pacemaker cells. The atria are beating much faster due to sympathetic activation (triggered by the low blood pressure) but the signals are

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not conducted through the AV nodal block. His symptoms of weakness, fatigue, dizziness, and confusion are a result of his low blood pressure that, in turn, is a result of his low ventricular rate and reduced cardiac output. Causes include drug toxicities (i.e., β-adrenergic blockers, calcium channel blockers), metabolic disturbances (i.e., hyperkalemia), anterior wall myocardial infarctions (i.e., septal ischemia), and cardiomyopathy (i.e., from a viral infection). Diagnostic tests will be conducted to determine what might be responsible for his condition. His treatment will involve implantation of a cardiac pacemaker. This is a subcutaneously implanted battery pack that sends repetitive stimuli through wire electrodes positioned in both the right atrium and right ventricle via the vena cava. This dual-chamber pacemaker will synchronize his atrial and ventricular beating rate at a more normal rate and rhythm and perhaps restore circulatory status and his activity levels back to normal.

CHAPTER SUMMARY ■

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Cardiac myocyte membrane potentials are a result of the relative permeability of the membrane to various ions and their concentration differences across the membrane. Action potentials of cardiac myocytes are a result of changes in the membrane permeability to various ions. Action potentials of cardiac myocytes have long plateau phases that generate long refractory periods and preclude summated or tetanic contractions. Action potentials are spontaneously generated by pacemaker cells in the SA node and are conducted from cell to cell via gap junctions throughout the entire heart. The rate of spontaneous diastolic depolarization of the SA nodal cells (and thus the heart rate) is modulated by the autonomic nervous system. Excitation of the cardiac myocyte initiates contraction by increasing the cytostolic calcium concentration that activates the contractile apparatus. Mechanical response of the myocyte depends on preload (determined by the initial resting length), afterload (determined by the tension that must be developed), and contractility (the degree of activation of the contractile apparatus dependent on the amount of calcium released on activation). The cardiac myocyte length–tension relationships are correlated with changes in volume and pressure in the intact ventricle.

STUDY QUESTIONS 1. A drug that promotes early activation of the “delayed rectifier” K+ channel (Ik) in cardiac muscle will do which of the following? A) The resting potential will be increased (hyperpolarized). B) The action potential’s duration will be decreased. C) The action potential’s peak amplitude will be decreased. D) The action potential conduction velocity will be increased. E) The absolute refractory period will be prolonged. 2. Action potential conduction velocity in cardiac muscle tissue is influenced by all of the following except A) cell diameter. B) resting membrane potential. C) extracellular potassium concentration. D) rate of rise (phase 0) of the action potential. E) duration of the plateau phase (phase 2) of the action potential. 3. The primary route of removal of [Ca2+] from the sarcoplasm during relaxation of a cardiac muscle cell is by A) active transport out of the cell. B) passive exchange with extracellular sodium. C) active transport into the sarcoplasmic reticulum. D) trapping of calcium by troponin in the myofilaments. E) passive movement out of the cell via L-type calcium channels. 4. A therapeutic strategy to improve the amount of active shortening of cardiac muscle might include which one of the following? A) decrease preload B) decrease afterload C) decrease contractility D) give a negative chronotropic agent E) give a negative inotropic agent 5. Your patient has accidentally been given a large bolus injection of potassium chloride and dies. Why? A) Cardiac muscle is depolarized and his heart has stopped in diastole. B) Cardiac muscle is depolarized and his heart has stopped in systole. C) Cardiac muscle is hyperpolarized and his heart has stopped in diastole. D) Action potential conduction is sped up and heart is fibrillating. E) Gap junctions between cardiac muscle cells are disrupted.

24 C

The Heart Pump Lois Jane Heller and David E. Mohrman

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Correlate the electrocardiographic events with the mechanical events during the cardiac cycle. List the major distinct phases of the cardiac cycle as delineated by valve opening and closure. Describe the pressure and volume changes in the atria, the ventricles, and the aorta during each phase of the cardiac cycle. Define and state normal values for (1) ventricular end-diastolic volume, end-systolic volume, stroke volume, diastolic pressure, and peak systolic pressure, and (2) aortic diastolic pressure, systolic pressure, and pulse pressure. State similarities and differences between mechanical events in the left and right heart pumps. State the origin of the heart sounds. Diagram the relationship between left ventricular pressure and volume during the cardiac cycle. Define cardiac output and cardiac index. State the relationship between cardiac output, heart rate, and stroke volume. Identify the major determinants of stroke volume. State Starling’s law of the heart. Predict the effect of altered ventricular preload on stroke volume and the ventricular pressure–volume relationship. Predict the effect of altered ventricular afterload on stroke volume and the ventricular pressure–volume relationship. Predict the effect of altered ventricular contractility (inotropic state) on stroke volume and the ventricular pressure–volume relationship. Draw a family of cardiac function curves describing the relationship between filling pressure and cardiac output under various levels of sympathetic tone. Summarize the effect of sympathetic neural stimulation on cardiac function. List the determinants of myocardial oxygen consumption.

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SECTION V Cardiovascular Physiology

This chapter describes (1) the basic mechanical features of the cardiac pump, (2) the factors that influence and/or regulate cardiac output, and (3) the sources of energy and the energy costs required for myocardial activity.

CARDIAC CYCLE LEFT PUMP The mechanical function of the heart can be described by the pressure, volume, and flow changes that occur within it during one cardiac cycle. A cardiac cycle is defined as one complete sequence of contraction and relaxation. The normal mechanical events of a cycle of the left heart pump are correlated in Figure 24–1. This important figure summarizes a great deal of information and should be studied carefully.

VENTRICULAR DIASTOLE The diastolic phase of the cardiac cycle begins with the opening of the atrioventricular (AV) valves. (Unless otherwise noted, systole and diastole denote phases of ventricular operation.) As shown in Figure 24–1, the mitral valve opens when left ventricular pressure decreases below left atrial pressure and the period of ventricle filling begins. Blood that had previously accumulated in the atrium behind the closed mitral valve empties rapidly into the ventricle and this causes an initial decrease in atrial pressure. Later, the pressures in both chambers slowly increase together as the atrium and ventricle continue passively filling with blood returning to the heart through the veins. Atrial contraction is initiated near the end of ventricular diastole by the depolarization of the atrial muscle cells, which causes the P wave of the electrocardiogram. As the atrial

A

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Cardiac cycle phase

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E

R T

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Lead II electrocardiogram Atrial

Muscle contraction

Ventricular

Incisura

Systolic pressure Aortic pressure

120

80

Pulse pressure Diastolic pressure

Pressure (mm Hg) Left ventricular pressure

40

Left atrial pressure

0 Closed

Aortic valve Mitral valve

S3

Heart sounds

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Open

S4

Closed S1

End-diastolic volume

Cardiac cycle—left heart. Cardiac cycle phases: A) diastole; B) systole that is divided into three periods; C) isovolumetric contraction; D) ejection, and E) isovolumetric relaxation. (Modified with permission from Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.)

S2

Stroke volume

Left ventricular volume (mL)

FIGURE 24–1

Closed

Open

End-systolic volume

60

Outflow Aortic flow 0

Inflow 0

0.2

0.4 Time (s)

0.6

0.8

Open S3

CHAPTER 24 The Heart Pump muscle cells develop tension and shorten, atrial pressure rises and an additional amount of blood is forced into the ventricle. At normal heart rates, atrial contraction is not essential for adequate ventricular filling. This is evident in Figure 24–1 showing that the ventricle has nearly reached its maximum (end-diastolic volume) before atrial contraction begins. Atrial contraction plays an increasingly significant role in ventricular filling as heart rate increases because the time interval between beats for passive filling becomes progressively shorter. Note that throughout diastole, atrial and ventricular pressures are almost the same. This is because a normal open mitral valve has very little resistance to flow and thus only a very small atrial–ventricular pressure difference is necessary to produce ventricular filling.

VENTRICULAR SYSTOLE Ventricular systole begins when the action potential breaks through the AV node and sweeps over the ventricular muscle resulting in the QRS complex of the electrocardiogram. Contraction of the ventricular muscle cells causes intraventricular pressure to increase above that in the atrium, which causes abrupt closure of the AV valve. Pressure in the left ventricle continues to increase sharply as the ventricular contraction intensifies. When the left ventricular pressure exceeds that in the aorta, the aortic valve opens. The period of time between mitral valve closure and aortic valve opening is referred to as the isovolumetric contraction phase because, during this interval, the ventricle is a closed chamber with a fixed volume. Ventricular ejection begins with the opening of the aortic valve. In early ejection, blood enters the aorta rapidly and causes the pressure there to rise. Pressure builds simultaneously in both the ventricle and the aorta as the ventricular muscle cells continue to contract in early systole. This interval is often called the rapid ejection period. Left ventricular and aortic pressures ultimately reach a maximum called peak systolic pressure. At this point, the strength of ventricular muscle contraction begins to wane. Muscle shortening and ejection continue, but at a reduced rate. Aortic pressure begins to decrease because blood is leaving the aorta and large arteries faster than blood is entering from the left ventricle. Throughout ejection, there are very small pressure differences between the left ventricle and the aorta because the aortic valve orifice is so large that it presents very little resistance to flow. Eventually, the strength of the ventricular contraction diminishes to the point where intraventricular pressure decreases below aortic pressure. This causes abrupt closure of the aortic valve. A dip, called the incisura or dicrotic notch, appears in the aortic pressure trace because a small volume of aortic blood must flow backward to fill the aortic valve leaflets as they close. After aortic valve closure, intraventricular pressure decreases rapidly as the ventricular muscle relaxes. For a brief interval, called the isovolumetric relaxation phase, the mitral valve is also closed. Ultimately, intraventricular

225

pressure decreases below atrial pressure, the AV valve opens, and a new cardiac cycle begins. Note that atrial pressure progressively increases during ventricular systole because blood continues to return to the heart and fill the atrium. The increased atrial pressure at the end of systole promotes rapid ventricular filling once the AV valve opens to begin the next heart cycle. The ventricle has reached its minimum (end-systolic volume) at the time of aortic valve closure. The amount of blood ejected from the ventricle during a single beat, the stroke volume, is equal to ventricular end-diastolic volume minus ventricular end-systolic volume. During the early, most rapid phase of systolic ejection, the aorta distends because more blood is being put into it from the left heart than is leaving it to the systemic organs. That distension is caused by the increasing pressure within the aorta. During the later, weakening phase of cardiac ejection, the opposite is true. The overall result is that the aortic pressure reaches a maximum value (systolic pressure) near the middle of ventricular systole. During diastole, the arterial pressure is maintained by the elastic recoil of walls of the aorta and other large arteries. Nonetheless, aortic pressure gradually decreases during diastole as the aorta supplies blood to the systemic vascular beds. The lowest aortic pressure, reached at the end of diastole, is called diastolic pressure. The difference between diastolic and peak systolic pressure in the aorta is called the arterial pulse pressure. Typical values for systolic and diastolic pressures in the aorta are 120 and 80 mm Hg, respectively, with a pulse pressure of 40 mm Hg. At a normal resting heart rate of about 70 beats/min, the heart spends approximately two thirds of the cardiac cycle in diastole and one third in systole. When increases in heart rate occur, both diastolic and systolic intervals become shorter. Action potential durations are shortened and conduction velocity is increased. Contraction and relaxation rates are also enhanced. This shortening of the systolic interval tends to blunt the potential adverse effects of increases in heart rate on diastolic filling time.

RIGHT PUMP Because the entire heart is served by a single electrical excitation system, similar mechanical events occur almost simultaneously in both the left heart and the right heart. Both ventricles have synchronous systolic and diastolic periods and the valves of the right and left heart normally open and close nearly in unison. Because the two sides of the heart are arranged in series in the circulation, they must pump the same amount of blood and therefore must have the same cardiac output. The major difference between the right and left pumps is in the magnitude of the peak systolic pressure. The pressures developed by the right heart as shown in Figure 24–2 are considerably lower than those for the left heart (Figure 24–1). This is because the pulmonary vessels provide considerably less resistance to blood flow than that offered collectively by

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SECTION V Cardiovascular Physiology

Lead II electrocardiogram Pulmonary artery pressure

Pressure (mm Hg)

25 20 15 10 5

Right atrial pressure

a

c

v

Right ventricular pressure

0 0.0

FIGURE 24–2

0.2

0.4 0.6 Time (s)

0.8

1.0

Cardiac cycle—right heart. (Modified with

permission from Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.)

those of the systemic organs. Therefore, less arterial pressure is required to drive the cardiac output through the lungs than through the systemic organs. Typical pulmonary artery systolic and diastolic pressures are 25 and 8 mm Hg, respectively. The pressure pulsations that occur in the right atrium are transmitted in retrograde fashion to the large veins near the heart. These pulsations, shown on the atrial pressure trace of Figure 24–2, can be visualized in the neck over the jugular veins in a recumbent individual. They are collectively referred to as the jugular venous pulse, and can provide clinically useful information about the heart. Atrial contraction produces the first pressure peak, called the a wave. The c wave, which follows shortly thereafter, coincides with the onset of ventricular systole and is caused by an initial bulging of the tricuspid valve into the right atrium. Right atrial pressure decreases after the c wave because of atrial relaxation and a downward displacement of the tricuspid valve during ventricular emptying. Right atrial pressure then begins to increase toward a third peak, the v wave, as the central veins and right atrium fill behind a closed tricuspid valve with blood returning to the heart from the peripheral organs. With the opening of the tricuspid valve at the conclusion of ventricular systole, right atrial pressure again decreases as blood moves into the relaxed right ventricle. Shortly afterward, right atrial pressure begins to increase once more toward the next a wave as returning blood fills the central veins, the right atrium, and right ventricle together during diastole.

HEART SOUNDS A record of the heart sounds, which occur in the cardiac cycle, is included in Figure 24–1. These sounds are normally heard by auscultation with a stethoscope placed on the chest. The first heart sound, S1, occurs at the beginning of systole because of the abrupt closure of the AV valves, which produces

vibrations of the cardiac structures and the blood in the ventricular chambers. S1 can be heard most clearly by placing the stethoscope over the apex of the heart. Note that this sound occurs immediately after the QRS complex of the electrocardiogram. The second heart sound, S2, arises from the closure of the aortic and pulmonic valves at the beginning of the period of isovolumetric relaxation. This sound is heard at about the time of the T wave in the electrocardiogram. The pulmonic valve usually closes slightly after the aortic valve. Because this discrepancy is enhanced during the inspiratory phase of the respiratory cycle, inspiration causes what is referred to as the physiological splitting of the second heart sound. The discrepancy in valve closure during inspiration may range from 30 to 60 milliseconds. One of the factors that leads to prolonged ejection of the right ventricle during inspiration is that the decreased intrathoracic pressure that accompanies inspiration transiently enhances venous return and diastolic filling of the right heart. For reasons that will be detailed later in this chapter, this extra filling volume will be ejected but a little extra time is required. The third and fourth heart sounds, shown in Figure 24–1, are not normally present. When they are present, however, they, along with S1 and S2, produce what are called gallop rhythms (resembling the sound of a galloping horse). When present, the third heart sound occurs shortly after S2 during the period of rapid passive ventricular filling and, in combination with heart sounds S1 and S2, produces what is called ventricular gallop rhythm. Although S3 may sometimes be detected in normal children, it is heard more commonly in patients with left ventricular failure. The fourth heart sound, which occasionally is heard shortly before S1, is associated with atrial contraction and rapid active filling of the ventricle. Thus, the combination of S1, S2, and S4 sounds produces what is called an atrial gallop rhythm. The presence of S4 often indicates an increased ventricular diastolic stiffness, which can occur with several cardiac disease states.

CARDIAC CYCLE PRESSURE–VOLUME & LENGTH–TENSION RELATIONSHIPS Intraventricular pressure and volume are intimately linked to the tension and length of the cardiac muscle cells in the ventricular wall. Figure 24–3A and B shows the correspondence between a ventricular pressure–volume loop and a cardiac muscle length–tension loop during one cardiac cycle. It is clear that cardiac muscle length–tension behavior is the underlying basis for ventricular function. Each major phase of the ventricular cardiac cycle has a corresponding phase of cardiac muscle length and tension change. During diastolic ventricular filling, for example, the progressive increase in ventricular pressure stretches the resting cardiac muscle to greater lengths along its resting length-tension curve and causes a corresponding increase in muscle tension. End-diastolic ventricular pressure is referred to as ventricular preload because it sets the end-

CHAPTER 24 The Heart Pump

227

A

Intraventricular pressure (mm Hg)

120

Ejection Reaches endsystolic volume Aortic valve opens

80 Systole Isovolumetric relaxation

Isovolumetric contraction

Mitral valve opens

Diastolic filling

Reaches end-diastolic volume

60

130 Stroke volume Intraventricular volume (mL)

B

Muscle tension

Shortening

Reaches endsystolic length Active

Isometric tension development

Isometric relaxation Passive stretch

Reaches end-diastolic length

FIGURE 24–3 Ventricular pressure–volume cycle (A), and corresponding cardiac muscle length–tension cycle (B). (Modified with permission from Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th

Muscle length

diastolic ventricular volume and therefore the resting length of the cardiac muscle fibers at the end of diastole. At the onset of systole, the ventricular muscle cells develop tension isometrically (during the isovolumetric contraction phase) and intraventricular pressure increases accordingly. After the intraventricular pressure increases sufficiently to open the outlet valve, ventricular ejection begins as a consequence of ventricular muscle shortening. Systemic arterial pressure is often referred to as the ventricular afterload because it determines the tension that must be developed by cardiac muscle fibers before they can shorten. It should be noted that other factors that influence the actual wall tension required to eject blood from the ventricle (such as end-diastolic volume, velocity of contraction, viscosity of the blood) do contribute to ventricular afterload but we choose to ignore them at this point. During cardiac ejection, cardiac muscle is simultaneously generating active tension and shortening (i.e., an afterloaded isotonic contraction). The stroke volume is determined by how far ventricular muscle cells are able to shorten during contraction. This, as already discussed, depends on the length– tension relationship of the cardiac muscle cells and the load

ed. New York: Lange Medical Books/McGraw-Hill, 2006.)

against which they are shortening. Once shortening ceases and the output valve closes, the cardiac muscle cells relax isometrically. Ventricular wall tension and intraventricular pressure decrease in unison during isovolumetric relaxation.

DETERMINANTS OF CARDIAC OUTPUT The cardiac output (liters of blood pumped by each of the ventricles per minute) is an extremely important cardiovascular variable that is continuously adjusted so that the cardiovascular system operates to meet the body’s moment-to-moment circulatory needs. In going from rest to strenuous exercise, for example, the cardiac output of an average person will increase from approximately 5.5 to perhaps 15 L/min. The extra cardiac output provides the exercising skeletal muscles with the additional nutritional supply needed to sustain an increased metabolic rate. To understand the cardiovascular system’s response not only to exercise, but also to all other physiological or pathological demands placed on it, we must understand what determines, and therefore controls, cardiac output.

SECTION V Cardiovascular Physiology

INFLUENCES ON STROKE VOLUME EFFECT OF CHANGES IN VENTRICULAR PRELOAD: STARLING’S LAW OF THE HEART The volume of blood that the heart ejects with each beat can vary significantly. One of the most important factors responsible for these variations in stroke volume is the extent of cardiac filling during diastole. This concept was introduced in Chapter 22 (Figure 22–7) and is known as Starling’s law of the heart. To review (and to reemphasize its importance), this law states that, with other factors equal, stroke volume increases as cardiac filling increases. As shown below, this phenomenon is based on the intrinsic mechanical properties of myocardial muscle. Figure 24–4A illustrates how increasing muscle preload will increase the extent of shortening during a subsequent contraction with a fixed total load. Recall from the nature of the resting length–tension relationship that an increased preload is necessarily accompanied by increased initial muscle fiber length. As was described in Chapter 23, when a muscle starts from a greater length, it has more distance to shorten before it reaches the length at which its tension-generating capability is no longer greater than the load upon it. Cardiac muscle cells exhibit the same behavior when they are operating in the ventricular wall. Increases in ventricular preload increase both end-diastolic volume and stroke volume almost equally, as illustrated in Figure 24–4B. The precise relationship between cardiac preload (cardiac filling pressure) and end-diastolic volume has especially important physiological and clinical consequences. Although the relationship is somewhat curvilinear, especially at very high filling pressures, it is nearly linear over the normal operating range of the heart. The low slope of this relationship indicates the incredible distensibility of the normal ventricle during diastole. (For example, a change in filling pressure of only 1 mm Hg normally will change end-diastolic volume by about 25 mL!)

A Muscle tension (g)

As stated in Chapter 22, cardiac output is the product of heart rate and stroke volume (CO = HR × SV). Therefore, all changes in cardiac output must be produced by changes in heart rate and/or stroke volume. Factors influencing heart rate do so by altering the characteristics of the diastolic depolarization of the pacemaker cells as discussed in Chapter 23 (see Figure 23–4). Recall that variations in activity of the sympathetic and parasympathetic nerves leading to cells of the sinoatrial (SA) node constitute the most important regulators of heart rate. Increases in sympathetic activity increase heart rate, whereas increases in parasympathetic activity decrease heart rate. These neural inputs have immediate effects (within one beat) and therefore can cause very rapid adjustments in cardiac output.

5 Peak isometric tension

4 3

More shortening

2 Resting tension Larger preload

1

Muscle length B 120 LV pressure (mm Hg)

228

80 More stroke volume 40 Larger ventricular preload 120

60 LV volume (mL)

FIGURE 24–4 Effect of changes in preload on cardiac muscle shortening during afterloaded contractions (A) and on ventricular stroke volume (B). (Modified with permission from Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.)

One form of heart failure is called diastolic failure and is characterized by an abnormally stiff ventricle and a disturbance in the relationship between cardiac filling pressure and end-diastolic volume. In this situation, diastolic filling is limited, stroke volume is reduced, cardiac output is inadequate, and function of the cardiovascular system is compromised. It should be noted in Figure 24–4A that increasing preload increases initial muscle length without significantly changing the final length to which the muscle shortens against a constant total load. Thus, increasing ventricular filling pressure increases stroke volume primarily by increasing end-diastolic volume. As shown in Figure 24–4B, this is not accompanied by a significant alteration in end-systolic volume.

EFFECT OF CHANGES IN VENTRICULAR AFTERLOAD Figure 24–5A shows how increased afterload, at constant preload, has a negative effect on cardiac muscle shortening because muscle cannot shorten beyond the length at which its peak isometric tension-generating potential equals the total load upon it. Thus, shortening must stop at a greater muscle length when afterload is increased.

CHAPTER 24 The Heart Pump

Larger total load

1

Muscle length

B LV pressure (mm Hg)

120

80 Lower stroke volume 40

60

Larger ventricular afterload

120 LV volume (mL)

FIGURE 24–5 Effect of changes in afterload on cardiac muscle shortening during afterloaded contractions (A) and on ventricular stroke volume (B). Dashed line shows how stroke volume is decreased by an increase in afterload. Dotted line shows the relationship between end-systolic pressure and end-systolic volume obtained at a constant preload but different afterloads. (Modified with permission from Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.)

Normally, mean ventricular afterload is nearly constant, because mean arterial pressure is held within tight limits by the cardiovascular control mechanisms described in Chapter 29. In many pathological situations such as hypertension (high blood pressure) and aortic valve obstruction, ventricular function is adversely influenced by abnormally high ventricular afterload. When this occurs, stroke volume may be decreased as shown by the changes in the pressure–volume loop indicated by the dashed line in Figure 24–5B. Under these conditions, note that stroke volume is decreased because endsystolic volume is increased. The relationship between end-systolic pressure and end-systolic volume obtained at a constant preload but different afterloads is indicated by the dotted line in Figure 24–5B. In a normally functioning heart, the effect of changes in afterload on end-systolic volume (and therefore stroke volume) is quite small (about 0.5 mL/mm Hg). However, in systolic cardiac failure, the end-systolic pressure-volume line is shifted downward and is flattened so that the effect of afterload on endsystolic volume is greatly exaggerated.

Afterloaded contraction

A

5 4 3

h

NE t ou ith

Peak isometric tension

NE

More shortening

2 1

Resting tension

E

Resting tension

2

N

3

Recall that activation of the sympathetic nervous system results in release of norepinephrine from cardiac sympathetic nerves, which increases contractility of the individual cardiac muscle cells. This results in an upward shift of the peak isometric length–tension curve. As shown in Figure 24–6A, such a shift will result in an increase in the shortening of a muscle contracting with constant preload and total load. Thus, as shown in Figure 24–6B, the norepinephrine released by sympathetic nerve stimulation will increase ventricular stroke volume by decreasing the end-systolic volume without directly influencing the end-diastolic volume. In addition to these changes in the extent of myocyte shortening, an increase in contractility will also cause an increase in the rates of myocyte tension development and of shortening. This will result in an increase in the rate of isovolumetric pressure development (dP/dt) and the rate of ejection during systole. Systolic failure is characterized by a severely depressed ability of the cardiac muscle cells to produce tension and shorten. In this situation, systolic contraction is limited, stroke volume

W it

Less shortening

W

4

Muscle tension (g)

Peak isometric tension

5

EFFECT OF CHANGES IN CARDIAC MUSCLE CONTRACTILITY

wi or With

ut th o

Muscle length B Wi th

120 LV pressure (mm Hg)

Muscle tension (g)

A

229

With o

NE ut N

E

80 Increased stroke volume 40

60

120

LV volume (mL)

FIGURE 24–6 Effect of norepinephrine (NE) on afterloaded contractions on cardiac muscle (A) and on ventricular stroke volume (B). (Modified with permission from Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.)

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SECTION V Cardiovascular Physiology

Negative chronotropic –

CARDIAC PARASYMPATHETIC NERVE ACTIVITY LEVEL

HEART RATE + Positive chronotropic CARDIAC SYMPATHETIC NERVE ACTIVITY LEVEL + CARDIAC OUTPUT +

Contractility (positive inotropic) ARTERIAL PRESSURE +

FIGURE 24–7

Influences on cardiac

output. (Modified with permission from Mohrman DE,

Afterload FILLING PRESSURE Preload

Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange

The major influences on cardiac output are summarized in Figure 24–7. Heart rate is controlled by chronotropic influences on the spontaneous electrical activity of SA nodal cells. Cardiac parasympathetic nerves have a negative chronotropic effect, and sympathetic nerves have a positive chronotropic effect on the SA node. Stroke volume is controlled by influences on the contractile performance of ventricular cardiac muscle—in particular its degree of shortening in the afterloaded situation. The three distinct influences on stroke volume are contractility, preload, and afterload. Increased cardiac sympathetic nerve activity tends to increase stroke volume by increasing the contractility of cardiac muscle (a positive inotropic effect). Increased arterial pressure tends to decrease stroke volume by increasing the afterload on cardiac muscle fibers. Increased ventricular filling pressure increases end-diastolic volume, which tends to increase stroke volume through Starling’s law of the heart. It is important to recognize at this point that both heart rate and stroke volume are subject to more than one influence. Thus, the fact that increased contractility tends to increase stroke volume should not be taken to mean that, in the intact cardiovascular system, stroke volume is always high when contractility is high. Following blood loss caused by hemorrhage, for example, stroke volume may be low in spite of a high level of sympathetic nerve activity and increased contractility. Because arterial pressure is normal or low following hemorrhage, the low stroke volume associated with severe blood loss must be (and is) the result of low cardiac filling pressure.

CARDIAC FUNCTION CURVES One very useful way to summarize the influences on cardiac function and the interactions between them is by cardiac function curves such as those shown in Figure 24–8. Cardiac filling pressure (“cardiac preload”) is plotted as the independent variable on the horizontal axis in this figure and cardiac output as the dependent variable on the vertical axis. Each curve in this figure shows the effect of changes in cardiac preload on

Activity levels of cardiac sympathetic nerves Greatly increased

Moderately increased

10.0 Cardiac output (L /min)

SUMMARY OF DETERMINANTS OF CARDIAC OUTPUT

+

(Starling’s law)

Medical Books/McGraw-Hill, 2006.)

is reduced, cardiac output is inadequate, and function of the cardiovascular system is compromised.

– STROKE VOLUME

8.0

Normal C

B

6.0

Decreased A

4.0

2.0

0

2.0

4.0

6.0

Cardiac filling pressure (mm Hg)

FIGURE 24–8 Influence of cardiac sympathetic nerves on cardiac function curves. (Modified with permission from Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/ McGraw-Hill, 2006.)

CHAPTER 24 The Heart Pump cardiac output at one constant level of cardiac sympathetic nerve activity. Different curves are used for different levels of cardiac sympathetic nerve activity. Thus, Figure 24–8 shows how the cardiac filling pressure and the activity level of cardiac sympathetic nerves interact to determine cardiac output. When cardiac filling pressure is 2 mm Hg and the activity of cardiac sympathetic nerves is normal, the heart will operate at point A and will have a cardiac output of 5 L/min. Each single curve in Figure 24–8 shows how cardiac output would be changed by changes in cardiac filling pressure if cardiac sympathetic nerve activity were held at a fixed level. For example, if cardiac sympathetic nerve activity remained normal, increasing cardiac filling pressure from 2 to 4 mm Hg would cause the heart to shift its operation from point A to point B on the cardiac function diagram. In this case, cardiac output would increase from 5 to 7 L/min solely as a result of the increased filling pressure (Starling’s law). If, on the other hand, cardiac filling pressure were fixed at 2 mm Hg while the activity of cardiac sympathetic nerves was moderately increased from normal, the heart would change from operating at point A to operating at point C. Cardiac output would again increase from 5 to 7 L/min. In this instance, however, cardiac output does not increase through the length-dependent mechanism because cardiac filling pressure did not change. Cardiac output increases at constant filling pressure with an increase in cardiac sympathetic activity for two reasons. First, increased cardiac sympathetic nerve activity increases heart rate. Second, but just as importantly, increased sympathetic nerve activity increases stroke volume by increasing cardiac contractility. Cardiac function graphs thus consolidate knowledge of many mechanisms of cardiac control, and are most helpful in describing how the heart interacts with other elements in the cardiovascular system. Furthermore, these graphs reemphasize the important point that a change in cardiac filling pressure alone will have a very potent effect on cardiac output at any level of sympathetic activity.

SUMMARY OF SYMPATHETIC NEURAL INFLUENCES ON CARDIAC FUNCTION The effects of the sympathetic nervous system on the electrical and mechanical properties of cardiac muscle, and thus on cardiac pumping ability, are initiated by the interaction of norepinephrine with β1-adrenergic receptors on cardiac muscle cells. This results in a cascade of events involving the Gs activation of adenylate cyclase, formation of cAMP, and activation of protein kinase A with subsequent phosphorylation of many molecules that play key regulatory roles in intracellular processes. These cellular events combine to evoke the following improvements in pumping capabilities of the heart: 1. an increase in heart rate (positive chronotropic effect) by activating the inward-going sodium if current in SA nodal cells;

231

2. a decrease in cardiac action potential duration by early activation of the delayed iK current in cardiac myocytes, which minimizes the detrimental effect of high heart rates on diastolic filling time; 3. an increase in the rate of action potential conduction, particularly evident in the AV node (positive dromotropic effect), by altering conductivity of gap junctions; 4. an increase in cardiac contractility (positive inotropic effect) by activating the iCa2+ current and increasing Ca2+ release from the sarcoplasmic reticulum, which increases the contractile ability of cardiac muscle at any given preload; and 5. an increase in rate of cardiac relaxation (positive lusitropic effect) by increasing Ca2+ uptake by the sarcoplasmic reticulum, which also helps minimize the detrimental effect of high heart rates on diastolic filling time. Most catecholamine influences on the heart are a result of increases in sympathetic neural activity. Although circulating catecholamines of adrenal origin can potentially evoke similar effects, their concentrations are normally so low that their contributions are negligible. Specific drugs called β1-adrenergic receptor blockers (antagonists) can block all of the effects of catecholamines from whatever source on cardiac muscle. These drugs may be useful in the treatment of coronary artery disease to thwart increased metabolic demands placed on the heart by activity of sympathetic nerves. As we will see in subsequent chapters, increases in sympathetic activity can also have indirect influences on cardiac function that are a consequence of sympathetic-induced alterations in arteriolar and venous tone (i.e., alterations in afterload and preload, respectively).

DETERMINANTS OF MYOCARDIAL OXYGEN CONSUMPTION In many pathological situations, such as severe coronary atherosclerosis, oxygen requirements of myocardial tissue may exceed the capacity of coronary blood flow to deliver oxygen to the heart muscle. This mismatch can result in severe chest pain or discomfort called angina pectoris. It is important to understand what factors determine energy costs, and therefore the myocardial oxygen consumption, because reduction of oxygen demand may be of significant clinical benefit to the patient. Because the heart derives its energy almost entirely from aerobic metabolism, myocardial oxygen consumption is directly related to myocardial ATP use. The basal metabolism of the heart tissue (the energy consumed in cellular processes other than contraction such as energy-dependent ion pumping) normally accounts for about 25% of myocardial ATP use and therefore myocardial oxygen consumption in a resting individual. The processes associated with muscle contraction account for about 75% of myocardial energy use. Primarily, this reflects ATP splitting associated with

232

SECTION V Cardiovascular Physiology

cross-bridge cycling during the isovolumetric contraction and ejection phases of the cardiac cycle. Some ATP is also used for Ca2+ sequestration at the termination of each contraction. The energy expended during the isovolumetric contraction phase of the cardiac cycle accounts for the largest portion (~50%) of total myocardial oxygen consumption despite the fact that the heart does no external work during this period. The energy needed for isovolumetric contraction is mainly dependent on the intraventricular pressure that must develop during this time, that is, on the cardiac afterload. Cardiac afterload then is a major determinant of myocardial oxygen consumption. Reductions in cardiac afterload can produce clinically significant reductions in myocardial energy requirements and therefore myocardial oxygen consumption. Energy utilization during isovolumetric contraction is actually more directly related to isometric wall tension development than to intraventricular pressure development. Recall that wall tension is related to intraventricular pressure and to ventricular radius through the law of Laplace (T = P × r). Consequently, reductions in cardiac preload (i.e., end-diastolic volume, radius) will also tend to reduce the energy required for isovolumetric contraction. It is during the ejection phase of the cardiac cycle that the heart actually performs external work and the energy the heart expends during ejection depends on how much external work it is doing. In a fluid system, work (force × distance) is equal to pressure (force/distance2) × volume (distance3). The external physical work done by the left ventricle in one beat, that is, the stroke work, is equal to the area enclosed by the left ventricular pressure–volume loop (see Figure 24–3A). Stroke work is increased either by an increase in stroke volume (increased “volume” work) or by an increase in afterload (increased “pressure” work). In terms of ATP utilization and oxygen consumption, increases in the pressure work of the heart are more costly than increases in volume work. Thus, reductions in afterload are especially helpful in reducing the myocardial oxygen requirements for doing external work. Changes in myocardial contractility can have important consequences on the oxygen requirement for basal metabolism, isovolumic wall tension generation, and external work. Heart muscle cells use more energy in rapidly developing a given tension and shortening by a given amount than in doing the same thing more slowly. Also, with increased contractility, more energy is expended in active Ca2+ transport. The net result of these influences is often referred to as the “energywasting” effect of increased contractility. Heart rate is one of the most important determinants of myocardial oxygen consumption because the energy costs per minute must equal the energy cost per beat times the number of beats per minute. In general, it has been found that it is more efficient (i.e., less oxygen is required) to achieve a given cardiac output with low heart rate and high stroke volume than with high heart rate and low stroke volume. This again appears to be related to the relatively high

energy cost of the isovolumetric pressure development phase of the cardiac cycle. The less pressure (wall tension) developed and the less often pressure development occurs, the less energy used.

CLINICAL CORRELATION A 40-year-old woman comes to the emergency room because of the sudden onset of weakness and dizziness about an hour earlier. In addition, she reports a sense of fluttering in her chest and throat. Examination reveals her heart rate to be rapid (165 beats/min; tachycardia) and regular and her blood pressure to be on the low side at 80/60 mm Hg. Her ECG shows a tachycardia associated with a narrow QRS complex. After attempts to restore normal rates by massaging the neck at the location of the carotid sinuses, and by putting a cold compress on her face, she was given an intravenous injection of adenosine that converted her heart rate to 80 beats/min and her blood pressure to 130/85 mm Hg. The primary complaint of weakness and dizziness suggests a decrease in systemic blood flow including the cerebral circulation caused by the low arterial pressure. This could be caused by a decrease either in cardiac output or in total peripheral resistance. In our patient, the very fast heart rate severely shortened the duration of diastole and, as a result, cardiac filling was significantly compromised. Because of Starling’s law of the heart relating end-diastolic volume with stroke volume, the decrease in filling results in a decrease in stroke volume. In spite of the rapid heart rate, the low stroke volume produces a significant decrease in cardiac output. The therapeutic strategy involves attempts to decrease heart rate. The ECG suggests a supraventricular tachycardia with either an atrial ectopic focus firing rapidly or a reentrant AV nodal circuit rapidly exciting the normal ventricular conduction system. (See Chapter 25 for more details.) Mechanical ways to interrupt these processes include strategies to increase vagal firing to the atrial tissue by (1) massage of neck at the region of the carotid sinus (carotid massage), stretching the arterial baroreceptors, and tricking the medullary cardiovascular centers to think arterial pressure is elevated (see Chapter 29) or (2) instituting the diving reflex with a cold compress on the face in which bradycardia is induced by activation of the trigeminal nerve afferents to the brain (see Chapter 71). The primary pharmacological strategy used in the emergency room involved intravenous injection of a bolus of adenosine. This can have a transient influence on supraventricular conduction within the heart and can often interrupt the abnormal reentrant pathway. Adenosine was effective in our patient. If it had

CHAPTER 24 The Heart Pump

not been, drugs such as β-adrenergic receptor blockers or calcium channel blockers can be effective. She was referred to a cardiologist who will perform extensive testing of her cardiac function to try to identify the anatomical source of her abnormal cardiac rhythm.

CHAPTER SUMMARY ■

■ ■

■

■

■

■

■

Effective cardiac pumping of blood requires coordinated filling of the chambers, excitation and contraction of the cardiac muscle cells, pressure generation within the chambers, opening and closing of cardiac valves, and one-way movement of blood through the chambers into the aorta or pulmonary artery. Except for lower ejection pressures, events of the right side of the heart are identical to those of the left side. Heart sounds associated with valve movements and detected on auscultation can be used to identify the beginnings of diastolic and systolic phases of the cardiac cycle. The events of a single ventricular cardiac cycle can be displayed as records of electrical, mechanical, pressure, sound, or flow changes against time or as a record of volume against pressure. Cardiac output is defined as the amount of blood pumped by either of the ventricles per minute and is determined by the product of heart rate and stroke volume. Stroke volume can be altered by changes in ventricular preload (filling), ventricular afterload (arterial pressure), and/or cardiac muscle contractility. A cardiac function curve describes the relationship between ventricular filling and cardiac output and can be shifted up (left) or down (right) by changes in sympathetic activity to the heart or by changes in cardiac muscle contractility. Energy for cardiac muscle contraction is derived primarily from aerobic metabolic pathways such that cardiac work is tightly related to myocardial oxygen consumption.

STUDY QUESTIONS 1. You are listening to your patient’s heart sounds and have identified the systolic and diastolic intervals. Four of the conditions listed below exist during the same phase of the cardiac cycle and one does not. Which one is the odd one? A) The mitral valve is open. B) The ST segment of the ECG is occurring. C) The “v” wave of the jugular venous pulse has just occurred. D) Ventricular volume is rapidly increasing. E) Aortic pressure is decreasing.

233

2. Your patient has coronary artery disease with significant occlusion of the left anterior descending coronary artery. Although all of the following will increase cardiac work, which of the following will be most likely to result in an attack of angina pectoris? A) high heart rates B) elevated arterial blood pressures C) increased end-diastolic volume D) low arterial blood pressure E) increased cardiac contractility 3. A drug is given that blocks cardiac β1-adrenergic receptors. What will be the direct consequences of this drug on the heart? A) Heart rate will increase. B) The PR interval of the ECG will shorten. C) Metabolic demands will be reduced. D) Coronary flow rate will increase. E) Cardiac contractility will increase. 4. A cannula is placed in the pulmonary artery (PA) of a normal healthy individual and pressure is reported to be 25/8 mm Hg. Which of the following can be surmised from these values? A) RV systolic pressure is 25 mm Hg; PA diastolic pressure is 8 mm Hg. B) RV systolic pressure is 25 mm Hg; left atrial pressure is 8 mm Hg. C) RV systolic pressure must be significantly higher than 25 mm Hg. D) RV diastolic pressure must be significantly higher than 8 mm Hg. E) Pulmonary capillary pressure is 8 mm Hg. 5. An individual has an autonomic nervous system dysfunction in which cardiac parasympathetic nerve activity abruptly increases while cardiac sympathetic activity decreases. Which of the following situations is most likely to occur? A) LV end-diastolic volume will increase. B) Cardiac output will increase. C) Heart rate will increase. D) LV end-systolic volume will decrease. E) Coronary blood flow will increase.

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25 C

Cardiac Function Assessments Lois Jane Heller and David E. Mohrman

H A

P

T

E

R

O B J E C T I V E S ■

■ ■ ■ ■ ■ ■ ■ ■

State the relationship between electrical events of cardiac excitation and the P, QRS, and T waves, the PR and QT intervals, and the ST segment of the electrocardiogram. State Einthoven’s basic electrocardiographic conventions and, given data, determine the mean electrical axis of the heart. Describe the standard 12-lead electrocardiogram. Detect common cardiac arrhythmias from the electrocardiogram, identify their physiological bases, and describe their physiological consequences. Calculate cardiac output using the Fick principle. Recognize echocardiographic images obtained during the cardiac cycle. Define ejection fraction and identify visualization methods used to determine it. Describe the end-systolic pressure–volume relationship. List stenotic and regurgitant valve abnormalities for the left heart and describe their consequences in terms of intracardiac and arterial pressures, flow patterns, and heart sounds that accompany them.

TECHNIQUES FOR ASSESSING CARDIAC FUNCTION There are a variety of methods available to assess cardiac function. Some of these are noninvasive (e.g., electrocardiography to evaluate electrical characteristics, auscultation of the chest to evaluate valve function, and echocardiography to visualize mechanical pumping action) and others require various types of invasive instrumentation. This chapter will provide a brief overview of some of these commonly used clinical tools and an introduction to some of the common cardiac functional abnormalities.

Ch25_235-250.indd 235

MEASUREMENT OF CARDIAC EXCITATION—THE ELECTROCARDIOGRAM The electrocardiogram is a powerful clinical tool that is used to evaluate cardiac beating rate, rhythm, and the conduction characteristics of cardiac tissue. As briefly described in Chapter 23, the electrocardiogram is the result of currents propagated through the extracellular fluid that are generated by the spread of the wave of excitation throughout the heart. Electrodes placed on the surface of the body record the small potential differences between various recording sites that vary over the time course of the cardiac cycle.

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11/26/10 10:00:28 AM

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SECTION V Cardiovascular Physiology

R 1 mV

Voltage

0.5 T

P 0 Q −0.5

PR segment

S

QRS interval

PR interval

ST segment

QT interval

Time

FIGURE 25–1

Typical electrocardiogram. (Modified with

permission from Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.)

A typical electrocardiographic record of voltages recorded on the surface of the body between the left leg and the right arm (called “lead II”) is indicated in Figure 25–1. The major features of the electrocardiogram are the P, QRS, and T waves that are caused by atrial depolarization, ventricular depolarization, and ventricular repolarization, respectively. The period of time from the initiation of the P wave to the beginning of QRS complex is designated as the PR interval and indicates the time it takes for an action potential to spread through the atria and the atrioventricular (AV) node. During the latter portion of the PR interval (PR segment), no voltages are detected on the body surface. This is because atrial muscle cells are depolarized (in the plateau phase of their action potentials), ventricular cells are still resting, and the electrical field set up by the action potential progressing through the small AV node is not intense enough to be detected. The duration of the normal PR interval ranges from 120 to 200 milliseconds. Shortly after the cardiac impulse breaks out of the AV node and into the rapidly conducting Purkinje system, all the ventricular muscle cells depolarize rapidly and cause the QRS complex. The R wave is the largest event in the electrocardiogram because ventricular muscle cells are so numerous and because they depolarize nearly in unison. The normal QRS complex lasts between 60 and 100 milliseconds. (The repolarization of atrial cells is also occurring during the time period in which ventricular depolarization generates the QRS complex on the electrocardiogram [see Figure 23–3]. Atrial repolarization is not evident on the electrocardiogram because it is a poorly synchronized event in a relatively small mass of heart tissue and is completely overshadowed by the major electrical events occurring in the ventricles at this time.) The QRS complex is followed by the ST segment. Normally, no electrical potentials are measured on the body surface during the ST segment because no rapid changes in membrane potential are occurring in any of the cells of the heart; atrial

cells have already returned to the resting phase, whereas ventricular muscle cells are in the plateau phase of their action potentials. (Myocardial injury or inadequate blood flow, however, can produce elevations or depressions in the ST segment.) When ventricular cells begin to repolarize, a voltage once again appears on the body surface and is measured as the T wave of the electrocardiogram. The T wave is wider and not as large as the R wave because ventricular repolarization is less synchronous than depolarization. At the conclusion of the T wave, all the cells in the heart are in the resting state. The QT interval roughly approximates the duration of the ventricular myocyte depolarization and thus the period of ventricular systole. At a normal heart rate of 60 beats/min, the QT interval is normally less than 380 milliseconds. No body surface potential is measured until the next impulse is generated by the sinoatrial (SA) node. The operation of the specialized conduction system is a primary factor in determining the normal electrocardiographic pattern. For example, the AV nodal transmission time determines the PR interval. Also, the effectiveness of the ventricular Purkinje system in synchronizing ventricular depolarization is reflected in the large magnitude and short duration of the QRS complex. Remember that nearly every heart muscle cell is inherently capable of rhythmicity and that all cardiac cells are electrically interconnected through gap junctions. Thus, a functional heart rhythm can and often does occur without the involvement of part or all of the specialized conduction system. Such a situation is, however, abnormal, and the existence of abnormal conduction pathways produces an abnormal electrocardiogram.

BASIC ELECTROCARDIOGRAPHIC CONVENTIONS Recording electrocardiograms is a routine diagnostic procedure standardized by universal application of certain conventions. The conventions for recording and analysis of electrocardiograms from the three standard bipolar limb leads are briefly described here and summarized in Figure 25–2. Recording electrodes are placed on both arms and the left leg— usually at the wrists and ankle. The arms and legs act as conductive extensions from the body, and voltage measurements are actually between points that form an equilateral triangle over the thorax. This is called Einthoven’s triangle in honor of the Dutch physiologist who devised it at the turn of the 19th century. Any single electrocardiographic trace is a recording of the voltage difference measured between any two vertices of Einthoven’s triangle. An example of the lead II electrocardiogram measured between the right arm and the left leg has already been shown in Figure 25–2. Similarly, lead I and lead III electrocardiograms represent voltage measurements taken along the other two sides of Einthoven’s triangle, as indicated in Figure 25–2. The + and – symbols in Figure 25–2 indicate polarity conventions that have been universally adopted. For example, an upward deflection in a lead II electrocardiogram

CHAPTER 25 Cardiac Function Assessments

−

+

Lead I

+

Lead selector and amplifier

+

II

Le

ad

ad

Le

III

−

Chart recorder

Left arm

−

Right arm

237

Left leg

Voltage scale

Paper speed

10 mm = +1 mV upward

25 mm = 1 s

FIGURE 25–2 Einthoven’s electrocardiographic conventions. (Modified with permission from Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/ McGraw-Hill, 2006.)

(as normally occurs during the P, R, and T waves) indicates that an electrical polarity exists at that instant between the left leg and the right shoulder electrodes, with the left leg electrode being positive. Conversely, a downward deflection in a lead II record indicates that an electrical polarity exists between this pair of electrodes but this time the electrode on the left leg is recording negative charges instead of positive charges. Similar polarity conventions have been established for lead I and lead III recordings and are indicated by the + and – symbols in Figure 25–2. In addition, electrocardiographic recording equipment is usually standardized so that a 1-cm deflection on the vertical axis always represents a potential difference of 1 mV, and that a 25-mm segment of the horizontal tracing of any electrocardiographic record represents 1 second. Most electrocardiographic records contain calibration signals so that abnormal rates and wave amplitudes can be easily detected. As shown in the subsequent section, many cardiac electrical abnormalities can be detected in recordings from a single electrocardiographic lead. However, certain clinically useful information can only be derived by combining the information obtained from two electrocardiographic leads. To understand these more complex electrocardiographic analyses, the way

Depolarized cells SA node − − −−

− − −

RA −

−

CARDIAC DIPOLES AND ELECTROCARDIOGRAPHIC RECORDS Einthoven’s conceptualization of how cardiac electrical activity causes potential differences on the surface of the body is illustrated in Figure 25–3. In this example, the heart is shown at one instant in the atrial depolarization phase. The cardiac impulse, after having arisen in the SA node, is spreading as a wavefront of depolarization through the atrial tissue. At each point along this wavefront of electrical activity, a small charge separation exists in the extracellular fluid between polarized membranes (positive outside) and depolarized membranes (negative outside). Thus, the wavefront may be thought of as a series of individual electrical dipoles (regions of charge separation). Each individual dipole is oriented in the direction of local wavefront movement. The large black arrow in

I

LA −

Wavefront of electrical activity Net dipole

Atria

voltages appear on the body surface as a result of the cardiac electrical activity must be examined.

III

II

FIGURE 25–3 Net cardiac dipole during atrial depolarization and its components on the limb leads. (Modified with permission from Mohrman DE, Heller LJ:

Ventricles LL

Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/ McGraw-Hill, 2006.)

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SECTION V Cardiovascular Physiology

Figure 25–3 represents the total net dipole created by the summed contributions of all the individual dipoles distributed along the wavefront of atrial depolarization. The salty extracellular fluid acts as an excellent conductor, allowing these instantaneous net dipoles generated on the surface of the heart muscle to be recorded by electrodes on the surface of the body. The net dipole that exists at any instant is oriented (i.e., points) in the general direction of wavefront movement at that instant. The magnitude or strength of the dipole (represented here by the arrow length) is determined by: (1) how extensive the wavefront is (i.e., how many cells are simultaneously depolarizing at the instant in question) and (2) the consistency of orientation between individual dipoles at different points in the wavefront (dipoles with the same orientation reinforce each other; dipoles with opposite orientation cancel each other). The net dipole in the example of Figure 25–3 causes the lower left portion of the body to be generally positive with respect to the upper right portion. This particular dipole will cause positive voltages to exist on all three of the electrocardiogram limb leads. As shown in the right half of Figure 25–3, this can be deduced from Einthoven’s triangle by observing that the net dipole has some component that points in the positive direction of leads I, II, and III. As illustrated in Figure 25–3, the component that a cardiac dipole has on a given electrocardiogram lead is found by drawing perpendicular lines from the appropriate side of Einthoven’s triangle to the tip and tail of the dipole. (It may be helpful to think of the component on each lead as the “shadow” cast by the dipole on that lead as a result of a “sun” located far beyond the corner of Einthoven’s triangle that is opposite the lead.) Note that the dipole in this example is most parallel to lead II and therefore has a large component in the lead II direction. Thus, it will create a larger voltage on lead II than on leads I or III. This dipole has a rather small component on lead III because it is oriented nearly perpendicular to lead III. The limb lead configuration may be thought of as a way to view the heart’s electrical activity from three different perspectives (or axes). The vector representing the heart’s instantaneous dipole strength and orientation is the object under observation, and its appearance depends on the position from which it is viewed. The instantaneous voltage measured on the axis of lead I, for example, indicates how the dipole being generated by the heart’s electrical activity at that instant appears when viewed from directly above. A cardiac dipole that is oriented horizontally appears large on lead I, whereas a vertically oriented cardiac dipole, however large, produces no voltage on lead I. Thus, it is necessary to have views from two directions to establish the magnitude and orientation of the heart’s dipole. A vertically oriented dipole would be invisible on lead I but would be readily apparent if viewed from the perspective of lead II or lead III. It is important to recognize that the example of Figure 25–3 pertains only to one instant during atrial depolarization. The net cardiac dipole continuously changes in magnitude and

orientation during the course of atrial depolarization. The nature of these changes will determine the shape of the P wave on each of the electrocardiogram leads. The P wave terminates when the wave of depolarization reaches the nonmuscular border between the atria and the ventricles and the number of individual dipoles becomes very small. At this time, the cardiac impulse is still being slowly transmitted toward the ventricles through the AV node. However, the electrical activity in the AV node involves so few cells that it generates no detectable net cardiac dipole. Thus, no voltages are measured on the surface of the body for a brief period following the P wave. A net cardiac dipole reappears only when the depolarization completes its passage through the AV node, enters the Purkinje system, and begins its rapid passage over the ventricular muscle cells. Because the Purkinje fibers terminate in the intraventricular septum and in the endocardial layers at the apex of the ventricles, ventricular depolarization occurs first in these areas and then proceeds outward and upward through the ventricular myocardium.

VENTRICULAR DEPOLARIZATION AND THE QRS COMPLEX It is the rapid and large changes in the magnitude and direction of the net cardiac dipoles that exist during ventricular depolarization that are responsible for the QRS complex of the electrocardiogram. The normal process is illustrated in Figure 25–4. The initial ventricular depolarization usually occurs on the left side of the intraventricular septum as diagrammed in the upper panel of the figure. Analysis of the cardiac dipole formed by this initial ventricular depolarization with the aid of Einthoven’s triangle shows that this dipole has a negative component on lead I, a small negative component on lead II, and a positive component on lead III. The upper right panel shows the actual deflections on each of the electrocardiographic limb leads that will be produced by this dipole. Note that it is possible for a given cardiac dipole to produce opposite deflections on different leads. For example, in Figure 25–4, Q waves appear on leads I and II but not on lead III. The second row of panels in Figure 25–4 shows the ventricles during the instant in ventricular depolarization when the number of individual dipoles is greatest and/or their orientation is most similar. This phase generates the large net cardiac dipole, which is responsible for the R wave of the electrocardiogram. In Figure 25–4, this net cardiac dipole is nearly parallel to lead II. As indicated, such a dipole produces large positive R waves on all three limbs leads. The third row of diagrams in Figure 25–4 shows the situation near the end of the spread of depolarization through the ventricles and indicates how the small net cardiac dipole present at this time produces the S wave. Note that an S wave does not necessarily appear on all electrocardiogram leads (as in lead I of this example). The bottom row of diagrams in Figure 25–4 shows that during the ST segment, all ventricular muscle cells are in a

CHAPTER 25 Cardiac Function Assessments

−

239

I

I

−

− II III

II

Q wave

III

−

I

−

−

II

R wave

I

II

III

III −

I

I

−

− II

S wave

II

III

III

−

I

I −

−

II ST segment

II

III

FIGURE 25–4 Ventricular depolarization and the generation of the QRS complex. (Modified with permission from Mohrman DE, Heller LJ:

III

Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.)

depolarized state. There are no waves of electrical activity moving through the heart tissue. Consequently, no net cardiac dipole exists at this time and no voltage differences exist between points on the body surface. All electrocardiographic traces will be flat at the isoelectric (zero voltage) level.

ventricular repolarization results in a positive T wave recorded, for example, on lead II. The T wave is broader and smaller than the R wave because the repolarization of ventricular muscle cells is less well synchronized than is their depolarization.

VENTRICULAR REPOLARIZATION AND THE T WAVE

MEAN ELECTRICAL AXIS AND AXIS DEVIATIONS

As illustrated in Figure 25–1, the T wave is normally positive on lead II as is the R wave. This indicates that the net cardiac dipole generated during ventricular repolarization is oriented in the same general direction as that which exists during ventricular depolarization. This may be somewhat surprising. However, recall from Figure 24–3 that the last ventricular cells to depolarize are the first to repolarize. The reasons for this are not well understood but the result is that the wavefront of electrical activity during ventricular repolarization tends to retrace, in reverse direction, the course followed during ventricular depolarization. Therefore, the dipole formed during repolarization has the same polarity as that during depolarization. This reversed wavefront propagation pathway during

The orientation of the cardiac dipole during the most intense phase of ventricular depolarization (i.e., at the instant the R wave reaches its peak) is called the mean electrical axis of the heart. It is used clinically as an indicator of whether or not ventricular depolarization is proceeding over normal pathways. The mean electrical axis is reported in degrees according to the convention indicated in Figure 25–5. Note that the downward direction is designated as plus 90° in this polar coordinate system describing axis orientation in the frontal plane (a vertical plane that divides the body into anterior and posterior sections.) As indicated, a mean electrical axis that lies anywhere in the patient’s lower lefthand quadrant is considered normal (between 0° and 90°). A left axis deviation exists when the mean electrical axis falls in

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SECTION V Cardiovascular Physiology

RA

LA −90 degrees 180 degrees

Right axis deviation > +90 degrees

Left axis deviation < 0 degrees

0 degrees

+90 degrees

Range of normal 0 to +90 degrees

LL

FIGURE 25–5

Mean electrical axis and axis deviations.

(Modified with permission from Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.)

the patient’s upper left-hand quadrant and may indicate any of the several conditions such as a physical displacement of the heart to the left, left ventricular hypertrophy, or loss of electrical activity in part of the right ventricle (e.g., after an infarct). A right axis deviation exists when the mean electrical axis falls in the patient’s lower right-hand quadrant and may indicate, among several conditions, a physical displacement of the heart to the right, right ventricular hypertrophy, or loss of electrical activity in part of the left ventricle. The mean electrical axis of the heart can be determined from the electrocardiogram. The process involves determining what single net dipole orientation will produce the R-wave amplitudes recorded on any two leads. For example, if the R waves on leads II and III are both positive (upright) and of equal magnitude, the mean electrical axis must be +90°. As should be obvious, in this case, the amplitude of the R wave on lead I will be zero. Alternatively, one can scan the electrocardiographic records for the lead tracing with the largest R waves and then deduce that the mean electrical axis must be nearly parallel to that lead. In Figure 25–4, for example, the largest R wave occurs on lead II. Lead II has an orientation of +60°, which is very close to the actual mean electrical axis in this example.

THE STANDARD 12-LEAD ELECTROCARDIOGRAM The standard clinical electrocardiogram involves voltage measurements recorded from 12 different leads. Three of these are the bipolar limb leads I, II, and III, which have already been discussed. The other nine leads are unipolar leads. Three of these leads are generated by using the limb electrodes. Two of the electrodes are electrically connected to form an indifferent electrode while the third limb electrode is made the positive pole of the pair. Recordings made from these electrodes are called augmented unipolar limb leads. The voltage record obtained between the electrode at the right arm and the indifferent electrode is called a lead aVR electrocardiogram. Similarly, lead aVL is recorded from the electrode on the left arm and lead aVF is recorded from the electrode on the left leg.

The standard limb leads (I, II, and III) and the augmented unipolar limb leads (aVR, aVL, and aVF) record the electrical activity of the heart as it appears from six different “perspectives.” As shown in Figure 25–6A, the axes for leads I, II, and III are those of the sides of Einthoven’s triangle, while those for aVR, aVL, and aVF are specified by lines drawn from the center of Einthoven’s triangle to each of its vertices. As indicated in Figure 25–6B, these six limb leads can be thought of as a hexaxial reference system for observing the cardiac vectors in the frontal plane. The other six leads of the standard 12-lead electrocardiogram are also unipolar leads that “look” at the electrical vector projections in the transverse plane (a horizontal plane that divides the body into superior and inferior segments). These potentials are obtained by placing an additional (exploring) electrode in six specified positions on the chest wall as shown in Figure 25–6C. The indifferent electrode in this case is formed by electrically connecting the limb electrodes. These leads are identified as precordial or chest leads and are designated as V1–V6. As shown in this figure, the wave of ventricular excitation sweeps away from V1, resulting in a downward deflection. The wave of ventricular excitation sweeps toward V6, resulting in an upward deflection. In summary, the electrocardiogram is a powerful tool for evaluating cardiac excitation characteristics. It must be recognized, however, that the ECG does not provide direct evidence of mechanical pumping effectiveness. For example, a leaky heart valve will usually have no direct electrocardiographic consequences but may adversely influence pumping ability of the heart.

ABNORMAL CARDIAC EXCITATION AND RHYTHMICITY The material presented here is an introduction to the more common abnormalities in cardiac rate and rhythm with an emphasis on the primary physiological consequences of these abnormal situations. Many cardiac excitation problems can be diagnosed from the information in a single lead of an electrocardiogram. The lead II electrocardiogram trace at the top of Figure 25–7 is identified as normal sinus rhythm based on the following characteristics: (1) the frequency of QRS complexes is ~1/s, indicating a normal beating rate of 60 beats/min; (2) the shape of the QRS complex is normal for lead II and its duration is less than 120 milliseconds, indicating rapid depolarization of the ventricles via normal conduction pathways; (3) each QRS complex is preceded by a P wave of proper configuration, indicating SA nodal origin of the excitation; (4) the PR interval is less than 200 milliseconds, indicating proper conduction delay of the impulse propagation through the AV node; (5) the QT interval is less than half of the R-to-R interval, indicating normal ventricular repolarization; and (6) there are no extra P waves, indicating that no AV nodal conduction block is present. The subsequent electrocardiographic tracings in Figures 25–7 and 25–9 represent irregularities commonly found in clinical practice. Examination of each of these traces with the above characteristics in mind will aid in the differential diagnosis.

CHAPTER 25 Cardiac Function Assessments

A

B RA

− −

I +

aV

R

− − −

aVF

II +

+ + LL

aV L +

+ LA −

aVR

−

−

C

−

+

241

+

−

aVL

+ I

III −

− + III

+ aVF

V6 V1

+ II

V2 V3

V4

V5

D

FIGURE 25–6. The standard 12-lead electrocardiogram. A and B) Leads in the frontal plane. C) Electrode positions for precordial leads in the transverse plane. D) A 12 lead ECG. The bottom line is a rhythm strip taken from lead V1 (Modified with permission from Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/McGraw-Hill, 2006. Fig. 25–6D courtesy of Dr. David Gutterman)

The physiological consequences of abnormal excitation and conduction in the heart depend on whether the electrical abnormality evokes a tachycardia, which will limit the time for cardiac filling between beats; evokes a bradycardia, which is inadequate to support sufficient cardiac output; or decreases the coordination of myocyte contraction, which will reduce stroke volume (SV).

SUPRAVENTRICULAR ABNORMALITIES Traces 2–6 below the normal trace in Figure 25–7 represent typical supraventricular arrhythmias (i.e., originating in the atria or AV node). Supraventricular tachycardia (shown in trace 2 of Figure 25–7 and sometimes called paroxysmal atrial tachycardia) occurs when the atria are abnormally excited and drive the ventricles at a very rapid rate. These paroxysms may begin abruptly, last for a few minutes to a few hours, and then, just as abruptly, disappear and heart rate reverts to normal. QRS complexes appear normal (albeit frequent) with simple paroxysmal atrial tachycardia because the ventricular conduction pathways operate normally. The P and T waves may be superimposed because of the high heart rate. Low blood pressure and dizziness may accompany bouts of this

arrhythmia because the extremely high heart rate does not allow sufficient diastolic time for ventricular filling. There are two mechanisms that may account for supraventricular tachycardia. First, an atrial region, usually outside the SA node, may become irritable (perhaps because of local interruption in blood flow) and begin to fire rapidly to take over the pacemaker function for the entire heart. Such an abnormal pacemaker region is called an ectopic focus. Alternatively, atrial conduction may become altered so that a single wave of excitation does not die out but continually travels around some abnormal atrial conduction loop. In this case, the continual activity in the conduction loop may drive the atria and AV node at a very high frequency. This self-sustaining process is called a reentry phenomenon and is diagrammed in Figure 25–8. This situation may develop as a result of abnormal repolarization and altered refractory periods in local areas of the myocardium. Atrial flutter is a special form of tachycardia of atrial origin in which a large reentrant pathway drives the atria at very fast rates (250–300 beats/min) and normal refractory periods of AV nodal tissue are overwhelmed. Thus, ventricular rate is often some fixed ratio of the atrial rate (2:1, 4:1) with frequencies often 150–220 beats/min.

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SECTION V Cardiovascular Physiology

1. Normal sinus rhythm 2. Supraventricular tachycardia 3. First-degree block 2:1

4:1

4. Second-degree block

5. Third-degree block

FIGURE 25–7 Supraventricular arrhythmias. (Reproduced with permission from

6. Atrial fibrillation

1 mV

Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed.

1s

New York: Lange Medical Books/McGraw-Hill, 2006.)

Conduction blocks occur at the AV node and generally represent impaired conduction through this tissue. In first-degree heart block (trace 3 of Figure 25–7), the only electrical abnormality is unusually slow conduction through the AV node. This condition is detected by an abnormally long PR interval (>0.2 second). Otherwise, the electrocardiogram may be normal. At normal heart rates, the physiological effects of a first-degree block are usually inconsequential. The danger, however, is that the slow conduction may deteriorate to an actual interruption of conduction. A second-degree heart block (trace 4 of Figure 25–7) is said to exist when some but not all atrial impulses are transmitted through the AV node to the ventricle. Impulses are blocked in the AV node if the cells of the region are still in a refractory period from a previous excitation. The situation is aggravated by high atrial rates and slower-than-normal conduction through the AV nodal region. In second-degree block, some but not all P waves are accompanied by corresponding QRS complexes and T waves. Atrial rate is often faster than ventricular rate by a certain ratio (e.g., 2:1, 3:1, 4:1). This condition may not represent a serious clinical problem as long as the ventricular rate is adequate to meet the pumping needs. In third-degree heart block (trace 5 of Figure 25–7), no impulses are transmitted through the AV node. In this event, some area in the ventricles—often in the common bundle or bundle branches near the exit of the AV node—assumes the pacemaker role for the ventricular tissue. Atrial rate and ventricular rate are completely independent, and P waves and QRS complexes are totally dissociated in the electrocardiogram. Ventricular rate is likely to be slower than normal (bradycardia) and sometimes is slow enough to impair cardiac output. Atrial fibrillation (trace 6 of Figure 25–8) is characterized by a complete loss of the normally close synchrony of the excitation and resting phases between individual atrial cells. Cells in different areas of the atria depolarize, repolarize, and are excited again randomly. Consequently, no P waves appear in the electrocardiogram although there may be rapid irregular small waves apparent throughout diastole. The ventricular rate is often very irregular in atrial fibrillation because impulses enter the AV

node from the atria at unpredictable times. Fibrillation is a selfsustaining process. The mechanisms behind it are not well understood, but impulses are thought to progress repeatedly around irregular conduction pathways (sometimes called circus pathways, which imply a reentry phenomenon as described earlier and in Figure 25–8). However, because atrial contraction usually plays a negligible role in ventricular filling, atrial fibrillation may be well tolerated by most patients as long as ventricular rate is sufficient to maintain the cardiac output. The real danger with atrial fibrillation lies in the tendency for blood to form clots in the atria in the absence of the normal vigorous, coordinated atrial contraction. These clots can fragment and move out of the heart to lodge in small arteries throughout the systemic or pulmonary circulation. These emboli can have devastating effects on function of critical organs. Consequently, anticoagulant therapy is used as prophylaxis for patients in atrial fibrillation.

VENTRICULAR ABNORMALITIES Traces 2–6 below the normal trace in Figure 25–9 show typical ventricular electrical abnormalities. Conduction blocks called bundle branch blocks or hemiblocks (trace 2 of Figure 25–9)

Normal pathway

Reentrant pathway

FIGURE 25–8 Normal and reentrant (circus) cardiac excitation pathways. (Modified with permission from Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.)

CHAPTER 25 Cardiac Function Assessments

243

1. Normal sinus rhythm

2. Bundle branch block 3. Premature ventricular contraction 4. Ventricular tachycardia

5. Long QT syndrome with torsades des pointes

FIGURE 25–9 1 mV 1s

can occur in either of the branches of the Purkinje system of the intraventricular septum often as a result of a myocardial infarction. Ventricular depolarization is less synchronous than normal in the half of the heart with the nonfunctional Purkinje system. This results in a widening of the QRS complex (>0.12 second) because a longer time is required for cell-to-cell ventricular depolarization of the blocked side to be completed. The direct physiological effects of bundle branch blocks are usually inconsequential. Premature ventricular contractions (PVCs; trace 3 of Figure 25–9) are caused by action potentials initiated by and propagated away from an ectopic focus in the ventricle. As a result, the ventricle depolarizes and contracts before it normally would. A PVC is often followed by a missed beat (called a compensatory pause) because the ventricular cells are still refractory when the next normal impulse emerges from the SA node. The highly abnormal ventricular depolarization pattern of a PVC produces the large-amplitude, long-duration deflections on the electrocardiogram. The shapes of the electrocardiographic records of these extra beats are highly variable and depend on the ectopic site of their origin and the depolarization pathways involved. The volume of blood ejected by the premature beat itself is smaller than normal (if a volume is ejected at all), whereas the stroke volume of the beat following the compensatory pause is larger than normal. This is partly due to the differences in filling times and partly to an inherent phenomenon of cardiac muscle called postextrasystolic potentiation. Single PVCs occur occasionally in most individuals and, although sometimes alarming to the individual experiencing them, are not dangerous. Frequent occurrence of PVCs, however, may be a signal of possible myocardial damage or perfusion problems and can lead to ventricular tachycardia and even ventricular fibrillation (discussed below). Ventricular tachycardia (trace 4 of Figure 25–9) occurs when the ventricles are driven at high rates, usually by impulses originating from a ventricular ectopic focus. Ventricular tachycardia is a very serious condition. Not only is diastolic

Ventricular arrhythmias.

(Modified with permission from Mohrman DE, Heller LJ:

6. Ventricular fibrillation

Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.)

filling time limited by the rapid rate, but also the abnormal excitation pathways make ventricular contraction less synchronous and therefore less effective than normal. In addition, ventricular tachycardia often precedes ventricular fibrillation. Prolonged QT intervals (left side of trace 5 in Figure 25–9) are a result of delayed ventricular myocyte repolarization, which may be due to inappropriate opening of sodium channels or prolonged closure of potassium channels during the action potential plateau phase. Although the normal QT interval varies with heart rate, it is normally less than 40% of the cardiac cycle length (except at very high heart rates). Long QT syndrome is identified when the QT interval is greater than 50% of the cycle duration. It may be genetic in origin (mutations influencing various ion channels involved with cardiac excitability), may be acquired from several electrolyte disturbances (low blood levels of Ca2+, Mg2+, or K+), or may be induced by several pharmacological agents (including some antiarrhythmic drugs). The prolongation of the myocyte refractory period, which accompanies the long QT syndrome, extends the vulnerable period during which extra stimuli can evoke tachycardia or fibrillation. Patients with long QT syndrome are predisposed to a particularly dangerous type of ventricular tachycardia called torsades de pointes (“twisting of points” as shown on the right side of trace 5 in Figure 25–9). This differs from the ordinary ventricular tachycardia in that the ventricular electrical complexes cyclically vary in amplitude around the baseline and can deteriorate rapidly into ventricular fibrillation. In ventricular fibrillation (trace 6 of Figure 25–9), various areas of the ventricle are excited and contract asynchronously. The mechanisms are similar to those in atrial fibrillation. The ventricle is especially susceptible to fibrillation whenever a premature excitation occurs at the end of the T wave of the previous excitation, that is, when most ventricular cells are in the “hyperexcitable” or “vulnerable” period of their electrical cycle. In addition, because some cells are repolarized and some are still refractory, circus pathways can be triggered easily at

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LV pressure (mm Hg)

A

Increased contractility

Normal contractility

120 Increased afterload 80

˙ X

Increased preload

40

60 LV volume (mL)

80

120

Cardiac failure patient d se es tility r p c De ntra co Untreated

co

120

No ntr rmal ac tilit y

Normal individual

B LV pressure (mm Hg)

niques. One of the most accurate methods of measuring cardiac output by invasive means makes use of the Fick principle, which is discussed in more detail in Chapter 26. Briefly, this principle states that the amount of a substance consumed by the tissues, Xtc, is equal to what goes in minus what goes out (which is the arterial–venous concentration difference in the ˙ ). This substance ([X]a – [X]v) times the blood flow rate, Q relationship can be algebraically arranged to solve for blood flow as follows:

Treated with afterload reducer

40

60

120

180

LV volume (mL)

FIGURE 25-10 Left ventricular end systolic pressurevolume relationships. A) The effect of increased contractility shifts the line upward and to the left. B) The effect of systolic cardiac failure shifts the line downward and to the right. (Modified with permission from Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.)

this time. Since no pumping action occurs with ventricular fibrillation, the situation is fatal unless quickly corrected by cardiac conversion (commonly referred to as external electrical defibrillation or cardioversion). During this procedure, the artificial application of large currents to the entire heart (via paddle electrodes applied across the chest) may be effective in depolarizing all heart cells simultaneously and thus allowing a normal excitation pathway to be reestablished. Cardiopulmonary resuscitation (CPR) must be administered until a defibrillation is achieved.

MEASUREMENT OF CARDIAC OUTPUT Fick Principle: Measurement of cardiac output is not a simple task and usually involves either some invasive maneuver or some significant assumptions based on noninvasive tech-

tc ˙ = ________ Q [X] _ [X] a

(1)

v

A common method of determining cardiac output is to use the Fick principle to calculate the collective flow through the systemic organs from (1) the whole body oxygen consumption ˙ tc), (2) the oxygen content of the arterial blood ([X]a), rate (X and (3) the concentration of oxygen in mixed venous blood ([X]v). Of the values required for this calculation, the oxygen content of mixed venous blood is the most difficult to obtain. Generally, the sample for venous blood oxygen measurement must be taken from a venous catheter positioned in the pulmonary artery to ensure that it is a mixed sample of venous blood from all systemic organs. The calculation of cardiac output from the Fick principle is best illustrated by an example. Suppose a patient is consuming 250 mL of O2/min when systemic arterial blood contains 200 mL of O2/L and the right ventricular blood contains 150 mL of O2/L. This means that, on the average, each liter of blood loses 50 mL of O2 as it passes through the systemic organs. In order for 250 mL of O2 to be consumed per minute, 5 L of blood must pass through the systemic circulation each minute: 250[mL O /min]

2 ˙ = __________________ = 5[L blood/min] Q 200–150[mL O /L blood]

(2)

2

Although use of the Fick Principle as described above provides the gold standard for cardiac output determination, there are several other techniques that give good estimates of cardiac output. Indicator dilution techniques involve injection of a known quantity of indicator (dye or a thermal bolus) into blood entering the right heart and appropriate detectors are arranged to continuously record the concentration of the indicator in blood as it leaves the left heart. The dilution of the indicator is proportional to the cardiac output. Other techniques for imaging the heart (echocardiography, ventricular angiography, radionuclide ventriculography) can be used to estimate stroke volume, cardiac output and other indices of ventricular function as are described below. Cardiac index is the cardiac output corrected for the individual’s size. For example, the cardiac output of a 50-kg woman will be significantly lower than that of a 90-kg man. It has been found, however, that cardiac output correlates better with body surface area than with body weight. Therefore, it is common to express the cardiac output per square meter of surface area. Under resting conditions, the cardiac index is normally approximately 3 (L/min)/m2.

CHAPTER 25 Cardiac Function Assessments

CARDIAC CONTRACTILITY ESTIMATIONS It is often important to assess an individual’s cardiac function without using major invasive procedures. Advances in several techniques have made it possible to obtain two- and threedimensional images of the heart throughout the cardiac cycle. Visual or computer-aided analysis of such images provides information useful in clinically evaluating cardiac function. Echocardiography is the most widely used of the several imaging techniques currently available. This noninvasive technique is based on the fact that sound waves reflect back toward the source when encountering abrupt changes in the density of the medium through which they travel. A transducer, placed at specified locations on the chest, generates pulses of ultrasonic waves and detects waves reflected from the cardiac tissue interfaces. The longer the time between the transmission of the wave and the arrival of the reflection, the deeper the structure is in the thorax. Such information can be reconstructed by computer in various ways to produce a continuous image of the heart and its chambers throughout the cardiac cycle. Echocardiography is especially well suited for detecting abnormal operation of cardiac valves or contractile function in portions of the heart walls. It also can provide estimates of heart chamber volumes at different times in the cardiac cycle that are used in a number of ways to assess cardiac function. Ejection fraction (EF) is an extremely useful clinical measurement that can be calculated from an echocardiogram. It is defined as the ratio of stroke volume (SV) to end-diastolic volume (EDV): SV EF = ____ EDV

(3)

Estimates of end-diastolic and -systolic volumes can be made from the images and SV calculated. EF is commonly expressed as a percentage and normally ranges from 55% to 80% (mean 67%) under resting conditions. EFs of less than 55% indicate depressed myocardial contractility. The end-systolic pressure–volume relationship is another useful clinical technique to assess cardiac contractility. Endsystolic volume for a given cardiac cycle is estimated by one of the imaging techniques described above while end-systolic pressure for that cardiac cycle can obtained from the arterial pressure recorded at the point of the closure of the aortic valve (the incisura). Values for several different cardiac cycles may be obtained during infusion of a vasoconstrictor (which increases afterload), and the data plotted as in Figure 25–10 in the context of overall ventricular pressure–volume loops. As shown, increases in myocardial contractility are associated with a leftward rotation in the end-systolic pressure–volume relationship. This method of assessing cardiac function is particularly important because it provides an estimate of contractility that is independent of the EDV (preload). (Recall from Figure 24–4 that increases in preload cause increases in SV without changing the end-systolic volume. Thus, only altera-

245

tions in contractility will cause shifts in the end-systolic pressure–volume relationship.) Note in Figure 25–10A that both the “normal” and “increased contractility” end-systolic pressure–volume lines nearly project to the origin at zero pressure, zero volume. Thus, it is possible to get a reasonable clinical estimate of the slope of the end-systolic pressure–volume relationship (read “myocardial contractility”) from a single measurement of end-systolic pressure and volume. This avoids the need to do multiple expensive tests with vasodilator or vasoconstrictor infusions. A decrease in contractility (as may be caused by heart disease) is associated with a downward shift of the end-systolic pressure–volume relationship and is known as systolic heart failure. In this situation, increases in sympathetic drive have limited influence on cardiac output. Part of the compensatory process involves a significant increase in body fluid retention that results in an increase in circulating blood volume and ventricular EDV (see Chapter 29). A left ventricular pressure– volume loop describing the events of a cardiac cycle from a failing heart (shown in Figure 25–10B) is displaced far to the right of that of a normal heart. The untreated patient described in this figure is in serious trouble with a reduced SV and EF and high filling pressure with possible pulmonary vascular congestion. Furthermore, the slope of the line describing the end-systolic pressure–volume relationship is shifted downward and is less steep, indicating the reduced contractility of the cardiac muscle. However, because of this flatter relationship, small reductions in cardiac afterload (i.e., arterial blood pressure) will produce substantial increases in EF and SV that will significantly help this patient.

ABNORMAL CARDIAC VALVE FUNCTION Pumping action of the heart is impaired when the valves do not function properly. A number of techniques, ranging from simple auscultation (listening to the heart sounds) to echocardiography or cardiac catheterization, are used to obtain information about the nature and extent of these valve malfunctions. Often, abnormal heart sounds called murmurs accompany cardiac valve defects. These sounds are caused by abnormal pressure gradients and turbulent blood flow patterns that occur during the cardiac cycle. In general, when a valve does not open fully (i.e., is stenotic), the chamber upstream of the valve has to develop more pressure during its systolic phase to achieve a given flow through the valve. This increase in “pressure” work will induce hypertrophy of cardiac muscle cells and thickening of the walls of that chamber. (This is analogous to the hypertrophied skeletal muscles of the weightlifter doing isometric or high-tension work.) When a valve does not close completely (i.e., is insufficient, regurgitant, or incompetent), the regurgitant blood flow represents an additional volume that must be ejected in order to get sufficient forward flow out of the ventricle into the tissues. This increase in “volume” work often leads to chamber dilation but

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not to an increase in wall thickness. (This is analogous to the nonhypertrophied but well-toned skeletal muscles of the longdistance runner doing isotonic or shortening work.) A second generality about valve abnormalities is that whenever there is an increase in the atrial pressure as a result of AV valve stenosis or regurgitation, this will result in higher pressures in the upstream capillary beds. If capillary hydrostatic pressures are increased, tissue edema will ensue with substantial negative consequences on the function of those upstream organs. A brief overview of four of the common valve defects influencing left ventricular function is given in Figure 25–11. The reader should note that similar stenotic and regurgitant abnor-

malities can occur in right ventricular valves with similar consequences on right ventricular function.

AORTIC STENOSIS Some characteristics of aortic stenosis are shown in Figure 25–11A. Normally, the aortic valve opens widely and offers a pathway of very low resistance through which blood leaves the left ventricle. If this opening is narrowed (stenotic), resistance to flow through the valve increases. A significant pressure difference between the left ventricle and the aorta may be required to eject blood through a

A

B

150

Aortic pressure 100 Left ventricular pressure Left atrial pressure

50

0 ECG Phonocardiogram

C

D Aortic pressure

100

Left ventricular pressure Left atrial pressure

50

0 ECG

Phonocardiogram

FIGURE 25–11 Common valve abnormalities. A) Aortic stenosis. B) Mitral stenosis. C) Aortic regurgitation (insufficiency). D) Mitral insufficiency. (Modified with permission from Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.)

CHAPTER 25 Cardiac Function Assessments stenotic aortic valve. As shown in Figure 25–11A, intraventricular pressures may rise to very high levels during systole while aortic pressure rises more slowly than normal to a systolic value that is subnormal. Pulse pressure is usually low with aortic stenosis. High intraventricular pressure development is a strong stimulus for cardiac muscle cell hypertrophy, and an increase in left ventricular muscle mass invariably accompanies aortic stenosis. This tends to produce a leftward deviation of the electrical axis. (The mean electrical axis will fall in the upper right-hand quadrant of Figure 25–5.) Blood being ejected through the narrowed orifice may reach very high velocities, and turbulent flow may occur as blood enters the aorta. This abnormal turbulent flow can be heard as a systolic (or ejection) murmur with a properly placed stethoscope. The primary physiological consequence of aortic stenosis is a high ventricular afterload that is caused by restriction of the outflow tract. This imposes an increased pressure workload on the left ventricle.

MITRAL STENOSIS Some characteristics of mitral stenosis are shown in Figure 25–11B. A pressure difference of more than a few millimeters of mercury across the mitral valve during diastole is distinctly abnormal and indicates that this valve is stenotic. The high resistance mandates an increased pressure difference to achieve normal flow across the valve (Q ˙ = ΔP/R). Consequently, as shown in Figure 25–11B, left atrial pressure is increased with mitral stenosis. The high left atrial workload may induce hypertrophy of the left atrial muscle. Increased left atrial pressure is reflected back into the pulmonary bed and, if high enough, causes pulmonary edema and pulmonary vascular congestion. A diastolic murmur associated with turbulent flow through the stenotic mitral valve can often be heard. The primary physiological consequences of mitral stenosis are increases in left atrial pressure and pulmonary capillary pressure. The latter can cause interference with normal gas exchange in the lungs, leading to dyspnea (shortness of breath).

AORTIC INSUFFICIENCY Typical characteristics of aortic regurgitation (insufficiency, incompetence) are shown in Figure 25–11C. When the leaflets of the aortic valve do not provide an adequate seal, blood regurgitates from the aorta back into the left ventricle during the diastolic period. Aortic pressure falls faster and further than normal during diastole, which causes a low diastolic pressure and a large pulse pressure. In addition, ventricular EDV and pressure are higher than normal because of the extra blood that reenters the chamber through the incompetent aortic valve during diastole. Turbulent flow of the blood reentering the left ventricle during early diastole produces a characteristic diastolic murmur. Often the aortic valve is altered so that it is both stenotic and insufficient. In these instances, both a sys-

247

tolic and a diastolic murmur are present. The primary physiological consequences of aortic insufficiency are a reduction in forward flow out to the tissues (if the insufficiency is severe) and an increase in the volume workload of the left ventricle.

MITRAL REGURGITATION Typical characteristics of mitral regurgitation (insufficiency, incompetence) are shown in Figure 25–11D. When the mitral valve is insufficient, some blood regurgitates from the left ventricle into the left atrium during systole. A systolic murmur may accompany this abnormal flow pattern. Left atrial pressure is increased to abnormally high levels, and left ventricular EDV and pressure increase. Mitral valve prolapse is a common form of mitral insufficiency in which the valve leaflets evert into the left atrium during systole. The primary physiological consequences of mitral regurgitation are somewhat similar to aortic insufficiency in that forward flow out of the left ventricle into the aorta may be compromised (if the insufficiency is severe) and there is an increase in the volume workload of the left ventricle. In addition, the elevated left atrial pressure can also lead to pulmonary effects with shortness of breath.

CLINICAL CORRELATION A 72-year-old man comes to the doctor’s office with complaints of diminished exercise tolerance. He has had dyspnea (shortness of breath) on exertion for several years but it has gotten worse lately. He now experiences chest pain and some dizziness with only mild exertion and, the day before his appointment, he fainted when getting out of bed. His heart rate is 75 beats/min and his blood pressure is 113/90 mm Hg. A loud systolic murmur is heard using a stethoscope placed above the aorta, and a slowly rising pulse is detected in his radial artery. An ECG reveals normal rate and rhythm but significant left ventricular hypertrophy (positive R wave in lead I, negative R wave in lead AVF , and large R-wave amplitudes in leads aVl, V5, and V6). Echocardiography indicated significant left ventricular wall thickening and significant narrowing of the aortic valve opening during systole. This man’s symptoms can all be a result of an increasing severity of aortic valve stenosis. Because of the elevated resistance to outflow (essentially an increased afterload), the left ventricular muscles must develop more force to generate sufficient pressure to eject blood during systole. Left ventricular pressure during systole will be much higher than aortic pressure during systole, thereby producing a significant pressure gradient. Over time, this increased workload induces hypertrophy of the left ventricular muscle that accounts for the leftward shift in the mean electrical axis. The dyspnea on exertion is a result of an exercise-induced imbalance in SV from the normal

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right side and the abnormal left side of the heart and blood backing up into the pulmonary circulation. Fainting may be a common symptom in patients with aortic stenosis and, although it certainly reflects a decrease in brain blood flow, the specific causes are not entirely clear. A popular theory is that because the left ventricular SV (and therefore cardiac output) is nearly fixed and not able to adjust to the many cardiovascular challenges associated with even mild exertion, arterial pressure decreases as a result of the unopposed decrease in peripheral vascular resistance. Other possibilities include a hypertrophyinduced predisposition to arrhythmias or a vasodilator reflex evoked by high left ventricular pressures. The chest pain (angina pectoris) is a result of inadequate coronary blood flow to meet the myocardial metabolic demands. Ischemia can be a result of either an impediment to coronary flow (as might occur with coronary artery disease or atherosclerosis) or an increase in metabolic demands. In this case, the increase in myocardial work because of the aortic stenosis plus the accompanying hypertrophy outstrips the ability of the coronary bed to provide sufficient flow. (Eventually, there will be ischemia even at rest and ECG signs of ventricular strain and subendocardial ischemia will appear. These signs include ST-segment depression and T-wave inversion.) The treatment for aortic stenosis is surgical replacement of the aortic valve.

CHAPTER SUMMARY ■

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The electrocardiogram is a record of the voltage changes that occur on the surface of the body as a result of the propagation of the action potential through the heart during a cardiac cycle. There are standardized conventions used for recording electrocardiograms. The magnitude and direction of the net dipole formed by the wavefront of the action potential at any instant in time can be deduced from the magnitude and orientation of the electrocardiographic deflections. The mean electrical axis describes the orientation of the net dipole at the instant of maximum wavefront propagation during ventricular depolarization and normally falls between 0° and +90° on a polar coordinate system. The standard 12-lead electrocardiogram is widely used to evaluate cardiac electrical activity and consists of a combination of bipolar and unipolar records from limb electrodes and chest electrodes. Cardiac arrhythmias can often be detected and diagnosed from a single electrocardiographic lead. Physiological consequences of abnormal excitation and conduction in the heart depend on whether the electrical abnormality limits the time for adequate cardiac filling or

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decreases the coordination of myocyte contractions resulting in inadequate pressure development and ejection. Supraventricular arrhythmias are a result of abnormal action potential initiation at the SA node or altered propagation characteristics through the atrial tissue and the AV node. Tachycardias may originate either in the atria or ventricles and are a result of increased pacemaker automaticity or of continuously circling pathways setting up a reentrant circuit. Abnormal conduction through the AV node results in conduction blocks. Abnormal conduction pathways in the Purkinje system or in the ventricular tissue result in significant QRS alterations. Ventricular tachycardia and ventricular fibrillation represent severe abnormalities that are incompatible with effective cardiac pumping. A variety of methods are available for measuring various aspects of cardiac mechanical function. These methods are based on the Fick principle and various imaging techniques including echocardiography. The ejection fraction (which is the stroke volume divided by the end-diastolic volume) and the ventricular end-systolic pressure–volume relationship are very useful indices of cardiac contractility. Failure of cardiac valves to open fully (stenosis) can result in elevated upstream chamber pressure and abnormal pressure gradients, congestion in upstream vascular beds, chamber wall hypertrophy, turbulent forward flow across the valve, and murmurs during systole or diastole. Failure of cardiac valves to close completely (insufficiency, incompetence, regurgitation) can result in large stroke volumes, abnormal pressure pulses, congestion in upstream vascular beds, turbulent backward flow across the valve, and murmurs during systole or diastole.

STUDY QUESTIONS 1. Your 75-year-old male patient is alert with complaints of general fatigue. His heart rate = 90 beats/min and arterial pressure = 140/50 mm Hg. A diastolic murmur is present. There are no ECG abnormalities identified and mean electrical axis = 10°. Cardiac catheterization indicate that LV pressure = 140/20 mm Hg and left atrial pressure = 10/3 mm Hg (as peak systolic/end diastolic). Which of the following is most consistent with these findings? A) aortic stenosis B) aortic insufficiency C) mitral stenosis D) mitral insufficiency E) right ventricular hypertrophy 2. Evaluation of your patient’s electrocardiogram shows that P waves occur at a regular rate of 90/min and QRS complexes occur at a regular rate of 37/min. Which of the following is the most likely diagnosis? A) supraventricular tachycardia B) first-degree heart block C) second-degree heart block D) third-degree heart block E) bundle branch block

CHAPTER 25 Cardiac Function Assessments 3. Given the following information, calculate cardiac output and determine whether this would be a normal value for a healthy 70 kg young adult: systemic arterial blood oxygen concentration, [O2]SA = 200 mL/L; pulmonary arterial blood oxygen concentration, [O2]PA = 140 mL/L; total body oxygen consumption, VO2 = 600 mL/min. A) 10 L/min that is normal for mild exercise B) 10 L/min that is abnormally low at rest C) 6 L/min that is close to a normal resting value D) 0.6 L/min that is abnormally low at rest E) 60 L/min that is impossible for normal individuals 4. Your patient takes a drug that decreases AV nodal action potential conduction velocity. The direct effect of this drug will be seen on the ECG as A) a decrease in QRS-wave frequency. B) an increase in P-wave amplitude. C) an increase in the PR interval. D) a widening of the QRS interval. E) an increase in the ST-segment duration.

5. Your patient’s ECG shows that R-wave amplitude on leads I and aVF is upright and equally large. Which of the following statements is true? A) This indicates a significant left electrical axis deviation. B) The mean electrical axis is +90°. C) The R-wave amplitude will be smallest on lead aVL. D) The R-wave amplitude will be positive on lead aVR. E) The left ventricle is hypertrophied.

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26 C

Peripheral Vascular System David E. Mohrman and Lois Jane Heller

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Define convective transport and diffusion and list the factors that determine the rate of each. Given data, use the Fick principle to calculate the rate of removal of a solute from blood as it passes through an organ. Describe how capillary wall permeability to a solute is related to the size and lipid solubility of the solute. List the factors that influence transcapillary fluid movement and, given data, predict the direction of transcapillary fluid movement. Describe the lymphatic vessel system and its role in preventing fluid accumulation in the interstitial space. Given data, calculate the vascular resistances of networks of vessels arranged in parallel and in series. Describe differences in the blood flow velocity in the various segments and how these differences are related to their total cross-sectional area. Describe laminar and turbulent flow patterns and the origin of flow sounds in the cardiovascular system. Identify the approximate percentage of the total blood volume that is contained in the various vascular segments in the systemic circulation. Define peripheral venous pool and central venous pool. Describe the pressure changes that occur as blood flows through a vascular bed and relate them to the vascular resistance of the various vascular segments. State how the resistance of each consecutive vascular segment contributes to an organ’s overall vascular resistance and, given data, calculate the overall resistance. Define total peripheral resistance (systemic vascular resistance) and state the relationship between it and the vascular resistance of each systemic organ. Define vascular compliance and state how the volume–pressure curves for arteries and veins differ. Predict what will happen to venous volume when venous smooth muscle contracts or when venous transmural pressure increases. Describe the role of arterial compliance in storing energy for blood circulation.

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Describe the auscultation technique of determining arterial systolic and diastolic pressures. Identify the physical bases of the Korotkoff sounds. Indicate the relationship between arterial pressure, cardiac output, and total peripheral resistance and predict how arterial pressure will be altered when cardiac output and/or total peripheral resistance change. Given arterial systolic and diastolic pressures, estimate mean arterial pressure. Indicate the relationship between pulse pressure, stroke volume, and arterial compliance and predict how pulse pressure will be changed by changes in stroke volume, or arterial compliance. Describe how arterial compliance changes with age and how this affects arterial pulse pressure.

OVERVIEW OF THE PERIPHERAL VASCULAR SYSTEM Homeostasis implies that each and every cell in the body is continuously bathed in a local environment of constant composition that is optimal for cell function. In essence, the peripheral vascular system is a sophisticated irrigation system. Blood flow is continuously delivering nutrients to and removing waste products from the local interstitial environment throughout the body. The heart supplies the pumping power required to create flow through the system. Because of the heart’s action, pressure at the inlet (the aorta) of the vascular network is higher than that at its outlets (the vena cavae). Everywhere within the vascular system, blood always flows from higher pressure to lower pressure according to well-known physical rules. Like water flowing downhill, blood seeks to travel along the path of least resistance. Consequently, the peripheral vascular system changes the resistance of its various pathways to direct blood flow to where it is needed. This chapter begins with a description of the mechanisms responsible for the transport of dissolved substances through the vascular system and the movement of these substances and fluid from capillaries to and from the interstitial space. Next, the basic equation for flow though a single vessel (Q = ΔP/R, presented in Chapter 22) is applied to the complex network of branching vessels that actually exists in the cardiovascular system. Then, the consequences of the elastic properties of the large diameter arteries and veins on overall cardiovascular system operation are considered. Finally, the principles of the routine clinical measurement of arterial blood pressure are presented along with the conclusions about overall cardiovascular function that can be made from the information.

CARDIOVASCULAR TRANSPORT THE FICK PRINCIPLE Substances are carried between organs within the cardiovascular system by the process of convective transport, the simple process of being swept along with the flow of the blood in which they are contained. The rate at which a substance (X) is transported by this process depends solely on the concentration of the substance in the blood and the blood flow: Transport rate = Flow × Concentration or . . X = Q [X]

(1) . . where X is the rate of transport of X (mass/time), Q is the blood flow (volume/time), and [X] is the concentration of X in blood (mass/volume). It is evident from the preceding equation that only two methods are available for altering the rate at which a substance is carried to an organ: (1) a change in the blood flow through the organ or (2) a change in the arterial blood concentration of the substance. The preceding equation might be used, for example, to calculate how much oxygen is carried to a certain skeletal muscle each minute. Note, however, that this calculation would not indicate whether the muscle actually used the oxygen carried to it. One can extend the convective transport principle to determine a tissue’s rate of utilization (or production) of a substance by simultaneously considering the transport rate of the substance to and from the tissue. The relationship that results is referred to as the Fick principle and may be formally stated as follows: . . Xtc= Q ([X]a − [X]v) (2)

CHAPTER 26 Peripheral Vascular System . . where X tc is the transcapillary efflux rate of X (mass/time), Q the blood flow (volume/time), and [X]a,v the arterial and venous concentrations of X. The Fick principle demonstrates that the amount of a. substance that goes into an organ in a given . period of time (Q[X]a) minus the amount that comes out (Q [X]v) must equal the tissue utilization rate of that substance. (If the tissue is producing substance X, then the above equation will yield a negative utilization rate.) Recall that one method for determining cardiac output (CO) described in Chapter 25 used the Fick principle to calculate the blood flow through the systemic circulation. In that case, the known variables included the systemic tissue oxygen consumption rate and the concentrations of oxygen in arterial blood and mixed venous blood and the. above equation was rearranged to solve for the blood flow (Q ).

TRANSCAPILLARY SOLUTE DIFFUSION Capillaries act as efficient exchange sites where most substances cross the capillary walls by passively diffusing from regions of high concentration to regions of low concentration (see Chapter 1). There are four factors that determine the diffusion rate of a substance between the blood and the interstitial fluid: (1) the concentration difference, Δ[X], (2) the surface area for exchange, A, (3) the diffusion distance, ΔL, and (4) the permeability of the capillary wall to the diffusing substance represented as the diffusion coefficient, D. These factors are combined in an equation (Fick’s first law of diffusion) that . describes the diffusion (X d) of a substance X across a barrier: . Δ[X] Xd= DA ____ (3) ΔL

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Capillary beds allow huge amounts of materials to enter and leave blood because they maximize the area across which exchange can occur while minimizing the distance over which the diffusing substances must travel. Capillaries are extremely fine vessels with a lumen (inner) diameter of about 5 μm, a wall thickness of approximately 1 μm, and an average length of perhaps 0.5 mm. (For comparison, a human hair is roughly 100 μm in diameter.) Capillaries are distributed in incredible numbers in organs and communicate intimately with all regions of the interstitial space. It is estimated that there are about 1010 capillaries in the systemic organs with a collective surface area of about 100 m2. That is roughly the area of one player’s side of a singles tennis court. Recall from Chapter 22 that most cells are no more than about 10 μm (less than one tenth the thickness of paper) from a capillary. Diffusion is a tremendously powerful mechanism for material exchange when operating over such a short distance and through such a large area. We are far from being able to duplicate—in an artificial lung or kidney, for example—the favorable geometry for diffusional exchange that exists in our own tissues. As diagrammed in Figure 26–1, the capillary wall itself consists of only a single thickness of endothelial cells joined to form a tube. The ease with which a particular solute crosses the capillary wall is expressed in a parameter called its capillary permeability. Permeability takes into account all the factors (diffusion coefficient, diffusion distance, and surface area)—except concentration difference—that affect the rate at which a solute crosses the capillary wall. Two fundamentally distinct pathways exist for transcapillary exchange. Lipid-soluble substances, such as the gases oxygen and carbon dioxide, cross the capillary wall easily. Because the lipid endothelial cell plasma membranes are not a significant diffusion barrier for lipid-soluble substances, transcapillary

Interstitium

Water-filled channels

Endothelial cell 1 μ m thick Plasma

Cytoplasm Plasma membranes

40 Å

Na+, K+ Cl– , H2O, glucose

O2, CO2, ethanol

Proteins Small water-soluble substances

Lipid-soluble substances

FIGURE 26–1 Pathways for transcapillary solute diffusion. (Modified with permission from Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.)

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SECTION V Cardiovascular Physiology

movement of these substances can occur through the entire capillary surface area. The capillary permeability to small polar particles such as sodium and potassium ions is about 10,000-fold less than that for oxygen. Nevertheless, the capillary permeability to small ions is several orders of magnitude higher than the permeability that would be expected if the ions were forced to move through the lipid plasma membranes. It is therefore postulated that capillaries are somehow perforated at intervals with waterfilled channels or pores (which may actually be clefts between the endothelial cells). Calculations from diffusion data indicate that the collective cross-sectional area of the pores relative to the total capillary surface area varies greatly between capillaries in different organs. Brain capillaries appear to be very tight (have few pores), whereas capillaries in the kidney and fluid-producing glands are much more leaky. On the average, however, pores constitute only a very small fraction of total capillary surface area—perhaps 0.01%. This area is, nevertheless, sufficient to allow very rapid equilibration of small watersoluble substances between the plasma and interstitial fluids of most organs. Thus, the concentrations of inorganic ions measured in a plasma sample can be taken to indicate their concentrations throughout the entire extracellular space. In general, albumin and other large plasma proteins cannot easily cross capillary walls. The precise mechanism for the low capillary permeability to proteins is in dispute. One hypothesis is that capillary pores are just physically smaller than the diameter of plasma protein molecules. Whatever the mechanism(s), the result is that much higher protein concentrations normally exist in blood plasma than in interstitial fluid.

ENDOTHELIAL CELLS In addition to forming capillaries, a layer of endothelial cells lines the entire cardiovascular system—including the heart chambers and valves. Because of their ubiquitous and intimate contact with blood, endothelial cells have evolved to serve many functions in addition to acting as a barrier to transcapillary solute and water exchange. For example, endothelial cell membranes contain specific enzymes that convert some circulating hormones from inactive to active forms. Endothelial cells are also intimately involved in producing substances that lead to blood clot formation and the stemming of bleeding in the event of tissue injury. Moreover, and as will be discussed in the next chapter, the endothelial cells lining muscular vessels such as arterioles can produce vasoactive substances that act on the smooth muscle cells that surround them to influence arteriolar diameter.

important for a host of physiological functions, including the maintenance of circulating blood volume, intestinal fluid absorption, tissue edema formation, and saliva, sweat, and urine production. Net fluid movement out of capillaries is referred to as filtration, and fluid movement into capillaries is called reabsorption. Fluid flows through transcapillary channels in response to pressure differences between the interstitial and intracapillary fluids according to the basic flow equation. However, both hydrostatic and osmotic pressures influence transcapillary fluid movement. How hydrostatic pressure provides the driving force for causing blood flow along vessels has been discussed previously. The hydrostatic pressure inside capillaries, Pc, is about 25 mm Hg and is the driving force that causes blood to return to the right heart from the capillaries of systemic organs. In addition, however, the 25-mm Hg hydrostatic intracapillary pressure tends to cause fluid to flow through the transcapillary pores into the interstitium where the hydrostatic pressure (Pi) is near 0 mm Hg. Thus, there is normally a large hydrostatic pressure difference favoring fluid filtration across the capillary wall. Our entire plasma volume would soon be in the interstitium if there were not some counteracting force tending to draw fluid into the capillaries. The balancing force is an osmotic pressure that arises from the fact that plasma has a higher protein concentration than interstitial fluid. Recall that water always tends to move from regions of low to regions of high total solute concentration in establishing osmotic equilibrium. Also recall that the driving force for osmotic water movement between one solution and another can be expressed as an osmotic pressure difference between the two. The osmotic pressure difference is directly related to the difference in total solute concentration in the two solutions in question. Because plasma and interstitial fluid are essentially identical except for their protein concentrations, plasma proteins are primarily responsible for the net osmotic pressure difference across capillary walls. The component of total osmotic pressure due to proteins has been given the special name, oncotic pressure (or colloid osmotic pressure). Because of plasma proteins, the oncotic pressure of plasma (πc) is about 25 mm Hg. Due to the absence of proteins, the oncotic pressure of the interstitial fluid (πi) is near 0 mm Hg. Thus, there is normally a large osmotic force for fluid reabsorption into capillaries. The forces that influence transcapillary fluid movement are summarized on the left side of Figure 26–2. The relationship among the factors that influence transcapillary fluid movement, known as the Starling hypothesis, can be expressed by the following equation: Net filtration rate = k[(Pc − Pi) − (πc − πi)]

TRANSCAPILLARY FLUID MOVEMENT In addition to providing a diffusion pathway for polar molecules, the water-filled channels that traverse capillary walls permit fluid flow through the capillary wall. Net shifts of fluid between the capillary and interstitial compartments are

(4)

where Pc is the hydrostatic pressure of intracapillary fluid, πc the oncotic pressure of intracapillary fluid, Pi and πi the hydrostatic and oncotic pressures for interstitial fluid, respectively, and k a constant expressing how readily fluid can move across capillaries (essentially the reciprocal of the resistance to fluid flow through the capillary wall).

CHAPTER 26 Peripheral Vascular System

Interstitium

Endothelial cell

Plasma Hydrostatic Pi

Pc

Osmotic πi

Net fluid filtration Pc – Pi > πc – πi

πc

No net movement Pc – Pi = πc – πi

Net fluid reabsorption Pc – Pi < πc – πi

FIGURE 26–2 Factors influencing transcapillary fluid movement. (Modified with permission from Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.)

Fluid balance within a tissue (the absence of net transcapillary water movement) occurs when the bracketed term in this equation is zero. This equilibrium may be upset by alterations in any of the four pressure terms. The pressure imbalances that cause capillary filtration and reabsorption are indicated on the right side of Figure 26–2. In most tissues, rapid net filtration of fluid is abnormal and causes tissue swelling as a result of excess fluid in the interstitial space (edema). For example, a substance called histamine is often released in damaged tissue. One of the actions of histamine is to increase capillary permeability to the extent that proteins leak into the interstitium. Net filtration and edema accompany histamine release, in part because the oncotic pressure difference (πc – πi) is reduced below normal. Transcapillary fluid filtration is not always detrimental. Indeed, fluid-producing organs such as salivary glands and kidneys utilize high intracapillary hydrostatic pressure to produce continuous net filtration. Moreover, in certain abnormal situations, such as severe loss of blood volume through hemorrhage, the net fluid reabsorption accompanying diminished intracapillary hydrostatic pressure helps restore the volume of circulating fluid.

LYMPHATIC SYSTEM Despite the extremely low capillary permeability to proteins, these molecules as well as other large particles such as long-chain fatty acids and bacteria find their way into the interstitial space. If such particles are allowed to accumulate in the interstitial space, filtration forces will ultimately exceed reabsorption forces and edema will result. The lymphatic system represents a pathway by which large molecules reenter the circulating blood.

255

The lymphatic system begins in the tissues with blind-end lymphatic capillaries that are roughly equivalent in size to but less numerous than regular capillaries. These capillaries are very porous and easily collect large particles accompanied by interstitial fluid. This fluid, called lymph, moves through the converging lymphatic vessels, is filtered through lymph nodes where bacteria and particulate matter are removed, and reenters the circulatory system through the thoracic duct near the point where the blood enters the right heart. Flow of lymph from the tissues toward the entry point into the circulatory system is promoted by (1) increases in tissue interstitial pressure (due to fluid accumulation or to movement of surrounding tissue), (2) contractions of the lymphatic vessels, and (3) valves located in these vessels to prevent backward flow. Roughly 2.5 L of lymphatic fluid enters the cardiovascular system each day. In the steady state, this indicates a total body net transcapillary fluid filtration rate of 2.5 L per day. When compared with the total amount of blood that circulates each day (about 7,000 L), this may seem like an insignificant amount of net capillary fluid leakage. However, lymphatic blockage is a very serious problem and is accompanied by severe swelling (lymphedema). Thus, the lymphatics play a critical role in keeping the interstitial protein concentration low and in removing excess capillary filtrate from the tissues.

BASIC VASCULAR FUNCTION RESISTANCE AND FLOW IN NETWORKS OF VESSELS In. Chapter 22, it was asserted that the basic flow equation (Q =ΔP/R) may be applied to networks of tubes as well as to individual tubes. The reason is that any network of resistances, however complex, can always be reduced to a single “equivalent” resistor that relates the total flow through the network to the pressure difference across the network. To do so, one must make use of the two equations below for series (one after another) and parallel (side-by-side) networks of individual vessels. When vessels with individual resistances R1, R2, …, Rn are connected in series, the overall resistance of the network is given by the following formula: Rs = R1 + R2 + … + Rn

(5)

Figure 26–3A shows an example of three vessels connected in series between some region where the pressure is Pi and another region with a lower pressure Po, so that the total pressure difference across the network, ΔP, is equal to Pi – Po. By the series resistance equation, the total resistance across this network (Rs) is equal to R1 + R2 + R3. By . the basic flow equation, the flow through the network. (Q ) is equal to ΔP/Rs. It should be intuitively obvious that Q is also the flow (volume/ time) through each of the elements in the series as indicated in Figure 26–3B. (Fluid particles may move with different

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SECTION V Cardiovascular Physiology

velocities [distance/time] in different elements of a series network, but the volume that passes through each element in a minute must be identical.) As shown in Figure 26–3C, a portion of the total pressure decrease across the network occurs within each element of the series. The pressure decrease across any element in the series can be calculated by applying . the basic flow equation to that element, for example, ΔP1 = Q R1. Note that the largest portion of the overall pressure decrease will occur across the element in the series with the largest resistance to flow (R2 in Figure 26–3). As indicated in Figure 26–4, when several tubes with individual resistances R1, R2, …, Rn are brought together to form a parallel network of vessels, one can calculate a single overall resistance for the parallel network Rp according to the following formula: 1 __ 1 1 __ = 1 + __ + … + __ Rp R1 R2 Rn

A

R1

R3

R2

Pi

P0

Q

b

a

c

d

Rs = R1 + R2 + R3 ΔP• = Pi − P0 Q = ΔP/Rs B

•

Flow

Q

a

d 70

C

(6)

c b Position along network

Pi

•

ΔP1 =Q ·R1

The total flow through a parallel network is determined by ΔP/Rp. As the preceding equation implies, the overall resistance of any parallel network will always be less than that of any of the elements in the network. (In the special case where the individual elements that form the network have identical resistances Rx, the overall resistance of the network is equal to the resistance of an individual element divided by the number (n) of parallel elements in the network: Rp = Rx/n.) In general, the more parallel elements that occur in the network, the lower the overall resistance of the network. Thus, for example, a capillary bed that consists of many individual capillary vessels in parallel can have a very low overall resistance to flow even though the resistance of a single capillary is relatively high. As indicated in Figure 26–4, the basic flow equation may be applied to any single element in the network or to the network as a whole. For example, the flow through only the first element . . of the network (Q 1) is given by Q 1 = ΔP/R1 , whereas the flow . through the entire parallel network is given by Qp = ΔP/Rp .

•

ΔP

Pressure

ΔP2 =Q ·R2 •

ΔP3 =Q ·R3 P0

a

FIGURE 26–3

b c Position along network

d

A–C) Series resistance network. (Modified with

permission from Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.)

PERIPHERAL BLOOD FLOW VELOCITIES It is important to make the distinction between blood flow (volume/time) and blood flow velocity (distance/time) in the peripheral vascular system. Linear velocity of flow at any point

•

Q1 = ΔP/R1

R1

Pi

•

Q2 = ΔP/R2

R2

P0

•

R3

Q3 = ΔP/R3 1 1 1 1 = + + Rp R1 R2 R3 ΔP = Pi − P0 •

•

•

•

Qtotal = Q1 + Q2 + Q3 •

Qtotal = ΔP/Rp

FIGURE 26–4

Parallel resistance network. (Modified with permission from Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange

Medical Books/McGraw-Hill, 2006.)

CHAPTER 26 Peripheral Vascular System

across the tube as shown on the left side of Figure 26–6. Velocity is fastest along the central axis of the tube and falls to zero at the wall. The concentric layers of fluid with different velocities slip smoothly over one another. Little mixing occurs between fluid layers so that individual particles move in straight streamlines parallel to the axis of the flow. Laminar flow is very efficient because little energy is wasted on anything but producing forward fluid motion. Because blood is a viscous fluid, its movement through a vessel exerts a shear stress on the walls of the vessel. This is a force that wants to drag the inside surface (the endothelial cell layer) of the vessel along with the flow. The endothelial cells that line a vessel are able to sense (and possibly respond to) changes in the rate of blood flow through the vessel by detecting changes in the shear stress on them. Shear stress may also be an important factor in certain pathological situations. For example, atherosclerotic plaques tend to form preferentially near branches of large arteries where, for complex hemodynamic reasons beyond the scope of this text, high shear stresses exist. When blood is forced to move with too high a velocity through a narrow opening, the normal laminar flow pattern may break down into the turbulent flow pattern shown on the right side of Figure 26–6. With turbulent flow, there is much internal mixing and friction. When the flow within a vessel is

is equal to the flow divided by the cross-sectional area. Consider the analogy of a stream whose water moves with greater velocity through shallow rapids than it does through an adjacent deep pool. The volume of water passing through the pool in a day (volume/time = flow), however, must equal that passing through the rapids in the same day. In such a series arrangement, the flow is the same at all points along the channel but the flow velocity varies inversely with the local cross-sectional area. The situation is the same in the peripheral vasculature, where blood flows most rapidly in the region with the smallest total cross-sectional area (the aorta) and most slowly in the region with the largest total cross-sectional area (the capillary beds). Regardless of the differences in velocity, when the CO (flow into the aorta) is 5 L/min, the flow through the systemic capillaries (or arterioles, or venules) is also 5 L/min. The changes in flow velocity that occur as blood passes through the peripheral vascular system are shown in the top trace of Figure 26–5. The important consequence of this slow flow through the capillaries is that it allows sufficient time for adequate solute and fluid exchange between the vascular and interstitial compartments. Blood normally flows through all vessels in the cardiovascular system in an orderly streamlined manner called laminar flow. With laminar flow, there is a parabolic velocity profile

Arteries

Arterioles

257

Capillaries

Venules and veins

500 mm/s

Flow velocity 0.5 mm/s

Blood volume 60% 12%

5%

2%

Systolic Mean 100 mm Hg 25 mm Hg Diastolic blood pressure

Vascular resistance

FIGURE 26–5 Flow velocities, blood volumes, blood pressures, and vascular resistances in the peripheral vasculature from aorta to right atrium. Approximately 20% of the total volume is contained in the pulmonary system and the heart chambers and is not accounted for in this figure. (Modified with permission from Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.)

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SECTION V Cardiovascular Physiology

Streamlines

FIGURE 26–6

Velocity profile

Laminar and turbulent flow patterns. Turbulent flow

(Modified with permission from Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.)

Laminar flow

turbulent, the resistance to flow is significantly higher than that predicted from the Poiseuille equation given in Chapter 22. Turbulent flow also generates sound, which can be heard with the aid of a stethoscope. Cardiac murmurs, for example, are manifestations of turbulent flow patterns generated by cardiac valve abnormalities. Detection of sounds from peripheral arteries (bruits) is abnormal and usually indicates a pathological reduction of a large vessel’s cross-sectional area or an abnormally high blood flow through an organ.

waves (traveling back toward the heart) caused by discontinuities such as branching points in the arterial system. A large pressure drop occurs in the arterioles, where the pulsatile nature of the pressure also nearly disappears. The average capillary pressure is approximately 25 mm Hg. Pressure continues to decrease in the venules and veins as blood returns to the right heart. The central venous pressure (which is the filling pressure for the right heart) is normally very close to 0 mm Hg.

PERIPHERAL BLOOD VOLUMES

PERIPHERAL VASCULAR RESISTANCES

The second trace in Figure 26–5 shows the approximate percentage of the total circulating blood volume that is contained in the different vascular regions of the systemic organs at any instant. Note that most of the circulating blood is contained within the veins of the systemic organs. This diffuse but large blood reservoir is often referred to as the peripheral venous pool. A second but smaller reservoir of venous blood, called the central venous pool, is contained in the great veins of the thorax and the right atrium. When peripheral veins constrict, blood is displaced from the peripheral venous pool and enters the central pool. An increase in the central venous volume, and thus pressure, enhances cardiac filling, which in turn augments stroke volume (SV) according to the Starling law of the heart. This is an extremely important mechanism of cardiovascular regulation and will be discussed in greater detail in Chapter 28.

The bottom trace in Figure 26–5 indicates the relative resistance to flow that exists in each of the consecutive vascular regions. Because arterioles have such a large vascular resistance in comparison to the other vascular segments, the overall vascular resistance of any organ is determined to a very large extent by the resistance of its arterioles. Arteriolar resistance is strongly influenced by arteriolar radius (R is proportional to 1/r4). Thus, the blood flow through an organ is primarily regulated by adjustments in the internal diameter of arterioles caused by contraction or relaxation of their muscular arteriolar walls. When the arterioles of an organ change diameter, not only does the flow to the organ change, but the manner in which the pressures decrease within the organ is also modified. The effects of arteriolar dilation and constriction on the pressure profile within a vascular bed are illustrated in Figure 26–7. Arteriolar constriction causes a greater decrease in pressure across the arterioles, and this tends to increase the arterial pressure while it decreases the pressure in capillaries and veins. Conversely, increased organ blood flow caused by arteriolar dilation is accompanied by decreased arterial pressure and increased capillary pressure. Because of the changes in capillary hydrostatic pressure, arteriolar constriction tends to cause transcapillary fluid reabsorption, whereas arteriolar dilation tends to promote transcapillary fluid filtration.

PERIPHERAL BLOOD PRESSURES Blood pressure decreases in the consecutive segments with the pattern shown in the third trace of Figure 26–5. Recall from Figure 24–1 that aortic pressure fluctuates between a systolic and a diastolic value with each heartbeat, and the same is true throughout the arterial system. The average pressure in the arch of the aorta, however, is about 100 mm Hg, and this mean arterial pressure decreases by only a small amount within the arterial system. As indicated in Figure 26–5, arterial pulse pressure actually increases with distance from the heart, a phenomenon referred to as peripheral peaking of pulse pressure. The hemodynamic reasons for this are very complex but involve the positive addition of primary pressure waves produced by the heart (that travel much faster than blood flow does) and reflected pressure

TOTAL PERIPHERAL RESISTANCE The overall resistance to flow through the entire systemic circulation is called the total peripheral resistance (TPR; sometimes called the systemic vascular resistance [SVR]). Because the systemic organs are generally arranged in parallel (see Figure 22–2), the vascular resistance of each organ contributes to the TPR according to the parallel resistance equation (6).

Distending pressure (mm Hg)

Blood pressure

CHAPTER 26 Peripheral Vascular System

Arteriolar dilation Normal

Arterial compartment 100

Arterioles

ΔP ΔV

50

D

Arteriolar constriction Arteries

Cons

Capillaries

0

Veins

FIGURE 26–7 Effect of changes in arteriolar resistance on vascular pressures. (Modified with permission from Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.)

ELASTIC PROPERTIES OF ARTERIES AND VEINS Arteries and veins contribute only a small portion to the overall resistance to flow through a vascular bed. Therefore, changes in their diameters have no significant effect on the blood flow through systemic organs. The elastic behavior of arteries and veins is, however, very important to overall cardiovascular function because they can act as reservoirs and substantial amounts of blood can be stored in them. Arteries or veins behave more like balloons with one pressure throughout rather than as resistive pipes with a flowrelated pressure difference from end-to-end. Thus, think of an “arterial compartment” and a “venous compartment,” each with an internal pressure that is related to the volume of blood within it at any instant and how easily its walls can be stretched. This is characterized by a parameter called compliance (C; see Chapter 1) given as follows that describes how much its volume changes (ΔV) in response to a given change in distending pressure (ΔP), which is the difference between the internal and external pressures on the vascular walls: ΔV C = ___ ΔP

(7)

Volume–pressure curves for the systemic arterial and venous compartments are shown in Figure 26–8. It is apparent from the disparate slopes of the curves in this figure that the elastic properties of arteries and veins are very different. For the arterial compartment, the ΔV/ΔP measured near a normal operating pressure of 100 mm Hg indicates a compliance of about 2 mL/mm Hg. By contrast, the venous pool has a compliance of over 100 mL/mm Hg near its normal operating pressure of 5–10 mm Hg. Because veins are so compliant, even small changes in peripheral venous pressure can cause a significant amount of the circulating blood volume to shift into or out of the peripheral venous pool. Standing upright, for example, increases venous pressure in the lower extremities and promotes blood accumulation

259

d tricte Norma Volume

l

Venous compartment C

B ΔP

A

ΔV

FIGURE 26–8 Volume–pressure curves of arterial and venous compartments. (Modified with permission from Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.)

(pooling) in these vessels as might be represented by a shift from point A to point B in Figure 26–8. Fortunately, this process can be counteracted by active venous constriction. The dashed line in Figure 26–8 shows the venous volume–pressure relationship that exists when veins are constricted by activation of venous smooth muscle. In constricted veins, volume may be normal (point C) or even below normal (point D) despite greater-thannormal venous pressure. Peripheral venous constriction tends to increase peripheral venous pressure and shift blood out of the peripheral venous compartment. The elasticity of arteries allows them to act as a reservoir on a beat-to-beat basis. Arteries play an important role in converting the pulsatile flow output of the heart into a steady flow through the vascular beds of systemic organs. During the early rapid phase of cardiac ejection, the arterial volume increases because blood is entering the aorta more rapidly than it is passing into systemic arterioles. Thus, part of the work the heart does in ejecting blood goes to stretching the elastic walls of arteries. Toward the end of systole and throughout diastole, arterial volume decreases because the flow out of arteries exceeds flow into the aorta. Previously stretched arterial walls recoil to shorter lengths, and in the process give up their stored potential energy. This reconverted energy is what actually does the work of propelling blood through the peripheral vascular beds during diastole. If arteries were rigid tubes that could not store energy by expanding elastically, arterial pressure would fall immediately to zero with the termination of each cardiac ejection.

MEASUREMENT OF ARTERIAL PRESSURE Recall that the systemic arterial pressure fluctuates with each heart cycle between a diastolic value (PD) and a higher systolic value (PS). Obtaining estimates of an individual’s systolic and

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SECTION V Cardiovascular Physiology

diastolic pressures is one of the most routine diagnostic techniques available to the clinician. The basic principles of the auscultation technique used to measure blood pressure are described as follows with the aid of Figure 26–9: 1. An inflatable cuff is wrapped around the upper arm, with a recording device attached to monitor the pressure within the cuff. The cuff is initially inflated with air to a pressure (usually 175–200 mm Hg) that is well above normal systolic values. This pressure collapses all blood vessels under the cuff. 2. After initial inflation, air is gradually “bled” from the cuff so that the pressure within it decreases slowly and steadily through the range of arterial pressure fluctuations. 3. The moment cuff pressure decreases below peak systolic arterial pressure, some blood is able to pass beneath the cuff during the systolic phase of the cycle. Because the flow through these partially compressed vessels is intermittent and turbulent, tapping sounds can be detected with a stethoscope placed over the radial artery at the elbow. As indicated in Figure 26–9, sounds of varying character, known collectively as Korotkoff sounds, are heard whenever the cuff pressure is between the systolic and diastolic arterial pressures. The highest cuff pressure at which tapping sounds are heard is taken as the systolic arterial pressure. 4. When the cuff pressure decreases below the diastolic pressure, blood flows through the vessels beneath the cuff without periodic interruption and again no sound is detected over the radial artery. The cuff pressure at which the sounds become muffled or disappear is taken as the diastolic arterial pressure.

DETERMINANTS OF ARTERIAL PRESSURE MEAN ARTERIAL PRESSURE Mean arterial pressure is a critically important cardiovascular variable because it is the average effective pressure that drives

blood through the systemic organs. One of the most fundamental equations of cardiovascular physiology is that which indi– cates how mean arterial pressure (Pa) is related to CO and TPR: – Pa = CO × TPR (8) The above equation is simply a rearrangement of the basic . flow equation Q = ΔP /R applied to the entire systemic circulation with the single assumption that central venous pressure is – approximately zero so that ΔP = Pa . Note that mean arterial pressure is influenced both by the heart (via CO) and by the peripheral vasculature (via TPR). All changes in mean arterial pressure result from changes in either CO or TPR. Calculating the true value of mean arterial pressure requires mathematically averaging the arterial pressure waveform over one or more complete heart cycles. Most often, however, we know from auscultation only the systolic and diastolic pressures, yet wish to make some estimate of the mean arterial pressure. Mean arterial pressure necessarily falls between the systolic and diastolic pressures. A useful rule of thumb is that – mean arterial pressure (Pa) is approximately equal to diastolic pressure (PD) plus one third of the difference between systolic and diastolic pressures (PS – PD).

ARTERIAL PULSE PRESSURE The arterial pulse pressure (Pp) is defined simply as systolic pressure minus diastolic pressure (PS – PD). To be able to use pulse pressure to deduce something about how the cardiovascular system is operating, one must do more than just define it. It is important to understand what determines pulse pressure, that is, what causes it to be what it is and what can cause it to change. In a previous section of this chapter, there was a brief discussion about how, as a consequence of the compliance of the arterial vessels, arterial pressure increases as arterial blood volume is expanded during cardiac ejection. The magnitude of the pressure increase (ΔP) caused by an increase in arterial volume depends on how large the volume change (ΔV) is and on how compliant (Ca) the arterial compartment is: ΔP = ΔV/Ca. If, for the moment, the fact that some blood leaves the arterial com-

Cuff pressure Arterial pressure A mm Hg

120

80 B

FIGURE 26–9 Blood pressure measurement by auscultation. Point A indicates systolic pressure and point B indicates diastolic pressure. (Modified with

Lou

der

fter

So

permission from Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.)

No sound

Korotkoff sounds

No sound

CHAPTER 26 Peripheral Vascular System partment during cardiac ejection is neglected, then the increase in arterial volume during each heartbeat is equal to the SV. Thus, pulse pressure is, to a first approximation, equal to SV divided by arterial compliance: SV ___ Pp ∼ − C

(9)

Arterial pulse pressure is about 40 mm Hg in a normal resting young adult because SV is about 80 mL and arterial compliance is about 2 mL/mm Hg. Pulse pressure tends to increase with age in adults because of a decrease in arterial compliance (and increase in arterial stiffness also referred to as “hardening of the arteries” or arteriosclerosis. This differs from atherosclerosis which involves deposition of fat in the vessel wall). Arterial volume–pressure curves for a 20- and a 70-year-old are shown in Figure 26–10. The increase in arterial stiffness with age is indicated by the steeper curve for the 70-year-old (more ΔP for a given ΔV) than for the 20-year-old. Thus, a 70-year-old will necessarily have a larger pulse pressure for a given SV than a 20-year-old. As indicated in Figure 26–10, the increase in arterial stiffness is sufficient to cause increased pulse pressure even though SV tends to decrease with age (Also see Figure 73–1). Figure 26–10 also illustrates the fact that arterial blood volume and mean arterial pressure tend to increase with age. The increase in mean arterial pressure is not caused by the decreased arterial compliance, however, because compliance changes do not directly influence either CO or TPR, which are the sole – determinants of Pa. Mean arterial pressure tends to increase with age because of an age-dependent increase in TPR that is controlled primarily by arterioles, not arteries. Arterial compliance also decreases with increasing mean arterial pressure as evidenced by the curvature of the volume– pressure relationships shown in Figure 26–10. Otherwise, arterial compliance is a relatively stable parameter. Thus, most acute changes in arterial pulse pressure are the result of changes

261

in SV. Changes in TPR, however, have little or no effect on pulse pressure, because a change in TPR causes parallel changes in both systolic and diastolic pressures. A common misconception in cardiovascular physiology is that the systolic pressure alone or the diastolic pressure alone indicates the status of a specific cardiovascular variable. The reader should not attempt to interpret systolic and diastolic pressure values independently. Interpretation is much more straightforward when the focus is on mean arterial pressure – (Pa = CO × TPR) and arterial pulse pressure (Pp ∼ − SV/Ca).

CLINICAL CORRELATION A 27-year-old woman comes to the clinic because of the overnight onset of a pain in her left leg and swelling in her left ankle and foot. She describes the pain as a cramping sort of deep ache. She had returned to the United States yesterday on a 12-hour flight from Brazil where she had spent several weeks on an expedition to the rain forests. She takes no drugs except birth control pills containing estrogen (see Chapter 68). She is 1.73-m tall and weighs 93 kg. Vital signs are all within normal ranges. On examination, it is noted that her left lower leg is sensitive to touch and her left foot feels warmer than her right. Furthermore, there is edema with her left ankle and foot significantly swollen compared to her right. The symptoms suggest that there is an imbalance between filtration and absorptive forces at work in the capillaries of the lower left leg. Because these symptoms are restricted to one leg and not both, overall circulatory abnormalities that might cause ankle edema can be eliminated (e.g., decreased

Arterial pressure (mm Hg)

200

20-year-old

ΔP

ΔP

100 ΔV

0

FIGURE 26–10

70-year-old

ΔV

Arterial volume

Effect of age on systemic arterial volumes and pressures and arterial stiffness. (Modified with permission from Mohrman DE,

Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.)

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plasma proteins which would decrease plasma oncotic pressure; or right-sided heart failure, liver or kidney disease which would increase fluid retention and peripheral venous pressure). Local factors that might cause fluid to accumulate in the interstitial space could include situations that either prevent lymphatic drainage of this space (i.e., lymphedema from tropical pathogenic filarial parasites) or increase hydrostatic pressure in the veins draining the tissue. Because of the rapid onset and symptoms, it is much more likely that a clot has formed in one of the large veins draining her left leg (deep vein thrombosis [DVT]) that has increased the upstream capillary hydrostatic pressure, and caused the pain, filtration of fluid out of the vascular space, and edema of the tissue. Being overweight and taking birth control pills containing estrogens are risk factors that predispose this woman toward the development of such a clot. In addition, a long period of time spent in a sitting position without moving her legs (as might have occurred on her long airplane ride) allows blood to pool in these lower extremities and is an added risk factor for DVT or inflammation of the more superficial veins (thrombophlebitis). In addition to the localized discomfort, there is the real danger that these clots can become dislodged from their anchorage in the leg vein, travel to the heart as an embolus, and become lodged in the lungs (pulmonary embolism). This can be a life-threatening event and requires immediate treatment. Doppler ultrasonic examination of the patient’s leg revealed the presence of DVT and she was treated with an anticoagulant (heparin at first and then warfarin) as well as drugs that can help dissolve clots. It is also possible that this patient has an increased tendency to form clots (i.e., she is hypercoagulable) in part due to being overweight. There are some inherited forms of hypercoagulability that she and her blood relatives can be tested for. It is possible that she will require lifelong treatment with anticlotting drugs. Finally, she will be encouraged to switch to a different birth control method, as estrogens can increase the tendency to form clots.

CHAPTER SUMMARY ■

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Within the cardiovascular system, convection is used to transport substances between capillary beds and diffusion is used to transport substances between blood and tissue. Water may move out of (filtration) or into (reabsorption) capillaries depending on the net balance of hydrostatic and osmotic forces across capillary walls. Plasma proteins are responsible for the major osmotic force across capillary walls. Lymphatic vessels serve to remove excess filtrate from tissues and keep interstitial protein concentration low. The velocity of blood flow is indirectly proportional to the total cross-sectional area of the vascular segment and is slowest in capillaries.

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Turbulent blood flow is usually abnormal and makes noise (murmurs and bruits). Veins contain most of the total blood volume. Arterioles contribute most to the resistance to flow through organs. Arteriolar constriction tends to reduce flow through an organ, reduce capillary hydrostatic pressure, and promote transcapillary fluid reabsorption within the organ. Venous constriction is important for cardiac filling and the ability to cope with blood loss. Because arteries and arterioles are elastic, the intermittent flow from the heart is converted to continuous flow through capillaries. Mean systemic arterial pressure is determined by the product of CO and TPR. Changes in arterial pulse pressure reflect changes in SV and/or the compliance of the arterial space.

STUDY QUESTIONS 1. Determine the rate of glucose uptake by an exercising skeletal muscle from the following data: arterial blood (glucose) = 50 mg per 100 mL blood; muscle venous blood (glucose) = 30 mg per 100 mL blood; muscle blood flow = 60 mL/min. A) 3,000 mg/min B) 1,200 mg/min C) 30 mg/min D) 20 mL/mg E) 12 mg/min 2. Which of the following conditions favor net absorption of fluid out of the interstitial space and into the capillary bed within an organ? A) increased interstitial protein concentration B) venous clot C) decreased plasma protein concentration D) increased capillary pore size E) arteriolar constriction 3. Which of the following is consistent with a normal mean arterial pressure but an abnormally high arterial pulse pressure? A) low stroke volume B) high heart rate C) decreased total peripheral resistance D) increased arterial stiffness E) aortic valve stenosis 4. Which of the following substances is likely to move most easily across a skeletal muscle capillary wall? A) potassium B) glucose C) oxygen D) water E) albumin 5. In which of the following vessels do red cells move with the fastest speed (distance/time)? A) arteries B) arterioles C) capillaries D) venules E) veins

27 C

Vascular Control David E. Mohrman and Lois Jane Heller

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Define basal tone. List several substances potentially involved in local metabolic control of vascular tone. State the local metabolic vasodilator hypothesis. Describe how vascular tone is influenced by locally produced endothelial factors and chemicals such as prostaglandins, histamine, and bradykinin. Describe the myogenic response of blood vessels. Define active and reactive hyperemia and indicate a possible mechanism for each. Define autoregulation of blood flow and briefly describe the metabolic, myogenic, and tissue pressure theories of autoregulation. Define neurogenic tone and describe how sympathetic (and parasympathetic) neural influences can alter it. Describe how vascular tone is influenced by circulating catecholamines, vasopressin, and angiotensin II. List the major influences on the diameter of veins. Describe in general how control of blood flow differs between organs with strong local metabolic control of arteriolar tone and organs with strong neurogenic control of arteriolar tone. State the relative importance of local metabolic and neural control of coronary blood flow. Define systolic compression and indicate its relative importance to blood flow in the endocardial and epicardial regions of the right and left ventricular walls. Describe the major mechanisms of blood flow control in skeletal muscle and brain.

VASCULAR SMOOTH MUSCLE The cardiovascular system must adjust the diameter of its vessels to efficiently distribute the cardiac output among tissues with different current needs (the job of arterioles), and to regulate the distribution of blood volume and cardiac filling (the job of veins). Vascular diameter adjustments are made by regulating the con-

Ch27_263-274.indd 263

tractile activity of vascular smooth muscle cells, which are present in the walls of all vessels except capillaries. Vascular smooth muscle is unique because it must maintain its vessel diameter in the face of the continuous distending pressure of the blood within it, and therefore sustain active tension for prolonged periods. The basics of smooth muscle operation were presented in Chapter 11. Here the focus is on the functional consequences of

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influences on vascular smooth muscle that have particular relevance to the operation of the cardiovascular system. In general, these influences on vascular smooth muscle can be separated into those that originate locally (and therefore have only local consequences) and those that have global influences on vessels throughout the body. Examples of the latter are general changes in autonomic nerve activity and changes in the blood concentrations of hormones that affect vascular smooth muscle. Such influences have much different functional consequences on arterioles than on veins. Consequently, the operations of arterioles and veins are described separately in this chapter.

of basal tone is that it serves as a baseline from which arteriolar tone can be regulated, either increased or decreased as necessary to meet the needs of changing situations. Another important consequence is that the basal tone of arterioles throughout the body collectively contributes directly to the total peripheral resistance (TPR) and thus to arterial blood pressure in a resting individual.

VASCULAR TONE

The arterioles that control flow through a given organ lie within the organ tissue itself. Thus, arterioles and the smooth muscle in their walls are exposed to the chemical composition of the interstitial fluid of the organ they serve. The interstitial concentrations of many substances reflect the balance between the metabolic activity of the tissue and its blood supply. Interstitial oxygen levels, for example, decrease when cells are using oxygen faster than it is being supplied to the tissue by blood flow. Conversely, interstitial oxygen levels increase whenever more oxygen is delivered than is used by a tissue. In nearly all vascular beds, exposure to low oxygen reduces arteriolar tone and causes vasodilation, whereas high oxygen levels cause arteriolar vasoconstriction. Thus, a local feedback mechanism exists that automatically operates on arterioles to regulate blood flow to a tissue in accordance with its metabolic needs. Many substances in addition to oxygen are present within tissues and can affect the tone of vascular smooth muscle. When the metabolic rate of skeletal muscle is increased by exercise, for example, tissue levels of carbon dioxide, H+, and K+ increase. These chemical alterations cause arteriolar dilation. In addition, with increased metabolic activity or oxygen deprivation, cells in many tissues may release adenosine, which is a potent vasodilator agent. At present, it is not known which of these (or possibly other) metabolically related chemical alterations within tissues are most important in the local metabolic control of blood flow. It is likely that arteriolar tone depends on the combined action of many factors. Figure 27–1 summarizes current understanding of local metabolic control. Vasodilator factors enter the interstitial

Vascular tone is a term commonly used to characterize the general contractile state of a vessel or a vascular region. The “vascular tone” of a region can be taken as an indication of the “level of activation” of the individual smooth muscle cells in that region. An increase in arteriolar tone is automatically taken to imply a decrease in arteriolar vessel diameter, the functional consequences of which are an increase in arteriolar resistance and a decrease in flow. The primary functional consequence of an increase in venous tone is a decrease in venous volume and thus a peripheral-to-central shift of blood volume that increases cardiac filling.

CONTROL OF ARTERIOLAR TONE As described in Chapter 26, the blood flow through any organ is determined largely by its vascular resistance, which is dependent primarily on the diameter of its arterioles. Consequently, an organ’s flow is controlled by factors that influence the arteriolar smooth muscle tone.

BASAL TONE The arterioles in a healthy individual at rest have a certain level of basal tone that lies somewhere between complete relaxation and maximum possible constriction. A myriad of influences on arteriolar smooth muscle contribute collectively to the establishment of this basal tone. One important consequence

LOCAL INFLUENCES ON ARTERIOLES Local Metabolic Influences

Release proportional to tissue metabolism Tissue cells

Vasodilator factors

FIGURE 27–1

Local metabolic vasodilator

Removal rate proportional to blood flow

Blood flow

hypothesis. (Modified with permission from Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.)

Arterioles

Capillaries

Veins

CHAPTER 27 Vascular Control space from the tissue cells at a rate proportional to tissue metabolism. These vasodilatory factors are removed from the tissue at a rate proportional to blood flow. Whenever tissue metabolism is at a rate for which the blood flow is inadequate, the interstitial vasodilator concentrations build up and cause the arterioles to dilate and blood flow to increase. The process continues until blood flow has increased sufficiently to appropriately match the tissue metabolic rate and prevent further accumulation of vasodilator factors. The same system also operates to reduce blood flow when it is greater than required by the tissue metabolic activity because the interstitial concentrations of metabolic vasodilator factors are decreased. Local metabolic mechanisms are usually the most important means of local blood flow control in most tissues. Individual organs are therefore able to regulate their own blood flow in accordance with their metabolic needs. As indicated below, there are several other types of local influences on blood vessels. However, many of these represent fine-tuning mechanisms and may be important only in certain, usually pathological, situations.

Local Nonmetabolic Influences An ever-increasing number of local factors unrelated to tissue metabolism have been shown to influence arterioles within an organ. Table 27–1 contains a list of some of these more important factors and summarizes some of the information about their actions. Many of these factors exert their vascular effects by action on endothelial cells. Thus, endothelial cells can actively participate in the control of arteriolar diameter by producing local chemicals that affect the tone of the surrounding smooth muscle cells. The vasodilatory influence produced by endothelial cells is mediated by nitric oxide (NO). NO is produced within endothelial cells from the amino acid, l-arginine, by the action of an enzyme, NO synthase, that is activated by an increase in the intracellular level of Ca2+. NO is a small lipid-soluble molecule that, once formed, easily diffuses into adjacent smooth muscle cells where it causes relaxation by stimulating cGMP production as mentioned in Chapter 11. Acetylcholine and several other agents (including bradykinin, vasoactive intestinal peptide, and substance P) stimulate endothelial cell NO production because their receptors on endothelial cells are linked to receptor-operated Ca2+ channels. Blood flow–related shear stresses on endothelial cells stimulate NO production through stretch-sensitive channels for Ca2+. This phenomenon may explain why exercise and increased blood flow through muscles of the lower leg can cause dilation of the bloodsupplying femoral artery at points far upstream from the exercising muscle itself.

Transmural Pressure The passive elastic mechanical properties of arteries and veins and how changes in transmural pressure affect their diameters were discussed in Chapter 26. The effect of transmural pressure on arteriolar diameter is actually more complex because arterioles respond both passively and actively to changes in

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transmural pressure. For example, a sudden increase in the internal pressure within an arteriole produces first an initial slight passive mechanical distention (slight because arterioles are relatively thick-walled and muscular), and second, an active constriction that, within seconds, may completely reverse the initial distention. A sudden decrease in transmural pressure elicits essentially the opposite response, that is, an immediate passive decrease in diameter followed shortly by a decrease in active tone that returns the arteriolar diameter to near that which existed before the pressure change. The active phase of such behavior is referred to as a myogenic response, because it seems to originate within the smooth muscle itself. The mechanism of the myogenic response is not known for certain, but stretch-sensitive ion channels on arteriolar vascular smooth muscle cells are likely candidates for involvement. All arterioles have some normal distending pressure to which they probably are actively responding. Therefore, the myogenic mechanism is likely to be a fundamentally important factor in determining the basal tone of arterioles everywhere. The myogenic response is potentially involved in the vascular reaction to any cardiovascular disturbance that involves a change in arteriolar transmural pressure, as will be discussed in the next section.

FLOW RESPONSES CAUSED BY LOCAL MECHANISMS In organs with a highly variable metabolic rate, such as skeletal and cardiac muscle, the blood flow closely follows the tissue metabolic rate. For example, skeletal muscle blood flow increases within seconds of the onset of muscle exercise and returns to control values shortly after exercise ceases. This phenomenon, which is illustrated in Figure 27–2A, is known as exercise or active hyperemia (hyperemia means high flow). It should be clear how active hyperemia could result from the local metabolic vasodilator feedback on arteriolar smooth muscle. As mentioned previously, once initiated by local metabolic influences on small resistance vessels, endothelial flow–dependent mechanisms may assist in propagating the vasodilation to larger vessels upstream, which helps promote the delivery of blood to the exercising muscle. Reactive or post-occlusion hyperemia is a greater-thannormal blood flow that occurs transiently after the removal of any restriction that has caused a period of lower-than-normal blood flow. The phenomenon is illustrated in Figure 27–2B. For example, flow through an extremity is greater than normal for a period after a tourniquet is removed from the extremity. Both local metabolic and myogenic mechanisms may be involved in producing reactive hyperemia. The magnitude and duration of reactive hyperemia depend on the duration and severity of the occlusion as well as the metabolic rate of the tissue. These findings are best explained by an interstitial accumulation of metabolic vasodilator substances during the period of flow restriction. However, unexpectedly large flow increases can follow arterial occlusions lasting only 1 or 2 seconds. These may be best explained by a myogenic dilation response to the

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TABLE 27–1 Local influences on vascular smooth muscle. Substance

Description

Vascular Response

Other Information

Nitric oxide (NO), endothelial-derived relaxing factor (EDRF)

From endothelial cells in response to: acetylcholine, vasoactive intestinal peptide, substance P, bradykinin, shear stress, others

Vasodilation

Basal release may reduce normal net resting tone of vascular smooth muscle locally throughout the body

Acetylcholine

Neurotransmitter—normal dilation mediated by NO

Vasodilation and/or vasoconstriction

Important local effects on GI circulation (from enteric plexus neurons)

-Constriction occurs when endothelium is absent/ damaged Vasoactive intestinal peptide (VIP)

Neurotransmitter (also a peptide hormone)—action is mediated by NO

Vasodilation

GI neurotransmitter from enteric plexus neuron, causes smooth muscle relaxation, promotes secretion in the gut

Substance P

Neurotransmitter—action is mediated by NO

Vasodilation

Important local roles in pain nociception, GI function, vomiting, skin circulation

Bradykinin

Polypeptide formed from plasma protein by action of enzyme, kallikrein—action is mediated by NO

Vasodilation

Shear stress

Action is mediated by NO

Vasodilation

Dependent on flow velocity

Endothelial-derived hyperpolarizing factor (EDHF)

Unknown factor from endothelial cells

Vasodilation

May be K+, cANP, electrogenic spread of hyperpolarization, other possible factors

Endothelin

Polypeptide from endothelial cells

Vasoconstriction

Basal release may reduce normal net resting tone of vascular smooth muscle locally in tissues throughout the body

Prostacyclin (PGI2)

Arachidonic acid (AA) metabolite of the cyclooxygenase (CO) pathway

Vasodilation

Inflammatory responses, blocked by cyclooxygenase inhibitors such as aspirin

Thromboxane

AA metabolite of the CO pathway (made by platelets)

Vasoconstriction

Important for platelet aggregation and blood clotting, also blocked by aspirin

Other prostaglandins

AA metabolites of the CO pathway

Vasoconstriction and/or vasodilation

Actions vary with the specific organ and local conditions

Leukotrienes

AA metabolites of the lipoxygenase pathway

Vasoconstriction and/or vasodilation

Increase vascular permeability during inflammatory responses

Histamine

Secretory granules of tissue mast cells and circulating basophils

Vasodilation

Leads to an increase in vascular permeability, edema formation

-Increases vascular permeability -Involved in pain mechanisms

-Involved in inflammatory and immune reactions

reduced intravascular pressure and decreased stretch of the arteriolar walls during the period of occlusion. Except when displaying active and reactive hyperemia, nearly all organs tend to keep their blood flow constant despite variations in arterial pressure—that is, they display autoregulation of blood flow. As shown in Figure 27–3A, an abrupt increase in arterial pressure is normally accompanied by an initial abrupt increase in organ blood flow that then gradually returns toward normal despite the sustained increase in arterial pressure. The initial increase in flow with increased pres˙ = Δ P / R). The sure is expected from the basic flow equation (Q subsequent return of flow toward the normal level is caused by a gradual increase in active arteriolar tone and resistance to blood flow. Ultimately, a new steady state is reached with only

slightly increased blood flow because the increased driving pressure is counteracted by a greater-than-normal vascular resistance. As with the phenomenon of reactive hyperemia, blood flow autoregulation may be caused by both local metabolic feedback mechanisms and myogenic mechanisms. The arteriolar vasoconstriction responsible for the autoregulatory response shown in Figure 27–3A, for example, may be partially due to (1) a “washout” of metabolic vasodilator factors from the interstitium by the excessive initial blood flow and (2) a myogenic increase in arteriolar tone stimulated by the increase in stretching forces that the increase in pressure imposes on the vessel walls. There is also a tissue pressure hypothesis of blood flow autoregulation for which it is assumed that an abrupt increase in arterial pressure causes transcapillary fluid

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267

A

Active hyperemia

Blood flow autoregulation

B

FIGURE 27–2 Organ blood flow responses caused by local mechanisms: A) active and B) reactive hyperemia. (Modified with permission from Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.)

filtration and thus leads to a gradual increase in interstitial fluid volume and pressure. Presumably the increase in extravascular pressure would cause a decrease in vessel diameter by simple compression. This mechanism might be especially important in organs such as the kidney and brain whose volumes are constrained by external structures. Although not illustrated in Figure 27–3A, autoregulatory mechanisms operate in the opposite direction in response to a decrease in arterial pressure below the normal value. One important general consequence of local autoregulatory mechanisms is that the steady-state blood flow in many organs tends to remain near the normal value over quite a wide range of arterial pressure. This is illustrated in the graph of Figure 27–3B. As will be discussed later, the inherent ability of certain organs to maintain adequate blood flow despite lower-than-normal arterial pressure is of considerable importance in situations such as hypotension (low arterial pressure) from blood loss.

NEURAL INFLUENCES ON ARTERIOLES Sympathetic Vasoconstrictor Nerves These neural fibers innervate arterioles in all systemic organs and provide by far the most important means of reflex control

Steady-state Organ blood flow

Reactive hyperemia

Period of arrested blood flow

Steady state

Autoregulatory range

Normal

Normal

B

Organ blood flow

Sustained pressure increase

Organ blood flow

Period of increased metabolic rate

Arterial pressure

Organ blood flow

A

100 200 Mean arterial pressure (mm Hg)

FIGURE 27–3

A and B) Autoregulation of organ blood flow.

(Modified with permission from Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.)

of the vasculature. Sympathetic vasoconstrictor nerves are the backbone of the system for controlling TPR and thus are essential participants in global cardiovascular tasks such as regulating arterial blood pressure. Sympathetic vasoconstrictor nerves release norepinephrine from their terminal structures in amounts generally proportional to their electrical activity. Norepinephrine causes an increase in the tone of arterioles after combining with an α1-adrenergic receptor on smooth muscle cells. Sympathetic vasoconstrictor nerves normally have a continuous or tonic firing activity. Thus, arterioles have a certain level of neurogenic tone as a normal component of their normal baseline state of contraction. When the firing rate of sympathetic vasoconstrictor nerves is increased above normal, arterioles constrict and cause organ blood flow to fall below normal. Conversely, vasodilation and increased organ blood flow occurs when the normal tonic activity of sympathetic vasoconstrictor nerves is reduced.

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Other Neural Influences Most blood vessels do not receive innervation from the parasympathetic division of the autonomic nervous system and systemic vascular resistance is not significantly influenced by parasympathetic nerve activity. However, parasympathetic vasodilator nerves, which release acetylcholine, are present in vessels of the brain and heart but their influence on arteriolar tone in these organs appears to be inconsequential. Parasympathetic vasodilator nerves are also present in the vessels of the salivary glands, pancreas, gastric mucosa, and external genitalia (where they are responsible for the vasodilation of inflow vessels responsible for erection).

HORMONAL INFLUENCES ON ARTERIOLES Circulating Catecholamines During activation of the sympathetic nervous system, catecholamines epinephrine and norepinephrine are released from the adrenal medulla into the bloodstream (see Chapter 65). Under normal circumstances, the concentrations of these agents in the blood are probably not high enough to cause significant cardiovascular effects. However, circulating catecholamines may have cardiovascular effects in situations (such as vigorous exercise or hemorrhagic shock) that involve increased activity of the sympathetic nervous system. In general, the cardiovascular effects of greatly increased levels of circulating catecholamines parallel the direct effects of sympathetic activation that have already been discussed; both epinephrine and norepinephrine can activate cardiac β1-adrenergic receptors to increase heart rate and myocardial contractility and can activate vascular α1-receptors to cause vasoconstriction. Recall that in addition to the α1-receptors that mediate vasoconstriction, arterioles in a few organs also possess β2-adrenergic receptors that mediate vasodilation. Because vascular β2-receptors are more sensitive to epinephrine than are vascular α1-receptors, moderately increased levels of circulating epinephrine can cause vasodilation—whereas higher levels cause α1-receptor-mediated vasoconstriction. Vascular β2-receptors are not innervated and therefore are not activated by norepinephrine released directly from sympathetic vasoconstrictor nerves. The physiological importance of these vascular β2-receptors is unclear because adrenal epinephrine release occurs during periods of increased sympathetic activity when arterioles would simultaneously be undergoing direct neurogenic vasoconstriction.

Vasopressin The polypeptide hormone vasopressin (also known as antidiuretic hormone (ADH), plays an important role in extracellular fluid homeostasis and is released into the bloodstream from the posterior pituitary gland in response to low blood volume and/or high extracellular fluid osmolarity (see Chapter 45). Vasopressin acts on collecting ducts in the kid-

neys to decrease renal excretion of water. Its role in body fluid balance has some very important indirect influences on cardiovascular function, which will be discussed in more detail in Chapter 29. Because it is such a potent vasoconstrictor agent, even the normally low levels of circulating vasopressin are likely to have some normal tonic effect on the basal tone of arterioles throughout the body. Moreover, abnormally high levels of vasopressin are clearly important in the intense arteriolar constriction that accompanies certain disturbances such as severe blood loss through hemorrhage.

Angiotensin II Angiotensin II is a circulating polypeptide that regulates aldosterone release from the adrenal cortex as part of the system for controlling body sodium balance. This system, to be discussed in greater detail in Chapter 29, is very important in blood volume regulation. Angiotensin II is also a very potent vasoconstrictor agent. Like vasopressin, even the normal low circulating level of angiotensin II likely has a role in producing the normal basal tone of arterioles throughout the body. In addition, an abnormally high blood level of angiotensin II seems to be an important contributing factor in certain forms of hypertension.

CONTROL OF VENOUS TONE Recall that venules and veins are relatively large-diameter vessels that have little resistance to flow but do contain relatively large amounts of blood. Therefore, venous tone or diameter has relatively little direct effect on the flow through organs. However, venous diameter does have a large effect on the fraction of total blood volume that is located in the periphery versus centrally. Consequently, when one considers what peripheral veins are doing, one should be thinking primarily about what the effects will be on central venous pressure and cardiac output. Veins contain vascular smooth muscle that is influenced by many of the same things that influence the vascular smooth muscle of arterioles. Constriction of the veins (venoconstriction) is largely mediated through activity of the sympathetic nerves that innervate them. As in arterioles, these sympathetic nerves release norepinephrine, which interacts with α1-receptors and produces an increase in venous tone and a decrease in vessel diameter. There are, however, several functionally important differences between veins and arterioles. Compared with arterioles, veins normally have little basal tone. Thus, veins are normally in a dilated state. One important consequence of the lack of basal venous tone is that vasodilator metabolites that may accumulate in the tissue have little effect on veins. Because of their thin walls, veins are much more susceptible to physical influences than are arterioles. The large effect of internal venous pressure on venous diameter was discussed in Chapter 26 and is evident in the pooling of blood in the veins of the lower extremities that occurs during prolonged standing (as will be discussed further in Chapter 30).

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External compression is an important determinant of venous volume. This is especially true of veins in skeletal muscle. Very high pressures are developed inside skeletal muscle tissue during contraction and cause venous vessels to collapse. Because veins and venules have one-way valves, the blood displaced from veins during skeletal muscle contraction is forced in the forward direction toward the right heart. In fact, rhythmic skeletal muscle contractions can produce a considerable pumping action, often called the skeletal muscle pump, which helps return blood to the heart during exercise.

organs is very strongly regulated by sympathetic nerve activity. Consequently, some organs are automatically forced to participate in overall cardiovascular reflex responses to a greater extent than are other organs. The overall plan seems to be that in cardiovascular emergency, flow to the brain and heart will be preserved at the expense of everything else.

SUMMARY OF PRIMARY VASCULAR CONTROL MECHANISMS

The details of vascular control in many specific organs are presented in several other sections of this book. Included below are descriptions of vascular control in some important organs that are not covered elsewhere.

Certain general factors dominate the primary control of the peripheral vasculature when it is viewed from the standpoint of overall cardiovascular system function; these influences are summarized in Figure 27–4. Basal tone, local metabolic vasodilator factors, and sympathetic vasoconstrictor nerves acting through α1-receptors are the major factors controlling arteriolar tone and therefore the blood flow through peripheral organs. Sympathetic vasoconstrictor nerves, internal pressure, and external compression are the most important influences on venous diameter and therefore on peripheral–central distribution of blood volume. The flow in organs such as the brain, heart muscle, and skeletal muscle is very strongly regulated by local metabolic control, whereas the flow in the kidneys, skin, and splanchnic

VASCULAR CONTROL OF CORONARY BLOOD FLOW

Reflex influences

Sympathetic constrictor nerves

Local influences

Basal tone NE α Vasodilator metabolites Arterioles

Sympathetic constrictor nerves

Passive distention

α NE

P

The major right and left coronary arteries that serve the heart tissue are the first vessels to branch off the aorta. Thus, the driving force for myocardial blood flow is the systemic arterial pressure, just as it is for other systemic organs. Most of the blood that flows through the myocardial tissue returns to the right atrium by way of a large cardiac vein called the coronary sinus.

Local Metabolic Control As emphasized before, coronary blood flow is controlled primarily by local metabolic mechanisms and thus it responds rapidly and accurately to changes in myocardial oxygen consumption. In a resting individual, the myocardium extracts 70–75% of the oxygen in the blood that passes through it, which is more than any other organ does. Myocardial oxygen extraction cannot increase significantly from its resting value. Consequently, increases in myocardial oxygen consumption must be accompanied by appropriate increases in coronary blood flow. The issue of which metabolic vasodilator factors play the dominant role in modulating the tone of coronary arterioles is unresolved. Many believe that adenosine, released from myocardial muscle cells in response to increased metabolic rate, may be an important local coronary metabolic vasodilator influence. Regardless of the specific details, myocardial oxygen consumption is the most important influence on coronary blood flow.

Systolic Compression P

External compression

Veins

FIGURE 27–4 Primary influences on arterioles and veins. NE, norepinephrine; α, alpha-adrenergic receptor; P, pressure. (Modified with permission from Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.)

VASCULAR CONTROL IN SPECIFIC ORGANS

Large forces and/or pressures are generated within the myocardial tissue during cardiac muscle contraction. Such intramyocardial forces press on the outside of coronary vessels and cause them to collapse during systole. Because of this systolic compression and the associated collapse of coronary vessels, coronary vascular resistance is greatly increased during systole. The result, at least for much of the left ventricular myocardium, is that coronary flow is lower during systole than

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Aortic pressure

Left ventricular pressure

0

Left coronary flow 0

FIGURE 27–5

Phasic flows in the left and right coronary arteries in relation to aortic and left ventricular pressures. (Modified with permission from Mohrman DE, Heller LJ: Cardiovascular

Right coronary flow

Physiology, 6th ed. New York: Lange Medical Books/ McGraw-Hill, 2006.)

0

during diastole, even though systemic arterial pressure (i.e., coronary perfusion pressure) is highest during systole. This is illustrated in the left coronary artery flow trace shown in Figure 27–5. Systolic compression has much less effect on flow through the right ventricular myocardium. This is because the peak systolic intraventricular pressure is much lower for the right heart than for the left, and the systolic compressional forces in the right ventricular wall are correspondingly less than those in the left ventricular wall. Because the endocardial surface of the left ventricle is exposed to intraventricular pressure (∼120 mm Hg during systole), and the epicardial surface is exposed only to intrathoracic pressure (∼0 mm Hg), systolic compressional forces on coronary vessels are greater in the endocardial layers of the left ventricular wall than in the epicardial layers. Thus, the flow to the endocardial layers of the left ventricle is impeded more than the flow to epicardial layers by systolic compression. Normally, the endocardial region of the myocardium can make up for the lack of flow during systole by a high flow in the diastolic interval. However, when coronary blood flow is limited—for example, by coronary disease and stenosis—the endocardial layers of the left ventricle are often the first regions of the heart to have difficulty maintaining a flow sufficient for their metabolic needs. Myocardial infarcts (areas of tissue killed by lack of blood flow) occur most frequently in the endocardial layers of the left ventricle.

Neural Influences on Coronary Flow Coronary arterioles are densely innervated with sympathetic vasoconstrictor fibers, yet when the activity of the sympathetic nervous system increases, the coronary arterioles normally vasodilate rather than vasoconstrict. This is because an increase in sympathetic tone increases myocardial oxygen

consumption by increasing heart rate and contractility. The increased local metabolic vasodilator influence outweighs the concurrent neurogenic vasoconstrictor. Whether these coronary vasoconstrictor fibers might be functionally important in certain pathological situations is an open question.

VASCULAR CONTROL OF SKELETAL MUSCLE BLOOD FLOW Because of the large mass of skeletal muscle, blood flow through it is an important factor in overall cardiovascular hemodynamics. Collectively, the skeletal muscles constitute 40–45% of body weight—more than any other single body organ. Even at rest, about 15% of the cardiac output goes to skeletal muscle, and during strenuous exercise skeletal muscle may receive more than 80% of the cardiac output. Resting skeletal muscle has a high level of intrinsic vascular tone. Because of this high tone of smooth muscle in resistance vessels of resting skeletal muscles, the blood flow per gram of tissue is low when compared with that of other organs such as the kidneys. However, resting skeletal muscle blood flow is still substantially above that required to sustain its metabolic needs. Resting skeletal muscles normally extract only 25–30% of the oxygen delivered to them in arterial blood. Thus, changes in the activity of sympathetic vasoconstrictor fibers can reduce resting muscle blood flow without compromising resting tissue metabolic processes. Local metabolic control of arteriolar tone is the most important influence on blood flow through exercising muscle. A particularly important characteristic of skeletal muscle is its very wide range of metabolic rates. During strenuous exercise, the oxygen consumption rate of and oxygen extraction by

CHAPTER 27 Vascular Control skeletal muscle tissue can reach the high values typical of the myocardium. In most respects, the factors that control blood flow to exercising muscle are similar to those that control coronary blood flow. Local metabolic control of arteriolar tone is very strong in exercising skeletal muscle, and muscle oxygen consumption is the most important determinant of its blood flow. Blood flow in skeletal muscle can increase 20-fold during a bout of strenuous exercise. Alterations in sympathetic neural activity can alter nonexercising skeletal muscle blood flow. For example, maximum sympathetic discharge rates can decrease blood flow in a resting muscle to less than one fourth its normal value, and, conversely, if all neurogenic tone is removed, resting skeletal muscle blood flow may double. This is a modest increase in flow compared with what can occur in an exercising skeletal muscle. Nonetheless, because of the large mass of tissue involved, changes in the vascular resistance of resting skeletal muscle brought about by changes in sympathetic activity are very important in the overall reflex regulation of arterial pressure. Alterations in sympathetic neural activity can influence exercising skeletal muscle blood flow. As will be discussed in Chapter 72, the cardiovascular response to muscle exercise involves a general increase in sympathetic activity. This reduces flow to susceptible organs, which include nonexercising muscles. In exercising muscles, the increased sympathetic vasoconstrictor nerve activity is not evident as outright vasoconstriction but does limit the degree of metabolic vasodilation. One important function that this seemingly counterproductive process may serve is preventing an excessive reduction in TPR during exercise. Indeed, if arterioles in most of the skeletal muscles in the body were allowed to dilate to their maximum capacity simultaneously, TPR would be so low that the heart could not possibly supply enough cardiac output to maintain arterial pressure. Rhythmic contractions can increase venous return from exercising skeletal muscle. As in the heart, muscle contraction produces large compressional forces within the tissue, which can collapse vessels and impede blood flow. Strong, sustained (tetanic) skeletal muscle contractions may actually stop muscle blood flow. About 10% of the total blood volume is normally contained within the veins of skeletal muscle, and during rhythmic exercise the skeletal muscle pump is very effective in displacing blood from skeletal muscle veins. Valves in the veins prevent reverse flow back into the muscles. Blood displaced from skeletal muscle into the central venous pool is an important factor in the hemodynamics of strenuous wholebody exercise. Veins in skeletal muscle can constrict in response to increased sympathetic activity. However, they are sparsely innervated with sympathetic vasoconstrictor fibers, and the rather small volume of blood that can be mobilized from skeletal muscle by sympathetic nerve activation is probably not of much significance to total body hemodynamics. This is in sharp contrast to the large displacement of blood from exercising muscle by the muscle pump mechanism. (This will be

271

discussed in more detail when postural reflexes are considered in Chapter 30.)

VASCULAR CONTROL OF CEREBRAL BLOOD FLOW Interruption of cerebral blood flow for more than a few seconds leads to unconsciousness. One rule of overall cardiovascular system function is that, in all situations, measures are taken that are appropriate to preserve adequate blood flow to the brain. Cerebral blood flow is regulated almost entirely by local mechanisms. The brain as a whole has a nearly constant rate of metabolism that, on a per gram basis, is nearly as high as that of myocardial tissue. Flow through the cerebrum is autoregulated very strongly and is little affected by changes in arterial pressure unless it falls below about 60 mm Hg. When arterial pressure decreases below 60 mm Hg, brain blood flow decreases proportionately. It is presently unresolved whether metabolic mechanisms or myogenic mechanisms or both are involved in the phenomenon of cerebral autoregulation. Local changes in cerebral blood flow may be influenced by local metabolic conditions. Presumably because the overall average metabolic rate of brain tissue shows little variation, total brain blood flow is remarkably constant in most situations. The cerebral activity in discrete locations within the brain, however, changes from situation to situation. As a result, blood flow to discrete regions is not constant but closely follows the local neuronal activity. The mechanisms responsible for this strong local control of cerebral blood flow are as yet undefined, but H+, K+, oxygen, and adenosine seem most likely to be involved. As in most organs, cerebral blood flow increases whenever the partial pressure of carbon dioxide (Pco2) in arterial blood increases and, conversely, cerebral blood flow decreases whenever Pco2 decreases below normal. This is the normal state of affairs in most tissues but it has important nonvascular consequences when it happens in the brain. For example, the dizziness, confusion, and even fainting that can occur when a person hyperventilates (and “blows off ” CO2) are direct results of cerebral vasoconstriction. It appears that cerebral arterioles respond not to changes in Pco2 but to changes in the extracellular H+ concentration (i.e., pH) caused by changes in Pco2. Cerebral arterioles also dilate whenever the partial pressure of oxygen (Po2) in arterial blood decreases significantly below normal values. However, higher-than-normal arterial blood Po2, such as that caused by pure oxygen inhalation, produces little decrease in cerebral blood flow. Sympathetic and parasympathetic neural influences on cerebral blood flow are minimal. Although cerebral vessels receive both sympathetic vasoconstrictor and parasympathetic vasodilator fiber innervation, cerebral blood flow is influenced very little by changes in the activity of either under normal circumstances. Sympathetic vasoconstrictor responses may, however, be important in protecting cerebral vessels from excessive passive distention following large, abrupt increases in arterial pressure.

272

SECTION V Cardiovascular Physiology

The blood–brain barrier refers to the tightly connected vascular endothelial cells that severely restrict transcapillary movement of all polar and many other substances. Because of this blood–brain barrier, the extracellular space of the brain represents a special fluid compartment in which the chemical composition is regulated separately from that in the plasma and general body extracellular fluid compartment. The extracellular compartment of the brain encompasses both interstitial fluid and cerebrospinal fluid (CSF) that surrounds the brain and spinal cord and fills the brain ventricles. The CSF is formed from plasma by selective secretion (not simple filtration) by specialized tissues, the choroid plexus, located within the cerebral ventricles. These processes regulate the chemical composition of the CSF. The interstitial fluid of the brain takes on the chemical composition of CSF through free diffusional exchange. The blood–brain barrier serves to protect the cerebral cells from ionic disturbances in the plasma because it is not very permeable to charged substances. Also, by exclusion and/or endothelial cell metabolism, it prevents many circulating hormones (and drugs) from influencing the parenchymal cells of the brain and the vascular smooth muscle cells in brain vessels. Brain capillaries have a special carrier system for glucose and present no barrier to oxygen and carbon dioxide diffusion. Thus, the blood–brain barrier does not restrict nutrient supply to the brain tissue.

VASCULAR INFLUENCES ON PULMONARY BLOOD FLOW See Chapter 34.

VASCULAR CONTROL OF RENAL BLOOD FLOW See Chapter 40.

VASCULAR CONTROL OF SPLANCHNIC BLOOD FLOW See Chapter 49.

VASCULAR CONTROL OF CUTANEOUS BLOOD FLOW See Chapter 70.

CLINICAL CORRELATION A 58-year-old man comes to the emergency room complaining of weakness and severe chest pain. He is a salesman in a high stress industry, has smoked two packs of

cigarettes a day for more than 25 years, and eats a high-fat, high-salt diet. He is overweight, pale, and sweaty and is clutching his chest. His heart rate is 110 beats/min and his blood pressure is 110/90 mm Hg. His medical record indicates that he has been treated with sublingual nitroglycerin for mild angina pectoris for several years and had been instructed about lifestyle changes. The angina has been getting more severe and required increasingly more nitroglycerin to achieve relief. This time, the nitroglycerin has not worked. An ECG indicates that he has a myocardial infarction in the anterior wall of the left ventricle. He is taken immediately to the cardiac catheterization laboratory and an angiogram reveals an almost complete occlusion of his left anterior descending coronary artery. A stent is placed in the artery and blood flow is restored to the ischemic tissue. The condition experienced by this man occurs whenever coronary blood flow decreases below that required to meet the metabolic needs of the heart. The myocardium becomes ischemic and pumping capability of the heart is impaired. The most common cause of coronary artery disease is atherosclerosis of the large coronary arteries and this man had several of the known risk factors (smoking, obesity, high stress, poor diet, high blood cholesterol). Localized lipid deposits called plaques develop within the arterial walls and with severe disease may become large enough to permanently narrow the lumen of arteries. If the coronary artery narrowing (stenosis) is not too severe, local metabolic vasodilator mechanisms may reduce arteriolar resistance sufficiently to compensate for the abnormally increased coronary arterial resistance. Coronary artery disease can jeopardize cardiac function in several ways. (1) Ischemic muscle cells are electrically irritable and the danger of fibrillation is enhanced (see Chapter 25) because ectopic pacemaker foci may develop. (2) Platelet aggregation and clotting function may be abnormal in atherosclerotic coronary arteries and the danger of thrombi or emboli formation is enhanced (see Chapter 22). (3) Myocardial ischemia produces intense, debilitating chest pain called angina pectoris. Anginal pain is often absent in individuals with coronary artery disease when they are resting but is induced during physical exertion or emotional excitement when sympathetic activity is increased and myocardial oxygen consumption is elevated. Primary treatment of coronary artery disease includes lifestyle alterations and attempts to lower blood lipids by dietary and pharmacological techniques. Treatment of angina that is a result of coronary artery disease may first involve quick-acting vasodilator drugs such as nitroglycerin to provide relief during an anginal attack. These “nitrate” drugs are NO donors and directly vasodilate coronary vessels to acutely increase coronary blood flow. In addition to increasing myocardial oxygen delivery, nitrates

CHAPTER 27 Vascular Control ■

reduce myocardial oxygen demand by dilating systemic veins (reducing preload) and by decreasing arterial resistance (reducing afterload). Second, β-adrenergic blocking agents such as propranolol may be used to block the effects of cardiac sympathetic nerves on heart rate and contractility. These agents limit myocardial oxygen consumption and prevent it from increasing above the level that the compromised coronary blood flow can sustain. Third, calcium channel blockers such as verapamil may be used to dilate coronary and systemic blood vessels, and to lower blood pressure and heart rate. These drugs, which block entry of calcium into the vascular smooth muscle cell, interfere with normal excitation–contraction coupling. Invasive or surgical interventions may be used to treat coronary artery stenosis. Fluoroscopic techniques combined with radio-opaque contrast injections can be used to visualize the coronary arteries. A balloon-tipped catheter can be threaded into the occluded region of the coronary artery and rapidly inflated to squeeze the plaque against the vessel wall and improve the patency of the vessel. This technique, called coronary angioplasty, may also be effective in opening occlusions produced by intravascular clots associated with acute myocardial infarction. A small, mesh tubular device called a stent is often implanted inside the vessel at the angioplasty site. This rigid implant has been shown to improve continued patency of the vessel over a longer period than angioplasty alone. If angioplasty and stent placement is inappropriate or unsuccessful, coronary bypass surgery may be performed. The stenotic coronary artery segments are bypassed by implanting parallel low-resistance pathways formed from either natural (e.g., saphenous vein or mammary artery) or artificial vessels.

CHAPTER SUMMARY ■

■ ■

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■

Continuous adjustments of vascular diameter are required to properly distribute the cardiac output to the various systemic tissues (the role of arterioles) and maintain adequate cardiac filling (the role of veins). Vascular adjustments are made by changes in the tone of vascular smooth muscle. Vascular smooth muscle has many properties that make it sensitive to a wide array of local and reflex stimuli and capable of maintaining tone for long periods of time. The tone of arterioles, but not veins, can be strongly influenced by local vasodilator factors produced by local tissue metabolism. In abnormal situations (such as tissue injury or severe blood volume depletion), certain local factors such as histamine and bradykinin, and hormonal factors such as vasopressin and angiotensin have significant vascular influences.

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273

Sympathetic vasoconstrictor nerves provide the primary reflex mechanisms for regulating both arteriolar and venous tone. Sympathetic vasoconstrictor nerves release norepinephrine, which interacts with α1-adrenergic receptors on vascular smooth muscle to induce vasoconstriction. The relative importance of local metabolic versus reflex sympathetic control of arteriolar tone (and therefore blood flow) varies from organ to organ. In many organs (such as brain, heart muscle, and exercising skeletal muscle), blood flow normally closely follows metabolic rate because of local metabolic influences on arterioles. In other organs (such as skin and kidneys), blood flow is normally regulated more by sympathetic nerves than by local metabolic conditions.

STUDY QUESTIONS 1. Vascular smooth muscle differs from cardiac muscle in that it A) contains no actin molecules. B) can be directly activated in the absence of action potentials. C) is unresponsive to changes in intracellular calcium levels. D) is unresponsive to changes in membrane potentials. E) is unresponsive to changes in muscle length. 2. Arteriolar constriction tends to do which of the following? A) decrease total peripheral resistance B) decrease mean arterial pressure C) decrease capillary hydrostatic pressure D) increase transcapillary fluid filtration E) increase blood flow through the capillary bed 3. When an organ responds to an increase in metabolic activity with a decrease in arteriolar resistance, this is known as A) active hyperemia. B) reactive hyperemia. C) autoregulation of blood flow. D) flow-dependent vasodilation. E) metabolic vasoconstriction. 4. A particular vascular bed demonstrates the phenomenon of autoregulation of blood flow. This means that A) when flow increases, capillary pressure increases. B) when metabolic activity increases, flow increases. C) when arterial pressure increases, arteriolar resistance increases. D) when blood flow is interrupted, arteriolar resistance decreases. E) when arterial pressure falls, sympathetic vasoconstriction occurs. 5. Which of the following is most likely to increase coronary blood flow? A) decreased arterial pressure B) decreased heart rate C) increased sympathetic neural activity D) reduced left ventricular end-diastolic volume E) reduced left ventricular ejection fraction

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28 C

Venous Return and Cardiac Output David E. Mohrman and Lois Jane Heller

H A

P

T

E

R

O B J E C T I V E S ■

■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■

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Describe the overall arrangement of the systemic circulation and identify the primary functional properties of each of its major components. Define mean circulatory filling pressure and state the primary factors that determine it. Define venous return and explain how it is distinguished from cardiac output. State why cardiac output and venous return must be equal in the steady state. List the factors that control venous return. Describe the relationship between central venous pressure and venous return and draw the normal venous return curve. Define peripheral venous pressure. List the factors that determine peripheral venous pressure. Predict the shifts in the venous return curve that occur with altered blood volume and altered venous tone. Describe how the output of the left heart pump is matched to that of the right heart pump. Draw the normal venous return and cardiac output curves on a graph and describe the significance of the point of curve intersection. Predict how normal venous return, cardiac output, and central venous pressure will be altered with any given combination of changes in cardiac sympathetic tone, peripheral venous sympathetic tone, or circulating blood volume. Identify conditions that may result in abnormally high or low central venous pressure.

INTERACTION OF SYSTEM COMPONENTS As illustrated in Figure 28–1, the systemic cardiovascular system is a closed hydraulic circuit that includes the heart, arteries, arterioles, capillaries, and veins. (Note: The pulmonary circuit and lymphatics are not included because they do not influence the major points to be made in this chapter.) The

Ch28_275-284.indd 275

venous side of this system is often conceptually separated into two different compartments: (1) a large and diverse peripheral section (the peripheral venous compartment) and (2) a smaller intrathoracic section that includes the venae cavae and the right atrium (the central venous compartment). Each of the segments of this circuit has a distinctly different role to play in the overall operation of the system because of inherent differences in anatomical volume, resistance to blood flow, and compliance that are summarized in Table 28–1.

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11/26/10 11:51:25 AM

276

SECTION V Cardiovascular Physiology

Th

Arteries

ora

x

Arterioles Ventricle

Atrium

Capillaries Central venous compartment

FIGURE 28–1 Major functionally distinct components of the systemic cardiovascular circuit. (Modified with permission from Mohrman DE, Heller

Peripheral venous compartment

LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.)

Note especially the surprisingly high ventricular diastolic compliance of 24 mL/mm Hg in Table 28–1. This value indicates how sensitive the ventricular end-diastolic volume (and therefore stroke volume and cardiac output) is to small changes in cardiac filling pressure (i.e., central venous pressure). Cardiac filling pressure is a crucial factor that determines how well the cardiovascular system functions.

MEAN CIRCULATORY FILLING PRESSURE Imagine the heart arrested in diastole with no flow around the circuit shown in Figure 28–1. It will take a certain amount of blood just to fill the anatomical space contained by the systemic system without stretching any of its walls or developing

any internal pressure. In a 70-kg adult, this amount is 3.5 L, as indicated by the total systemic circuit volume (V0) in Table 28–1. Normally, however, the systemic circuit contains about 4.5 L of blood and thus is somewhat inflated. From the total systemic circuit compliance (C) given in Table 28–1, one can see that an extra 1,000 mL of blood would result in an internal pressure of about 7 mm Hg (i.e., 1,000 mL/140 mL/mm Hg). This theoretical pressure is called the mean circulatory filling pressure and is the pressure that would exist throughout the system in the absence of flow. The two major factors that affect mean circulatory filling pressure are the circulating blood volume and the state of the peripheral venous vessel tone. In the latter case, look at Figure 28–1 and imagine how constriction of the vessels of the large venous compartment (increasing venous tone) will significantly increase pressure throughout the system. In con-

TABLE 28–1 Typical properties of the major components of the systemic cardiovascular circuit.a Compartment

V0 (mL)

C (mL/mm Hg)

R (mm Hg/(L/min))

Ventricle in diastole

30

24

0

Arteries

600

2

1

Arterioles

100

0

13

Capillaries

250

0

5

2,500

110

1

80

4

0

3,560

140

20

Peripheral venous compartment Central venous compartment Entire circuit a

Values are for a normal, young, resting 70-kg adult. V0, anatomical volume of compartment at zero pressure: C, compliance of compartment; R, resistance to flow through compartment. Reproduced with permission from Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.

CHAPTER 28 Venous Return and Cardiac Output

Venous return

Central venous compartment

277

Cardiac output

FIGURE 28–2 Distinction between cardiac output and venous return. (Modified with permission from Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/

Great veins in thorax and right atrium

trast, squeezing on arterioles (increasing arteriolar tone) will have a negligible effect on mean circulatory filling pressure because arterioles contain so little blood in any state. The other major components of the system (arteries and capillaries) do not actively change their contained volume.

FLOW-INDUCED DISTRIBUTION OF BLOOD VOLUME AND PRESSURE The presence of flow around the circuit does not change the total volume of blood in the system or the mean circulatory filling pressure. The flow caused by cardiac pumping action does, however, tend to shift some of the blood volume from the venous side of the circuit to the arterial side. This causes pressures on the arterial side to increase above the mean circulatory pressure while pressures on the venous side decrease below it. Because veins are about 50 times more compliant than arteries (Table 28–1), the flow-induced decrease in venous pressure is only about 1/50th as large as the accompanying increase in arterial pressure. Thus, flow or no flow, pressure in the peripheral venous compartment is normally quite close to the mean circulatory filling pressure.

CENTRAL VENOUS PRESSURE: AN INDICATOR OF CIRCULATORY STATUS The cardiovascular system must continuously adjust to meet changing metabolic demands of the body. Because the cardiovascular system is a closed hydraulic loop, adjustments in any one part of the circuit will have pressure, flow, and volume effects throughout the circuit. Because of the critical influence of cardiac filling on cardiovascular function, the remainder of this chapter will focus on the factors that determine the pressure in the central venous compartment. In addition, the way in which measures of central venous pressure can provide

McGraw-Hill, 2006.)

clinically useful information about the state of the circulatory system will be discussed. The central venous compartment corresponds roughly to the volume enclosed by the right atrium and the great veins in the thorax. Blood leaves the central venous compartment by entering the right ventricle at a rate that is equal to the cardiac output. Venous return, in contrast, is the rate at which blood returns to the thorax from the peripheral vascular beds and thus is the rate at which blood enters the central venous compartment. The important distinction between venous return to the central venous compartment and cardiac output from the central venous compartment is illustrated in Figure 28–2. In any stable situation, venous return must equal cardiac output or blood would gradually accumulate in either the central venous compartment or the peripheral vasculature. However, there often are temporary differences between cardiac output and venous return. Whenever such differences exist, the volume of the central venous compartment must be changing. Because the central venous compartment is enclosed by elastic tissues, any change in central venous volume produces a change in central venous pressure. As discussed in Chapter 24, the central venous pressure (i.e., cardiac filling pressure) has an extremely important positive influence on cardiac output (Starling’s law of the heart). As explained below, central venous pressure has an equally important negative effect on venous return. Thus, central venous pressure is always automatically driven to a value that makes cardiac output equal to venous return.

INFLUENCE OF CENTRAL VENOUS PRESSURE ON VENOUS RETURN The important factors involved in the process of venous return can be summarized as shown in Figure 28–3A. Anatomically the peripheral venous compartment is scattered throughout the systemic organs, but functionally it can be viewed as a single vascular space that has a particular pressure

278

SECTION V Cardiovascular Physiology

A Thorax

Intrathoracic pressure ≅ 0 mm Hg From capillaries

P PV ≅ 7 mm Hg

Venous return

P CV

Cardiac output

Peripheral venous compartment Venous resistance

Central venous compartment

B

Venous return (L/min)

8

6

Ve n

ou

s

fu

nc

4

tio

n

cu

rv

e

2

0

FIGURE 28–3

2 4 6 8 Central venous pressure (mm Hg)

10

Venous Return A) Factors influencing venous return. B) The venous function curve. (Modified with permission from Mohrman DE,

Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.)

(PPV) at any instant. The normal operating pressure in the peripheral venous compartment is usually very close to mean circulatory filling pressure. Moreover, the same factors that influence mean circulatory filling pressure have essentially equal influences on peripheral venous pressure. Thus, “peripheral venous pressure” can be viewed as essentially equivalent to “mean circulatory filling pressure.” The blood flow between the peripheral venous compartment and the central venous compartment is governed by the basic flow ˙ = Δ P/R, where ΔP is the pressure decrease between equation Q the peripheral and central venous compartments and R the small resistance associated with the peripheral veins. In the example in Figure 28–3, peripheral venous pressure is assumed to be 7 mm Hg. Thus, there will be no venous return when the central venous pressure (PCV) is also 7 mm Hg as shown in Figure 28–3B. If the peripheral venous pressure remains at 7 mm Hg, decreasing central venous pressure will increase the pressure difference across the venous pathway and consequently cause an increase in venous return to the central venous pool. This relationship is summarized by the venous function curve, which shows how venous return increases as central venous

pressure decreases. There are two minor additional points to be made about this venous function curve. First, changes in venous resistance can influence the slope of the venous function curve but, in the example given, venous return will be 0 L/min when PCV = 7 mm Hg at any level of venous vascular resistance. Second, if central venous pressure reaches very low values and decreases below the intrathoracic pressure, the veins in the thorax collapse and tend to limit venous return. In the example of Figure 28–3, intrathoracic pressure is taken to be 0 mm Hg and the flat portion of the venous function curve indicates that lowering central venous pressure below 0 mm Hg produces no additional increase in venous return. Just as a cardiac function curve shows how central venous pressure influences cardiac output, a venous function curve shows how central venous pressure influences venous return. (By convention, these relationships are plotted with the independent variable on the horizontal axis and the dependent variable on the vertical axis and they must be read in that sense. For example, Figure 28–3B says that increasing central venous pressure tends to cause decreased venous return. Figure 28–3B does not imply that increasing venous return will tend to lower central venous pressure.)

CHAPTER 28 Venous Return and Cardiac Output

Venous return (L/min)

As can be deduced from Figure 28–3A, it is the pressure difference between the peripheral and central venous compartments that determines venous return. Therefore, an increase in peripheral venous pressure can be just as effective in increasing venous return as a decrease in central venous pressure. The two ways in which peripheral venous pressure can change were discussed in Chapter 26. First, because veins are elastic vessels, changes in the volume of blood contained within the peripheral veins alter the peripheral venous pressure. Moreover, because the veins are much more compliant than any other vascular segment, changes in circulating blood volume produce larger changes in the volume of blood in the veins than in any other vascular segment. For example, blood loss by hemorrhage or loss of body fluids through severe sweating, vomiting, or diarrhea will decrease circulating blood volume and significantly reduce the volume of blood contained in the veins and thus decrease the peripheral venous pressure. Conversely, transfusion, fluid retention by the kidney, or transcapillary fluid reabsorption will increase circulating blood volume and venous blood volume. Whenever circulating blood volume increases, so does peripheral venous pressure. Recall from Chapter 27 that the second way that peripheral venous pressure can be altered is through changes in venous tone produced by increasing or decreasing the activity of sympathetic vasoconstrictor nerves supplying the venous smooth muscle. Peripheral venous pressure increases whenever the activity of sympathetic vasoconstrictor fibers to veins increases. In addition, an increase in any force compressing veins from the outside has the same effect on the pressure inside veins as an increase in venous tone. Thus, such things as muscle exercise and wearing elastic stockings tend to increase peripheral venous pressure. Whenever peripheral venous pressure is altered, the relationship between central venous pressure and venous return is also altered. For example, whenever peripheral venous pressure is increased by increases in blood volume or by sympathetic stimulation, the venous function curve shifts upward and to the right (Figure 28–4). This phenomenon can be most easily understood by focusing first on the central venous pressure at which there will be no venous return. When peripheral venous pressure is 7 mm Hg, venous return is 0 L/min when central venous pressure is 7 mm Hg. When peripheral venous pressure is increased to 10 mm Hg, considerable venous return occurs with a central venous pressure of 7 mm Hg, and venous return stops only when central venous pressure is increased to 10 mm Hg. Thus, increasing peripheral venous pressure shifts the whole venous function curve to the right. By similar logic, decreased peripheral venous pressure caused by blood loss or decreased sympathetic vasoconstriction of peripheral veins shifts the venous function curve to the left.

10

In

cr

8

ea

se

d

6

bl o

od

Co

nt

4

or

0

De

vo l

um

ro

2

lv en

e

or ve s no ve ea f un us no se ct us d b to i o ne l n to oo cu ne d rv vo e lu m e cr

ou

2 4 6 8 Central venous pressure (mm Hg)

10

FIGURE 28–4 Effect of changes in blood volume and venous tone on venous function curves. (Modified with permission from Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/ McGraw-Hill, 2006.)

CENTRAL VENOUS PRESSURE DETERMINES BOTH CARDIAC OUTPUT AND VENOUS RETURN The significance of the fact that central venous pressure simultaneously affects both cardiac output and venous return can be best seen by plotting the cardiac function curve (the Starling curve) and the venous function curve on the same graph, as in Figure 28–5.

Cardiac output or Venous return (L/min)

INFLUENCE OF PERIPHERAL VENOUS PRESSURE ON VENOUS RETURN

279

10

8 Cardiac function curve 6

4 Venous function curve 2

0

2 4 6 8 10 Central venous pressure (mm Hg)

FIGURE 28–5 Interaction of cardiac output and venous return through central venous pressure. (Modified with permission from Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.)

SECTION V Cardiovascular Physiology

Central venous pressure, as defined earlier, is the filling pressure of the right heart. Strictly speaking, this pressure directly affects only the stroke volume and output of the right heart pump. In most contexts, however, “cardiac output” implies the output of the left heart pump. How is it then, as has often been previously implied, that central venous pressure (the filling pressure of the right heart) profoundly affects cardiac output (the output of the left heart)? The short answer is that in the steady state, the right and left hearts have equal outputs. (Since the right and left hearts always beat with identical rates, this implies that their stroke volumes must be equal in the steady state.) The detailed answer is that changes in central venous pressure automatically cause essentially parallel changes in the filling pressure of the left heart (i.e., in left atrial pressure). Consider, for example, the following sequence of consequences that a small step-wise increase in central venous pressure has on a heart that previously was in a steady state: (1) Increased central venous pressure → (2) increased right ventricular stroke volume via Starling’s law → (3) increased output of right heart → (4) right heart output temporarily exceeds that of the left heart → (5) as long as this imbalance exists, blood accumulates in the pulmonary vasculature and raises pulmonary venous and left atrial pressure → (6) increased left atrial pressure increases left ventricular stroke volume via Starling’s law → (7) very quickly, a new steady state will be reached when left atrial pressure has risen sufficiently to make left ventricular stroke volume exactly equal to the increased right ventricular stroke volume. The major conclusion here is that left atrial pressure will change in the correct direction to match left ventricular stroke volume to the current right ventricular stroke volume. Consequently, it is usually an acceptable simplification to say that central venous pressure affects cardiac output as if the heart consisted only of a single pump as is shown in Figure 28–1. Note that in Figure 28–5, cardiac output and venous return are equal (at 5 L/min) only when the central venous pressure is 2 mm Hg. If central venous pressure were to decrease to 0 mm Hg, cardiac output would decrease (to 2 L/min) and venous return would increase (to 7 L/min). With a venous return of 7 L/min and a cardiac output of 2 L/min, the volume of the central venous compartment would necessarily be increasing and this would produce a progressively increasing central venous pressure. In this manner, central venous pressure would return to the original level (2 mm Hg) in a very short time. Moreover, if central venous pressure were to increase from 2 to 4 mm Hg, venous return would decrease (to 3 L/min) and cardiac output would increase (to 7 L/min). This would quickly reduce the volume of blood in the central venous pool, and the central venous pressure would soon fall back to the original level. The cardiovascular system automatically adjusts to operate at the point where the cardiac and venous function curves intersect. Central venous pressure is always inherently driven to the value that makes cardiac output and venous return equal. Cardiac output and venous return always stabilize at the level where the cardiac function and venous function curves intersect.

Cardiac output or Venous return (L /min)

280

10 Normal cardiac function curve 8

6

4

N

or

Fu

m

al

nc

tio

2

n

0

ve n

cu

rv e

ou

s

2 4 6 8 Central venous pressure (mm Hg)

10

FIGURE 28–6 Families of cardiac function and venous function curves. Intersection points indicate equilibrium values for cardiac output, venous return, and central venous pressure. (Modified with permission from Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.)

Recall from Chapter 24 that cardiac output is affected by more than just cardiac filling pressure and that at any moment, the heart may be operating on any one of a number of cardiac function curves, depending on the existing level of cardiac sympathetic tone (see Figure 24–8). The family of possible cardiac function curves may be plotted along with the family of possible venous function curves, as shown in Figure 28–6. At a particular moment, the existing influences on the heart dictate the cardiac function curve on which it is operating, and similarly, the existing influences on peripheral venous pressure dictate the venous function curve that applies. Thus, the influences on the heart and on the peripheral vasculature determine where the cardiac and venous function curves intersect and thus what the central venous pressure and cardiac output (and venous return) are in the steady state. In the intact cardiovascular system, cardiac output can rise only when the point of intersection of the cardiac and venous function curves is raised. All changes in cardiac output are caused by a shift in the cardiac function curve, a shift in the venous function curve, or both. The cardiac function and venous function curves are useful for understanding the complex interactions that occur in the intact cardiovascular system. With the help of Figure 28–7, let us consider, for example, what happens to the cardiovascular system when there is a significant loss of blood (hemorrhage). Assume that before the hemorrhage, sympathetic activity to the heart and peripheral vessels is normal, as is the blood volume. Therefore, cardiac output is related to central venous pressure as indicated by the “normal” cardiac function curve in Figure 28–7. In addition, venous return is determined by central venous pressure as indicated by the

Cardiac output or Venous return (L /min)

CHAPTER 28 Venous Return and Cardiac Output

Increased cardiac sympathetic nerve activity

10

8 Normal cardiac function curve 6 A

D 4

Venous constriction after hemorrhage

C B

Normal venous function curve

2 Hemorrhage 0

2

4

6

8

10

Central venous pressure (mm Hg)

FIGURE 28–7

Cardiovascular adjustments to hemorrhage.

(Modified with permission from Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.)

“normal” venous function curve shown. The normal cardiac and venous function curves intersect at point A, so cardiac output is 5 L/min and central venous pressure is 2 mm Hg in the normal state. When blood volume decreases due to hemorrhage, the peripheral venous pressure decreases and the venous function curve is shifted to the left. In the absence of any reflex responses, the cardiovascular system must switch its operation to point B because this is now the point at which the cardiac function curve and the new venous function curve intersect. This automatically occurs because at the moment of blood loss, the venous function curve is shifted to the left and venous return decreases below cardiac output at the central venous pressure of 2 mm Hg. This is what leads to the decrease in the central venous compartment’s volume and pressure that causes the shift in operation from point A to point B. By comparing points A and B in Figure 28–7, note that blood loss itself decreases cardiac output and central venous pressure by shifting the venous function curve. In going from point A to point B, cardiac output decreases solely because of decreased filling pressure and Starling’s law of the heart. Subnormal cardiac output evokes a number of compensatory mechanisms to bring cardiac output back to more normal levels. One of these is an increase in the activity of cardiac sympathetic nerves that, as discussed in Chapter 24, causes a shift to a cardiac function curve that is higher than normal. The effect of increasing cardiac sympathetic activity is illustrated by a shift in cardiovascular operation from point B to point C. In itself, the increased cardiac sympathetic nerve activity increases cardiac output (from 3 to 4 L/min) but causes a further decrease in central venous pressure. This decrease in central venous pressure occurs because points B and C lie on

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the same venous function curve. Cardiac sympathetic nerves do not affect the venous function curve. Venous return is higher at point C than at point B, but the venous function curve has not shifted. An additional compensatory mechanism evoked by blood loss is increased activity of the sympathetic nerves leading to veins. Recall that this increases peripheral venous pressure and causes a rightward shift of the venous function curve. Therefore, increased sympathetic activity to veins tends to shift the venous function curve, originally decreased by blood loss, back toward normal. As a consequence of the increased peripheral venous tone and the shift to a more normal venous function curve, the cardiovascular operation shifts from point C to point D in Figure 28–7. Thus, peripheral venous constriction raises cardiac output by increasing central venous pressure and moving upward along a fixed cardiac function curve. It must be pointed out that separating the response to hemorrhage into distinct, progressive steps (i.e., A to B to C to D) is only a conceptualization for appreciating the individual effects of the different processes involved. In reality, the reflex venous and cardiac responses occur simultaneously and so quickly that they will keep up with the blood loss as it occurs. Thus, the actual response to hemorrhage would follow nearly a straight line from point A to point D. In summary, point D illustrates that normal cardiac output can be sustained in the face of blood loss by the combined effect of peripheral and cardiac adjustments. Hemorrhage is only one of the numerous potential disturbances to the cardiovascular system. Plots such as those shown in Figure 28–7 are very useful for understanding the many disturbances to the cardiovascular system and the ways by which they may be compensated.

CLINICAL IMPLICATIONS OF ABNORMAL CENTRAL VENOUS PRESSURES Although there is no way to actually determine the position of either cardiac function or venous function curves, important information about a patient’s circulatory status can be obtained from measures of central venous pressure. From what has been presented in this chapter, it is possible to conclude that a patient with abnormally high central venous pressure must have a depressed cardiac function curve, a right-shifted venous function curve, or both. Very high central venous pressures are a hallmark of patients with congestive heart failure because they have the combination of dysfunctional heart muscle (depressed cardiac function curve) and excessive fluid volume (right-shifted venous function curve). Abnormally low central venous pressures, on the other hand, could theoretically be caused by either an increased cardiac function curve or a leftshifted venous function curve. The clinical reality is that abnormally low central venous pressures are invariably the

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result of a left shift of the venous function curve caused by either low blood volume or lack of venous tone. Rough estimates of a patient’s central venous pressure can be obtained by observing the external jugular veins. Because gravity keeps veins in the head and neck collapsed when a normal individual is upright, there is no distention (or retrograde pulsations from atrial contractions) observed in these neck veins. Conversely, when fully recumbent, neck veins are full and pulsations are detected. If a normal individual is placed in a semi-recumbent position so that external jugular veins are positioned at 7 cm above the right atrium, the point between the collapsed venous segment and the filled segment can often be visualized. Abnormally high central venous pressure is associated with neck vein distention at a higher level (perhaps even when the patient is upright). Because of its diagnostic value in critical care situations, central venous pressure is often monitored continuously via a catheter inserted in a peripheral vein and advanced centrally until its tip is in the central venous compartment (i.e., near or in the right atrium). In some situations, it is desirable to assess left atrial pressure, which is the filling pressure for the left side of the heart. This is commonly done with a specialized, flow-directed venous catheter with a small inflatable balloon at its tip to drag it with the blood flow through the right ventricle and pulmonic valve into the pulmonary artery. The balloon is then deflated and the cannula is advanced further until it wedges into a terminal branch of the pulmonary vasculature. The pulmonary wedge pressure recorded at this junction provides a useful estimate of left atrial pressure because there are no valves between the left atrium and the catheter tip.

CLINICAL CORRELATION A 75-year-old woman visits her doctor complained of increasing weakness and fatigue, shortness of breath on minimal exertion, and a recent increase in body weight. She often has to get up at night to urinate and has noticed that her feet and ankles seem to be swollen. She reports several episodes of waking up at night feeling like she could not catch her breath until she got out of bed and stood at her open window. She has been physically well until this condition developed over the last few months. She does not smoke or drink and takes no medicines except for an occasional aspirin or antacid. She is 5′3″ (160 cm), 146 lb (66 kg) with heart rate of 88 beats/min and blood pressure 165/95 mm Hg (normal values 120–140/80–90 mm Hg). Auscultation of the chest with a stethoscope indicates normal heart sounds but abnormal breath sounds with fine crackles heard over both lung bases late in expiration. An ECG indicates mild left ventricular hypertrophy and her chest x-ray shows an enlarged cardiac silhouette and pleural effusion, an accumulation of fluid between the visceral

pleura and parietal pleura. An echocardiogram revealed dilated cardiac chambers, thickened left ventricular wall, and a left ventricular ejection fraction of 0.35 (normal value >0.55) (see Chapter 25). She was diagnosed with chronic congestive heart failure secondary to chronic hypertension. She was treated with a diuretic to increase her urine output and relieve her symptoms of congestion and an angiotensin converting enzyme (ACE) inhibitor to reduce her high blood pressure. Once her condition stabilizes, she will be treated with beta-adrenergic receptor blockers at a low dose to decrease sympathetic stimulation of the heart. Chronic heart failure (CHF) exists whenever ventricular function is depressed through conditions that directly impair the mechanical performance of heart muscle such as (1) progressive coronary artery disease, (2) sustained increase in cardiac afterload as that which accompanies arterial hypertension or aortic valve stenosis, (3) reduced functional muscle mass following myocardial infarction, or (4) primary cardiomyopathy. Regardless of the precipitating cause, most forms of heart failure are associated ultimately with a reduced myocyte function. Systolic heart failure is associated with a left ventricular ejection fraction of less than 0.40. This also implies that the heart is operating on a lowerthan-normal cardiac function curve, that is, a reduced cardiac output at any given filling pressure. An example of the progression of events leading to CHF is well illustrated by the cardiac output and venous function curves shown in Figure 28–8. Initially, normal cardiac output and normal venous function curves will intersect at point A with cardiac output of 5 L/min at a central venous pressure of less than 2 mm Hg. With an abrupt heart failure as might accompany a myocardial infarction and severe damage to the ventricular muscle, the heart’s operation will shift to a much lower-than-normal cardiac output curve and the “equilibrium” will shift from the normal point A to point B—that is, cardiac output decreases below normal while central venous pressure increases above normal. The decreased cardiac output leads to decreased arterial pressure and reflex activation of the cardiovascular sympathetic nerves. Increased sympathetic nerve activity tends to (1) raise the cardiac function curve toward normal and (2) increase peripheral venous pressure through venous constriction and thus raises the venous function curve above normal. The heart’s operation will now shift from point B to point C. Thus, the depressed cardiac output is substantially improved by the immediate consequences of increased sympathetic nerve activity. Note, however, that the cardiac output at point C is still below normal. The arterial pressure associated with cardiovascular operation at point C is likely to be near normal, however, because higher-than-normal total peripheral resistance

CHAPTER 28 Venous Return and Cardiac Output

↑↑ Fluid retention

283

Normal heart

Cardiac output or Venous return (L/min)

12 Normal sympathetic activity ↑ Fluid retention 10 ↑ Venous tone

↑↑ Sympathetic activity

8 ↑ Sympathetic activity

Normal 6 A

C

D

4

E

Failing heart

Normal sympathetic activity

B

2

0

2

4

6

8

10

Central venous pressure (mm Hg)

FIGURE 28–8

Cardiovascular alterations with compensated chronic systolic heart failure. (Modified with permission from Mohrman DE, Heller

LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.)

will also accompany higher-than-normal sympathetic nerve activity. In the long term, cardiovascular operation cannot remain at point C in Figure 28–8. Operation at point C involves higher-than-normal sympathetic activity, and this will inevitably cause a gradual increase in blood volume by mechanisms that will be described in Chapter 29. Over several days, there is a progressive rise in the venous function curve as a result of increased blood volume and, consequently, increased mean circulatory filling pressure. This will progressively shift the cardiovascular operating point from C to D to E. Note that increased fluid retention (C → D → E in Figure 28–8) causes a progressive increase in cardiac output toward normal and simultaneously allows a reduction in sympathetic nerve activity toward the normal value. Reduced sympathetic activity is beneficial for several reasons. First, decreased arteriolar constriction permits renal and splanchnic blood flow to return toward more normal values. Second, myocardial oxygen consumption may fall as sympathetic nerve activity falls, even though cardiac output tends to increase. Recall that increased heart rate and increased cardiac contractility greatly increase myocardial oxygen consumption. Reduced myocardial oxygen consumption is especially beneficial in situations where inadequate coronary blood flow is the cause of the heart failure. In any case, once a normal cardiac output has been achieved, the individual is said to be in a “compensated” state. The extracellular fluid volume remains expanded

after reaching the compensated state even though sympathetic activity may have returned to near-normal levels. (Net fluid loss from this new steady state with expanded body fluid volume requires a period of less-than-normal sympathetic activity.) Unfortunately, the consequences of fluid retention in cardiac failure are not all beneficial. Note in Figure 28–8 that fluid retention (C → D → E) will cause both peripheral and central venous pressures to be much higher than their normal values. Chronically high central venous pressure causes chronically increased end-diastolic volume (cardiac dilation). Up to a point, cardiac performance is improved by increased cardiac filling volume through Starling’s law. Excessive cardiac dilation, however, can impair cardiac function because according to the law of Laplace, increased total wall tension is required to generate pressure within an enlarged ventricular chamber. The high venous pressure associated with fluid retention also adversely affects organ function because high venous pressure produces transcapillary fluid filtration, edema formation, and congestion (hence the commonly used term congestive heart failure). Left heart failure may lead to pulmonary edema with dyspnea (shortness of breath) and respiratory crisis. Patients often complain of difficulty breathing especially during the night (paroxysmal nocturnal dyspnea). Being recumbent promotes a fluid shift from the extremities into the central venous pool and lungs, making the horizontal patient’s pulmonary problems worse. Such patients often sleep more comfortably when propped

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up. Right heart failure results in distended neck veins, ankle edema, and fluid accumulation in the abdomen (ascites) with liver congestion and dysfunction. Plasma volume expansion combines with abnormal liver function to reduce the concentration of plasma proteins by as much as 30%. This reduction in plasma oncotic pressure further contributes to the development of interstitial edema of congestive heart failure. In the example shown in Figure 28–8, the depression in the cardiac output curve because of heart failure is only moderately severe. Thus, it is possible, through moderate fluid retention, to achieve a new steady state with a normal cardiac output and essentially normal sympathetic activity (point E). The situation at point E is relatively stable because the stimuli for further fluid retention have been removed. If, however, the heart failure is more severe, the cardiac output curve may be so depressed that normal cardiac output cannot be achieved by any amount of fluid retention. In these cases fluid retention is extremely marked, as is the elevation in venous pressure, and the complications of congestion are very serious problems.

CHAPTER SUMMARY ■

■

■

■

■ ■

Mean circulatory filling pressure is a theoretical measure of pressure in the systemic circuit when flow is stopped and is influenced primarily by blood volume and peripheral venous tone. Central venous pressure has a negative influence on venous return that can be illustrated graphically as a venous function curve. Peripheral venous pressure has a positive influence on venous return and can be elevated by increased blood volume and/or increased venous tone. Because of its opposing influences on cardiac output and venous return, central venous pressure automatically attains a value that makes cardiac output and venous return equal. Central venous pressure gives clinically relevant information about circulatory status. Central venous pressure can be estimated noninvasively by noting the fullness of a patient’s jugular veins.

STUDY QUESTIONS 1. In a severely dehydrated patient, you would expect to find A) a depressed cardiac function curve. B) an increased mean circulatory filling pressure. C) an increased central venous pressure. D) distended jugular veins. E) decreased cardiac output. 2. If you gave a blood transfusion to a patient who had recently experienced a severe hemorrhage, you would expect A) to expand arterial volume. B) to expand venous volume. C) to decrease central venous pressure. D) to decrease the mean circulatory filling pressure. E) to reduce cardiac output. 3. Which of the following would directly (by themselves in the absence of any compensatory responses) tend to decrease central venous (cardiac filling) pressure? A) increased sympathetic nerve activity to only the heart B) increased parasympathetic nerve activity to only the heart C) increased blood volume D) decreased total peripheral resistance E) immersion in water up to the waist 4. Which of the following will decrease the mean circulatory filling pressure? A) increased circulating blood volume B) increased cardiac output C) decreased arteriolar tone D) decreased venous tone E) increased arterial stiffness 5. In a steady state, venous return will be greater than cardiac output when A) peripheral venous pressure is higher than normal. B) blood volume is higher than normal. C) heart rate is lower than normal. D) cardiac contractility is lower than normal. E) Never, because in a steady state venous return must equal cardiac output.

29 C

Arterial Pressure Regulation David E. Mohrman and Lois Jane Heller

H A

P

T

E

R

O B J E C T I V E S ■

■ ■

■

■ ■

■

■ ■ ■

Identify the sensory receptors, afferent pathways, central integrating centers, efferent pathways, and effector organs that participate in the arterial baroreceptor reflex. State the location of the arterial baroreceptors and describe their operation. Describe how changes in the afferent input from arterial baroreceptors influence the activity of the sympathetic and parasympathetic preganglionic fibers. Describe how the sympathetic and parasympathetic outputs from the medullary cardiovascular centers change in response to changes in arterial pressure. Diagram the chain of events that are initiated by the arterial baroreceptor reflex to compensate for a change in arterial pressure. Describe how inputs to the medullary cardiovascular centers from cardiopulmonary baroreceptors, and arterial and central chemoreceptors influence sympathetic activity, parasympathetic activity, and mean arterial pressure. Describe and indicate the mechanisms involved in the cerebral ischemic response, the Cushing reflex, the alerting reaction, blushing, vasovagal syncope, and the cardiovascular responses to emotion and pain. Describe baroreceptor adaptation. Describe the influence of changes in body fluid volume on arterial pressure and diagram the steps involved in this process. Describe how mean arterial pressure is adjusted in the long term to that which causes fluid output rate to equal fluid intake rate.

REGULATION OF ARTERIAL PRESSURE Appropriate systemic arterial pressure is the single most important requirement for the proper function of the cardiovascular system. Without sufficient arterial pressure, the brain and the heart do not receive adequate blood flow no matter what adjustments are made in their vascular resistance by local control mechanisms. In contrast, excessive arterial pressure

Ch29_285-294.indd 285

puts unnecessary demands on the heart and vessels. Arterial pressure is continuously monitored by sensors located within the body. Whenever arterial pressure varies from normal, multiple reflex responses are initiated that cause the adjustments in cardiac output and total peripheral resistance necessary to return arterial pressure to its normal value. In the short term (seconds), these adjustments are brought about by changes in the activity of the autonomic nerves leading to the heart and peripheral vessels. In the long term (minutes to days), other mechanisms such as changes in cardiac output

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brought about by changes in blood volume play an increasingly important role in the control of arterial pressure. The short- and long-term regulations of arterial pressure will be discussed in order in this chapter.

nerves. The effector organs are the heart and peripheral blood vessels.

Efferent Pathways Previous chapters have discussed the many actions of the sympathetic and parasympathetic nerves leading to the heart and blood vessels. For both systems, postganglionic fibers, whose cell bodies are in ganglia outside the central nervous system, form the terminal link to the heart and vessels. The influences of these postganglionic fibers on key cardiovascular variables are summarized in Figure 29–1. The activity of the terminal postganglionic fibers of the autonomic nervous system is determined by the activity of preganglionic fibers whose cell bodies lie within the central nervous system (see Chapter 19). In the sympathetic pathways, the cell bodies of the preganglionic fibers are located within the spinal cord. These preganglionic neurons have spontaneous activity that is modulated by excitatory and inhibitory inputs, which arise from centers in the brainstem and descend

SHORT-TERM REGULATION OF ARTERIAL PRESSURE ARTERIAL BARORECEPTOR REFLEX The arterial baroreceptor reflex is the single most important mechanism providing short-term regulation of arterial pressure. Recall that the usual components of a reflex pathway include sensory receptors, afferent pathways, integrating centers in the central nervous system, efferent pathways, and effector organs. As shown in Figure 29–1, the efferent pathways of the arterial baroreceptor reflex are the cardiovascular sympathetic and cardiac parasympathetic

Medulla Spinal cord

rvlm −

+ +

−

nts

+ na

rn

Sympathetic preganglionic fibers

??

Parasympathetic preganglionic fibers

+ + Ganglia

+ Ganglia

Pcv

− + + SV × HR = CO

+

Central venous pool

Arterial baroreceptor + − Pa = CO × TPR

Heart

Systemic organs Veins

Arterioles

Ppv +

TPR +

FIGURE 29–1 Components of the arterial baroreceptor reflex pathway. nts, nucleus tractus solitarius; rvlm, rostral ventrolateral medullary group; rn, raphe nucleus; na, nucleus ambiguus; ??, incompletely mapped integration pathways that may also involve structures outside the medulla. (Modified with permission from Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.)

CHAPTER 29 Arterial Pressure Regulation in distinct excitatory and inhibitory spinal pathways. In the parasympathetic system, the cell bodies of the preganglionic fibers are located within the brainstem. Their spontaneous activity is modulated by inputs from adjacent centers in the brainstem.

Afferent Pathways Sensory receptors, called arterial baroreceptors, are found in abundance in the walls of the aorta and carotid arteries. Major concentrations of these receptors are found near the arch of the aorta (the aortic baroreceptors) and at the bifurcation of the common carotid artery into the internal and external carotid arteries on either side of the neck (the carotid sinus baroreceptors). The receptors are mechanoreceptors that sense arterial pressure indirectly from the degree of stretch of the elastic arterial walls. In general, increased stretch causes an increased action potential generation rate by the arterial baroreceptors. Baroreceptors actually sense not only absolute stretch, but also the rate of change of stretch. For this reason, both the mean arterial pressure and arterial pulse pressure affect baroreceptor firing rate as indicated in Figure 29–2. The dashed curve shows how baroreceptor firing rate is affected by different levels of a steady arterial pressure. The solid curve indicates how baroreceptor firing rate is affected by the mean value of a pulsatile arterial pressure. Note that the presence of pulsations increases the baroreceptor firing rate at any given level of mean arterial pressure. Note also that changes in mean arterial pressure near the normal value of 100 mm Hg produce the largest changes in baroreceptor discharge rate and there is very little output at low pressures. If arterial pressure remains above normal over a period of several days, the arterial baroreceptor firing rate will gradually return toward normal. Thus, arterial baroreceptors are said to adapt to long-term changes in arterial pressure. For this reason, the arterial baroreceptor reflex does not serve as a mechanism for the long-term regulation of arterial pressure.

Baroreceptor nerve activity

Max

Pulsatile Steady

0

50 100 150 200 Mean arterial pressure (mm Hg)

FIGURE 29–2 Effect of mean arterial pressure on baroreceptor nerve activity. (Modified with permission from Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/ McGraw-Hill, 2006.)

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Central Integration Much of the central integration involved in reflex regulation of the cardiovascular system occurs in the medulla oblongata in what are traditionally referred to as the medullary cardiovascular centers. The neural interconnections between the diffuse structures in this area are complex and not completely mapped. Moreover, these structures appear to serve multiple functions including respiratory control. What is known with a fair degree of certainty is where the cardiovascular afferent and efferent pathways enter and leave the medulla. As indicated in Figure 29–1, the afferent sensory information from the arterial baroreceptors enters the medullary nucleus tractus solitarius, where it is relayed via polysynaptic pathways to other structures in the medulla (and higher brain centers, such as the hypothalamus, as well). The cell bodies of the efferent vagal parasympathetic cardiac nerves are located primarily in the medullary nucleus ambiguus. The sympathetic autonomic efferent information leaves the medulla predominantly from the rostral ventrolateral medulla group of neurons (via an excitatory spinal pathway) or the raphe nucleus (via an inhibitory spinal pathway). The intermediate processes involved in the actual integration of the sensory information into appropriate sympathetic and parasympathetic responses are not well understood. Much of this integration takes place within the medulla, but higher centers such as the hypothalamus are probably involved as well. In this context, knowing the details of the integration process is not as important as appreciating the overall effects that changes in arterial baroreceptor activity have on the activities of parasympathetic and sympathetic cardiovascular nerves. Several functionally important points about the central control of the autonomic cardiovascular nerves are illustrated in Figure 29–1. The major external influence on the cardiovascular centers comes from the arterial baroreceptors. Because the arterial baroreceptors are active at normal arterial pressures, they supply a tonic input to the central integration centers. As indicated in Figure 29–1, the integration process is such that increased input from the arterial baroreceptors tends to simultaneously: (1) inhibit the activity of the spinal sympathetic excitatory tract, (2) stimulate the activity of the spinal sympathetic inhibitory tract, and (3) stimulate the activity of parasympathetic preganglionic nerves. Thus, an increase in the arterial baroreceptor discharge rate (caused by increased arterial pressure) causes a decrease in the tonic activity of cardiovascular sympathetic nerves and a simultaneous increase in the tonic activity of cardiac parasympathetic nerves. Conversely, decreased arterial pressure causes increased sympathetic and decreased parasympathetic activity.

OPERATION OF THE ARTERIAL BARORECEPTOR REFLEX The arterial baroreceptor reflex is a continuously operating control system that automatically makes adjustments to prevent disturbances in the heart and/or vessels from causing

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↓ Mean arterial pressure (primary disturbance) 29 ↓ Baroreceptor discharge 29 29

29 Medullary cardiovascular centers ↓ Parasympathetic activity

↑ Sympathetic activity 27

24

27 ↑ Arteriolar tone

↑ Venous tone 27 27

↑ Cardiac contractility

↑ Blood volume ↑ Peripheral venous pressure 27

28

23

23

28

Transcapillary fluid reabsorption

+ − Central venous pressure

26

↓ Capillary pressure ↑ Vasoconstriction

26

26 ↑ Total peripheral resistance 26

24

24

↑ Stroke volume 24

↑ Heart rate

↑ Cardiac output

24

26

↑ Mean arterial pressure (counteracting response)

FIGURE 29–3 Immediate cardiovascular adjustments caused by a decrease in arterial blood pressure. Circled numbers indicate the chapter in which each interaction is discussed. (Modified with permission from Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.)

large changes in mean arterial pressure. The arterial baroreceptor reflex mechanism acts to regulate arterial pressure in a negative feedback fashion as was described in Chapter 1. Figure 29–3 shows many events in the arterial baroreceptor reflex pathway that occur in response to a disturbance of decreased mean arterial pressure. All of the events shown in Figure 29–3 have already been discussed, and each should be carefully examined (and reviewed if necessary) at this point because a great many of the interactions that are essential to understanding cardiovascular physiology are summarized in this figure. Note in Figure 29–3 that the overall response of the arterial baroreceptor reflex to the disturbance of decreased mean arterial pressure is to increase mean arterial pressure (i.e., the response tends to counteract the disturbance). A disturbance of increased mean arterial pressure would elicit events opposite to those shown in Figure 29–3 and produce a decrease in mean arterial pressure; again, the response tends to counteract the disturbance. Recall that neural control of vessels is more

important in some areas such as the kidney, the skin, and the splanchnic organs than in the brain and heart muscle. Thus, the reflex response to a decrease in arterial pressure may, for example, include a significant increase in renal vascular resistance and a decrease in renal blood flow without changing the cerebral vascular resistance or blood flow. The peripheral vascular adjustments associated with the arterial baroreceptor reflex take place primarily in organs with strong sympathetic vascular control.

OTHER CARDIOVASCULAR REFLEXES & RESPONSES In spite of the arterial baroreceptor reflex mechanism, large and rapid changes in mean arterial pressure occur in certain physiological and pathological situations. These reactions are caused by influences on the medullary cardiovascular centers other than those from the arterial baroreceptors. As outlined

CHAPTER 29 Arterial Pressure Regulation in the following sections, these inputs to the medullary cardiovascular centers arise from many types of peripheral and central receptors as well as from “higher centers” in the central nervous system such as the hypothalamus and the cortex. An analogy was made between the arterial baroreceptor reflex operating to control arterial pressure to a home heating system acting to control room temperature (see Chapter 1). The temperature setting on the thermostat determines the set point for temperature regulation. Most of the influences that are about to be discussed influence arterial pressure as if they changed the arterial baroreceptor reflex’s set point for pressure regulation. Consequently, the arterial baroreceptor reflex does not resist most of these pressure disturbances but actually assists in producing them.

REFLEXES FROM RECEPTORS IN HEART & LUNGS A host of mechanoreceptors and chemoreceptors that elicit reflex cardiovascular responses have been identified in the atria, ventricles, coronary vessels, and lungs. The role of these cardiopulmonary receptors in the control of the cardiovascular system is, in most cases, incompletely understood, but they are likely involved in many physiological and pathological states. Cardiopulmonary baroreceptors (sometimes referred to as low-pressure receptors) sense the pressure (or volume) in the atria and central venous pool. Increased central venous pressure (or volume) causes activation of these receptors by stretch, and elicits a reflex decrease in sympathetic activity. Decreased central venous pressure (or volume) produces the opposite response. These cardiopulmonary baroreflexes normally exert a tonic inhibitory influence on sympathetic activity. Alterations in sympathetic activity evoked by increases or decreases in central venous pressure not only have short-term influences on arterial pressure, but also influence renal mechanisms that influence blood volume and long-term regulation of arterial pressure.

CHEMORECEPTOR REFLEXES Low Po2, low pH, and/or high Pco2 levels in the arterial blood cause reflex increases in breathing and mean arterial pressure. These responses appear to be a result of increased activity of arterial chemoreceptors, located in the carotid arteries and the arch of the aorta, and central chemoreceptors, located within the central nervous system. Chemoreceptors probably play little role in the normal regulation of arterial pressure because arterial blood Po2 and Pco2 are normally held very nearly constant by respiratory control mechanisms. See Chapter 38 for more details. An extremely strong reaction called the cerebral ischemic response is triggered by inadequate blood flow (ischemia) to the brain and can produce a more intense sympathetic vasoconstriction and cardiac stimulation than is elicited by any other influence on the cardiovascular control centers. Presum-

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ably the cerebral ischemic response is initiated by chemoreceptors located within the central nervous system. However, if cerebral blood flow is severely inadequate for several minutes, the cerebral ischemic response wanes and is replaced by marked loss of sympathetic activity. This results when function of the nerve cells in the cardiovascular centers becomes directly depressed by the unfavorable chemical conditions in the cerebrospinal fluid. Whenever intracranial pressure is increased—for example, by increased cerebral spinal fluid (CSF) pressure or traumainduced bleeding within the rigid cranium—there is a parallel increase in arterial pressure. This is called the Cushing reflex. It can cause mean arterial pressures of more than 200 mm Hg in severe cases of increased intracranial pressure. The benefit of the Cushing reflex is that it prevents collapse of cranial vessels and thus preserves adequate brain blood flow in the face of large increases in intracranial pressure. The mechanisms responsible for the Cushing reflex are not known but could involve the central chemoreceptors. A hallmark of the Cushing reflex is acutely increased arterial pressure in spite of accompanying bradycardia. It seems as if the short-term arterial baroreceptor reflex is attempting to counteract this disturbance by activating parasympathetic nerves to the SA node of the heart.

CARDIOVASCULAR RESPONSES ASSOCIATED WITH EMOTION Cardiovascular responses are frequently associated with certain states of emotion. These responses originate in the cerebral cortex and reach the medullary cardiovascular centers through corticohypothalamic pathways. The least complicated of these responses is the blushing that is often detectable in individuals with lightly pigmented skin during states of embarrassment. The blushing response involves a loss of sympathetic vasoconstrictor activity only to particular cutaneous vessels, and this produces the blushing by allowing engorgement of the cutaneous venous sinuses. Excitement or a sense of danger often elicits a complex behavioral pattern called the alerting reaction (also called the “defense” or “fight-or-flight” response). The alerting reaction involves a host of responses such as pupillary dilation and increased skeletal muscle tenseness that are generally appropriate preparations for some form of intense physical activity. The cardiovascular component of the alerting reaction is an increase in blood pressure caused by a general increase in cardiovascular sympathetic nervous activity and a decrease in cardiac parasympathetic activity. Some individuals respond to situations of extreme stress by fainting, a situation referred to clinically as vasovagal syncope. The loss of consciousness is due to decreased cerebral blood flow that is itself produced by a sudden dramatic loss of arterial blood pressure that occurs as a result of a sudden loss of sympathetic tone and a simultaneous large increase in parasympathetic tone and decrease in heart rate.

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CENTRAL COMMAND

phasize that the arterial baroreceptors normally and continuously supply the major input to the medullary centers. The arterial baroreceptor input is shown as inhibitory because an increase in arterial baroreceptor firing rate results in a decrease in sympathetic output. (Decreased sympathetic output should be taken to imply also a simultaneous increase in parasympathetic output that is not shown in this figure.) As is indicated in Figure 29–4, the nonarterial baroreceptor influences on the medullary cardiovascular centers fall into two categories: (1) those that increase arterial pressure by raising the set point for the arterial baroreceptor reflex and thus cause an increase in sympathetic activity and (2) those that decrease arterial pressure by lowering the set point for the arterial baroreceptor reflex and thus cause a decrease in sympathetic activity.

The term central command is used to imply an input from the cerebral cortex to lower brain centers during voluntary muscle exercise. The concept is that the same cortical drives that initiate somatomotor (skeletal muscle) activity also simultaneously initiate cardiovascular (and respiratory) adjustments appropriate to support that activity. In the absence of any other obvious causes, central command is at present the best explanation as to why both mean arterial pressure and respiration increase during voluntary exercise.

REFLEX RESPONSES TO PAIN Pain can have either a positive or a negative influence on arterial pressure. Generally, superficial or cutaneous pain causes an increase in blood pressure in a manner similar to that associated with the alerting response and perhaps over many of the same pathways. Deep pain from receptors in the viscera or joints, however, often causes a cardiovascular response similar to that which accompanies vasovagal syncope, that is, decreased sympathetic tone, increased parasympathetic tone, and a significant decrease in blood pressure. This response may contribute to the state of shock that often accompanies crushing injuries and/or joint displacement.

LONG-TERM REGULATION OF ARTERIAL PRESSURE Long-term regulation of arterial pressure is a topic of clinical relevance because of the prevalence of hypertension (sustained excessive arterial blood pressure) in our society. The most long-standing and generally accepted theory of long-term pressure regulation is that it crucially involves the kidneys, their sodium handling, and ultimately the regulation of blood volume. This theory is sometimes referred to as the “renalMAP set point” or “fluid balance” model of long-term arterial blood pressure control. In essence, this theory asserts that in the long term, mean arterial pressure is whatever it needs to be to maintain an appropriate blood volume through arterial pressure’s direct effects on renal function.

SUMMARY The influences on the medullary cardiovascular centers that have been discussed in the preceding sections are summarized in Figure 29–4. This figure is intended first to reem-

Response to exercise (central command) Sense of danger (alerting/defense reaction) Cerebral ischemic response ↑ Intracranial pressure (cushing reflex) ↓ PO2, ↑ PCO2 in arterial blood ↓ Central venous pressure (cardiopulmonary baroreflexes) Cutaneous pain Increase set point

+ Sympathetic output

Medullary centers

−

Arterial baroreceptor

−

FIGURE 29–4

Summary of the factors that influence the set point of the arterial baroreceptor reflex. (Modified with permission from Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.)

Lower set point Vasovagal syncope Deep pain ↑ Central venous pressure (cardiopulmonary baroreflexes)

input

CHAPTER 29 Arterial Pressure Regulation

FLUID BALANCE & ARTERIAL PRESSURE

pressure, hours or even days may be required before a change in urinary output rate produces a significant accumulation or loss of total body fluid volume. What this fluid volume mechanism lacks in speed, however, it more than makes up for in persistence. As long as there is any inequality between the fluid intake rate and the urinary output rate, body fluid volume is changing and this fluid volume mechanism has not completed its adjustment of arterial pressure. The fluid volume mechanism is in equilibrium only when the urinary output rate equals the fluid intake rate. (In the present discussion, assume that fluid intake rate represents that in excess of the obligatory fluid losses that normally occur in the feces and by transpiration from the skin and structures in the respiratory tract. The processes that regulate thirst are not well understood but seem to involve many of the same factors that influence urinary output.) In the long term, the arterial pressure must be that which makes the urinary output rate equal to the fluid intake rate. The arterial baroreceptor reflex is, of course, essential for counteracting rapid changes in arterial pressure. The fluid volume mechanism, however, determines the long-term level of arterial pressure because it slowly overwhelms all other influences. Through adaptation, the baroreceptor mechanism adjusts itself so that it operates to prevent acute changes in blood pressure from the prevailing long-term level as determined through fluid balance.

Several key factors in the long-term regulation of arterial blood pressure have already been considered. First is the fact that the baroreceptor reflex, however well it counteracts temporary disturbances in arterial pressure, cannot effectively regulate arterial pressure in the long term for the simple reason that the baroreceptor firing rate adapts to prolonged changes in arterial pressure. The second pertinent fact is that circulating blood volume can influence arterial pressure because: ↑ blood volume → ↑ peripheral venous pressure → right shift of venous function curve → ↑ central venous pressure → ↑ cardiac output → ↑ arterial pressure. Arterial pressure has a profound influence on urinary output rate and thus affects total body fluid volume. Because blood volume is one of the components of the total body fluid, blood volume alterations accompany changes in total body fluid volume. The mechanisms are such that a decrease in arterial pressure causes a decrease in urinary output rate and thus an increase in blood volume. But, as outlined in the preceding sequence, increased blood volume tends to increase arterial pressure. Thus, the complete sequence of events that are initiated by a decrease in arterial pressure can be listed as follows: ↓ Arterial pressure (disturbance) → ↓ urinary output rate → ↑ fluid volume → ↑ blood volume → ↑ cardiac output → ↑ arterial pressure (compensation). As indicated in Figure 29–5, both the arterial baroreceptor reflex and this fluid volume mechanism are negative feedback loops that regulate arterial pressure. Whereas the arterial baroreceptor reflex is very quick to counteract disturbances in arterial

SHORT-TERM

LONG-TERM

Baroreceptor reflex

Fluid balance

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EFFECT OF ARTERIAL PRESSURE ON URINARY OUTPUT RATE As discussed above, an increase in arterial pressure normally leads to an increase in urine output rate. Many mechanisms are involved in this phenomenon and are discussed in detail

Fluid intake rate

Blood volume −

−

+

TPR +

CO +

+ Fluid Volume

Arterial pressure

− Kidney +

Urinary output rate

FIGURE 29–5 Mechanisms of short- and long-term regulations of arterial pressure. TPR, total peripheral resistance; CO, cardiac output. (Modified with permission from Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.)

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Heathy person

ic t

2

1

Normal fluid intake

N

Un tre ate d

he rap y

Hypertensive person

Diu ret

Urine output rate × normal

3

A C B 50

100

Restricted fluid intake 150

200

Mean arterial pressure (mm Hg)

FIGURE 29–6 Renal function curves in a normal person and in a hypertensive person with and without antihypertensive therapy. (Modified with permission from Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.)

in Section 7. At this point, it is only important to recognize that, because of many synergistic influences, arterial pressure has a huge positive effect on renal urine output rate as is indicated by the very steep slope of the relationship shown in Figure 29–6. In a steady state, urine output (plus fluid lost from the body by other means) is equal to fluid intake (point N in this figure). At arterial pressures below point N, fluid intake exceeds urinary output and bodily fluid volume will necessarily be increasing. The opposite is true at arterial blood pressure higher than that at point N. Thus, a healthy person with a normal fluid intake rate will have, as a long-term average, the arterial pressure associated with point N in Figure 29–6. Because of the steepness of the curve shown in Figure 29–6, even marked changes in fluid intake rate have minor influences on the arterial pressure of a normal individual.

CLINICAL CORRELATION A 35-year-old African American male has come to the doctor for a general physical exam. He has not been to see a physician for at least 10 years. At present, he has no specific complaints about health conditions, but admits to not getting as much exercise as he did while in his twenties. His father had a mild heart attack at 50 years of age, received a coronary artery stent, and has been treated for hypertension for the 15 years since that time. His mother has recently been diagnosed with type 2 diabetes mellitus. He is 5′11″ (180 cm), 240 lb (109 kg), and has a heart rate of 64 beats/min and an arterial pressure of 150/92 mm Hg. Chest sounds and heart sounds are normal. All other aspects of the physical exam are within normal ranges. An

ECG shows left deviation of the ventricular mean electrical axis (−35°) (see Chapter 25). A tentative diagnosis of chronic hypertension is made. He has access to blood pressure monitoring equipment at home and was instructed to monitor his blood pressure daily for 1 week and to report his results to the doctor. At that time, a decision about therapeutic strategies will be made. Systemic hypertension is defined as a chronic increase in mean systemic arterial pressure above 140/90 mm Hg. It is an extremely common cardiovascular problem, affecting more than 20% of the adult population of the Western world. It has been established that hypertension increases the risk of coronary artery disease, myocardial infarction, heart failure, stroke, and many other serious cardiovascular problems. Moreover, it has been clearly demonstrated that the risk of serious cardiovascular incidents is reduced by proper treatment of hypertension. In approximately 90% of cases, the primary abnormality that produces high blood pressure is unknown. (This condition is sometimes referred to as primary or essential hypertension because the elevated level was previously thought to be “essential” to drive the blood through the systemic circulation, particularly the brain.) Genetic factors contribute importantly to the development of hypertension (generally being more common in males than females and in blacks than whites) and environmental factors such as obesity, high-salt diets, diabetes mellitus, and/or certain forms of psychological stress may either aggravate or precipitate hypertension in susceptible individuals. Structural changes in the left heart and arterial vessels occur in response to hypertension. Early alterations include hypertrophy of muscle cells and thickening of the walls of the ventricle and resistance vessels. Late changes associated with deterioration of function include increases in connective tissue and increased tissue stiffness. The established phase of hypertension is associated with increased total peripheral resistance. Cardiac output and/or blood volume may be increased during the early developmental phase, but are usually normal after the hypertension is established. The increased total peripheral resistance associated with established hypertension may be due to microvessel rarefaction (decrease in density), pronounced structural adaptations of the peripheral vascular bed, increased basal vascular smooth muscle tone, increased sensitivity and reactivity of the vascular smooth muscle cells to external vasoconstrictor stimuli, and/or diminished production and/or effect of endogenous vasodilator substances (e.g., nitric oxide). Chronic hypertension is not due to a sustained increase in sympathetic vasoconstrictor neural discharge nor is it due to a sustained increase of any blood-borne vasoconstrictive factor. (Both neural and hormonal influences,

CHAPTER 29 Arterial Pressure Regulation

however, may help initiate primary hypertension.) Blood pressure–regulating reflexes (both the short-term arterial and cardiopulmonary baroreceptor reflexes and the long-term, renal-dependent, pressure-regulating reflexes) become adapted or “reset” to regulate blood pressure at a higher-than-normal level. Disturbances in renal function contribute importantly to the development and maintenance of primary hypertension. Recall that, in the long term, arterial pressure can stabilize only at the level that makes urinary output rate equal to fluid intake rate. As shown by point N in Figure 29–6, this pressure is approximately 100 mm Hg in a normal individual. All forms of hypertension involve an alteration somewhere in the chain of events by which changes in arterial pressure produce changes in urinary output rate such that the renal function curve is shifted rightward as indicated in Figure 29–6. Higher-than-normal arterial pressure is required to produce a normal urinary output rate in a hypertensive individual. The untreated hypertensive individual in Figure 29–6 would have a very low urinary output rate at the normal mean arterial pressure of 100 mm Hg. With a normal fluid intake rate, this untreated hypertensive patient retains fluid to ultimately stabilize at point A (mean arterial pressure = 150 mm Hg). Baroreceptors adapt within days so that they will have a normal discharge rate at the prevailing average arterial pressure. Thus, once the hypertensive individual has been at point A for a week or more, even the baroreceptor mechanism will begin resisting acute changes from the 150-mm Hg pressure level. In certain hypertensive individuals, dietary salt restriction produces a substantial reduction in blood pressure because of the reduced requirement for water retention to osmotically balance the salt load. This effect is illustrated by a shift from point A to point B. The efficacy of lowering salt intake to lower arterial pressure depends heavily on the slope of the renal function curve in the hypertensive individual. The arterial pressure of a normal individual, for example, is affected only slightly by changes in salt intake because the normal renal function curve is so steep. A second common treatment of hypertension is diuretic therapy (see Chapters 44 and 46). The net effect of diuretic therapy is that the urinary output rate for a given arterial pressure is increased, that is, diuretic therapy shifts the renal function curve upward. The combined result of restricted fluid intake and diuretic therapy for the hypertensive individual of Figure 29–6 is illustrated by point C. A variety of antihypertensive pharmacological approaches are available that may include β-adrenergic blockers, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and calcium channel blockers (see Section 7). Alterations in lifestyle, including reduction of stress, decreases in caloric intake, limitation

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of the amount of saturated fats in the diet, and establishment of a regular exercise program, may also help reduce blood pressure in certain individuals.

CHAPTER SUMMARY ■ ■

■

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Arterial pressure is closely regulated to ensure adequate blood flow to the tissues. The arterial baroreceptor reflex is responsible for regulating arterial pressure in the short term on a second-to-second and moment-to-moment basis. The arterial baroreceptor reflex involves the following: pressure sensing by stretch-sensitive baroreceptor nerve endings in the walls of arteries, neural integrating centers in the brainstem that adjust autonomic nerve activity in response to the pressure information they receive from the arterial baroreceptors, and responses of the heart and vessels to changes in autonomic nerve activity. Overall, the arterial baroreflex operates such that increases in arterial pressure lead to an essentially immediate decrease in sympathetic nerve activity and a simultaneous increase in parasympathetic nerve activity (and vice versa). The brainstem integrating centers also receive nonarterial baroreceptor inputs that can raise or lower the set point for short-term arterial pressure regulation. In the long term, arterial pressure is regulated by changes in blood volume that come about because arterial pressure has a strong influence on urinary output rate by the kidney.

STUDY QUESTIONS 1. In the normal operation of the arterial baroreceptor reflex, a cardiovascular disturbance that decreases mean arterial pressure will evoke a decrease in A) urine output rate. B) sympathetic nerve activity. C) heart rate. D) total peripheral resistance. E) myocardial contractility. 2. Which one of the following, after all reflex adjustments are complete, will result in an increase in mean arterial pressure? A) low carbon dioxide levels in arterial blood B) increased intracranial pressure C) decreased cardiac filling pressure D) low blood volume E) supraventricular tachycardia 3. An individual has higher-than-normal mean arterial pressure and lower-than-normal pulse rate. Which of the following is most likely to cause such a combination? A) low oxygen levels in arterial blood B) anxiety C) exercise D) significant blood loss E) a drug that selectively stimulates alpha-adrenergic receptors

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4. Which of the following best describes, first, the immediate direct effect and, second, the reflex cardiovascular consequences of giving a normal person a drug that blocks beta1-adrenergic receptors? A) decreased heart rate, increased total peripheral resistance B) decreased ejection fraction, decreased total peripheral resistance C) increased heart rate, increased urine production D) increased cardiac output, decreased total peripheral resistance E) decreased end-diastolic volume, increased heart rate

5. An increase in arterial baroreceptor firing rate will reflexly result in A) an increase in vagal activity to the heart. B) an increase in sympathetic activity to arterioles in the brain. C) an increase in renal blood flow. D) an increase in mean arterial pressure. E) an increase in cardiac ejection fraction.

30 C

Cardiovascular Responses to Physiological Stress Lois Jane Heller and David E. Mohrman

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Identify the primary disturbance(s) that any given normal homeostatic disturbance (such as changes in body position) places on the cardiovascular system. List how any such given primary disturbance changes the influence on the medullary cardiovascular centers from (1) arterial baroreceptors and (2) other sources. State what immediate reflex compensatory changes will occur in sympathetic and parasympathetic nerve activities as a result of the altered influences on the medullary cardiovascular centers. Indicate what immediate compensatory changes will occur to influence mean arterial pressure in response to any given primary disturbance, including changes in: heart rate, cardiac contractility, stroke volume, arteriolar tone, venous tone, peripheral venous pressure, central venous pressure, total peripheral resistance, resistance in any major organ, blood flow through any major organ, cutaneous blood flow, transcapillary fluid movement, and long-term renal adjustments in urine output and total body fluid balance. State how gravity influences arterial, venous, and capillary pressures at any height above or below the heart in a standing individual. Describe and explain the changes in central venous pressure and the changes in transcapillary fluid balance and venous volume in the lower extremities caused by standing upright. Describe the operation of the “skeletal muscle pump” and explain how it simultaneously promotes venous return and decreases capillary hydrostatic pressure in the muscle vascular beds. Identify the primary disturbances and compensatory responses evoked by acute changes in body position. Describe the chronic effects of long-term bed rest on cardiovascular variables. List the cardiovascular consequences of respiratory activity. Identify the major maternal cardiovascular adjustments that occur during pregnancy. Follow the pathway of blood flow through the fetal heart and describe the changes that occur at birth. Indicate the normal changes that occur in cardiovascular variables during childhood. Identify age-dependent changes that occur in cardiovascular variables Describe gender-dependent differences in cardiovascular variables.

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CARDIOVASCULAR RESPONSES TO PHYSIOLOGICAL STRESSES

EFFECT OF GRAVITY

A wide variety of normal, everyday situations can disturb homeostasis within the cardiovascular system and can evoke an equally wide variety of reflex responses. The key to understanding the cardiovascular adjustments in each situation is to recall that the arterial baroreceptor reflex and renal fluid balance mechanisms always act to blunt changes in arterial pressure. The overall result is that adequate blood flow to the brain and the heart muscle is maintained in any circumstance. The cardiovascular alterations in the following example is produced by the combined effects of (1) the primary, direct influences of the disturbance on the cardiovascular variables and (2) the reflex compensatory adjustments that are triggered by the primary disturbances. As you will see in later sections of this book, the general pattern of reflex adjustment is similar in all situations. Rather than trying to memorize the cardiovascular alterations that accompany each situation, the reader should strive to understand each response in terms of the primary disturbances and reflex compensatory reactions involved.

A

RESPONSES TO CHANGES IN BODY POSITION Significant cardiovascular readjustments accompany changes in body position because gravity has an effect on pressures within the cardiovascular system. In the preceding chapters, the influence of gravity was ignored and pressure differences between various points in the systemic circulation were related only to ˙ R). As shown in Figure flow and vascular resistance (Δ P = Q 30–1, this is approximately true only for a recumbent individual. In a standing individual, additional cardiovascular pressure differences exist between the heart and regions that are not at heart level. This is most important in the lower legs and feet of a standing individual. As indicated in Figure 30–1B, intravascular pressures in the feet may be increased by 90 mm Hg simply from the weight of the blood in the arteries and veins leading to and from the feet. Note by comparing Figure 30–1A and B that standing upright does not in itself change the flow through the lower extremities, since gravity has the same effect on arterial and venous pressures and thus does not change the arteriovenous pressure difference at any given level above or below the heart.

RECUMBENT

P = 100 mm Hg

P = 95 mm Hg

Arteries Arterioles Capillaries

Heart Veins

Foot P = 25 mm Hg

Valves

P = 0 mm Hg

P = 5 mm Hg

STANDING Surface P = 0 mm Hg

P = 100 mm Hg

Heart level P = 0 mm Hg

P = 95 mm Hg P = 95 mm Hg

Foot level P = 90 mm Hg

P =100 mm Hg

Arteries

Lymphatics

Veins

1.5-m depth

P = 0 mm Hg

P = 185 mm Hg

P = 185 mm Hg Filtration P = 115 mm Hg

P = 20 mm Hg

P = 105 mm Hg

P = 185 mm Hg P = 40 mm Hg

Without compensation With sympathetic stimulation During skeletal muscle contraction Shortly after contraction

B

C

D

E

FIGURE 30–1 Effect of gravity on vascular pressure (A and B) with compensatory influences of sympathetic stimulation (C) and the skeletal muscle pump (D and E). (Modified with permission from Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/ McGraw-Hill, 2006.)

CHAPTER 30 Cardiovascular Responses to Physiological Stress There are, however, two major direct effects of the increased pressure in the lower extremities that are shown in Figure 30–1B: (1) the increase in venous transmural pressure distends the compliant peripheral veins and greatly increases peripheral venous volume by as much as 500 mL in a normal adult and (2) the increase in capillary transmural hydrostatic pressure causes a tremendously high transcapillary filtration rate. For reasons to be described, reflex activation of sympathetic nerves accompanies the transition from a recumbent to an upright position. However, Figure 30–1C shows how vasoconstriction from sympathetic activation is only marginally effective in ameliorating the adverse effects of gravity on the lower extremities. Arteriolar constriction can cause a greater pressure drop across arterioles, but this has only a limited effect on capillary pressure because venous pressure remains extremely high. Filtration will continue at a very high rate. In fact, the normal cardiovascular reflex mechanisms alone are incapable of dealing with upright posture without the aid of the skeletal muscle pump. A person who remained upright without intermittent contraction of the skeletal muscles in the legs would lose consciousness in 10–20 minutes because of the decreased brain blood flow that would stem from diminished central blood volume, stroke volume, cardiac output, and arterial pressure. The effectiveness of the skeletal muscle pump in counteracting venous blood pooling and edema formation in the lower extremities during standing is illustrated in Figure 30–1D and E. The compression of vessels during skeletal muscle contraction expels both venous blood and lymphatic fluid from the lower extremities (Figure 30–1D). Immediately after a skeletal muscle contraction, both veins and lymphatic vessels are relatively empty because their one-way valves prevent the backflow of previously expelled fluid (Figure 30–1E). Most important, the weight of the venous and lymphatic fluid columns is temporarily supported by the closed one-way valve leaflets. Consequently, venous pressure is drastically lowered immediately after skeletal muscle contraction and rises only gradually as veins refill with blood from the capillaries. Thus, capillary pressure and transcapillary fluid filtration rate are dramatically reduced for some period after a skeletal muscle contraction. Some transcapillary fluid filtration is still present, but the increased lymphatic flow resulting from the skeletal muscle pump is normally sufficient to prevent noticeable edema formation in the feet. The actions of the skeletal muscle pump, however beneficial, do not completely prevent an increase in the average venous pressure and blood pooling in the lower extremities on standing. Thus, assuming an upright position upsets the cardiovascular system and elicits reflex cardiovascular adjustments, as shown in Figure 30–2. As with all cardiovascular responses, the key to understanding the alterations associated with standing is to distinguish the primary disturbances from the compensatory responses. As shown in the top part of Figure 30–2, the immediate consequence of standing is an increase in both arterial and venous pressures in the lower extremities. The latter causes a major redistribution of blood volume out of the central venous pool. By the chain of events shown, the primary disturbances influ-

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ence the cardiovascular centers by lessening the normal input from both the arterial and the cardiopulmonary baroreceptors. The result of a decreased baroreceptor input to the cardiovascular centers will be reflex adjustments appropriate to increase blood pressure—that is, decreased cardiac parasympathetic nerve activity and increased activity of the cardiovascular sympathetic nerves as shown in the bottom part of Figure 30–2. Heart rate and cardiac contractility will increase, as will arteriolar and venous constriction in most systemic organs (brain and heart excepted). Heart rate and total peripheral resistance are greater when an individual stands than when the individual is lying down. Note that these particular cardiovascular variables are not directly influenced by standing but are changed by the compensatory responses. Stroke volume and cardiac output, conversely, are usually decreased below their recumbent values during quiet standing despite the reflex adjustments that tend to increase them. This is because the reflex adjustments do not quite overcome the primary disturbance on these variables caused by standing. This is in keeping with the general dictum that short-term cardiovascular compensations never completely correct the initial disturbance. Mean arterial pressure is often found to increase when a person changes from the recumbent to the standing position. At first glance, this is a violation of many rules of cardiovascular system operation. How can a compensation be more than complete? Moreover, how is increased sympathetic activity compatible with higher-than-normal mean arterial pressure in the first place? In the case of standing, there are many answers to these apparent puzzles. First, the average arterial baroreceptor discharge rate can actually decrease in spite of a small increase in mean arterial pressure if there is simultaneously a sufficiently large decrease in pulse pressure. Second, the influence on the medullary cardiovascular centers from cardiopulmonary receptors is interpreted as a decrease in blood volume and may increase arterial pressure by mechanisms that increase the set point. Third, mean arterial pressure determined by sphygmomanometry from the arm of a standing individual overestimates the mean arterial pressure actually being sensed by the baroreceptors in the carotid sinus region of the neck because of gravitational effects. The kidney is especially susceptible to changes in sympathetic nerve activity (as will be discussed in Section 7). Consequently, as shown in Figure 30–2, every reflex alteration in sympathetic activity has influences on fluid balance that become important in the long term. Standing, which is associated with an increase in sympathetic tone, ultimately results in an increase in fluid volume. The ultimate benefit of this is that an increase in blood volume generally reduces the magnitude of the reflex alterations required to tolerate upright posture.

RESPONSES TO LONG-TERM BED REST The cardiovascular system of an individual who is subjected to long-term bed rest undergoes a variety of adaptive changes. The most significant immediate change that occurs on

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Standing

↑ Venous pressure (lower extremities)

↑ Arterial pressure (lower extremities)

Primary disturbances (uncompensated)

Central → Peripheral blood volume shift

↑ Capillary pressure (lower extremities)

↓ Blood volume

Capillary filtration (lower extremities)

↓ Central venous pressure

Edema (lower extremities)

↓ Stroke volume

↓ Cardiac output ↓ Pulse pressure

↓ Mean arterial pressure

↓ Firing rate of cardiopulmonary baroreceptors

↓ Firing rate of arterial baroreceptors (increases set point)

FIGURE 30–2

Cardiovascular mechanisms involved when changing from a recumbent to a standing position. (Modified with permission from

Compensatory responses

Medullary cardiovascular centers ↓ Parasympathetic activity

↑

Heart rate

↑ Contractility

↑ Sympathetic activity

↑ Venous constriction

Heart

↑ Arteriolar constriction

Systemic organs

↑ Fluid retention Kidney

Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.)

assuming a recumbent position is a shift of fluid from the lower extremities to the upper portions of the body. The consequences of this shift include distention of the head and neck veins, facial edema, nasal stuffiness, and decreases in calf girth and leg volume. In addition, the increase in central blood volume stimulates the cardiopulmonary mechanoreceptors, which influence renal function by neural and hormonal pathways to reduce sympathetic drive and promote fluid loss. The individual begins to lose weight and, within just a few days, becomes hypovolemic. When the bedridden patient initially tries to stand up, the normal responses to gravity as described in Figure 30–2 are not as effective, primarily because of the substantial decrease in circulating blood volume. Upon standing, blood shifts out of the central venous pool into the peripheral veins, stroke volume decreases, and the individual often becomes dizzy and may faint due to a dramatic decrease in blood pressure. This phenomenon is referred to as orthostatic or postural hypotension. Because there are other cardiovascular changes that may accompany bed rest, complete reversal of this orthostatic intol-

Immediate

Long-term

erance may take several days or even weeks. Efforts made to diminish the cardiovascular changes for the bedridden patient may include intermittent sitting up or tilting the bed to lower the legs and trigger fluid retention mechanisms.

NORMAL CARDIOVASCULAR ADAPTATIONS RESPONSES TO RESPIRATORY ACTIVITY The physical processes associated with inhaling air into and exhaling air out of the lungs have major effects on venous return and cardiac output. The decrease in intrathoracic pressure with inspiration transiently increases the pressure gradient between the peripheral and central venous pools and contributes to venous return from the systemic vascular beds to the right side

CHAPTER 30 Cardiovascular Responses to Physiological Stress of the heart. Because the one-way valves in peripheral veins prevent backflow during expiration, the thoracic pressure changes constitute a respiratory pump (also called the thoracoabdominal pump). Details of the effects of the respiratory pump on venous return in exercise and the effects of positive pressure ventilation on venous return and cardiac output are presented in Chapters 34 and 72. A variety of complex signals from cardiopulmonary receptors during the respiratory cycle contribute to a respiratory-based cardiac arrhythmia that is mediated primarily by changing activity of vagal efferents to the SA node. There are other instances when the cardiovascular effect of respiratory efforts has physiological consequences (i.e., yawning, coughing, laughing). One of the more important situations occurs during the Valsalva maneuver, which is a forced expiration against a closed glottis. This maneuver is normally performed by individuals during defecation (“straining at stool”), or when attempting to lift a heavy object. The sustained increase in intrathoracic pressure leads to decreases in venous return and blood pressure, which evokes a compensatory reflex increase in heart rate and peripheral vasoconstriction. (During this period, the red face and distended peripheral veins are indicative of high peripheral venous pressures.) At the cessation of the maneuver, there is an abrupt decrease in pressure for a few heart beats due to the reduction of intrathoracic pressure. Venous blood then moves rapidly into the central venous pool; stroke volume, cardiac output, and arterial pressure increase rapidly; and a reflex bradycardia occurs. The combination of an episode of high peripheral venous pressure followed by an episode of high arterial pressure and pulse pressure is particularly dangerous for people who are candidates for cerebral vascular accidents (strokes) because this combination may rupture a weakened blood vessel.

CARDIOVASCULAR CHANGES DURING PREGNANCY Pregnancy causes alterations in vascular structure and blood flow to many maternal organs in order to support growth of the developing fetus. These organs include not only the

A

B Foramen ovale pv

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uterus and developing placenta, but also the kidneys and the gastrointestinal organs. However, one of the most striking cardiovascular changes of pregnancy is the nearly 50% increase in circulating blood volume. The placenta, being a low-resistance organ added in parallel with the other systemic organs, reduces the overall systemic total peripheral resistance by about 40%. Without the substantial increase in circulating blood volume to support cardiac filling, the necessary increase in cardiac output to balance the decrease in total peripheral resistance would not be possible and pregnancy would result in a substantial decrease in mean arterial pressure. At birth, the loss of the placenta contributes to an abrupt increase of maternal total peripheral resistance back toward normal levels.

FETAL CIRCULATION & CHANGES AT BIRTH During fetal development, the exchange of nutrients, gases, and waste products between fetal and maternal blood occurs in the placenta. This exchange occurs by diffusion between separate fetal and maternal capillaries without any direct connection between the fetal and maternal circulations. From a hemodynamic standpoint, the placenta represents a temporary additional large systemic organ for both the fetus and the mother. The fetal component of the placenta has a low vascular resistance and receives a substantial portion of the fetal cardiac output. Blood circulation in the developing fetus almost completely bypasses the collapsed, fluid-filled fetal lungs. Very little blood flows into the pulmonary artery because the vascular resistance in the collapsed fetal lungs is very high. By the special structural arrangements shown in Figure 30–3, the fetal right and left hearts operate in parallel to pump blood through the systemic organs and the placenta. As shown in Figure 30–3A, fetal blood returning from the systemic organs and placenta fills both the left and right hearts together because of an opening in the intra-atrial septum called the foramen ovale. As indicated in Figure 30–3B, most of the blood that is pumped

Ductus arteriosus a

pv pa la

vc ra

rv

lv

rv

lv

FIGURE 30–3 Fetal circulation (A) during cardiac filling and (B) during cardiac ejection. pv, pulmonary veins; la, left atrium; lv, left ventricle; rv, right ventricle; ra, right atrium; vc, venae cavae; a, aorta; pa, pulmonary artery. (Modified with permission from Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/ McGraw-Hill, 2006.)

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SECTION V Cardiovascular Physiology

by the fetal right heart does not enter the constricted pulmonary circulation but rather is diverted into the aorta through a vascular connection between the pulmonary artery and the aorta called the ductus arteriosus. At birth, an abrupt decrease in pulmonary vascular resistance occurs in the newborn with the onset of lung ventilation. This is a partly a result of the introduction of oxygen into the airways and the decrease in hypoxic pulmonary vasoconstriction as discussed in Chapter 34. This permits more blood to flow into the lungs from the pulmonary artery and tends to lower pulmonary arterial pressure. Meanwhile, total systemic vascular resistance of the newborn increases greatly because of the interruption of flow through the placenta. This causes an increase in aortic pressure. The combination of the reduced pulmonary and elevated systemic arterial pressure retards or even reverses the flow through the ductus arteriosus. Through mechanisms that are incompletely understood but clearly linked to an increase in blood oxygen tension, the ductus arteriosus gradually constricts and completely closes in a few hours to a few days. The circulatory changes that occur at birth tend to simultaneously increase the pressure afterload on the left ventricle and decrease that on the right ventricle. This indirectly causes left atrial pressure to increase above that in the right atrium so that the pressure gradient for flow through the foramen ovale is reversed. Reverse flow through the foramen ovale is, however, prevented by a flaplike valve that covers the opening in the left atrium. Normally, the foramen ovale eventually is closed permanently by the growth of fibrous tissue.

PEDIATRIC CARDIOVASCULAR CHARACTERISTICS Cardiovascular variables change significantly during the childhood. The normal neonate has, by adult standards, a high resting heart rate (average of 140 beats/min) and a low arterial blood pressure (average of 60/35 mm Hg). These values rapidly change over the first year (to 120 beats/min and 100/65 mm Hg, respectively). By the time the child enters adolescence, these values are near adult levels. Pulmonary vascular resistance decreases precipitously at birth as described above and then continues to decline during the first year, at which time pulmonary vascular pressures resemble adult levels. These resistance changes appear to be due to a progressive remodeling of the microvascular arterioles from thick-walled, small-diameter vessels to thin-walled, large-diameter microvessels. Also as the lung grows, the number of alveoli and therefore pulmonary vessels increases. (At birth there are only about 20 million alveoli, compared to 300–450 million in adults. Most of the growth occurs in the first 8 years). It is noteworthy that distinct differences between right and left ventricular mass and wall thickness develop only after birth. Presumably these differences arise because of a hypertrophic response of the left ventricle to the increased afterload it must assume at birth. Accordingly, the electrocardiogram of children shows an early right ventricular dominance (electri-

cal axis orientation) that converts to the normal left ventricular dominance during childhood. Heart murmurs are also quite common in childhood and have been reported to be present in as many as 50% of healthy children. Most of these murmurs fall in the category of “innocent” murmurs resulting from normal cardiac tissue vibrations, high flow through valves, and thin chest walls that make noises from the vasculature easy to hear. Less than 1% of them result from various congenital heart defects. Growth and development of the vascular system parallels growth and development of the body with most of the local and reflex regulatory mechanisms becoming operational shortly after birth.

CARDIOVASCULAR CHANGES WITH NORMAL AGING Changes in cardiovascular function occur over the normal human lifetime. These changes are generally associated with a slowing of some of the basic processes and a reduction in the ability of the cardiovascular system as a whole to respond to various stresses. Details of the aging process are discussed in Chapter 73. Age-dependent cardiac alterations include: (1) a decrease in the resting and maximum cardiac index, (2) a decrease in the maximum heart rate, (3) an increase in the contraction and relaxation times of the heart muscle, (4) an increase in the myocardial stiffness during diastole, (5) a decrease in number of functioning myocytes, and (6) an accumulation of pigment in the myocardial cells. Age-dependent vascular changes include: (1) a decrease in capillary density in some tissues, (2) a decrease in arterial and venous compliance, and (3) an increase in total peripheral vascular resistance. These changes combine to produce the age-dependent increases in arterial pulse pressure and mean arterial pressure that were discussed in Chapter 26 (see Figure 26–10). The increases in arterial pressure impose a greater afterload on the heart, and this may be partially responsible for the age-dependent decreases in cardiac index. Arterial baroreceptor–induced responses to changes in blood pressure are blunted with age. This is due in part to a decrease in afferent activity from the arterial baroreceptors because of the age-dependent increase in arterial rigidity. In addition, the total amount of norepinephrine contained in the sympathetic nerve endings of the myocardium decreases with age, and the myocardial responsiveness to catecholamines declines. Thus, the efferent component of the reflex is also compromised. These changes may partially account for the apparent age-dependent sluggishness in the responses to postural changes and recovery from exercise.

EFFECT OF GENDER There are a few well-documented gender-dependent differences in the cardiovascular system. Compared with age-matched men, premenopausal women have a lower left ventricular mass

CHAPTER 30 Cardiovascular Responses to Physiological Stress to body mass ratio, which may reflect a lower cardiac afterload in women. This may result from their lower arterial blood pressure, greater aortic compliance, and improved ability to induce vasodilatory mechanisms (such as endothelial-dependent flowmediated vasodilation). These differences are thought to be related to protective effects of estrogen and may account for the lowered risk of premenopausal women for developing cardiovascular disease. After menopause, these gender differences disappear. In fact, older women with ischemic heart disease often have a worse prognosis than men. There are also gender-dependent differences in cardiac electrical properties. Women often have lower intrinsic heart rates and longer QT intervals than do men. They are at greater risk for developing long-QT syndrome and torsades de pointes. They are also twice as likely as men to have atrioventricular nodal reentry tachycardias.

CLINICAL CORRELATION An elderly man was hunting with some friends when he inadvertently shot himself in the foot. This resulted in a significant loss of blood and, by the time he was brought to the hospital, he was very weak and pale, his skin was cold and clammy, and he was somewhat confused. His heart rate was 105 beats/min, and blood pressure was 85/65 mm Hg. His breathing was rapid and shallow and jugular venous pulses could not be observed when he was recumbent. An intravenous catheter advanced from a peripheral vein into his right atrium recorded central venous pressure to be 0 mm Hg (normal 2–6 mm Hg). A

blood sample was obtained and his hematocrit was 34 (normal 41–53%). The most immediate problem was determined to be hemorrhagic hypovolemic shock and he was given a liter of blood. Within an hour, his heart rate was 90 beats/min and his blood pressure was 115/85 mm Hg. He was still weak and pale but more alert. He had not yet urinated and was very thirsty. Additional blood was infused and his vital signs returned to normal. Circulatory shock exists whenever there is a severe reduction in blood supply to the body tissues and the metabolic needs of the tissues are not met. Even with all cardiovascular compensatory mechanisms activated, arterial pressure is usually (though not always) low in shock. The shock state is precipitated by one of the following two conditions: (1) severely depressed myocardial function or (2) grossly inadequate cardiac filling due to low mean circulatory filling pressure. The former situation is called cardiogenic shock and the latter situation can result from a variety of non-cardiac causes. These shock states are described in Table 30–1 along with the primary disturbance on the cardiovascular system and the consequences on cardiac filling pressure. The common primary disturbances in all forms of shock lead to decreased mean arterial pressure and decreased arterial baroreceptor discharge rate. In the case of hypovolemic, anaphylactic, and septic shock, diminished activity of the cardiopulmonary baroreceptors due to a decrease in central venous pressure and/or volume acts on the medullary cardiovascular centers to stimulate sympathetic output. In the case of cardiogenic shock, central venous pressure will increase, and in the case of neurogenic shock, central venous pressure cannot be predicted because both cardiac

TABLE 30–1 Circulatory Shock Type of Shock

Causes

Primary Disturbance

Effect on Central Venous Pressure

Cardiogenic

-Myocardial infarction

-Decreased cardiac output

-Increased CVP

-Severe arrhythmia

-Right shift of cardiac function curve

-Abrupt valve malfunction Hypovolemic

-Hemorrhage -Severe burns

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-Decreased circulating blood volume

-Decreased CVP

-Chronic vomiting or diarrhea -Dehydration Anaphylactic

-Severe systemic allergic reaction associated with release of histamine, prostaglandins, leukotrienes, bradykinin

-Decreased total peripheral resistance, reduced venous tone

-Decreased CVP

Septic

-Circulating infective agents releasing vasodilator substances such as endotoxin (lipopolysaccharide) inducing NO synthesis

-Decreased total peripheral resistance, reduced venous tone

-Decreased CVP

Neurogenic

-Reduced sympathetic and/or increased parasympathetic activity (vasovagal syncope)

-Decreased cardiac output, total peripheral resistance, and venous tone

-Variable effect on CVP because both cardiac output and venous return will decrease

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output and venous return are likely to be depressed. If arterial pressure decreases below the autoregulatory range for cerebral blood flow (below about 60 mm Hg), perfusion of the brain begins to decrease, eliciting the cerebral ischemic response that causes the most intense of all signals to activate sympathetic nerves. Unless the primary disturbance precludes these compensatory responses, the increase in sympathetic activity (and decrease in parasympathetic activity) will lead to an increase in cardiac output (by increasing heart rate and cardiac contractility), an increase in total peripheral resistance (by generalized arteriolar constriction), and an increase in peripheral venous tone (which will shift blood into the central venous pool). Many of the commonly recognized symptoms of shock (e.g., pallor, cold clammy skin, rapid heart rate, muscle weakness, venous constriction) are a result of greatly increased sympathetic nerve activity. When the immediate compensatory processes are inadequate, the individual may also show signs of abnormally low arterial pressure, such as dizziness, confusion, or loss of consciousness. Additional compensatory processes during a shock state may include (1) rapid, shallow breathing, which promotes venous return to the heart by action of the respiratory pump (see Chapter 72), (2) release of various powerful vasoconstrictor hormones such as epinephrine (see Chapter 19), angiotensin II, and vasopressin (see Chapter 45), which contribute to the increase in total peripheral resistance, (3) a net shift of fluid from the interstitial space into the vascular space due to the very low capillary hydrostatic pressure downstream of the vasoconstricted arterioles, and (4) an increase in extracellular osmolarity (as a result of increased glycogenolysis in the liver induced by epinephrine and norepinephrine) that will induce a shift of fluid from the intracellular space into the extracellular (including intravascular) space. The latter two processes result in a sort of autotransfusion that can move as much as a liter of fluid into the vascular space in the first hour after the onset of the shock episode (see Chapter 26). This fluid shift accounts for the reduction in hematocrit that is commonly observed in hemorrhagic shock. In addition to the immediate compensatory responses described above, fluid retention mechanisms are evoked that promote renal retention of fluid and an increase in circulating blood volume. These processes are described in detail in Chapter 45 and contribute to the replenishment of extracellular fluid volume within a few days of the shock episode. If the primary disturbances are not corrected soon, the strong compensatory responses can reduce perfusion of

tissues (other than the heart and brain) despite nearly normal arterial pressure. Intense sympathetic activation can lead to renal, splanchnic, or hepatic ischemic damage. If this ischemia is prolonged, self-reinforcing decompensatory mechanisms (positive feedback described in Chapter 1) will progressively drive arterial pressure down and unless corrective measures are taken quickly, death will ultimately result.

CHAPTER SUMMARY ■

■

■ ■

Cardiovascular responses to physiological stresses should be evaluated in terms of the initial effects of the primary disturbance and the subsequent effects of the reflex compensatory responses. Gravity, and hence body position, has a significant effect on the cardiovascular system, and various reflex compensatory mechanisms are required to overcome venous pooling that accompanies the upright position. Long-term bed rest causes decreases in circulating blood volume that contributes to orthostatic hypotension. Cardiovascular characteristics are influenced by a variety of conditions including respiratory activity, gender, pregnancy, growth and development from the fetal period, through birth, pediatric stages, adulthood, and old age.

STUDY QUESTIONS 1. All of the following tend to occur when a person lies down. Which one is the primary disturbance that causes all the others to happen? A) Heart rate will decrease. B) Stroke volume will decrease. C) Sympathetic activity will decrease. D) Parasympathetic activity will increase. E) Central venous pressure will increase. 2. A 35-year-old man has had a severe bout of the flu with vomiting and diarrhea for several days. All of the following conditions would be expected to be present except A) orthostatic hypotension. B) increased cardiac preload. C) increased cardiac ejection fraction. D) increased hematocrit. E) increased total peripheral vascular resistance. 3. Total systemic peripheral vascular resistance of a newborn baby undergoes an abrupt and sustained increase at birth. This is because A) circulating blood volume increases. B) the high-resistance lungs inflate. C) the low-resistance placental circulation is removed. D) sympathetic neural stimulation is increased. E) cardiac output increases.

CHAPTER 30 Cardiovascular Responses to Physiological Stress 4. Vertical immersion to the chest in tepid water produces a diuresis in many individuals. What mechanisms might account for this phenomenon? A) an increase in sympathetic activity to the kidney B) an increase in mean arterial pressure C) a shift of blood from the central to the peripheral venous pool D) decreased firing of arterial baroreceptors E) increased firing of the cardiopulmonary baroreceptors

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5. All of the following help maintain circulation during states of hypovolemic shock except A) an increase in heart rate. B) rapid respiratory effort to promote venous return of blood to the heart. C) vasoconstrictive contributions from increases in circulating epinephrine. D) autotransfusion of interstitial fluid into capillary beds. E) transcapillary filtration of plasma into interstitial space.

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SECTION VI PULMONARY PHYSIOLOGY

31 C

Function and Structure of the Respiratory System Michael Levitzky

H A

P

T

E

R

O B J E C T I V E S ■ ■ ■ ■

Describe the exchange of oxygen and carbon dioxide with the atmosphere and relate gas exchange to the metabolism of the tissues of the body. List the functions of the lungs. Describe functions and structures of the conducting airways, the alveolar–capillary unit, and the chest wall. Describe the central nervous system initiation of breathing and the innervation of the respiratory muscles.

The main functions of the respiratory system are to obtain oxygen from the external environment and supply it to the cells, and to remove from the body the carbon dioxide produced by cellular metabolism. The respiratory system is composed of the lungs, the conducting airways, the parts of the central nervous system concerned with the control of the muscles of respiration, and the chest wall. The chest wall consists of the muscles of respiration— the diaphragm, the intercostal muscles, and the abdominal muscles—and the rib cage.

FUNCTIONS OF THE RESPIRATORY SYSTEM The functions of the respiratory system include gas exchange, acid–base balance, phonation, pulmonary defense and metabolism, and the handling of bioactive materials.

Ch31_305-312.indd 305

GAS EXCHANGE The exchange of carbon dioxide for oxygen takes place in the lungs. As shown in Figure 31–1, fresh air, containing oxygen, is inspired into the lungs through the conducting airways. The forces needed to cause the air to flow are generated by the respiratory muscles, acting on commands initiated by the central nervous system. At the same time, venous blood returning from the various body tissues is pumped into the lungs by the right ventricle of the heart. This mixed venous blood has a high carbon dioxide content and a low oxygen content. In the pulmonary capillaries, carbon dioxide is exchanged for oxygen. The blood leaving the lungs, which now has a high oxygen content and a lower carbon dioxide content, is distributed to the tissues of the body by the left side of the heart. During expiration, gas with a high concentration of carbon dioxide is expelled from the body.

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EXTERNAL ENVIRONMENT High O2, Low CO2

Expiration

Inspiration

O2

CONDUCTING AIRWAYS

CO2 ALVEOLI O2 CO2 PULMONARY CAPILLARIES

PULMONARY ARTERY

PULMONARY VEINS

Low O2 High CO2

High O2 Low CO2 LEFT ATRIUM

RIGHT VENTRICLE

LEFT VENTRICLE

RIGHT ATRIUM

VEINS

Low O2 High CO2

High O2 Low CO2 SYSTEMIC CAPILLARIES

AORTA

O2

CO2 METABOLIZING TISSUES

FIGURE 31–1

Schematic representation of gas exchange between the tissues of the body and the environment. (Modified with

permission from Levitzky MG: Pulmonary Physiology, 7th ed. New York: McGraw-Hill Medical, 2007.)

OTHER FUNCTIONS OF THE RESPIRATORY SYSTEM Acid–Base Balance In the body, increases in carbon dioxide lead to increases in hydrogen ion concentration (and vice versa) because of the following reaction: CO2 + H2O

H2CO3

H+ + HCO3–

The respiratory system can therefore participate in acid– base balance by removing CO2 from the body. The central nervous system has sensors for the CO2 and the hydrogen ion levels in the arterial blood and in the cerebrospinal fluid that send information to the controllers of breathing. Acid–base balance is discussed in greater detail in Chapter 37; the control of breathing is discussed in Chapter 38.

Phonation Phonation is the production of sounds by the movement of air through the vocal cords. Speech, singing, and other sounds are produced by the actions of the central nervous system controllers on the muscles of respiration, causing air to flow through the vocal cords and the mouth. The physiology of speech is discussed in Chapter 21.

Pulmonary Defense Mechanisms Each breath brings into the lungs a small sample of the local atmospheric environment. This may include microorganisms such as bacteria, dust, particles of silica or asbestos, toxic gases, smoke (cigarette and other types), and other pollutants. In addition, the temperature and humidity of the local atmosphere can vary tremendously. As will be described below, as

CHAPTER 31 Function and Structure of the Respiratory System air passes through the airways, it is warmed to body temperature and filtered to remove particulate matter. Most of the particles in inspired air are removed before they reach the alveoli. The mechanisms by which these impurities are removed from the respiratory tract are described in the section “Structure of the Respiratory System.”

Pulmonary Metabolism and the Handling of Bioactive Materials The cells of the lung must metabolize substrates to supply energy and nutrients for their own maintenance. Some specialized pulmonary cells also produce substances necessary for normal pulmonary function. These substances include pulmonary surfactant, which is synthesized in type II alveolar epithelial cells (described below) and released at the alveolar surface. Surfactant plays an important role in reducing the alveolar elastic recoil due to surface tension and in stabilizing the alveoli, as discussed later in Chapter 32. Histamine, lysosomal enzymes, prostaglandins, leukotrienes, plateletactivating factor, neutrophil and eosinophil chemotactic factors, and serotonin can be released from mast cells in the lungs in response to conditions such as pulmonary embolism (see Chapter 34) and anaphylaxis (an acute life-threatening systemic allergic reaction). These substances may cause bronchoconstriction or immune or inflammatory responses, or they may initiate cardiopulmonary reflexes. Many substances are also produced by cells of the lung and released into the alveoli and airways, including mucus and other tracheobronchial secretions; surface enzymes, proteins, and other factors; and immunologically active substances. These substances are produced by goblet cells, submucosal gland cells, Clara cells, and macrophages. Substances produced by lung cells and released into the blood under various circumstances include bradykinin, histamine, serotonin, heparin, prostaglandins E2 and F2α, and the endoperoxides (prostaglandins G2 and H2). In addition, the pulmonary capillary endothelium contains a great number of enzymes that can produce, metabolize, or modify naturally occurring vasoactive substances. For exam-

ple, prostaglandins E1, E2, and F2α are nearly completely removed in a single pass through the lungs. On the other hand, prostaglandins A1, A2, and I2 (prostacyclin) are not affected by the pulmonary circulation. Similarly, about 30% of the norepinephrine in mixed venous blood is removed by the lung, but epinephrine is unaffected. It appears that some substances released into specific vascular beds for local effects are inactivated or removed as they pass through the lungs, preventing them from entering the systemic circulation; other substances, apparently intended for more general effects, are not affected.

STRUCTURE OF THE RESPIRATORY SYSTEM THE AIRWAYS Air enters the respiratory system through the nose or mouth. Air entering through the nose is filtered, warmed to body temperature, and humidified as it passes through the nose and nasal turbinates. The upper airways (airways above the trachea) are shown in Figure 31–2. The mucosa of the nose, the nasal turbinates, the oropharynx, and the nasopharynx have a rich blood supply and constitute a large surface area. The nasal turbinates alone have a surface area said to be about 160 cm2. As inspired air passes through these areas and continues through the tracheobronchial tree, it is warmed to body temperature and humidified. This protective function is more effective if one is breathing through the nose than through the mouth. Because the olfactory receptors are located in the posterior nasal cavity rather than in the trachea or alveoli, a person can sniff to attempt to detect potentially hazardous gases or dangerous material in the inspired air. This rapid, shallow inspiration brings gases into contact with the olfactory sensors without bringing them into the lung. Chapter 17 discusses the physiology of olfaction (the sense of smell).

  



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FIGURE 31–2 Schematic drawing of the upper airways. (Reproduced with permission from Proctor DF. Physiology of the upper airway. In: Fenn WO, Rahn H, eds. Handbook of Physiology, sec 3: Respiration. Vol. 1. Washington, DC: American Physiological Society; 1964:309–345.)

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SECTION VI Pulmonary Physiology

Conducting zone

Name of branches

Number of tubes in branch

Trachea

1

Bronchi

2

4 8 Bronchioles

16 32

Terminal bronchioles

6 x 104

Respiratory zone

Respiratory bronchioles 5 x 105

Alveolar ducts

Alveolar sacs

8 x 106

FIGURE 31–3 Schematic representation of airway branching in the human lung. (Reproduced with permission from Weibel ER. Morphometry of the Human Lung. Berlin; Springer; 1963.)

Air then passes through the glottis and the larynx and enters the tracheobronchial tree. After passing through the conducting airways, the inspired air enters the alveoli, where it comes into contact with the mixed venous blood in the pulmonary capillaries. Starting with the trachea, the air may pass through as few as 10 or as many as 23 generations, or branchings, on its way to the alveoli. The branchings of the tracheobronchial tree and its nomenclature are shown in Figure 31–3. Alveolar gas exchange units are denoted by the U-shaped sacs. The first 16 generations of airways, the conducting zone, contain no alveoli and thus are anatomically incapable of gas exchange with the venous blood. They constitute the anatomic dead space, which is discussed in Chapter 33. Alveoli start to appear at the 17th to the 19th generations, in the respiratory bronchioles, which constitute the transitional zone. The 20th to 22nd generations are lined with alveoli. These alveolar ducts and the alveolar sacs, which terminate the tracheobronchial tree, are referred to as the respiratory zone. The portion of the lung supplied by a primary respiratory bronchiole is called an acinus. All of the airways of an acinus participate in gas exchange. The numerous branchings of the airways result in a tremendous total cross-sectional area

of the distal portions of the tracheobronchial tree, even though the diameters of the individual airways are quite small.

Structure of the Airways The structure of the airways varies considerably, depending on their location in the tracheobronchial tree. The trachea is a fibromuscular tube supported ventrolaterally by C-shaped cartilage and completed dorsally by smooth muscle. The cartilage of the large bronchi is semicircular, like that of the trachea, but as the bronchi enter the lungs, the cartilage rings disappear and are replaced by irregularly shaped cartilage plates. They completely surround the bronchi and give the intrapulmonary bronchi their cylindrical shape. These plates, which help support the larger airways, diminish progressively in the distal airways and disappear in airways about 1 mm in diameter. Airways with no cartilage are termed bronchioles. Because the bronchioles and alveolar ducts contain no cartilage support, they are subject to collapse when compressed, as will be discussed later in this chapter. This tendency is partly opposed by the attachment of the alveolar septa, containing elastic tissue, to their walls, as seen in Figure 31–4, a scanning electron micrograph of the alveolar–capillary surface (also shown schematically in Figure 32–18). As the cartilage plates become irregularly distributed around distal airways, the muscular layer completely surrounds these airways. The muscular layer is intermingled with elastic fibers. As the bronchioles proceed toward the alveoli, the muscle layer becomes thinner, although smooth muscle can even be found in the walls of the alveolar ducts. The outermost layer of the bronchiolar wall is surrounded by dense connective tissue with many elastic fibers. The entire respiratory tract, except for part of the pharynx, the anterior third of the nose, and the respiratory units distal to the terminal bronchioles, is lined with ciliated cells interspersed with mucus-secreting goblet cells and other secretory cells. In the bronchioles, the goblet cells become less frequent and are replaced by another type of secretory cell, the Clara cell. The ciliated epithelium, along with mucus secreted by glands along the airways and the goblet cells and the secretory products of the Clara cells, constitutes an important mechanism for the protection of the lung called the mucociliary escalator.

Filtration and Removal of Inspired Particles by the Airways Filtration of Inspired Air Air passing through the nose is first filtered by passing through the nasal hairs, or vibrissae. This removes most particles larger than 10–15 μm in diameter. Most of the particles greater than 10 μm in diameter are removed on impact in the large surface area of the nasal septum and turbinates (Figure 31–2). The inspired air stream changes direction abruptly at the nasopharynx so that many of these larger particles impact the posterior wall of the pharynx. The tonsils and adenoids are located near this impaction site, providing immunologic defense against biologically active material filtered at this point. Air entering the trachea contains few particles larger than 10 μm, and most

CHAPTER 31 Function and Structure of the Respiratory System

FIGURE 31–4 Scanning electron micrograph of human lung parenchyma. A, alveolus; S, alveolar septa; D, alveolar duct; PK, pore of Kohn; PA, small branch of the pulmonary artery. (Reproduced with permission from Fishman AP, Elias JA: Fishman’s Pulmonary Diseases and Disorders, 3rd ed. New York: McGraw-Hill, Health Professions Division, 1998.)

of these will impact mainly at the carina or within the bronchi. Sedimentation of most particles in the size range of 2–5 μm occurs by gravity in the smaller airways, where airflow rates are extremely low. Thus, most of the particles between 2 and 10 μm in diameter are removed by impaction or sedimentation and become trapped in the mucus that lines the upper airways, trachea, bronchi, and bronchioles. Smaller particles and all foreign gases reach the alveolar ducts and alveoli. Some smaller particles (0.1 μm and smaller) are deposited as a result of Brownian motion due to their bombardment by gas molecules. The other particles, between 0.1 and 0.5 μm in diameter, mainly stay suspended as aerosols, and about 80% of them are exhaled.

Removal of Filtered Material Filtered or aspirated material trapped in the mucus that lines the respiratory tract can be removed in several ways. Mechanical or chemical stimulation of receptors in the nose, trachea, larynx, or elsewhere in the respiratory tract may produce bronchoconstriction to prevent deeper penetration of the irritant into the airways and may also produce a cough or a sneeze. A sneeze results from stimulation of receptors in the nose or nasopharynx; a cough results from

309

stimulation of receptors in the trachea. In either case, a deep inspiration is followed by a forced expiration against a closed glottis. Pressure in the chest surrounding the lungs (intrapleural pressure) may rise to more than 100 mm Hg during this phase of the reflex. The glottis opens suddenly, and pressure in the airways decreases rapidly, resulting in compression of the airways and an explosive expiration, with linear airflow velocities said to approach the speed of sound. Such high airflow rates through the narrowed airways are likely to carry the irritant, along with some mucus, out of the respiratory tract. In a sneeze, the expiration is via the nose; in a cough, the expiration is via the mouth. The cough or sneeze reflex is also useful in helping to move the mucous lining of the airways toward the nose or mouth. The term “cough” is not specific to this complete involuntary respiratory reflex. Coughs can be initiated by many causes, including postnasal drip from allergies or viral infections, asthma, gastroesophageal reflux, as an adverse effect of the very commonly prescribed angiotensin-converting enzyme inhibitors, mucus production from chronic bronchitis, infections, and other airway disorders. Voluntary coughs are not usually as pronounced as the violent involuntary reflex described above. Particles that are trapped in the mucus lining the airways can be removed by the mucociliary escalator, which has an estimated total surface area of 0.5 m2. The mucus is a complex polymer of mucopolysaccharides. The mucous glands are found mainly in the submucosa near the supporting cartilage of the larger airways. In pathologic states, such as chronic bronchitis, the number of goblet cells may increase and the mucous glands may hypertrophy, resulting in greatly increased mucous gland secretion and increased viscosity of mucus. The cilia lining the airways beat in such a way that the mucus covering them is always moved up the airway, away from the alveoli and toward the pharynx. The mucous blanket appears to be involved in the mechanical linkage between the cilia. The cilia beat at frequencies between 600 and 900 beats/min, and the mucus moves progressively faster as it travels from the periphery. Several studies have shown that ciliary function is inhibited or impaired by cigarette smoke. The mucociliary escalator is an especially important mechanism for the removal of inhaled particles that come to rest in the airways. Material trapped in the mucus is continuously moved upward toward the pharynx. This movement can be greatly increased during a cough, as described previously. Mucus that reaches the pharynx is usually swallowed, expectorated, or removed by blowing one’s nose. Patients who cannot clear their tracheobronchial secretions (e.g., an intubated patient or a patient who cannot cough adequately) continue to produce secretions. If the secretions are not removed from the patient by suction or other means, airway obstruction may develop.

THE ALVEOLAR–CAPILLARY UNIT The alveolar–capillary unit is the site of gas exchange in the lung. The alveoli, traditionally estimated to number about 300 million in the adult (a more recent study calculated the mean

310

SECTION VI Pulmonary Physiology the lung to injury. As type I alveolar epithelial cells are injured, type II cells proliferate to reestablish a continuous epithelial surface. Studies in animals have shown that these type II cells can develop into type I cells after injury. A cross-section of a pulmonary capillary is shown in the transmission electron micrograph in Figure 31–6. An erythrocyte is seen in cross-section in the lumen of the capillary. Capillaries are formed by a single layer of squamous epithelial cells that are aligned to form tubes. The nucleus of one of the capillary endothelial cells can be seen in the micrograph. The barrier to gas exchange between the alveoli and pulmonary capillaries can also be seen in the figure. It consists of the alveolar epithelium, the capillary endothelium, and the interstitial space between them. Gases must also pass through the fluid lining the alveolar surface (not visible in Figure 32–6) and the plasma in the capillary. The barrier to diffusion is normally 0.2–0.5 μm thick. Gas exchange by diffusion is discussed in Chapter 35.

FIGURE 31–5 Scanning electron micrograph of the surface and cross-section of an alveolar septum. Capillaries (C) are seen sectioned in the foreground, with erythrocytes (EC) within them. A, alveolus; D, alveolar duct; PK, pore of Kohn; AR, alveolar entrance to duct; *, connective tissue fibers. The encircled asterisk is at a junction of three septa. (Reproduced with permission from Fishman AP, Elias JA: Fishman’s Pulmonary Diseases and Disorders, 3rd ed. New York: McGraw-Hill, Health Professions Division, 1998.)

number of alveoli to be 480 million), are almost completely enveloped in pulmonary capillaries. There may be as many as 280 billion pulmonary capillaries, or approximately 500–1,000 pulmonary capillaries per alveolus. The result of these staggering numbers of alveoli and pulmonary capillaries is a vast area of contact between alveoli and pulmonary capillaries— probably 50–100 m2 of surface area available for gas exchange by diffusion. The alveoli are about 200–250 μm in diameter. Figure 31–5 shows an even greater magnification of the site of gas exchange than that shown in Figure 31–4. The alveolar septum appears to be almost entirely composed of pulmonary capillaries. Red blood cells (erythrocytes) can be seen inside the capillaries at the point of section. Elastic and connective tissue fibers, not visible in the figure, are found between the capillaries in the alveolar septa. Also shown in these figures are the pores of Kohn that are interalveolar communications. The alveolar surface is mainly composed of a single thin layer of squamous epithelial cells, the type I alveolar cells. Interspersed among these are the larger cuboidal type II alveolar cells that produce the fluid layer that lines the alveoli. Although there are about twice as many type II cells as there are type I cells in the human lung, type I cells cover 90–95% of the alveolar surface, because the average type I cell has a much larger surface area than the average type II cell does. A third cell type, the free-ranging phagocytic alveolar macrophage, is found in varying numbers in the extracellular lining of the alveolar surface. These cells patrol the alveolar surface and phagocytize inspired particles such as bacteria. The type II alveolar epithelial cell also plays a major role in the response of

FIGURE 31–6

Transmission electron micrograph of a crosssection of a pulmonary capillary. An erythrocyte (EC) is seen within the capillary. C, capillary; EN, capillary endothelial cell (note its large nucleus); EP, alveolar epithelial cell; IN, interstitial space; BM, basement membrane; FB, fibroblast processes; 2, 3, and 4, diffusion pathway through the alveolar–capillary barrier, the plasma, and the erythrocyte, respectively.

(Reproduced with permission from Weibel, E.R. : Morphometric estimation of pulmonary diffusion capacity, I. Model and method. Respir Physiol 1970;11:54–75.)

CHAPTER 31 Function and Structure of the Respiratory System

Removal of Material from the Alveolar Surface Inspired material that reaches the terminal airways and alveoli may be removed in several ways, including ingestion by alveolar macrophages, enzymatic destruction, entry into the lymphatics, and immunologic reactions. Inhaled particles engulfed by alveolar macrophages may be destroyed by their lysosomes (see Chapter 1). Most bacteria are digested in this manner. Some material ingested by the macrophages, however, such as silica, is not degradable by the macrophages and may even be toxic to them. If the macrophages carrying such material are not removed from the lung, the material will be redeposited on the alveolar surface on the death of the macrophages. The mean life span of alveolar macrophages is believed to be 1–5 weeks. The main exit route of macrophages carrying such nondigestible material is migration to the mucociliary escalator via the pores of Kohn and eventual removal through the airways. Particle-containing macrophages may also migrate from the alveolar surface into the septal interstitium, from which they may enter the lymphatic system or the mucociliary escalator. Macrophage function has been shown to be inhibited by cigarette smoke. Alveolar macrophages are also important in the lung’s immune and inflammatory responses. They secrete many enzymes, arachidonic acid metabolites, immune response components, growth factors, cytokines, and other mediators that modulate the function of other cells, such as lymphocytes. Some particles reach the mucociliary escalator because the alveolar fluid lining itself is slowly moving upward toward the respiratory bronchioles. Others penetrate into the interstitial space or enter the blood, where they are phagocytized by interstitial macrophages or blood phagocytes, or enter the lymphatics. Particles may be destroyed or detoxified by surface enzymes and factors in the serum and in airway secretions.

THE MUSCLES OF RESPIRATION AND THE CHEST WALL The muscles of respiration and the chest wall are essential components of the respiratory system. The lungs are not capable of inflating themselves—the force for this inflation must be supplied by the muscles of respiration. The chest wall must be intact and able to expand if air is to enter the alveoli normally. The interactions among the muscles of respiration and the chest wall and the lungs are discussed in detail later in Chapter 32. The primary components of the chest wall include the rib cage; the external and internal intercostal muscles and the diaphragm, which are the main muscles of respiration; and the

311

lining of the chest wall, the visceral and parietal pleura. Other muscles of respiration include the abdominal muscles, including the rectus abdominis; the parasternal intercartilaginous muscles; and the sternocleidomastoid and scalenus muscles.

THE CENTRAL NERVOUS SYSTEM AND THE NEURAL PATHWAYS Another important component of the respiratory system is the central nervous system. Unlike cardiac muscle, the muscles of respiration do not contract spontaneously. Each breath is initiated in the brain, and this message is carried to the respiratory muscles via the spinal cord and the nerves innervating the respiratory muscles. Spontaneous automatic breathing is generated by groups of neurons located in the medulla. This medullary respiratory center is also the final integration point for influences from higher brain centers, for information from chemoreceptors in the blood and cerebrospinal fluid, and for afferent information from neural receptors in the airways, joints, muscles, skin, and elsewhere in the body. The control of breathing is discussed in Chapter 38.

CHAPTER SUMMARY ■

■

The main function of the respiratory system is the exchange of oxygen from the atmosphere for carbon dioxide produced by the cells of the body. Other functions of the respiratory system include participation in the acid–base balance of the body, phonation, pulmonary defense, and metabolism.

STUDY QUESTIONS 1. The functions of the respiratory system include A) gas exchange. B) acid–base balance. C) phonation. D) pulmonary defense and metabolism. E) handling bioactive materials. F) all of the above. 2. Particulate matter in the inspired air that enters the airways or alveoli may be removed by A) the mucociliary escalator. B) alveolar macrophages. C) surface enzymes. D) the lymphatics. E) all of the above.

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32 C

Mechanics of the Respiratory System Michael Levitzky

H A

P

T

E

R

O B J E C T I V E S ■ ■ ■ ■

■ ■ ■ ■ ■ ■

Describe the generation of a pressure gradient between the atmosphere and the alveoli. Describe the passive expansion and recoil of the alveoli. Define the mechanical interaction of the lung and the chest wall. Describe the pressure–volume characteristics of the lung and the chest wall, and predict changes in the compliance of the lung and the chest wall in different physiologic and pathologic conditions. State the roles of pulmonary surfactant and alveolar interdependence in the recoil and expansion of the lung. Define the functional residual capacity (FRC), and predict changes in FRC in different physiologic and pathologic conditions. Define airway resistance and list the factors that contribute to or alter the resistance to airflow. Describe the dynamic compression of airways during a forced expiration. List the factors that contribute to the work of breathing. Predict alterations in the work of breathing in different physiologic and pathologic states.

Air, like other fluids, moves from a region of higher pressure to one of lower pressure. Therefore, for air to be moved into or out of the lungs, a pressure difference between the atmosphere and the alveoli must be established. If there is no pressure gradient, no airflow will occur. Under normal circumstances, inspiration is accomplished by causing alveolar pressure to decrease below atmospheric pressure. When the mechanics of breathing are being discussed, atmospheric pressure is conventionally referred to as 0 cm H2O, so lowering alveolar pressure below atmospheric pressure is known as negative-pressure breathing. When a pressure gradient sufficient to overcome the resistance to airflow offered by the conducting airways is established between the atmosphere and the alveoli, air flows into the lungs. It is also possible to cause air to flow into the lungs by increasing the pressure at the nose or mouth above alveolar pressure. This positive-pressure ventilation is generally used on patients unable to generate a pressure gradi-

Ch32_313-330.indd 313

ent between the atmosphere and the alveoli by normal negative-pressure breathing. Air flows out of the lungs when alveolar pressure is sufficiently greater than atmospheric pressure to overcome the resistance to airflow offered by the conducting airways.

GENERATION OF A PRESSURE GRADIENT BETWEEN THE ATMOSPHERE AND THE ALVEOLI During normal negative-pressure breathing, alveolar pressure is made lower than atmospheric pressure. This is accomplished by causing the muscles of inspiration to contract, which increases the volume of the alveoli, thus lowering the alveolar pressure according to Boyle’s law: at constant temperature, the product of the pressure and the volume of a gas is constant. 313

12/15/10 11:46:29 AM

314

SECTION VI Pulmonary Physiology atmospheric pressure: 0 cm H2O

atmospheric pressure: 0 cm H2O

no air flow: atmospheric pressure = alveolar pressure

air flows in : atmospheric pressure>alveolar pressure outward recoil of chest wall

alveolar pressure: 0 cm H2O

force generated by inspiratory muscles

alveolar pressure: 1 cm H2O inward recoil of alveoli

intrapleural pressure: 5 cm H2O

transmural pressure  0 cm H2O(5 cm H2O)5 cm H2O

END EXPIRATION

intrapleural pressure: 8 cm H2O

transmural pressure  1 cm H2O (8 cm H2O)7 cm H2O DURING INSPIRATION

FIGURE 32–1 Representation of the interaction of the lung and chest wall. Left: At end expiration, the muscles of respiration are relaxed. The inward elastic recoil of the lung is balanced by the outward elastic recoil of the chest wall. Intrapleural pressure is –5 cm H2O; alveolar pressure is 0. The transmural pressure gradient across the alveolus is therefore 0 – (–5) cm H2O, or 5 cm H2O. Since alveolar pressure is equal to atmospheric pressure, no airflow occurs. Right: During inspiration, contraction of the muscles of inspiration causes intrapleural pressure to become more negative. The transmural pressure gradient increases and the alveoli are distended, decreasing alveolar pressure below atmospheric pressure, which causes air to flow into the alveoli. (Modified with permission from Levitzky MG: Pulmonary Physiology, 7th ed. New York: McGraw-Hill Medical, 2007.) The alveoli are not capable of expanding themselves. They expand passively in response to an increased distending pressure across the alveolar wall. This increased transmural pressure gradient, generated by the muscles of inspiration, further opens the highly distensible alveoli and thus decreases the alveolar pressure. The transmural pressure gradient is conventionally calculated by subtracting the outside pressure (in this case, the intrapleural pressure) from the inside pressure (in this case, the alveolar pressure). The pressure in the thin, liquid-filled space between the visceral and parietal pleura is normally slightly less than atmospheric pressure, even when no inspiratory muscles are contracting. This negative intrapleural pressure (sometimes also referred to as negative intrathoracic pressure) of –3 to –5 cm H2O is mainly caused by the mechanical interaction between the lung and the chest wall. At the end of expiration, when all the respiratory muscles are relaxed, the lung and the chest wall are acting on each other in opposite directions. The lung is tending to decrease its volume because of the inward elastic recoil of the distended alveolar walls; the chest wall is tending to increase its volume because of its outward elastic recoil. Thus, the chest wall is acting to hold the alveoli open in opposition to their elastic recoil. Similarly, the lung is acting by its elastic recoil to hold the chest wall in. Because of this interaction, the pressure is negative at the surface of the very thin (about 10–30 μm in thickness at normal lung volumes),

fluid-filled pleural space, as seen on the left in Figure 32–1. There is normally no free gas in the intrapleural space, and the lung is held against the chest wall by the thin layer of serous intrapleural liquid, estimated to have a total volume of about 15–25 mL in the average adult. Initially, before any airflow occurs, the pressure inside the alveoli is the same as atmospheric pressure—by convention 0 cm H2O. Alveolar pressure is greater than intrapleural pressure because it represents the sum of the intrapleural pressure plus the alveolar elastic recoil pressure: Alveolar pressure = Intrapleural pressure + Alveolar elastic recoil pressure

(1)

The muscles of inspiration act to increase the volume of the thoracic cavity. As the inspiratory muscles contract, expanding the thoracic volume and increasing the outward stress on the lung, the intrapleural pressure becomes more negative. Therefore, the transmural pressure gradient tending to distend the alveolar wall (also called the transpulmonary pressure) increases as shown in Figure 32–1, and the alveoli enlarge passively. Increasing alveolar volume lowers alveolar pressure and establishes the pressure gradient for airflow into the lung. In reality, only a small percentage of the total number of alveoli are directly exposed to the intrapleural surface pressure, and at first thought, it is difficult to see how alveoli located centrally in the lung could be expanded by a more negative intrapleural

CHAPTER 32 Mechanics of the Respiratory System

Intrapleural pressure

315

Negative pressure breathing (A)

Interdependence of alveolar units

Positive pressure ventilation (B)

FIGURE 32–2 Structural interdependence of alveolar units. The pressure gradient across the outermost alveoli is transmitted mechanically through the lung via the alveolar septa. The insets show the author’s idea of what might happen in negative-pressure breathing and positive-pressure ventilation. In negative-pressure breathing (inset A), the mechanical stress would likely be transmitted from the more exterior alveoli (those closest to the chest wall) to more interior alveoli, so the exterior alveoli might be more distended. In positive-pressure ventilation (inset B), the lungs must push against the diaphragm and rib cage to move them. The outermost alveoli might be more compressed than those located more interiorly. (Modified with permission from Levitzky MG: Pulmonary Physiology, 7th ed. New York: McGraw-Hill Medical, 2007.)

pressure. However, careful analysis has shown that the pressure at the pleural surface is transmitted through the alveolar walls to more centrally located alveoli and small airways. This structural interdependence of alveolar units is depicted in Figure 32–2.

THE MUSCLES OF RESPIRATION Inspiratory Muscles The muscles of respiration are skeletal muscles and their activity is normally initiated by the nervous system.The muscles of inspiration include the diaphragm, the external intercostal muscles, and the accessory muscles of inspiration. The diaphragm is a large (about 250 cm2 in surface area), domeshaped muscle that separates the thorax from the abdominal cavity. It is the primary muscle of inspiration. When a person is in the supine position, the diaphragm is responsible for about two thirds of the air that enters the lungs during normal quiet breathing (which is called eupnea). When a person is standing or seated in an upright posture, the diaphragm may be responsible for only about one third to one half of the tidal

volume. It is innervated by the two phrenic nerves, which are motor nerves that leave the spinal cord at the third to the fifth cervical segments. The muscle fibers of the diaphragm are inserted into the sternum and the six lower ribs and into the vertebral column by the two crura. The other ends of these muscle fibers converge to attach to the fibrous central tendon, which is also attached to the pericardium on its upper surface (Figure 32–3). During normal quiet breathing, contraction of the diaphragm causes its dome to descend 1–2 cm into the abdominal cavity, with little change in its shape. This elongates the thorax and increases its volume. These small downward movements of the diaphragm are possible because the abdominal viscera can push out against the relatively compliant abdominal wall. During a deep inspiration, the diaphragm can descend as much as 10 cm. With such a deep inspiration, the limit of the abdominal wall to expand is reached, abdominal pressure increases, and the indistensible central tendon becomes fixed against the abdominal contents. After this point, contraction of the diaphragm against the fixed central tendon elevates the lower ribs as shown in the figure. Contraction of the external intercostal, parasternal intercostal, and scalene muscles raises and enlarges the rib cage.

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SECTION VI Pulmonary Physiology

Pleura Rib cage Mediastinum Pericardium Central tendon Diaphragm Crura

END EXPIRATION

FIGURE 32–3

DEEP INSPIRATION

Illustration of the actions of diaphragmatic contraction in expanding the thoracic cavity. (Modified with permission from

Levitzky MG: Pulmonary Physiology, 7th ed. New York: McGraw-Hill Medical, 2007.)

Figure 32–4 demonstrates how contraction of these muscles increases the anteroposterior dimension of the chest as the ribs rotate upward about their axes and also increases the transverse dimension of the lower portion of the chest. These muscles are innervated by nerves leaving the spinal cord at the 1st to the 11th thoracic segments. During inspiration, the diaphragm and inspiratory rib cage muscles contract simultaneously. If the diaphragm contracted alone, the rib cage muscles would be pulled inward (this is called retraction). If the

INSPIRATION

inspiratory muscles of the rib cage contracted alone, the diaphragm would be pulled upward into the thorax. The accessory muscles of inspiration are not involved during normal quiet breathing but may be called into play during exercise, during the inspiratory phase of coughing or sneezing, or in a pathologic state, such as asthma. Dyspnea, the feeling that breathing is difficult, is probably often related to fatigue of the inspiratory muscles. Other potential causes of dyspnea will be discussed in Chapter 38.

ACTIVE EXPIRATION

Accessory muscles

External intercostals Internal intercostals

Diaphragm

Abdominal muscles Posterior

FIGURE 32–4

Anterior

Illustration of the actions of contraction of the intercostal muscles, abdominal muscles, and accessory muscles.

(Modified with permission of the publisher from by Weibel ER: The Pathway for Oxygen. Cambridge, MA: Harvard University Press, p. 304. Copyright © 1984 by the President and Fellows of Harvard College.)

CHAPTER 32 Mechanics of the Respiratory System

Expiratory Muscles Expiration is passive during normal quiet breathing, and no respiratory muscles contract. As the inspiratory muscles relax, the increased elastic recoil of the distended alveoli is sufficient to decrease the alveolar volume and raise alveolar pressure above atmospheric pressure, establishing the pressure gradient for airflow from the lung. Although the diaphragm is usually considered to be completely relaxed during expiration, it is likely that some diaphragmatic muscle tone is maintained, especially when one is in the horizontal position. Active expiration occurs during exercise, speech, singing, the expiratory phase of coughing or sneezing, and in pathologic states such as chronic bronchitis. The main muscles of expiration are the muscles of the abdominal wall and the internal intercostal muscles. When the abdominal muscles contract, they increase abdominal pressure and push the abdominal contents against the relaxed diaphragm, forcing it upward into the thoracic cavity. They also help depress the lower ribs and pull down the anterior part of the lower chest. Contraction of the internal intercostal muscles depresses the rib cage downward in a manner opposite to the actions of the external intercostals. Active expiration compresses the thorax and causes positive intrapleural pressure. This has important effects on the respiratory system, which will be discussed later

in this chapter, and on pulmonary blood flow, which will be discussed in Chapter 34.

SUMMARY OF THE EVENTS OCCURRING DURING THE COURSE OF A BREATH The events occurring during the course of an idealized normal quiet breath (summarized in Table 32–1) are shown in Figure 32–5. For the purpose of clarity, inspiration and expiration are considered to be of equal duration, although during normal quiet breathing, the expiratory phase is longer than the inspiratory phase. Initially, alveolar pressure equals atmospheric pressure, so no air flows into the lung. Intrapleural pressure is –5 cm H2O. Contraction of the inspiratory muscles causes intrapleural pressure to become more negative as the lungs are pulled open and the alveoli are distended. As the alveoli are distended, the pressure inside them decreases below atmospheric pressure and air flows into the alveoli, as seen in the tidal volume panel. As the air flows into the alveoli, alveolar pressure returns to 0 cm H2O and airflow into the lung ceases. At the vertical line, the inspiratory effort ceases and the inspiratory muscles relax. Intrapleural pressure becomes less negative, and the elastic recoil of the

TABLE 32–1 Events involved in a normal tidal breath. Inspiration 1. Brain initiates inspiratory effort 2. Nerves carry the inspiratory command to the inspiratory muscles 3. Diaphragm (and/or external intercostal muscles) contracts 4. Thoracic volume increases as the chest wall expandsa 5. Intrapleural pressure becomes more negative 6. Alveolar transmural pressure gradient increases 7. Alveoli expand (according to their individual compliance curves) in response to the increased transmural pressure gradient. This increases alveolar elastic recoil 8. Alveolar pressure falls below atmospheric pressure as the alveolar volume increases, thus establishing a pressure gradient for airflow 9. Air flows into the alveoli until alveolar pressure equilibrates with atmospheric pressure Expiration (passive) 1. Brain ceases inspiratory command 2. Inspiratory muscles relax 3. Thoracic volume decreases, causing intrapleural pressure to become less negative and decreasing the alveolar transmural pressure gradientb 4. Decreased alveolar transmural pressure gradient allows the increased alveolar elastic recoil to return the alveoli to their preinspiratory volumes 5. Decreased alveolar volume increases alveolar pressure above atmospheric pressure, thus establishing a pressure gradient for airflow 6. Air flows out of the alveoli until alveolar pressure equilibrates with atmospheric pressure a

Note that numbers 4–8 occur simultaneously.

b

317

Note that numbers 3–5 occur simultaneously.

Reproduced with permission from Levitzky MG, Cairo JM, Hall SM: Introduction to Respiratory Care. Philadelphia: WB Saunders and Company, 1990.

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SECTION VI Pulmonary Physiology

100

–5

–10 +1

cm H2O

Alveolar pressure

0

75 Total lung volume, %

Intrapleural pressure

cm H2O

Expiration

Inspiration 50

25

–1 +0.5 L/sec

Air flow

0 –0.5

FIGURE 32–6

0.5

20 10 30 Transpulmonary pressure cm H2O

40

Pressure–volume curve for isolated lungs.

(Modified with permission from Levitzky MG: Pulmonary Physiology, 7th ed.

Change in lung volume

L

0 Onset of inspiration

0

End of inspiration

End of expiration

FIGURE 32–5 Volume, pressure, and airflow changes during a single idealized respiratory cycle. Described in text. (Reproduced with permission from Kibble J, Halsey CR: The Big Picture, Medical Physiology. New York: McGraw-Hill, 2009.)

alveolar walls (which is increased at the higher lung volume) is allowed to compress the alveolar gas. This raises alveolar pressure above atmospheric pressure so that air flows out of the lung until an alveolar pressure of 0 cm H2O is restored. At this point, airflow ceases until the next inspiratory effort.

PRESSURE–VOLUME RELATIONSHIPS IN THE RESPIRATORY SYSTEM The relationship between changes in the pressure distending the alveoli and changes in lung volume is important to understand because it dictates how the lung inflates with each breath. As mentioned before, the alveolar-distending pressure is often referred to as the transpulmonary pressure.

COMPLIANCE OF THE LUNG AND THE CHEST WALL The pressure–volume characteristics of the lung can be inspected in several ways. One of the simplest is to remove the

New York: McGraw-Hill Medical, 2007.)

lungs from an animal or a cadaver and then graph the changes in volume that occur for each change in transpulmonary pressure to which the lungs are subjected (Figure 32–6). Figure 32–6 shows that as the transpulmonary pressure increases, the lung volume increases. Of course, this relationship is not a straight line: the lung is composed of living tissue, and although the lung distends easily at low lung volumes, at high lung volumes the distensible components of alveolar walls have already been stretched, and large increases in transpulmonary pressure yield only small increases in volume. The lung also is difficult to distend at very low lung volumes because some alveoli may be collapsed and extra energy is necessary to reopen them. The slope between two points on a pressure–volume curve is known as the compliance. Compliance is defined as the change in volume divided by the change in pressure. Lungs with high compliance have a steep slope on their pressure–volume curves, that is, a small change in distending pressure will cause a large change in volume. It is important to remember that compliance is the inverse of elasticity, or elastic recoil. Compliance denotes the ease with which something can be stretched or distorted; elasticity refers to the tendency for something to oppose stretch or distortion, as well as to its ability to return to its original configuration after the distorting force is removed. There are several other interesting things to note about an experiment like that illustrated in Figure 32–6. The curve obtained is the same whether the lungs are inflated with positive pressure (by forcing air into the trachea) or with negative pressure (by suspending the lung, except for the trachea, in a closed chamber and pumping out the air around the lung). So when the lung alone is considered, only the transpulmonary pressure is important, not how the transpulmonary pressure is generated. A second feature of the curve in Figure 32–6 is that there is a difference between the pressure–volume curve for

CHAPTER 32 Mechanics of the Respiratory System

Clinical Evaluation of the Compliance of the Lung and the Chest Wall The compliance of the lung and the chest wall provides very useful data for the clinical evaluation of a patient’s respiratory system because many diseases or pathologic states affect the compliance of the lung, the chest wall, or both. The lung and the chest wall are physically in series with each other, and therefore their compliances add as reciprocals: 1 ____________ = Total compliance 1 1 _________________ + ____________________ Compliance of the lung Compliance of the chest wall

(2)

Compliances in parallel add directly. Therefore, both lungs together are more compliant than either one alone. The compliance curve for the lungs can be generated by having the patient take a very deep breath and exhale in stages, stopping periodically for pressure and volume determinations. During these determinations, no airflow is occurring; alveolar pressure therefore equals atmospheric pressure, 0 cm H2O. Similar measurements can be made as the patient inhales in stages from a low lung volume to a high lung volume. Such curves are called static compliance curves because all measurements are made when no airflow is occurring. The compliance of the chest wall is normally obtained by determining the compliance of the total system and the compliance of the lungs alone and then calculating the compliance of the chest wall according to the above formula. Dynamic compliance assesses pressure–volume characteristics during the breath. Representative static compliance curves for the lungs are shown in Figure 32–7. Note that these curves correspond to the expiratory curve in Figure 32–6. Many pathologic states shift the curve to the right; that is, for any increase in transpulmonary pressure, there is a smaller increase in lung volume. A proliferation of connective tissue called fibrosis may occur in sarcoidosis or after chemical or thermal injury to the lungs. This will make the lungs less compliant, or “stiffer,” and increase alveolar elastic recoil. Similarly, pulmonary vascular engorgement or areas of collapsed alveoli (atelectasis) also make the lung less compliant. Other conditions that interfere with the lung’s ability to expand (such as the presence of air, excess fluid, or blood in the intrapleural space) will decrease the measured compliance of the lungs. Emphysema increases

Compliance =

Δ Lung volume ΔV = Δ (P alv – P ip) Δ P tp

Increased compliance

Lung volume (ml)

inflation and the curve for deflation, as shown by the arrows. Such a difference is called hysteresis. One possible explanation for this hysteresis is the stretching on inspiration and the compression on expiration of the surfactant that lines the air– liquid interface in the alveoli (discussed later in this chapter). Another is that some alveoli or small airways may open on inspiration (“recruitment”) and close on expiration (“derecruitment”) as noted above. Some researchers believe that lung volume changes primarily by recruitment and derecruitment of alveoli rather than by volume changes of individual alveoli. Finally, it can be helpful to think of each alveolus as having its own pressure–volume curve like that shown in the figure.

319

0

Normal compliance

Decreased compliance

Transpulmonary pressure (P tp) (P alv – P ip)

FIGURE 32–7 Representative static pulmonary compliance curve for normal lungs; lungs with low compliance, for example, lungs with fibrosis; and lungs with high compliance, for example, lungs with emphysema. (Reproduced with permission from Widmaier EP, Raff H, Strang KT: Vander’s Human Physiology, 11th ed. McGraw-Hill, 2008.)

the compliance of the lungs because it destroys the alveolar septal tissue that normally opposes lung expansion. The compliance of the chest wall is decreased in obese people, for whom moving the diaphragm downward and the rib cage up and out is much more difficult. Musculoskeletal disorders that lead to decreased mobility of the rib cage, such as kyphoscoliosis, also decrease the chest wall compliance. Because they must generate greater transpulmonary pressures to breathe in the same volume of air, people with decreased compliance of the lungs must do more work to inspire than those with normal pulmonary compliance. Similarly, more muscular work must be done when chest wall compliance is decreased.

ELASTIC RECOIL OF THE LUNG So far, the elastic recoil of the lungs has been discussed as though it were only due to the elastic properties of the pulmonary parenchyma itself. However, there is another component of the elastic recoil of the lung—the surface tension at the air– liquid interface in the alveoli. Surface tension forces occur at any gas–liquid interface and are generated by the cohesive forces between the molecules of the liquid. These cohesive forces balance each other within the liquid phase but are unopposed at the surface of the liquid. Surface tension causes water to bead and form droplets, and a liquid to shrink to form the smallest possible surface

320

SECTION VI Pulmonary Physiology

Saline

200

Air

Volume (mL)

150 T

P

T  Pr

T

100

50 Resolved direction of tension 0

4

8 12 16 Pressure (cm H2O)

T

FIGURE 32–9 Relationship between the pressure inside a distensible sphere, such as an alveolus, and its wall tension.

20

FIGURE 32–8

Pressure–volume curves for excised cat lungs inflated with air or saline. (Modified from Radford EP. Recent studies of

(Modified with permission from Levitzky MG: Pulmonary Physiology, 7th ed. New York: McGraw-Hill Medical, 2007.)

mechanical properties of mammalian lungs. In: Remington JW. Tissue Elasticity. Washington: American Physiological Society; 1957.)

area. The role of the surface tension forces in the elastic recoil of the lung can be demonstrated in an experiment shown in Figure 32–8. In this experiment, a pressure–volume curve for an excised lung was first generated with air inflation, so an air–liquid interface was present in the lung, and surface tension forces contributed to alveolar elastic recoil. Then, all the gas was removed from the lung, and it was inflated again, this time with saline instead of with air. In this situation, surface tension forces were absent because there was no air–liquid interface. The elastic recoil was due only to the lung tissue itself. Note that there is no hysteresis with saline inflation. Whatever causes the hysteresis appears to be related to surface tension in the lung. The curve at left (saline inflation) therefore represents the elastic recoil due to only the lung tissue itself; the curve at right demonstrates the recoil due to both the lung tissue and the surface tension forces. The difference between the two curves is the recoil due to surface tension forces. The demonstration of the large role of surface tension forces in the recoil pressure of the lung led to consideration of how surface tension affects the alveoli. One traditional way of thinking about this has been to consider the alveolus to be a sphere hanging from the airway, as in Figure 32–9. The relationship between the pressure inside the alveolus and the wall tension of the alveolus would then be given by Laplace’s law (units in brackets): 2 × tension [dyn/cm] Pressure [dyn/cm ] = _______________ Radius [cm] 2

(3)

If two alveoli of different sizes are connected by a common airway (Figure 32–10) and the surface tension of the two alveoli is equal, then according to Laplace’s law, the pressure in the small alveolus is greater than that in the larger alveolus and the smaller alveolus will empty into the larger alveolus. If surface tension is independent of surface area, the smaller the alveolus on the right becomes, the higher the pressure in it. Thus, if the lung were composed of interconnected alveoli of different sizes (which it is) with a constant surface tension at the air–liquid interface, it would be inherently unstable, with a tendency for smaller alveoli to collapse into larger ones. This is usually not the case, which is fortunate because collapsed alveoli require very great distending pressures to reopen, partly because of the cohesive forces at the liquid–liquid interface of collapsed alveoli. At least two factors cause the alveoli to be more stable than this prediction based on constant surface

T

P1 r

P1 

(4)

where T is the wall tension, P the pressure inside the alveolus, and r the radius of the alveolus. The surface tension of most liquids (such as water) is constant and not dependent on the area of the air–liquid interface.

2r

T r P2 

This can be rearranged as follows: Pr T = __ 2

T P2

T 2r

FIGURE 32–10 Schematic representation of two alveoli of different sizes connected to a common airway. If the surface tension is the same in both alveoli, then the smaller alveolus will have a higher pressure and will empty into the larger alveolus. (Modified with permission from Levitzky MG: Pulmonary Physiology, 7th ed. New York: McGraw-Hill Medical, 2007.)

CHAPTER 32 Mechanics of the Respiratory System tension. The first factor is a substance called pulmonary surfactant, which is produced by specialized alveolar cells, and the second is the structural interdependence of the alveoli.

Pulmonary Surfactant Pulmonary surfactant decreases the elastic recoil due to surface tension, thereby increasing the compliance of the lungs above that predicted by an air–water interface and decreasing the inspiratory work of breathing. Pulmonary surfactant has a second major effect. It decreases the surface tension of smaller alveoli. This helps equalize alveolar pressures throughout the lung (so the end-expiratory pressure of all the alveoli is 0 cm H2O and the situation depicted in Figure 32–10 does not occur) and to stabilize alveoli. Pulmonary surfactant is a complex consisting of about 85–90% lipids and 10–15% proteins. The lipid portion is about 85% phospholipid, approximately 75% of which is dipalmitoyl phosphatidylcholine. This complex is produced by type II alveolar epithelial cells (described above). Pulmonary surfactant appears to be continuously produced in the lung, but it is also continuously cleared from the lung. Some pulmonary surfactant is taken back into the type II cells (reuptake), where it is recycled and secreted again, or it is degraded and used to synthesize other phospholipids. Surfactant is also cleared from the alveoli by alveolar macrophages, absorption into the lymphatics, or migration up to the small airways and the mucociliary escalator (discussed in Chapter 31). Type II alveolar epithelial cells may also help remove liquid from the alveolar surface by actively pumping sodium and water from the alveolar surface into the interstitium. The clinical consequences of a lack of functional pulmonary surfactant occur in several conditions. Surfactant is not produced by the fetal lung until about the fourth month of gestation, and it may not be fully functional until the seventh month or later. Prematurely born infants who do not have functional pulmonary surfactant experience great difficulty in inflating their lungs, especially on their first breaths. Even if their alveoli are inflated for them with positive-pressure ventilation, the tendency toward spontaneous collapse is great because their alveoli are much less stable without pulmonary surfactant. Therefore, the lack of functional pulmonary surfactant in a prematurely born neonate may be a major factor in the infant respiratory distress syndrome. Pulmonary surfactant may also be important in maintaining the stability of small airways. Alveolar hypoxia or hypoxemia (low oxygen in the arterial blood), or both, may lead to a decrease in surfactant production or an increase in surfactant destruction. This condition may be a contributing factor in the acute respiratory distress syndrome (also known as adult respiratory distress syndrome or “shock lung syndrome”) that can occur in patients after trauma or surgery. One approach to maintain patients with acute or infant respiratory distress syndrome is to ventilate their lungs with positive-pressure ventilators and to keep their alveolar pressure above atmospheric pressure during expiration (this is known as positive end-expiratory pressure [PEEP]). This process opposes the increased elastic recoil of

321

the alveoli and the tendency for spontaneous atelectasis to occur because of a lack of pulmonary surfactant. Exogenous pulmonary surfactant is now administered directly into the airway of neonates with infant respiratory distress syndrome. In summary, pulmonary surfactant helps decrease the work of inspiration by lowering the surface tension of the alveoli, thus reducing the elastic recoil of the lung and making the lung more compliant. Surfactant also helps stabilize the alveoli by lowering even further the surface tension of smaller alveoli, equalizing the pressure inside alveoli of different sizes.

Alveolar Interdependence A second factor tending to stabilize the alveoli is their mechanical interdependence, which was discussed at the beginning of this chapter. Alveoli do not hang from the airways like a “bunch of grapes” (the translation of the Latin word “acinus”), and they are not spheres. They are mechanically interdependent polygons with flat walls shared by adjacent alveoli. Alveoli are normally held open by the chest wall pulling on the outer surface of the lung, as shown in Figure 32–2. If an alveolus were to begin to collapse, it would increase the stresses on the walls of the adjacent alveoli, which would tend to hold it open. This process would oppose a tendency for isolated alveoli with a relative lack of pulmonary surfactant to collapse spontaneously. Conversely, if a whole subdivision of the lung (such as a lobule) has collapsed, as soon as the first alveolus is reinflated, it helps to pull other alveoli open by its mechanical interdependence with them. Thus, both pulmonary surfactant and the mechanical interdependence of the alveoli help stabilize the alveoli and oppose alveolar collapse (atelectasis).

MECHANICAL INTERACTION OF THE LUNG AND CHEST WALL The inward elastic recoil of the lung normally opposes the outward elastic recoil of the chest wall, and vice versa. If the integrity of the lung–chest wall system is disturbed by breaking the seal of the chest wall (e.g., by a penetrating knife wound), the inward elastic recoil of the lung is no longer opposed by the outward recoil of the chest wall, and their interdependence ceases. Lung volume decreases, and alveoli have a much greater tendency to collapse, especially if air moves in through the wound (causing a pneumothorax) until intrapleural pressure equalizes with atmospheric pressure and abolishes the transpulmonary pressure gradient. At this point, nothing is tending to hold the alveoli open and their elastic recoil is causing them to collapse. Similarly, the chest wall tends to expand because its outward recoil is no longer opposed by the inward recoil of the lung. When the lung–chest wall system is intact and the respiratory muscles are relaxed, the volume of gas left in the lungs is determined by the balance of these two forces. The volume of gas in the lungs at the end of a normal tidal expiration, when no respiratory muscles are actively contracting, is known as the

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functional residual capacity (FRC). For any given situation, the FRC will be that lung volume at which the outward recoil of the chest wall is equal and opposite to the inward recoil of the lungs. If the lung volume increases above the FRC, the increased inward elastic recoil of the lung exceeds the decreased outward elastic recoil of the chest wall. At high lung volumes (above about 70% of the total lung capacity [TLC]), the chest wall also has inward elastic recoil. Therefore, at high lung volumes, the elastic recoil of both the lung and chest wall are inward. At lung volumes below the FRC, the outward recoil of the chest wall is greater than the reduced inward recoil of the lungs. A change from the upright to the supine position decreases FRC. The reason for this decrease of about 30% is the effect of gravity on the mechanics of the chest wall, especially the diaphragm. When standing up or sitting, the contents of the abdomen are being pulled away from the diaphragm by gravity. When lying down, the abdominal contents are pushing inward against the relaxed diaphragm. This decreases the overall outward recoil of the chest wall and decreases the lung volume at which the outward recoil of the chest wall is equal and opposite to the inward recoil of the lungs.

AIRWAY RESISTANCE Several factors besides the elastic recoil of the lungs and the chest wall must be overcome to move air into or out of the lungs. These factors are primarily the frictional resistance of the lung and chest wall tissue, and the frictional resistance of the airways to the flow of air. Pulmonary tissue resistance is caused by the friction encountered as the lung tissues move against each other as the lung expands. The airway resistance plus the pulmonary tissue resistance is often referred to as the pulmonary resistance. Pulmonary tissue resistance normally contributes about 20% of the pulmonary resistance, with airway resistance responsible for the other 80%. Pulmonary tissue resistance can be increased in such conditions as pulmonary sarcoidosis and fibrosis. Because airway resistance is the major component of the total resistance and because it can increase tremendously both in healthy people and in those suffering from various diseases, the remainder of this chapter will concentrate on airway resistance.

LAMINAR, TURBULENT, AND TRANSITIONAL FLOW As was discussed in Chapter 22, the relationship among pressure, flow, and resistance is: Pressure difference = Flow × Resistance

(5)

The resistance to airflow is analogous to electrical resistance in that resistances in series are added directly: Rtot = R1 + R2 + …

(7)

Resistances in parallel are added as reciprocals: 1 1 __ ___ = __ + 1 +… Rtot R1 R2

(8)

Airflow, like that of other fluids, can occur as either laminar or turbulent flow, as was discussed in Chapter 26 (see Figure 26–6). When a fluid such as air is in laminar flow through rigid, smooth bore tubes, its behavior is governed by Poiseuille’s law, as was discussed in Chapter 22. Turbulent flow tends to occur if airflow is high, gas density is high, the tube radius is large, or all three conditions exist. True laminar flow probably occurs only in the smallest airways, where the linear velocity of airflow is extremely low. Linear velocity (cm/s) is equal to the flow (cm3/s) divided by the cross-sectional area. The sum of the cross-sectional areas of the smallest airways is very large, so the linear velocity of airflow is very low. The airflow in the trachea and larger airways is usually either turbulent or a mixture of laminar and turbulent flow.

DISTRIBUTION OF AIRWAY RESISTANCE About 25–40% of the total resistance to airflow is located in the upper airways: the nose, nasal turbinates, oropharynx, nasopharynx, and larynx. Resistance is higher when one breathes through the nose than when one breathes through the mouth. The vocal cords open slightly during normal inspirations and close slightly during expirations. During deep inspirations, they open widely. The muscles of the oropharynx also contract during normal inspiration; this dilates and stabilizes the upper airway. During deep forced inspirations, the development of negative pressure could cause the upper airway to be pulled inward and partly or completely obstruct airflow. Reflex contraction of these pharyngeal dilator muscles normally keeps the airway open. The component with the highest individual resistance of the tracheobronchial tree is obviously the smallest airway, which has the smallest radius. Nevertheless, because the smallest airways are arranged in parallel, their resistances add as reciprocals, so that the total resistance to airflow offered by the numerous small airways is extremely low during normal, quiet breathing. Therefore, the greatest resistance to airflow usually resides in the medium-sized bronchi.

Therefore, we have: Pressure difference [cm H O] Flow [L/s]

2 Resistance = _____________________

(6)

This means that resistance is a meaningful term only during flow. When airflow is considered, the units of resistance are usually cm H2O/[L/s].

CONTROL OF BRONCHIAL SMOOTH MUSCLE The smooth muscle of the airways from the trachea down to the alveolar ducts is under the control of efferent fibers of the

CHAPTER 32 Mechanics of the Respiratory System

Active control of the airways.

Constrict Parasympathetic stimulation Acetylcholine Histamine Leukotrienes Thromboxane A2 Serotonin α-Adrenergic agonists Decreased Pco2 in small airways Dilate Sympathetic stimulation (β2 receptors) Circulating β2 agonists Nitric oxide Increased Pco2 in small airways Decreased Po2 in small airways

100 Airway resistance (% maximum)

TABLE 32–2

323

75

50

25 RV

TLC

0 0

2

4

6

8

Lung volume (L)

autonomic nervous system (see Chapter 19). Stimulation of the cholinergic parasympathetic postganglionic nerves causes constriction of bronchial smooth muscle as well as increased glandular mucus secretion. The preganglionic fibers travel in the vagus nerve. Stimulation of the adrenergic sympathetic nerves causes dilation of bronchial and bronchiolar smooth muscle as well as inhibition of glandular secretion. This dilation of the airway smooth muscle is mediated by beta2 (β2) receptors, which predominate in the airways. Selective stimulation of the alpha (α) receptors with pharmacologic agents causes bronchoconstriction. Adrenergic transmitters carried in the blood may be as important as those released from the sympathetic nerves in causing bronchodilation. The bronchial smooth muscle is normally under greater parasympathetic tone than sympathetic tone. Inhalation of chemical irritants, smoke, or dust; stimulation of the arterial chemoreceptors; and substances such as histamine cause constriction of the airways. Decreased CO2 in the branches of the conducting system causes a local constriction of the smooth muscle of the nearby airways; increased CO2 or decreased O2 causes a local dilation. This may help balance ventilation and perfusion (see Chapter 35). Many other substances can have direct or indirect effects on airway smooth muscle (Table 32–2). Leukotrienes usually cause bronchoconstriction, as do some prostaglandins.

FIGURE 32–11 Relationship between lung volume and airway resistance. Total lung capacity (TLC) is at right; residual volume (RV) is at left. (Reproduced with permission from Kibble J, Halsey CR: The Big Picture, Medical Physiology. New York: McGraw-Hill, 2009.)

resistance, even with so many parallel pathways. To increase lung volume, a person breathing normally takes a “deep breath,” that is, makes a strong inspiratory effort. This effort causes intrapleural pressure to become much more negative than –7 or –10 cm H2O in a normal, quiet breath. The transmural pressure gradient across the wall becomes much more positive, and small airways are distended. A second reason for the decreased airway resistance at higher lung volumes is that the traction on the small airways increases. As shown in the schematic drawing in Figure 32–12, the small airways traveling through the lung form attachments to the walls of alveoli. As the alveoli expand during the course of a deep inspiration, the elastic recoil in their walls increases; this elastic recoil is transmitted to the attachments at the airway, pulling it open.

LUNG VOLUME AND AIRWAY RESISTANCE Airway resistance decreases with increasing lung volume, as shown in Figure 32–11. There are two reasons for this relationship; both mainly involve the small airways that, as described in this chapter, have little or no cartilaginous support. The small airways are therefore rather distensible and also compressible. Thus, the transmural pressure gradient across the wall of the small airways is an important determinant of the radius of the airways: since resistance is inversely proportional to the radius to the fourth power, changes in the radii of small airways can cause dramatic changes in airway

AIRWAY

Traction on airway by elastic recoil of alveolar septa

FIGURE 32–12 Representation of “traction” of the alveolar septa on a small distensible airway. Compare this figure with the picture of the alveolar duct in Figure 31–4. (Modified with permission from Levitzky MG: Pulmonary Physiology, 7th ed. New York: McGraw-Hill Medical, 2007.)

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DYNAMIC COMPRESSION OF AIRWAYS

pressure gradient would generate very high rates of airflow. However, the airways are not uniformly rigid and the smallest airways, which have no cartilaginous support and rely on the traction of alveolar septa to help keep them open, may be compressed or may even collapse. Whether or not they actually collapse depends on the transmural pressure gradient across the walls of the smallest airways. The situation during a normal passive expiration at the same lung volume (note the same alveolar elastic recoil pressure) is shown in the left part of Figure 32–13. The transmural pressure gradient across the smallest airways is +1 – (–8) cm H2O = +9 cm H2O tending to hold the airway open. During the forced expiration at right, the transmural pressure gradient is 30 – 25 cm H2O, or only 5 cm H2O holding the airway open. The airway may then be slightly compressed, and its resistance to airflow will be even greater than that during the passive expiration. This increased resistance during a forced expiration is called dynamic compression of airways. Consider what occurs during a maximal forced expiration. As the expiratory effort is increased to attain a lower lung volume, intrapleural pressure is getting more and more positive, and more and more dynamic compression will occur. Furthermore, as lung volume decreases, there will be less alveolar elastic recoil pressure and the difference between

Airway resistance is extremely high at low lung volumes, as shown in Figure 32–11. To achieve low lung volumes, a person must make a forced expiratory effort by contracting the muscles of expiration, mainly the abdominal and internal intercostal muscles. This effort generates a positive intrapleural pressure, which can be as high as 120 cm H2O during a maximal forced expiratory effort. (Maximal inspiratory intrapleural pressures can be as low as –80 cm H2O.) The effect of this high positive intrapleural pressure on the transmural pressure gradient during a forced expiration can be seen at right in Figure 32–13, a schematic drawing of a single alveolus and airway. The muscles of expiration are generating a positive intrapleural pressure of +25 cm H2O. Pressure in the alveolus is higher than intrapleural pressure because of the alveolar elastic recoil pressure of +10 cm H2O, which, together with intrapleural pressure, gives an alveolar pressure of +35 cm H2O. The alveolar elastic recoil pressure decreases at lower lung volumes because the alveolus is not as distended. In the figure, a gradient has been established from the alveolar pressure of +35 cm H2O to the atmospheric pressure of 0 cm H2O. If the airways were rigid and incompressible, the large expiratory

0

0

0.25

3

8

8

5

25

25

10

0.5 8

8

25

15

25

20 25

8

8

25

1

10

10 8

2

10

10

35 10

10 8

25

25

30

Contraction of internal intercostals and accessory muscles of expiration

10

10 25

Relaxed diaphragm pushed up by abdominal muscle contraction PASSIVE EXPIRATION

FORCED EXPIRATION

FIGURE 32–13 Schematic diagram illustrating dynamic compression of airways and the equal pressure point hypothesis during a forced expiration. Left: Passive (eupneic) expiration. Intrapleural pressure is –8 cm H2O, alveolar elastic recoil pressure is +10 cm H2O, and alveolar pressure is +2 cm H2O. Right: Forced expiration at the same lung volume. Intrapleural pressure is +25 cm H2O, alveolar elastic recoil pressure is +10 cm H2O, and alveolar pressure is +35 cm H2O. (Modified with permission from Levitzky MG: Pulmonary Physiology, 7th ed. New York: McGraw-Hill Medical, 2007.)

alveolar pressure and intrapleural pressure will decrease. At any instant during a forced expiration, there is a point along the airways where the pressure inside the airway is just equal to the pressure outside the airway. At that point (the “equal pressure point”), the transmural pressure gradient is 0 (note the arrows in Figure 32–13). Above that point, the transmural pressure gradient is negative: the pressure outside the airway is greater than the pressure inside it, and the airway will collapse if cartilaginous support or alveolar septal traction is insufficient to keep it open. As the forced expiratory effort continues, the equal pressure point is likely to move down the airway from larger to smaller airways. This movement happens because, as the muscular effort increases, intrapleural pressure increases and because, as lung volume decreases, alveolar elastic recoil pressure decreases. As the equal pressure point moves down the airway, dynamic compression increases and the airways begin to collapse. This airway closure can be demonstrated only at especially low lung volumes in healthy subjects, but the closing volume may occur at higher lung volumes in patients with high lung compliance as in emphysema. The closing volume will be discussed in Chapter 33. During a passive expiration, the pressure gradient for air˙ R) is simply alveolar pressure minus atmoflow (ΔP in ΔP = V spheric pressure. But if dynamic compression occurs, the effective pressure gradient is alveolar pressure minus intrapleural pressure (which equals the alveolar elastic recoil pressure) because intrapleural pressure is greater than atmospheric pressure and because intrapleural pressure can exert its effects on the compressible portion of the airways. Thus, during a forced expiration, when intrapleural pressure becomes positive and dynamic compression occurs, the effective driving pressure for airflow from the lung is the alveolar elastic recoil pressure. Alveolar elastic recoil is also important in opposing dynamic compression of the airways because of its role in the traction of the alveolar septa on small airways, as shown in Figure 32–12. The effects of alveolar elastic recoil on airflow during a forced expiration are illustrated in Figure 32–14.

ASSESSMENT OF AIRWAY RESISTANCE The resistance to airflow cannot be measured directly but must be calculated from the pressure gradient and airflow during a breath: ΔP R = ___ ˙ V

(9)

The above formula is an approximation because it presumes that all airflow is laminar, which is not true. But there is a second problem: how can the pressure gradient be determined? To know the pressure gradient, the alveolar pressure—which also cannot be measured directly—must be known. Alveolar pressure can be calculated using a body plethysmograph, an expensive piece of equipment described in the next chapter, but this procedure is not often done. Instead, airway resistance is usually assessed indirectly. The assessment of airway resis-

PA  Ppl ( Pel)

CHAPTER 32 Mechanics of the Respiratory System

Intrapleural pressure

325

Dynamic compression

Traction

Alveolar elastic recoil

Alveolar elastic recoil

Pel

Pel PA Pel

Pel

FIGURE 32–14 Representation of the effects of alveolar elastic recoil on airflow during a forced expiration. When dynamic compression occurs, alveolar elastic recoil helps to oppose it by traction on the small airways. The alveolar elastic recoil pressure becomes the effective driving pressure for airflow from the lung. PA, alveolar pressure; Ppl, intrapleural pressure; Pel, the alveolar elastic recoil pressure. (Modified with permission from Levitzky MG: Pulmonary Physiology, 7th ed. New York: McGraw-Hill Medical, 2007.)

tance during expiration will be emphasized because that factor is of interest in patients with lung disease.

Forced Vital Capacity One way of assessing expiratory airway resistance is to look at the results of a forced expiration into a spirometer, as shown in Figure 32–15. This measurement is called a forced vital capacity (FVC). The vital capacity (VC) is the volume of air a subject is able to expire after a maximal inspiration to the TLC. An FVC means that a maximal expiratory effort was made during this maneuver. In an FVC test, a person makes a maximal inspiration to the TLC. After a moment, he or she makes a maximal forced expiratory effort, blowing as much air as possible out of the lungs. At this point, only a residual volume (RV) of air is left in the lungs. (The lung volumes will be described in detail in the next chapter.) This procedure takes only a few seconds, as can be seen on the time scale. The part of the curve most sensitive to changes in expiratory airway resistance is the first second of expiration. The volume of air expired in the first second of expiration (the FEV1, or forced expiratory volume in 1 second), especially when expressed as a ratio with the total amount of air expired

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7

Volume (L)

6 5

Normal

4

FEV1 / FVC  80% FEV1  3.6 L

3

Obstruction

RV

FEV1 / FVC  50%

2

FVC  4.5 L FVC  3.0 L

FEV1  1.5 L

1 TLC

RV

0

1

2

3 4 Time (s)

5

6

FIGURE 32–15 Forced vital capacity (FVC) maneuver using a rolling seal spirometer. FVCs from a normal subject and from a patient with obstructive disease. FEV1, forced expiratory volume in the first second. Note that the total lung capacity (TLC) is at the bottom of the curves and the residual volumes (RVs) are at the top; volume therefore refers to the volume exhaled into the spirometer in the bottom trace. The time scale is from left to right. (Modified with permission from Levitzky MG: Pulmonary Physiology, 7th ed. New York: McGraw-Hill Medical, 2007.)

during the FVC, is a good index of expiratory airway resistance. In normal subjects, the FEV1/FVC is greater than 0.80; that is, at least 80% of the FVC is expired in the first second. A patient with an airway obstruction would be expected to have an FEV1/FVC far below 0.80, as shown in Figure 32–16, which shows FVC curves obtained from a commonly used rolling seal spirometer. Note that the TLC is at the bottom left, and the RVs are at the top right. The time scale is left to right. Note the calculations of the FEV1 to FVC ratios for a healthy person and for one with airway obstruction. Figure 32–15 clearly shows that elevated airway resistance takes time to overcome.

Flow–Volume Curves Flow–volume curves are also used to assess airway resistance. A family of flow–volume curves such as that depicted in Figure 32–16 is obtained by having a subject make repeated expiratory maneuvers with different degrees of effort. Flow rates are plotted against lung volume for expiratory efforts of different intensities. There are two interesting points about this family of curves. At high lung volumes, the airflow rate is effort-dependent, which can be seen in the left-hand portion of the curves. As the subject exhales with greater effort, flow rate increases. At low lung volumes, however, the expiratory efforts of different initial intensities all merge into the same effort-independent curve, as seen in the right-hand portion of the curve. This difference is because intrapleural pressures high enough to cause dynamic compression are necessary to attain very low lung volumes, no matter what the initial expiratory effort. Also, at low lung volumes there is less alveolar elastic recoil, so there is less traction on the same airways and a smaller pressure gradient for airflow. The maximal flow–volume curve is used as a diagnostic tool, as shown in Figure 32–17, because it helps distinguish between two major classes of pulmonary diseases—airway obstructive diseases and restrictive diseases, such as fibrosis.

Obstructive diseases interfere with airflow; restrictive diseases restrict the expansion of the lung. Figure 32–17 shows that both obstruction and restriction can cause a decrease in the maximal flow rate that the patient can attain, the peak expiratory flow (PEF; shown in Figure 32–16), but that this decrease occurs for different reasons. Restrictive lung diseases, which usually entail increased alveolar elastic recoil, may have decreased PEF because the TLC (and thus the VC) is decreased. The effort-independent part of the curve is similar to normal lungs. In fact, the FEV1/FVC is usually normal or even above normal since both the FEV1 and FVC are decreased because the lung has a low volume and because alveolar elastic recoil pressure may be increased. On the other hand, with obstructive diseases, the PEF and FEV1/FVC are both low. Obstructive diseases—such as asthma, bronchitis, and emphysema—are often associated with high lung volumes, which is helpful because the high volumes increase the alveolar elastic recoil pressure. The RV may be greatly increased if airway closure occurs at relatively high lung volumes. A second important feature of the flow–volume curve of a patient with obstructive disease is the effort-independent portion of the curve, which is depressed inward: flow rates are low for any relative volume. Flow–volume curves are very useful in assessing obstructions of the upper airways and the trachea. Flow–volume loops can help distinguish between fixed obstructions (those not affected by the inspiratory or expiratory effort) and variable obstructions (changes in the transmural pressure gradient caused by the inspiratory or expiratory effort result in changes in the cross-sectional area of the obstruction). If the obstruction is variable, flow–volume loops can demonstrate whether the obstruction is extrathoracic or intrathoracic (Figure 32–18). A fixed obstruction affects both expiratory and inspiratory airflow (Figure 32–18A). Both the expiratory and inspiratory flow–volume curves are truncated, with decreased peak expiratory and peak inspiratory flows. The flow–volume loop is unable to distinguish between a fixed extrathoracic and a fixed intrathoracic obstruction, which

CHAPTER 32 Mechanics of the Respiratory System 10

Peak expiratory flow

327

Maximal curve

Airflow (L/s)

Expiration

Effort independence

Effort dependence 5

Inspiration

0

RV

TLC

5

Maximal curve

10 Volume (L)

FIGURE 32–16 Flow–volume curves of varying intensities, demonstrating effort dependence at high lung volumes and effort independence at low lung volumes. Note that there is no effort independence in inspiration. The peak expiratory flow (PEF) is labeled for the maximal expiratory curve. TLC, total lung capacity; RV, residual volume. (Modified with permission from Levitzky MG: Pulmonary Physiology, 7th ed. New York: McGraw-Hill Medical, 2007.)

would usually be determined with a bronchoscope. Fixed obstructions can be caused by foreign bodies or by scarring that makes a region of the airway too stiff to be affected by the transmural pressure gradient. During a forced expiration, the cross-sectional area of a variable extrathoracic obstruction increases as the pressure inside the airway increases (Figure 32–18B). The expiratory flow–volume curve is therefore nearly normal or not affected.

However, during a forced inspiration, the pressure inside the upper airway decreases below atmospheric pressure, and unless the stability of the upper airway is maintained by reflex contraction of the pharyngeal muscles or by other structures, the cross-sectional area of the upper airway will decrease. Therefore, the inspiratory flow–volume curve is truncated with variable extrathoracic obstructions. Variable extrathoracic obstructions can be caused by tumors, fat deposits,

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SECTION VI Pulmonary Physiology

15 Normal

Airflow (L/s)

12 Restrictive disease 9

Obstructive disease

6

3 0 9

FIGURE 32–17

8

7

6

5 4 Lung volume (L)

3

2

1

0

Maximal expiratory flow–volume curves representative of obstructive and restrictive diseases. (Modified with

permission from Levitzky MG: Pulmonary Physiology, 7th ed. New York: McGraw-Hill Medical, 2007.)

Expiration

Flow

A.

Inspiration

Expiration

TLC

RV

Inspiration

Fixed (intra- or extrathoracic) expiration

Flow

B.

TLC Paw < Patm Inspiration

Inspiratory and expiratory flow–volume curves representing the patterns in: A) fixed intrathoracic or extrathoracic obstruction; B) variable extrathoracic obstruction; C) variable intrathoracic obstruction. TLC, total lung capacity; RV, residual volume; Paw, airway pressure; Patm, atmospheric pressure; Ppl, intrapleural pressure. (Modified with permission from Burrows B, Knudson RJ, Quan SF, Kettel LJ: Respiratory Disorders: A Pathophysiologic Approach,

Paw > Patm Expiration

Inspiration

Variable extrathoracic Expiration

C.

TLC Flow

FIGURE 32–18

Paw > Ppl

Paw < Ppl

Inspiration

Expiration

Inspiration

2nd ed. Copyright © 1983 by Year Book Medical Publishers, Chicago.)

RV

Variable intrathoracic

RV

CHAPTER 32 Mechanics of the Respiratory System weakened or flabby pharyngeal muscles (as in obstructive sleep apnea), paralyzed vocal cords, enlarged lymph nodes, or inflammation. During a forced expiration, positive intrapleural pressure decreases the transmural pressure gradient across a variable intrathoracic tracheal obstruction, decreasing its crosssectional area and decreasing the PEF (Figure 32–18C). During a forced inspiration, as large negative intrapleural pressures are generated, the transmural pressure gradient across the variable intrathoracic obstruction increases and its cross-sectional area increases. Thus, the inspiratory flow–volume curve is nearly normal or not affected. Variable intrathoracic obstructions of the trachea are most commonly caused by tumors.

CLINICAL CONSEQUENCES OF INCREASED AIRWAY RESISTANCE AND DECREASED ALVEOLAR COMPLIANCE As discussed at the beginning of this chapter, the lung has millions of small airways and hundreds of millions of alveoli. If we think of a pair of hypothetical alveoli supplied by the same airway, we can consider the time courses of their changes in volume in response to an abrupt increase in airway pressure (a “step” increase). If the resistances and compliances of the two units were equal, the two alveoli would fill with identical time courses to identical volumes. If the resistances were equal, but the compliance of one were half that of the other, then the two alveoli would fill with nearly identical time courses but the less compliant one would receive only half the volume received by the other. If the compliances of the two units were equal but one was supplied by an airway with twice the resistance to airflow of the one supplying the other, the two units would ultimately fill to the same volume. However, the one supplied by the airway with elevated resistance will fill more slowly than the other because of its elevated resistance. This difference means that at high breathing frequencies, the one that fills more quickly will receive a larger volume of air per breath; the one that fills more slowly will receive less ventilation per breath. Now let us extrapolate this two-unit situation to a lung with millions of airways supplying hundreds of millions of alveoli. In a patient with small airways disease, many alveoli may be supplied by airways with higher resistance to airflow than normal. These alveoli are sometimes referred to as “slow alveoli” or alveoli with long “time constants.” As the patient increases the breathing frequency, the slowest alveoli will not have enough time to fill. As the frequency increases, more and more slow alveoli will drop out. This can also be a problem during positive-pressure ventilation. There may be enough time for alveoli to fill because air is forced into them by the ventilator. However, because expiration is passive, there may not be enough time for the alveoli to empty, resulting in overinflation, especially of more compliant alveoli, causing lung injury.

329

THE WORK OF BREATHING The major points discussed in this chapter can be summarized by considering the work of breathing. The work done in breathing is proportional to the pressure change times the volume change. The volume change is the volume of air moved into and out of the lung—the tidal volume. The pressure change is the change in transpulmonary pressure necessary to overcome the elastic work of breathing and the resistive work of breathing. The elastic work of breathing is the work done to overcome the elastic recoil of the chest wall and the pulmonary parenchyma and the work done to overcome the surface tension of the alveoli. Restrictive diseases are those diseases in which the elastic work of breathing is increased. For example, the work of breathing is elevated in obese patients (who have decreased outward chest wall elastic recoil) and in patients with pulmonary fibrosis or a relative lack of pulmonary surfactant (who have increased elastic recoil of the alveoli). The resistive work of breathing is the work done to overcome the tissue resistance and the airway resistance. The tissue resistance may be elevated in conditions such as sarcoidosis, asbestosis, or silicosis. Elevated airway resistance is much more common and occurs in obstructive diseases such as asthma, bronchitis, and emphysema; upper airway obstruction; and accidental aspiration of foreign objects. Normally, most of the resistive work is that done to overcome airway resistance. The resistive work of breathing can be very great during a forced expiration, when dynamic compression occurs. This is especially true in patients who already have elevated airway resistance during normal, quiet breathing. For example, in patients with emphysema, a disease that attacks and obliterates alveolar walls, the work of breathing can be tremendous because of the destruction of the elastic tissue support of their small airways, which allows dynamic compression to occur unopposed. Also, the decreased elastic recoil of alveoli leads to a decreased pressure gradient for expiration.

CLINICAL CORRELATION A 26-year-old man comes to the emergency department because of sudden dyspnea (a feeling that breathing is difficult, also called “shortness of breath”) and pain in the upper part of the left side of his chest. He has no history of any medical problems. He is 183-cm (6′2″) tall and weighs about 63.5 kg (140 lb). Blood pressure is 125/80 mm Hg, heart rate is 90/min, and respiratory rate is 22/min (usually12–15/min in a healthy adult). There are no breath sounds on the left side of his chest, which is hyperresonant (louder and more hollow-sounding) to percussion (the physician tapping on the chest with his or her fingers). The patient has a pneumothorax. Air has entered the pleural space on the left side of his chest and he is unable to expand his left lung. Therefore, there are no breath sounds

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on the left side of his chest and it is hyperresonant to percussion. In this case, the pneumothorax is a primary spontaneous pneumothorax because it occurred suddenly, and is not attributable to an underlying pulmonary disease (secondary spontaneous pneumothorax) or trauma (traumatic pneumothorax). The inability to ventilate his left lung, combined with pain and anxiety, explains his high respiratory rate, as will be discussed in Chapters 33 and 38. Primary spontaneous pneumothorax is most common in tall, thin males between 10 and 30 years of age, although the reason for this is not known. It is believed to occur when overexpanded alveoli (“blebs”) rupture, perhaps as a result of a cough or sneeze. If the pneumothorax is mild and the patient is not in too much distress, it may resolve without treatment other than observation. More severe pneumothorax is treated by inserting a catheter or chest tube through the skin and intercostal muscles into the pleural space to allow removal of the air by external suction. A tension pneumothorax is a potentially life-threatening disorder that most commonly occurs as a result of trauma or lung injury. Air enters the pleural space on inspiration but cannot leave on expiration, progressively increasing intrapleural pressure above atmospheric. This can compress the structures on the affected side of the chest (e.g., blood vessels, heart, etc.) and eventually the structures on the other side of the chest as well.

CHAPTER SUMMARY ■ ■

■

■

■

■

A pressure gradient between the atmosphere and the alveoli must be established to move air into or out of the alveoli. During inspiration, alveoli expand passively in response to an increased transmural pressure gradient; during normal quiet expiration, the elastic recoil of the alveoli returns them to their original volume. The volume of gas in the lungs at the end of a normal tidal expiration (the FRC), when no respiratory muscles are actively contracting, is determined by the balance point of the inward recoil of the lungs and the outward recoil of the chest wall. At the FRC, intrapleural pressure is negative because the pleural liquid is between the opposing forces of the inward recoil of the lungs and the outward recoil of the chest wall. Alveoli are more compliant (and have less elastic recoil) at low volumes; alveoli are less compliant (and have more elastic recoil) at high volumes. Pulmonary surfactant increases alveolar compliance and helps prevent atelectasis by reducing surface tension in the alveoli.

■

■

During forced expiration, when intrapleural pressure becomes positive, small airways are compressed (dynamic compression) and may even collapse. The two main components of the work of breathing are the elastic recoil of the lungs and chest wall and the resistance to airflow.

STUDY QUESTIONS 1. In a normal healthy adult at the functional residual capacity A) alveolar pressure is greater than atmospheric pressure. B) alveolar pressure is less than atmospheric pressure. C) the inward recoil of the lungs is equal and opposite to the outward recoil of the chest wall. D) intrapleural pressure is positive. E) the alveolar transmural pressure gradient is negative. 2. Which of the following would be expected to cause increased static lung compliance (i.e., shift the pulmonary pressure– volume curve upward and to the left)? A) a relative lack of functional pulmonary surfactant B) diffuse interstitial alveolar fibrosis C) pulmonary vascular congestion D) emphysema E) diffuse alveolar collapse 3. The compliance of the lungs is A) greater at low lung volumes than it is at high lung volumes. B) in parallel with the compliance of the chest wall. C) increased in a person after surgical removal of one lobe of the lung. D) increased in a person with pulmonary interstitial fibrosis. E) less than the compliance of a single lobe of the lung. 4. During a forced expiration to the residual volume A) intrapleural pressure becomes more negative. B) alveolar elastic recoil is increasing. C) the outward recoil of the chest wall is increasing. D) intrapleural pressure is greater than alveolar pressure. E) airflow remains dependent on expiratory effort. 5. Which of the following will likely decrease the work of breathing? A) doubling the tidal volume at the same breathing frequency B) breathing through the mouth instead of the nose C) doubling the breathing frequency at the same tidal volume D) breathing through a 1-cm diameter, 3-ft long tube E) gaining 100 lb of body weight 6. The resistance to airflow in a normal healthy person would be greatest A) during a eupneic inspiration. B) during a eupneic expiration. C) during a forced inspiration. D) during a forced expiration. E) at the functional residual capacity.

33 C

Alveolar Ventilation Michael Levitzky

H A

P

T

E

R

O B J E C T I V E S ■ ■ ■ ■ ■ ■ ■ ■ ■ ■

Define alveolar ventilation. Define the standard lung volumes. Predict the effects of alterations in lung and chest wall mechanics, due to normal or pathologic processes, on the lung volumes. Define anatomic dead space and relate the anatomic dead space and the tidal volume to alveolar ventilation. Calculate alveolar ventilation. Define and calculate physiologic and alveolar dead space. Predict the effects of alterations of alveolar ventilation on alveolar carbon dioxide and oxygen levels. Describe and explain the regional differences in alveolar ventilation found in the normal lung. Define the closing volume. Predict how changes in pulmonary mechanics affect the closing volume.

Alveolar ventilation is the exchange of gas between the alveoli and the external environment. It is the process by which oxygen is brought into the lungs from the atmosphere and by which the carbon dioxide carried into the lungs in the mixed venous blood is expelled from the body. Although alveolar ventilation is usually defined as the volume of fresh air entering the alveoli per minute, a similar volume of alveolar air leaving the body per minute is implicit in this definition.

THE LUNG VOLUMES The volume of gas in the lungs at any instant depends on the mechanics of the lungs and chest wall and the activity of the muscles of inspiration and expiration. The size of the lungs depends the height and weight or body surface area, as well as age and sex. Therefore, the lung volumes are usually compared with “predicted” lung volumes matched to age, sex, and body

Ch33_331-340.indd 331

size, and are normally expressed as the body temperature and ambient barometric pressure and saturated with water vapor (BTPS).

THE STANDARD LUNG VOLUMES AND CAPACITIES There are four standard lung volumes and four standard lung capacities, which consist of two or more of the standard lung volumes (Figure 33–1).

The Tidal Volume The tidal volume (VT) is the volume of air entering or leaving the nose or mouth per breath. During normal, quiet breathing (eupnea), the VT of a 70-kg adult is about 500 mL per breath, but this volume can increase substantially, for example, during exercise.

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SECTION VI Pulmonary Physiology

maximal inspiration

INSPIRATORY CAPACITY (IC) 3.0 L

(Modified with permission from Levitzky MG: Pulmonary

VITAL CAPACITY (VC) 4.5 L

TIDAL VOLUME (VT) 0.5 L

TOTAL LUNG CAPACITY (TLC) 6.0 L

FIGURE 33–1 The standard lung volumes and capacities. Typical values for a 70-kg adult are shown.

INSPIRATORY RESERVE VOLUME (IRV) 2.5 L

FUNCTIONAL RESIDUAL CAPACITY (FRC) 3.0 L

resting volume

EXPIRATORY RESERVE VOLUME (ERV) 1.5 L maximal expiration RESIDUAL VOLUME (RV) 1.5 L no air in lungs

Physiology, 7th ed. New York: McGraw-Hill Medical, 2007.)

The Residual Volume The residual volume (RV) is the volume of gas remaining in the lungs after a maximal forced expiration. It is determined by the force generated by the muscles of expiration and the inward elastic recoil of the lungs as they oppose the outward elastic recoil of the chest wall. Dynamic compression of the airways during the forced expiratory effort may also be an important determinant of the RV as airway collapse occurs and traps gas in the alveoli. The RV of a healthy 70-kg adult is about 1.5 L, but it can be much greater in emphysema, a lung disease with increased compliance in which inward alveolar elastic recoil is diminished and airway collapse and gas trapping occur. The RV is important to a healthy person because it prevents the lungs from collapsing at very low lung volumes. Such collapsed alveoli would require great inspiratory efforts to reinflate.

The Expiratory Reserve Volume The expiratory reserve volume (ERV) is the volume of gas that is expelled from the lungs during a maximal forced expiration that starts at the end of a normal tidal expiration. It is therefore determined by the difference between the functional residual capacity (FRC, see below) and the RV. The ERV is about 1.5 L in a healthy 70-kg adult.

The Inspiratory Reserve Volume The inspiratory reserve volume (IRV) is the volume of gas that is inspired into the lungs during a maximal forced inspiration starting at the end of a normal tidal inspiration. It is determined by the strength of contraction of the inspiratory muscles, the inward elastic recoil of the lung and the chest wall, and the starting point, which is the FRC plus the VT . The IRV of a healthy 70-kg adult is about 2.5 L.

The Functional Residual Capacity The FRC is the volume of gas remaining in the lungs at the end of a normal tidal expiration. It represents the balance point

between the inward elastic recoil of the lungs and the outward elastic recoil of the chest wall, as discussed in Chapter 32. During exercise, the FRC may be lower than the relaxation volume because of active contraction of the expiratory muscles. The FRC, as seen in Figure 33–1, consists of the RV plus the ERV and is therefore about 3 L in a healthy 70-kg adult.

The Inspiratory Capacity The inspiratory capacity (IC) is the volume of air that is inhaled into the lungs during a maximal inspiratory effort that begins at the end of a normal tidal expiration (the FRC). It is therefore equal to the VT plus the IRV, as shown in Figure 33–1. The IC of a healthy 70-kg adult is about 3 L.

The Total Lung Capacity The total lung capacity (TLC) is the volume of air in the lungs after a maximal inspiratory effort. It is determined by the strength of contraction of the inspiratory muscles and the inward elastic recoil of the lungs and the chest wall. The TLC is the sum of all four lung volumes: the RV, the VT, the IRV, and the ERV. It is about 6 L in a healthy 70-kg adult.

The Vital Capacity The vital capacity (VC), discussed in Chapter 32, is the volume of air expelled from the lungs during a maximal forced expiration starting after a maximal forced inspiration. It is therefore equal to the TLC minus the RV, or about 4.5 L in a healthy 70-kg adult. The VC is also equal to the sum of the VT and the IRV and ERV. It is determined by the factors that determine the TLC and RV.

MEASUREMENT OF THE LUNG VOLUMES Measurement of the lung volumes is important clinically because many pathologic states can alter specific lung volumes or their

CHAPTER 33 Alveolar Ventilation relationships to one another. The lung volumes, however, can also change for normal physiologic reasons. Changing from a standing to a supine posture decreases the FRC because gravity is no longer pulling the abdominal contents away from the diaphragm. This decreases the outward elastic recoil of the chest wall, as noted in Chapter 32. Determination of the lung volumes can be useful diagnostically in differentiating between two major types of pulmonary disorders—the restrictive diseases and the obstructive diseases. Restrictive diseases such as alveolar fibrosis reduce the compliance of the lungs, increase elastic recoil, and lead to compressed lung volumes (Figure 33–2). The VT may even be decreased, with a corresponding increase in breathing frequency, to minimize the work of breathing. Obstructive diseases such as emphysema and chronic bronchitis cause increased resistance to airflow. Airways may become completely obstructed because of mucous plugs and because of the high intrapleural pressures generated to overcome the elevated airway resistance during a forced expiration. This is especially a problem in emphysema, in which destruction of alveolar septa leads to decreased elastic recoil of the alveoli and less radial traction, which normally help hold small airways open. For these reasons, the RV, the FRC, and the TLC may be greatly increased in obstructive diseases, as seen in Figure 33–2. The VC and ERV are usually decreased. The breathing frequency may be decreased to reduce the work expended overcoming the airway resistance, with a corresponding increase in the VT.

Spirometry The spirometer is a simple device for measuring gas volumes. As the person breathes in and out through a mouthpiece (a nose clip prevents airflow via the nose) and a tube connected to the spirometer, the volumes of gas entering and leaving the spirom-

333

eter can be determined. The spirometer can therefore measure only the lung volumes that the subject can exchange with it. As is the case with many pulmonary function tests, the subject must be conscious and cooperative and understand the instructions for performing the test. Figure 33–3 shows that the VT, IRV, ERV, IC, and VC can all be measured with a spirometer (as can the forced expiratory volume in 1 second [FEV1], forced vital capacity [FVC], and the FEV1/FVC, as discussed in Chapter 32). The RV, the FRC, and the TLC, however, cannot be determined with a spirometer because the subject cannot exhale all the gas in the lungs into the spirometer.

Measurement of Lung Volumes Not Measurable with Spirometry The lung volumes not measurable with spirometry can be determined by the nitrogen-washout technique, the heliumdilution technique, and body plethysmography. The FRC is usually determined, and RV (which is equal to FRC minus ERV) and the TLC (which is equal to VC plus RV) are then calculated from volumes obtained by spirometry.

Nitrogen-washout technique In the nitrogen-washout technique, the person breathes 100% oxygen through a one-way valve to wash all of the nitrogen out of the alveoli. The expired gas is collected and the volume of nitrogen washed out of the person’s lungs is calculated. The total volume of nitrogen in the person’s lungs at the beginning of the test can thus be determined. Nitrogen constitutes about 80% of the person’s initial lung volume, so multiplying the initial nitrogen volume by 1.25 gives the person’s initial lung volume. If the test starts at the end of a normal tidal expiration, the volume determined is the FRC.

IRV IC

VC VT

TLC IC

IRV

VT

ERV

VC

TLC

IC

IRV FRC VC

ERV

RV

VT TLC

FRC

ERV RV

FRC RV

normal

restrictive

obstructive

FIGURE 33–2 Illustration of typical alterations in the lung volumes and capacities in restrictive and obstructive diseases. The pattern shown for obstructive diseases is more characteristic for emphysema and asthma than for chronic bronchitis. IC, inspiratory capacity; TLC, total lung capacity; FRC, functional residual capacity; IRV, inspiratory reserve volume; VT, tidal volume; ERV, expiratory reserve volume; RV, residual volume; VC, vital capacity. (Modified with permission from Levitzky MG: Pulmonary Physiology, 7th ed. New York: McGraw-Hill Medical, 2007.)

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SECTION VI Pulmonary Physiology

SPIROMETER TRACE (SPIROGRAM) Maximal inspiration

volume (L)

Inspiratory reserve volume Inspiratory capacity

Vital capacity

FIGURE 33–3 Determination of the tidal volume, vital capacity, inspiratory capacity, inspiratory reserve volume, and expiratory reserve volume from a spirometer trace. (Modified with permission

Tidal volume

Expiratory reserve volume Maximal expiration

from Levitzky MG: Pulmonary Physiology, 7th ed. New York: McGraw-Hill Medical, 2007.)

Helium-dilution technique The helium-dilution technique makes use of the following relationship: if the total amount of a substance dissolved in a volume is known and its concentration can be measured, the volume in which it is dissolved can be determined. Helium is used for this test because it is not taken up by the pulmonary capillary blood, so the total amount of helium used in the test does not change during the test. The person breathes in and out of a spirometer filled with a mixture of helium and oxygen. When an equilibrium is reached, the concentration of helium is the same in the lungs as it is in the spirometer, and the test is stopped at the end of a normal tidal expiration, in other words, at the FRC. The calculated increase in the volume of distribution of helium therefore represents the lung volume. Since it may take several minutes for the helium concentration to equilibrate between the lungs and the spirometer, CO2 is absorbed from the system and oxygen is added to the spirometer at the rate at which it is used by the person. Both the nitrogen-washout and helium-dilution methods can be used on unconscious patients.

Body plethysmography A problem common to both the nitrogen-washout technique and the helium-dilution technique is that neither can measure trapped gas because nitrogen trapped in alveoli supplied by closed airways cannot be washed out and because the helium cannot enter alveoli supplied by closed airways. Furthermore, if the lungs have many alveoli served by airways with high resistance to airflow (the “slow alveoli” discussed at the end of Chapter 32), it may take a long time for all the nitrogen to wash out of the lungs or for the inspired and expired helium concentrations to equilibrate. In such patients, measurements of the lung volumes with a body plethysmograph are much more accurate because they do include trapped gas.

Time (s)

The body plethysmograph makes use of Boyle’s law: for a closed container at a constant temperature, the pressure times the volume of a gas mixture is constant. The body plethysmograph is an airtight chamber large enough that the patient can sit inside it and breathe through a mouthpiece and tubing. The patient breathes in for an instant against a closed airway and the pressures at the mouth and in the plethysmograph are monitored. As the patient breathes in against the closed airway, the chest expands and the pressure measured in the plethysmograph increases because the volume of air in the plethysmograph decreases by the amount the chest volume increased. The pressure measured at the mouth decreases as the patient breathes in against a closed airway. Boyle’s law is used to calculate the changes in volumes of the body plethysmograph and the lungs to determine the FRC.

ANATOMIC DEAD SPACE AND ALVEOLAR VENTILATION The volume of air entering and leaving the nose or mouth per minute, the minute volume, is not equal to the volume of air entering and leaving the alveoli per minute. Alveolar ventilation is less than the minute volume because the last part of each inspiration remains in the conducting airways and does not reach the alveoli. Similarly, the last part of each expiration remains in the conducting airways and is not expelled from the body. The anatomic dead space is illustrated in Figure 33–4. When a person breathes in a tidal volume of 500 mL, not all the air reaches the alveoli: the final 150 mL of the inspired air remains in the conducting airways. The volume of gas reaching the alveoli is equal to the volume inspired minus the volume of the anatomic dead space, in this case 500 – 150 mL, or 350 mL. During expiration, the first gas breathed out is inspired air that remained in the anatomic dead space; the last 150 mL is alveolar gas that

CHAPTER 33 Alveolar Ventilation

335

150 ml Tidal volume = 500 ml 350 ml

Volume in conducting airways left over from preceding breath

150 ml

Anatomic dead space = 150 ml

Conducting airways

150 ml

350 ml

FIGURE 33–4 Illustration of the anatomic dead space. Of a 500-mL tidal volume, 150 mL remains in the conducting airways and does not participate in gas exchange; only 350 mL enters the alveoli. (Reproduced with

Alveolar gas 150 ml

permission from Widmaier EP, Raff H, Strang KT: Vander’s Human Physiology, 11th ed. McGraw-Hill, 2008.)

remains in the anatomic dead space. Therefore, for any respiratory cycle, not all the tidal volume reaches the alveoli because the last part of each inspiration and each expiration remains in the dead space. The relationship for the VT breathed in and out through the nose or mouth, the dead space volume (VD), and the volume of gas entering and leaving the alveoli per breath (VA) is: VT = VD + VA

(2)

The alveolar ventilation (per minute) can be determined by multiplying both sides of the above equation by the breathing frequency (f) in breaths per minute: f (VA) = f (VT ) – f (VD )

For a healthy subject, the anatomic dead space can be estimated by referring to a table of standard values matched to sex, age, height, and weight or body surface area. The anatomic dead space is not measured clinically; a reasonable estimate of anatomic dead space is 1 mL of dead space per pound (2.2 kg) of ideal body weight.

(1)

or VA = VT – VD

Estimation of Anatomic Dead Space

(3)

Thus, for f = 12 breaths/min in the above example, we have: 4,200[mL/min] = 6,000[mL/min] – 1,800[mL/min] (4) . The alveolar ventilation (VA) in liters per minute is equal to . the minute volume (VE) minus . the volume wasted ventilating the dead space per minute (VD): . . . VA = VT – VD (5) . The dot over the letter V indicates per minute. The symbol VE is used because expired gas is usually collected. There is a difference between the volume of gas inspired and the volume of gas expired because as air is inspired, it is warmed to body temperature and humidified and also because normally less carbon dioxide is produced than oxygen is consumed.

MEASUREMENT OF ALVEOLAR VENTILATION Alveolar ventilation cannot be measured directly but must be determined from the VT, the breathing frequency, and the dead space ventilation, as noted in the previous section.

Physiologic Dead Space: The Bohr Equation The air in the anatomic dead space may not be the only inspired air that does not participate in gas exchange. The alveolar dead space is the volume of gas that enters unperfused alveoli per breath. Alveolar dead space is therefore alveoli that are ventilated but not perfused with pulmonary capillary blood. No gas exchange occurs in these alveoli for physiologic, rather than anatomic, reasons. A healthy person has little or no alveolar dead space, but a person with a low cardiac output might have significant alveolar dead space, for reasons explained in Chapter 34. The Bohr equation permits the determination of the sum of the anatomic and the alveolar dead space. The anatomic dead space plus the alveolar dead space is known as the physiologic dead space: Physiologic dead space = Anatomic dead space + Alveolar dead space

(6)

The Bohr equation makes use of a simple concept: any measurable volume of carbon dioxide found in the mixed expired gas must come from alveoli that are both ventilated and perfused because there are negligible amounts of carbon dioxide in inspired air. Inspired air remaining in the anatomic dead space or entering unperfused alveoli will leave the body as it entered (except for having been warmed to body temperature and humidified), contributing little or no carbon dioxide to the mixed expired air, as shown in the following Bohr equation:

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SECTION VI Pulmonary Physiology

50 End-tidal

FIGURE 33–5

Partial pressure of carbon dioxide at the mouth during a breath. During inspiration, the Pco2 rapidly decreases to near zero (0.3 mm Hg). The first expired gas comes from the anatomic dead space and therefore also has a Pco2 near zero. After exhalation of a mixture of gas from alveoli and anatomic dead space, the gas expired is a mixture from all ventilated alveoli. The slope of the alveolar plateau normally rises slightly because the alveolar Pco2 increases a few mm Hg between inspirations. The last alveolar gas expired before inspiration is called end-tidal. (Modified with permission

Pco2 (mm Hg)

40

30

20

10

0 0

1

2

3

5

Inspiration starts

Expiration starts

from Levitzky MG: Pulmonary Physiology, 7th ed. New York: McGraw-Hill

4

Time (s)

Medical, 2007.)

VDco Paco2 – PEco2 2 ____ = _________ Paco2 VT

(7)

where VDco2 is the dead space for CO2 (the physiologic dead space), VT the tidal volume, Paco2 the arterial partial pressure of carbon dioxide, and PEco2 the mixed expired partial pressure of carbon dioxide. The arterial Pco2 must be determined from an arterial blood sample; the Pco2 of the collected mixed expired gas can be determined with a CO2 meter. After the physiologic dead space is calculated using the Bohr equation, the estimated anatomic dead space can be subtracted from it to calculate the alveolar dead space. The CO2 meter can also used to estimate the mean alveolar Pco2 by analyzing the gas expelled at the end of a normal tidal expiration, the “end-tidal CO2” (Figure 33–5). In a person with significant alveolar dead space, however, the estimated alveolar Pco2 obtained in this fashion may not reflect the Pco2 of alveoli that are ventilated and perfused because some of this mixed end-tidal gas comes from unperfused alveoli. This gas dilutes the CO2 coming from alveoli that are both ventilated and perfused. There is, however, an equilibrium between the Pco2 of perfused alveoli and their end-capillary Pco2 (see Chapter 35 for detailed discussion), so that in patients without significant venous-to-arterial shunts, the arterial Pco2 represents the mean Pco2 of the perfused alveoli. If the arterial Pco2 is greater than the mixed alveolar Pco2 determined by sampling the end-tidal CO2, then the physiologic dead space is probably greater than the anatomic dead space, that is, a significant arterial–alveolar CO2 difference means that there is significant alveolar dead space; a person with no alveolar dead space has an arterial–end-tidal CO 2 difference of zero. As already noted, this difference is determined from the Pco2 from an arterial blood gas sample and from the end-tidal Pco2 . Young healthy people have no alveolar dead

space, so their physiologic dead space is equal to their anatomic dead space. Situations in which alveoli are ventilated but not perfused include those in which portions of the pulmonary vasculature have been occluded by blood clots or other material in the venous blood (pulmonary emboli), those in which there is low venous return leading to low right ventricular output (hemorrhage), and those in which alveolar pressure is high (positive-pressure ventilation with positive endexpiratory pressure). These will be discussed in greater detail in Chapter 34. The anatomic dead space can be altered by bronchoconstriction, which decreases VD; bronchodilation, which increases VD; or traction or compression of the airways, which increases and decreases VD, respectively.

ALVEOLAR VENTILATION & ALVEOLAR OXYGEN AND CARBON DIOXIDE LEVELS The levels of oxygen and carbon dioxide. in alveolar gas are determined .by the alveolar ventilation (VA), the oxygen consumption . (VO2) of the body, and the carbon dioxide production (VCO2 )of the body.

PARTIAL PRESSURES OF RESPIRATORY GASES According to Dalton’s law, in a gas mixture, the pressure exerted by each individual gas is independent of the pressures of other gases in the mixture. The partial pressure of a particular gas is equal to its fractional concentration times

CHAPTER 33 Alveolar Ventilation the total pressure of all the gases in the mixture. Thus, for any gas in a mixture (gas1), its partial pressure is given as follows: Pgas = Total gas (%) × Ptot 1

(8)

Oxygen constitutes 20.93% of dry atmospheric air. At a standard barometric pressure of 760 mm Hg, we have: PO2 = 0.2093 × 760 mm Hg = 159 mm Hg

(9)

Carbon dioxide constitutes only about 0.04% of dry atmospheric air, so we have: PCO2 = 0.0004 × 760 mm Hg = 0.3 mm Hg

PO2

PCO2

PN2

PH2O

Dry air

159

0.3

601

0

Inspired air

149

0.3

564

47

Alveolar air

104

40

569

47

Expired air

120

27

566

47

inspiration. Expired air is a mixture of about 350 mL of alveolar air and 150 mL of air from the dead space. Therefore, the Po2 of mixed expired air is higher than alveolar Po2 and lower than the inspired Po2, or approximately 120 mm Hg. Similarly, the Pco2 of mixed expired air is much higher than the inspired Pco2 but lower than the alveolar Pco2 , or about 27 mm Hg. The expected partial pressures of oxygen, carbon dioxide, nitrogen, and water vapor in dry air, inspired air, alveolar air, and expired air at an atmospheric pressure of 760 mm Hg are shown in Table 33–1.

(11)

where PB is the barometric pressure and PH2O the water vapor pressure. Then we have: 0.2093(760 – 47) mm Hg = 149 mm Hg

TABLE 33–1 Partial pressures in mm Hg of oxygen, carbon dioxide, nitrogen, and water vapor in dry air, inspired air, alveolar air, and expired air at a barometric pressure of 760 mm Hg.

(10)

As air is inspired through the upper airways, it is warmed and humidified, as discussed in Chapter 31. The partial pressure of water vapor is a relatively constant 47 mm Hg at body temperature, so the humidification of 1 L of dry gas in a closed container at 760 mm Hg would increase its total pressure to 760 + 47 mm Hg = 807 mm Hg. In the body, the gas will expand, according to Boyle’s law, so that 1 L of gas at 760 mm Hg is diluted by the added water vapor. The Po2 of inspired air, or PIo2 (saturated with water vapor at a standard barometric pressure), then is equal to the fractional concentration of inspired oxygen (FIo2) times the barometric pressure minus the water vapor pressure: PIo2 = FIo2 (PB – PH2O)

337

(12)

The Pco2 of inspired air (PIco2 ) is equal to FIco2 (PB – PH2O) or 0.0004(760 – 47) mm Hg = 0.29 mm Hg (rounded up to 0.3 mm Hg). Alveolar gas is composed of 2.5–3.0 L of gas already in the lungs at the FRC and approximately 350 mL per breath entering and leaving the alveoli. About 300 mL of oxygen is continuously diffusing from the alveoli into the pulmonary capillary blood per minute at rest and is being replaced by alveolar ventilation. Similarly, about 250 mL of carbon dioxide is diffusing from the mixed venous blood in the pulmonary capillaries into the alveoli per minute and is then removed by alveolar ventilation. (The Po2 and Pco2 of mixed venous blood are about 40 and 45–46 mm Hg, respectively.) Therefore, the partial pressures of oxygen and carbon dioxide in the alveolar air are determined by the alveolar ventilation, pulmonary capillary perfusion, oxygen consumption, and carbon dioxide production. Alveolar ventilation is normally adjusted by the respiratory control center in the brain to keep mean arterial and alveolar Pco2 at about 40 mm Hg (see Chapter 38). Mean alveolar Po2 is about 104 mm Hg (usually considered to be 100 mm Hg for convenience). The alveolar Po2 increases by 2–4 mm Hg with each normal tidal inspiration and decreases slowly until the next inspiration. Similarly, the alveolar Pco2 decreases 2–4 mm Hg with each inspiration and increases slowly until the next

ALVEOLAR VENTILATION AND CARBON DIOXIDE The concentration of carbon dioxide in the alveolar gas is, as already discussed, dependent on the alveolar ventilation and on the rate of carbon dioxide production by the body (and its delivery to the lung in the mixed venous blood). . The volume of carbon dioxide expired. per unit of time (VEco2 ) is equal to the alveolar ventilation (VA ) times the alveolar fractional concentration of CO2 (FAco2 ). No carbon dioxide comes from the dead space: . . VEco2 = VA FAco2 (13) Similarly, the fractional concentration of carbon dioxide in the alveoli is directly proportional to the carbon dioxide pro. duction by the body (Vco2) and inversely proportional to the alveolar ventilation: .

Vco . FAco2 ∝ ___ 2

VA

(14)

Since FAco2 (PB – PH2O) = PAco2 , we have: . V ___ PAco2 ∝ co. 2 VA

(15)

In healthy people, alveolar Pco2 is in equilibrium with arterial Pco2 (Paco2 ). Thus, if alveolar ventilation is doubled (and carbon dioxide production is unchanged), then the alveolar and arterial Pco2 are reduced by one half. If alveolar ventilation is cut in half, then alveolar and arterial Pco2 will double. This can be seen in the upper part of Figure 33–6.

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REGIONAL DISTRIBUTION OF ALVEOLAR VENTILATION

150

100 PACO2 (mm Hg) 50

0

2

4 6 Alveolar ventilation (L/min)

8

10

2

4 6 Alveolar ventilation (L/min)

8

10

150

100 PAO2 (mm Hg) 50

0

FIGURE 33–6 Predicted alveolar gas tensions for different levels of alveolar ventilation. (Modified with permission from Nunn JF: Applied Respiratory Physiology, 4th ed. 1993. Reprinted by permission of Elsevier Science Limited.)

ALVEOLAR VENTILATION AND OXYGEN As alveolar ventilation increases, the alveolar Po2 will also increase. Doubling alveolar ventilation, however, cannot double PAo2 in a person whose alveolar Po2 is already 104 mm Hg because the highest PAo2 one could possibly achieve breathing air at sea level is the inspired Po2 of about 149 mm Hg. The alveolar Po2 can be calculated by using the alveolar air equation: PAco PAo2 = PIo2 – ____ +F R

(16)

2

. Vco2 . ) and F a small where R is the respiratory exchange ratio ( ___ Vo2

correction factor. As already noted, PIo2 = FIo2(PB – PH2O). F is usually ignored. Therefore, we have: PA

co PAo2 = FIo2(PB – PH2O)– ____ R 2

(17)

As alveolar ventilation increases, the alveolar Pco2 decreases, bringing the alveolar Po2 closer to the inspired Po2, as can be seen in the lower part of Figure 33–6. Note that the alveolar Po2 obtained using the alveolar air equation is a calculated idealized average alveolar Po2. It represents what alveolar Po2 should be, not necessarily what it is.

As previously discussed, a 70-kg person has about 2.5–3.0 L of gas in the lungs at the FRC. Each breath brings about 350 mL of fresh gas into the alveoli and removes about 350 mL of alveolar air from the lung. Studies performed on healthy subjects standing or seated upright have shown that alveoli in the lower regions of the lungs receive more ventilation per unit volume than do those in the upper regions of the lung. The lower regions of the lung are relatively better ventilated than the upper regions of the lung. If a similar study is done on a subject lying on his or her left side, the regional differences in ventilation between the anatomic upper, middle, and lower regions of the lung disappear, although there is better relative ventilation of the left lung than of the right lung. The regional differences in ventilation are therefore mainly a result of the effects of gravity, with regions of the lung lower with respect to gravity (the “dependent” regions) relatively better ventilated than those regions above them (the “nondependent” regions). The explanation for these regional differences in ventilation is regional differences in intrapleural pressure. In Chapter 32, the intrapleural surface pressure was discussed as if it were uniform throughout the thorax, which is not the case. The intrapleural surface pressure is less negative in the lower, gravity-dependent regions of the thorax than it is in the upper, nondependent regions. There is a gradient of the intrapleural surface pressure such that for every centimeter of vertical displacement down the lung (from nondependent to dependent regions), the intrapleural surface pressure increases by about +0.2 to +0.5 cm H2O. This gradient is caused by gravity and by mechanical interactions between the lung and the chest wall. The influence of this gradient of intrapleural surface pressure on regional alveolar ventilation can be explained by predicting its effect on the transpulmonary pressure gradients in upper and lower regions of the lung. In the left side of Figure 33–7, alveolar pressure is assumed to be zero in both regions of the lung at the FRC, as discussed in Chapter 32. Since the intrapleural pressure is more negative in upper regions of the lung than it is in lower regions of the lung, the transpulmonary pressure (alveolar minus intrapleural) is greater in upper regions of the lung than it is in lower regions of the lung. Because the alveoli in upper regions of the lung are subjected to greater distending pressures than those in more dependent regions of the lung, they have greater volumes than the alveoli in more dependent regions. It is this difference in volume that leads to the difference in ventilation between alveoli located in dependent and nondependent regions of the lung. This can be seen on the hypothetical pressure–volume curve shown on the right side of Figure 33–7. This curve is similar to the pressure–volume curve for a whole lung shown in Figure 32–6, except that this curve is drawn with the pressure–volume characteristics of single alveoli in mind. The abscissa is the transpulmonary

CHAPTER 33 Alveolar Ventilation pressure (alveolar pressure minus intrapleural pressure). The ordinate is the volume of the alveolus expressed as a percent of its maximum. Because of the greater transpulmonary pressure, the alveolus in the upper region of the lung has a greater volume than the alveolus in a more gravity-dependent region of the lung. At the FRC, the alveolus in the upper part of the lung is on a less steep portion of the alveolar pressure–volume curve (i.e., it is less compliant) in Figure 33–7 than is the more compliant alveolus in the lower region of the lung. Therefore, any change in the transpulmonary pressure during a normal respiratory cycle will cause a greater change in volume in the alveolus in the lower, gravity-dependent region of the lung than it will in the alveolus in the nondependent region of the lung, as shown by the arrows in the figure. Because the alveoli in the lower parts of the lung have a greater change in volume per inspiration and per expiration, they are better ventilated than those alveoli in nondependent regions (during eupneic breathing from the FRC). A second effect of the intrapleural pressure gradient in a person seated upright is on regional static lung volume, as is evident from the above discussion. At the FRC, most of the alveolar air is in upper regions of the lung because those alveoli have larger volumes. Most of the ERV is also in upper portions of the lung. On the other hand, most of the IRV and IC are in lower regions of the lung. Even at low lung volumes, the upper alveoli are larger in volume than are the lower gravitydependent alveoli. They therefore constitute most of the RV. Patients with emphysema have greatly decreased alveolar elastic recoil, leading to high FRCs, extremely high RVs, and airway closure in dependent parts of the lung even at high lung

339

volumes, so they have relatively more ventilation of nondependent alveoli.

THE CLOSING VOLUME During a forced expiration, the lung volume at which airway closure begins to occur is known as the closing capacity; the volume of air exhaled from the time the first airways close until the subject reaches the RV and can exhale no more air is called the closing volume. (The terms are often used interchangeably.) Because people with emphysema have diminished alveolar elastic recoil to provide traction on the airways and help get air out of the alveoli during a forced expiration, they have very high closing capacities. That is, their airways begin to close at high lung volumes, trapping gas in the affected alveoli. They learn to breathe at higher lung volumes to optimize their elastic recoil. As discussed in Chapter 73, even healthy people lose alveolar elastic recoil as they age, resulting in higher closing capacities.

CLINICAL CORRELATION A 38-year-old man with an obvious curvature of the spine in the coronal and sagittal planes is seen by a pulmonologist because of dyspnea that has gotten worse during the last few months. He is 163-cm (5′4″) tall and weighs 61.2 kg (135 lb). Blood pressure is 135/95 mm Hg, heart rate is 80/min, and his respiratory rate is tachypnic at

FRC 100 Pleural pressure (cm H2O) 8.5

80

35 cm

1.5 40

Volume (%)

60

20

10

30 0 10 20 Transpulmonary pressure (cm H2O)

0 40

FIGURE 33–7 Effect of the pleural surface pressure gradient on the distribution of inspired gas at the functional residual capacity (FRC). (Modified with permission from Milic-Emili J: Pulmonary statics. In: Widdicombe JG, ed. MTP International Review of Sciences: Respiratory Physiology. London, England: Butterworth; 1974:105–137.)

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SECTION VI Pulmonary Physiology

25 breaths/min. His respiratory muscle strength appears to be normal. The pulmonologist orders pulmonary function tests and an arterial blood gas (with reference ranges in parenthesis) with the following results: TLC: 45% of predicted; VC: 40% of predicted; RV: 75% of predicted; FRC: 50% of predicted; FEV1: 40% of predicted; FVC: 40% of predicted; FEV1/FVC: 80% of predicted; arterial Po2: 75 mm Hg (80–100 mm Hg); arterial Pco2: 46 mm Hg (35–45 mm Hg); arterial pH: 7.38 (7.35–7.45). The patient has kyphoscoliosis that is a lateral curvature of the spine (scoliosis) as well as a sagittal curvature (kyphosis). It can be congenital; secondary to many disorders, including muscular dystrophy, poliomyelitis, spina bifida, and cerebral palsy; or it may be idiopathic (of unknown cause). Kyphoscoliosis results in decreased compliance of the rib cage with much less outward recoil of the chest wall at low thoracic volumes and much greater inward recoil at higher volumes. Kyphoscoliosis is therefore a restrictive disease. It is difficult for the patient to breathe in and, as a result, his inspiratory work of breathing is increased. It explains his increased resting respiratory rate (normally 12–15 breaths/min) because taking smaller tidal volumes at an increased breathing frequency decreases his work of breathing. The effects of the changes in the mechanics of his thorax can be seen in the lung volumes and capacities determined in this patient (see Figure 33–2). His FRC is low because, with less outward recoil of his chest wall, the balance point between the outward recoil of the chest wall and the inward recoil of his lungs occurs at a lower lung volume. His TLC is low because his ability to inhale maximally is severely impaired. His RV is also lower than predicted, but not as much as the TLC, because his ability to exhale is not as impaired. His VC, FVC, and FEV1 are all lower than predicted because his TLC is very low—he cannot exhale very much because he is unable to inhale very much. On the other hand, this patient does not have airway obstruction. Although both his FEV1 and FVC are low, the FEV1/FVC is within the normal range. The blood gases demonstrate that the increased work of breathing has resulted in decreased alveolar ventilation. His arterial Pco2 is high and his arterial Po2 is low. Treatment of patients with kyphoscoliosis is aimed at improving alveolar ventilation, for example, with noninvasive mechanical ventilation at night. Orthopedic surgery to help correct the problem may be effective in some patients.

CHAPTER SUMMARY ■

■ ■ ■

■

Alveolar ventilation is less than the volume of air entering or leaving the nose or mouth per minute (the minute volume) because the last part of each inspiration remains in the conducting airways (the anatomic dead space). Alveoli that are ventilated but not perfused constitute alveolar dead space. The physiologic dead space is the sum of the anatomic dead space and the alveolar dead space. At constant carbon dioxide production, alveolar Pco2 is approximately inversely proportional to alveolar ventilation; alveolar Po2 is calculated using the alveolar air equation. At or near the FRC, alveoli in lower regions of the upright lung are relatively better ventilated than those in upper regions of the lung.

STUDY QUESTIONS 1. Which of the following conditions are reasonable explanations for a functional residual capacity that is significantly less than predicted? A) third trimester of pregnancy B) pulmonary fibrosis C) obesity D) emphysema E) all of the above F) A, B, and C 2–5. An unconscious patient’s ventilation is maintained with positive-pressure ventilation with a tidal volume of 450 mL and a rate of 10 breaths/min. She weighs 100 lb. Her arterial Pco2 is 42 mm Hg, her end-tidal Pco2 is 35 mm Hg, and her mixed expired Pco2 is 28 mm Hg. 2. What is her minute volume? A) 350 mL/min B) 1,000 mL/min C) 3,500 mL/min D) 4,500 mL/min E) 5,500 mL/min 3. What is her alveolar ventilation? A) 350 mL/min B) 1,000 mL/min C) 3,500 mL/min D) 4,500 mL/min E) 5,500 mL/min 4. What is her physiologic dead space? A) 50 mL B) 100 mL C) 150 mL D) 200 mL E) 300 mL 5. What is her alveolar dead space? A) 50 mL B) 100 mL C) 150 mL D) 200 mL E) 300 mL

34 C

Pulmonary Perfusion Michael Levitzky

H A

P

T

E

R

O B J E C T I V E S ■ ■ ■ ■ ■ ■ ■ ■

■

■ ■

Compare and contrast the bronchial circulation and the pulmonary circulation. Describe the anatomy of the pulmonary circulation, and explain its physiologic consequences. Compare and contrast the pulmonary circulation and the systemic circulation. Describe and explain the effects of lung volume on pulmonary vascular resistance. Describe and explain the effects of elevated intravascular pressures on pulmonary vascular resistance. List the neural and humoral factors that influence pulmonary vascular resistance. Describe the effect of gravity on pulmonary blood flow. Describe the interrelationships of alveolar pressure, pulmonary arterial pressure, and pulmonary venous pressure and their effects on the regional distribution of pulmonary blood flow. Predict the effects of alterations in alveolar pressure, pulmonary arterial and venous pressures, and body position on the regional distribution of pulmonary blood flow. Describe hypoxic pulmonary vasoconstriction and discuss its role in localized and widespread alveolar hypoxia. Describe the causes and consequences of pulmonary edema.

The lung receives blood flow via both the bronchial circulation and the pulmonary circulation. Bronchial blood flow constitutes a very small portion of the output of the left ventricle and supplies part of the tracheobronchial tree with systemic arterial blood. Pulmonary blood flow constitutes the entire output of the right ventricle and supplies the lung with the mixed venous blood draining all the tissues of the body. It is this blood that undergoes gas exchange with the alveolar air in the pulmonary capillaries. Because the right and left ventricles are arranged in series after birth, pulmonary blood flow is approximately equal to 100% of the output of the left ventricle (the cardiac output).

Ch34_341-352.indd 341

About 280 billion pulmonary capillaries supply the approximately 300–480 million alveoli, resulting in a potential surface area for gas exchange estimated to be 50–100 m2. As was shown in Figure 31—5, the alveoli are completely enveloped in pulmonary capillaries.

THE BRONCHIAL CIRCULATION The bronchial arteries supply arterial blood to the tracheobronchial tree and to other structures of the lung down to the level of the terminal bronchioles. They also provide blood flow

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342

SECTION VI Pulmonary Physiology

CONDUCTING AIRWAYS

ALVEOLI

PULMONARY ARTERY (Mean  15)

RIGHT

12

PULMONARY CAPILLARIES

8

PULMONARY VEINS

25/8 VENTRICLE 25/0

ATRIUM 5

ATRIUM 2

VENTRICLE 120/0 120/80

VEINS 15

SYSTEMIC CAPILLARIES

LEFT

AORTA (Mean  100)

30

TISSUES

FIGURE 34–1

Pressures, expressed in mm Hg, in the systemic and pulmonary circulations. (Modified with permission from Levitzky MG:

Pulmonary Physiology, 7th ed. New York: McGraw-Hill Medical, 2007.)

to other thoracic structures. Lung structures distal to the terminal bronchioles, including the respiratory bronchioles, alveolar ducts, alveolar sacs, and alveoli, receive oxygen directly by diffusion from the alveolar air and nutrients from the mixed venous blood in the pulmonary circulation. The bronchial circulation may be important in the “air conditioning” of inspired air (discussed in Chapter 31). The blood flow in the bronchial circulation constitutes about 2% of the output of the left ventricle. Blood pressure in the bronchial arteries is the same as that in the other systemic arteries. This is much higher than the blood pressure in the pulmonary arteries (Figure 34–1). The venous drainage of the bronchial circulation is atypical. Although some of the bronchial venous blood enters the azygos and hemiazygos veins, a substantial portion of bronchial venous blood enters the pulmonary veins. The blood in the pulmonary veins has undergone gas exchange with the alveolar air—that is, the pulmonary veins contain “arterial” blood. Therefore, the bronchial venous blood entering the pulmonary venous blood is part of the normal anatomic right-to-left shunt, which will be discussed in Chapter 35.

THE PULMONARY CIRCULATION The walls of the vessels of the pulmonary circulation are much thinner than corresponding parts of the systemic circulation. This is particularly true of the main pulmonary artery and its

branches. The pulmonary artery rapidly subdivides into terminal branches that have thinner walls and greater internal diameters than do corresponding branches of the systemic arterial tree. There is much less vascular smooth muscle in the walls of the vessels of the pulmonary arterial tree, and there are no highly muscular vessels that correspond to the systemic arterioles. The pulmonary arterial tree rapidly subdivides over a short distance, ultimately branching into the approximately 280 billion pulmonary capillaries, where gas exchange occurs.

PULMONARY VASCULAR RESISTANCE The thin walls and small amount of smooth muscle found in the pulmonary arteries have important physiologic consequences. The pulmonary vessels offer much less resistance to blood flow than do the systemic arterial vessels. They are also much more distensible and compressible than systemic arterial vessels. These factors lead to much lower intravascular pressures than those found in the systemic arteries. The pulmonary vessels are located in the thorax and are subject to alveolar and intrapleural pressures that can change greatly, ranging from as low as −80 cm H2O during a maximal inspiratory effort to more than 100 cm H2O during a maximal forced expiration. Therefore, factors other than the tone of the

CHAPTER 34 Pulmonary Perfusion pulmonary vascular smooth muscle may have profound effects on pulmonary vascular resistance (PVR). PVR cannot be measured directly but an approximation can be calculated using the Poiseuille equation, as was discussed in Chapter 22. For the pulmonary circulation, the PVR is equal to the mean pulmonary artery pressure (Pa, the upstream pressure) minus the mean left atrial pressure (the downstream pressure), divided by pulmonary blood flow (the cardiac output). However, the mean left atrial pressure may not be the effective downstream pressure for the calculation of PVR under all lung conditions (see the section on zones of the lung later in this chapter). Because the right and left circulations are in series, the outputs of the right and left ventricles must be approximately equal to each other. (If they are not, blood and fluid will build up in the lungs or periphery.) If the two outputs are the same and the measured pressure drops across the systemic circulation and the pulmonary circulation are about 98 and 10 mm Hg, respectively (see Figure 34–1), then the PVR must be about one tenth that of the total peripheral resistance (TPR). TPR is sometimes called systemic vascular resistance (SVR).

DISTRIBUTION OF PULMONARY VASCULAR RESISTANCE The distribution of PVR can be estimated by the decrease in pressure across each of the three major components of the pulmonary vasculature: the pulmonary arteries, the pulmonary capillaries, and the pulmonary veins. In Figure 34–1, the resistance is fairly evenly distributed among the three components. At rest, about one third of the resistance to blood flow is located in the pulmonary arteries, about one third is located in the pulmonary capillaries, and about one third is located in the pulmonary veins. This is in contrast to the systemic circulation, in which about 70% of the resistance to blood flow is located in the systemic arteries, mostly in the highly muscular systemic arterioles.

CONSEQUENCES OF DIFFERENCES IN PRESSURE BETWEEN THE SYSTEMIC AND PULMONARY CIRCULATIONS The left ventricle must maintain a relatively high mean arterial pressure because such high pressures are necessary to overcome hydrostatic forces and pump blood to the brain. The apices of the lungs are a much shorter distance above the right ventricle, so such high pressures are unnecessary. The high arterial pressure in the systemic circulation allows the redistribution of left ventricular output and the control of blood flow to different tissues. In the pulmonary circulation, redistribution of right ventricular output is usually unnecessary because all alveolar–capillary units that are participating in gas exchange are performing the same function. The pressure is low and the small amount of smooth muscle in the pulmonary vessels (which is in large part responsible for the low pressure head) makes such local redistributions unlikely. An exception to this will be described in the section “Hypoxic Pulmonary Vasoconstriction.”

343

Another consequence of the pressure differences between the systemic and pulmonary circulations is that the workload and metabolic demand of the left ventricle is much greater than that of the right ventricle. The difference in wall thickness of the left and right ventricles of the adult is a reminder of the much greater workload of the left ventricle. The relatively small amounts of vascular smooth muscle, low intravascular pressures, and high distensibility of the pulmonary circulation lead to a much greater importance of extravascular effects (passive factors) on PVR. Gravity, body position, lung volume, alveolar and intrapleural pressures, intravascular pressures, and right ventricular output all can have profound effects on PVR without any alteration in the tone of the pulmonary vascular smooth muscle.

LUNG VOLUME AND PULMONARY VASCULAR RESISTANCE For distensible–compressible vessels, the transmural pressure gradient is an important determinant of the vessel diameter (see discussion of airway resistance in Chapter 32). As the transmural pressure gradient (which is equal to pressure inside minus pressure outside) increases, the vessel diameter increases and resistance decreases; as the transmural pressure decreases, the vessel diameter decreases and the resistance increases. Negative transmural pressure gradients lead to compression or even collapse of the vessel. Two different groups of pulmonary vessels must be considered when the effects of lung volume changes on PVR are analyzed—namely, the alveolar and extra-alveolar vessels (Figure 34–2).

ALVEOLUS

“alveolar”

“extraalveolar”

ALVEOLUS

During inspiration

FIGURE 34–2 Illustration of alveolar and extra-alveolar pulmonary vessels during an inspiration. The alveolar vessels (pulmonary capillaries) are exposed to the expanding alveoli and elongated. The extra-alveolar vessels, here shown exposed to the intrapleural pressure, expand as the intrapleural pressure becomes more negative and as radial traction increases during the inspiration. (Modified with permission from Levitzky MG: Pulmonary Physiology, 7th ed. New York: McGraw-Hill Medical, 2007.)

SECTION VI Pulmonary Physiology

Pulmonary vascular resistance

As lung volume increases during a normal negative-pressure inspiration, the alveoli increase in volume. While the alveoli expand, the vessels between them, mainly pulmonary capillaries, are elongated. As these vessels are stretched, their diameters decrease, just as stretching a rubber tube causes its diameter to narrow. Resistance to blood flow through the alveolar vessels increases as the alveoli expand because the alveolar vessels are longer and because their radii are smaller. At high lung volumes, then, the resistance to blood flow offered by the alveolar vessels increases; at low lung volumes, the resistance to blood flow offered by the alveolar vessels decreases. One group of the extra-alveolar vessels, the larger arteries and veins, is exposed to the intrapleural pressure. As lung volume is increased by making the intrapleural pressure more negative, the transmural pressure gradient of the larger arteries and veins increases and they distend. Another factor tending to decrease the resistance to blood flow offered by the extraalveolar vessels at higher lung volumes is radial traction by the connective tissue and alveolar septa holding the larger vessels in place in the lung. (Look at the small branch of the pulmonary artery at the bottom of Figure 31–4.) Thus, at high lung volumes (attained by normal negative-pressure breathing), the resistance to blood flow offered by the extra-alveolar vessels decreases. During a forced expiration to low lung volumes, however, intrapleural pressure becomes very positive. Extraalveolar vessels are compressed, and as the alveoli decrease in size, they exert less radial traction on the extra-alveolar vessels. The resistance to blood flow offered by the extra-alveolar vessels therefore increases (see left side of Figure 34–3). Because the alveolar and extra-alveolar vessels may be thought of as two groups of resistances in series with each

Stretching of pulmonary capillaries

Compression of extraalveolar vessels

FRC = Lowest PVR

other, the resistances of the alveolar and extra-alveolar vessels are additive at any lung volume. Thus, the effect of changes in lung volume on the total PVR gives the U-shaped curve seen in Figure 34–3. PVR is lowest near the functional residual capacity and increases at both high and low lung volumes. Also note that during mechanical positive-pressure ventilation, alveolar pressure (PA) and intrapleural pressure are positive during inspiration. In this case, both the alveolar and extraalveolar vessels are compressed as lung volume increases.

RECRUITMENT AND DISTENTION During exercise, cardiac output can increase several-fold without a correspondingly great increase in mean pulmonary artery pressure. Although the mean pulmonary artery pressure does increase, the increase is only a few millimeters of mercury, even if cardiac output has doubled or tripled. Since the pressure drop across the pulmonary circulation is proportional to the cardiac output times the PVR (i.e., ΔP = Q ˙ × R), this must indicate a decrease in PVR. Like the effects of lung volume on PVR, this decrease appears to be passive—that is, it is not a result of changes in the tone of pulmonary vascular smooth muscle caused by neural mechanisms or humoral agents. In fact, a decrease in PVR in response to increased blood flow or even an increase in perfusion pressure can be demonstrated in a vascularly isolated perfused lung, as was used to obtain the data summarized in Figure 34–4. (Note that the graph has blood pressure on the x-axis; blood flow has a similar effect.) Increasing the left atrial pressure also decreases PVR. There are two different mechanisms that can explain this decrease in PVR in response to elevated blood flow and

Pulmonary vascular resistance

344

Recruitment & distention of pulmonary capillaries

Lung volume Pulmonary blood flow

FIGURE 34–3

The effects of lung volume on pulmonary vascular resistance (PVR). PVR is lowest near the functional residual capacity (FRC) and increases at both high and low lung volumes because of the combined effects on the alveolar and extra-alveolar vessels. (Reproduced with permission from Kibble J, Halsey CR: The Big Picture,

FIGURE 34–4 The effect of pulmonary blood flow (or blood pressure) on pulmonary vascular resistance. Increased pulmonary artery blood pressure or pulmonary blood flow decreases pulmonary vascular resistance. (Reproduced with permission from Kibble J, Halsey CR: The

Medical Physiology. New York: McGraw-Hill, 2009.)

Big Picture, Medical Physiology. New York: McGraw-Hill, 2009.)

CHAPTER 34 Pulmonary Perfusion

Recruitment

345

Distention

FIGURE 34–5 Illustration of the mechanisms by which increased mean pulmonary artery pressure may decrease pulmonary vascular resistance. The upper figure shows a group of pulmonary capillaries, some of which are perfused. At left, the previously unperfused capillaries are recruited (opened) by the increased perfusion pressure. At right, the increased perfusion pressure has distended those vessels already open. (Modified with permission from Levitzky MG: Pulmonary Physiology, 7th ed. New York: McGraw-Hill Medical, 2007.)

perfusion pressure: recruitment and distention (Figure 34–5). As indicated in the diagram, at resting cardiac outputs, not all the pulmonary capillaries are perfused. A substantial number of capillaries are probably unperfused because of hydrostatic effects that will be discussed later in this chapter. Others may be unperfused because they have a relatively high critical opening pressure. That is, these vessels, because of their high vascular smooth muscle tone or other factors such as positive alveolar pressure, require a higher perfusion pressure than that solely necessary to overcome hydrostatic forces. Under normal circumstances, it is not likely that the critical opening pressures for pulmonary blood vessels are very great because they have so little smooth muscle. Increasing blood flow increases the mean pulmonary artery pressure, which opposes hydrostatic forces and exceeds the critical opening pressure in previously unopened vessels. This series of events opens new parallel pathways for blood flow, which lowers the PVR. This opening of new pathways is called recruitment. Note that decreasing the cardiac output or pulmonary artery pressure can result in a derecruitment of pulmonary capillaries. As perfusion pressure increases, the transmural pressure gradient of the pulmonary blood vessels increases, causing distention of the vessels. This increases their radii and decreases their resistance to blood flow. Both recruitment and distention cause the decreased PVR with elevated perfusion pressure or blood flow. Note that recruitment increases the surface area for gas exchange and

may decrease alveolar dead space. Derecruitment caused by low right ventricular output or high alveolar pressures decreases the surface area for gas exchange and may increase alveolar dead space.

CONTROL OF PULMONARY VASCULAR SMOOTH MUSCLE Pulmonary vascular smooth muscle is responsive to both neural and humoral influences. These produce active alterations in PVR, as opposed to the passive factors discussed in the previous section. A final passive factor, gravity, will be discussed later in this chapter. The main passive and active factors that influence PVR are summarized in Tables 34–1 and 34–2. The pulmonary vasculature is innervated by both sympathetic and parasympathetic fibers of the autonomic nervous system. The innervation of pulmonary vessels is relatively sparse in comparison with that of systemic vessels, and the autonomic nervous system has much less influence on the pulmonary vessels. There is relatively more innervation of the larger vessels and less of the smaller, more muscular vessels. There appears to be no innervation of vessels smaller than 30 μm in diameter, with little innervation of intrapulmonary veins and venules. Sympathetic stimulation of the innervation of the pulmonary vasculature may increase PVR or decrease the distensibility of

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TABLE 34–1 Passive influences on pulmonary vascular resistance. Cause

Effect on Pulmonary Vascular Resistance

Mechanism

Increased lung volume (above FRC)

Increases

Lengthening and compression of alveolar vessels

Decreased lung volume (below FRC)

Increases

Compression of and less traction on extra-alveolar vessels

Increased pulmonary artery pressure, increased left atrial pressure, increased pulmonary blood volume, increased cardiac output

Decreases

Recruitment and distention

Gravity, body position

Decreases in gravity-dependent regions of the lungs

Hydrostatic effects lead to recruitment and distention

Increased (more positive) interstitial pressure

Increases

Compression of vessels

Increased blood viscosity

Increases

Viscosity directly increases resistance

Increased alveolar pressure

Increases

Compression and derecruitment of alveolar vessels

Positive intrapleural pressure

Increases

Compression of extra-alveolar vessels; compression of vena cava decreases pulmonary blood flow and leads to derecruitment

Positive-pressure ventilation

FRC, functional residual capacity.

the larger vessels. Stimulation of the parasympathetic innervation of the pulmonary vessels generally causes vasodilation. The catecholamines epinephrine and norepinephrine both increase PVR when injected into the pulmonary circulation. Histamine, found in the lung in mast cells, is also a pulmonary vasoconstrictor. Certain prostaglandins and related substances, such as PGF2α, PGE2, and thromboxane,

TABLE 34–2 Active influences on pulmonary vascular resistance. Increase

Decrease

Stimulation of sympathetic innervation (may have greater effect by decreasing large-vessel distensibility)

Stimulation of parasympathetic innervation (if vascular tone is already elevated)

Norepinephrine, epinephrine

Acetylcholine

α-Adrenergic agonists

β-Adrenergic agonists

PGF2α, PGE2

PGE1

Thromboxane

Prostacyclin (PGI2)

Endothelin

Nitric oxide

Angiotensin

Bradykinin

Histamine (primarily a pulmonary venoconstrictor) Alveolar hypoxia Alveolar hypercapnia Low pH of mixed venous blood PG, prostaglandin.

are also pulmonary vasoconstrictors, as is endothelin. Alveolar hypoxia and hypercapnia also cause pulmonary vasoconstriction, as will be discussed later in this chapter. Acetylcholine, the β-adrenergic agonist isoproterenol, nitric oxide (NO), and certain prostaglandins, such as PGE1 and PGI2 (prostacyclin), are pulmonary vasodilators.

THE REGIONAL DISTRIBUTION OF PULMONARY BLOOD FLOW: THE ZONES OF THE LUNG Gravity is another important passive factor affecting local PVR and the relative perfusion of different regions of the lung. The interaction of the effects of gravity and extravascular pressures may have a profound influence on the relative perfusion of different areas of the lung.

THE REGIONAL DISTRIBUTION OF PULMONARY BLOOD FLOW If a radioactive substance such as the gas xenon (133Xe) is dissolved in saline and infused into the venous blood, it can be used to determine regional pulmonary blood flow. The greater the radioactivity measured over a specific region, the greater the blood flow. A pattern like that shown in Figure 34–6 is observed in a healthy person seated upright or standing up. There is greater blood flow per unit volume (per alveolus) to lower regions of the lung than to upper regions of the lung. Note that the test was made with the subject at the total lung capacity.

CHAPTER 34 Pulmonary Perfusion

THE INTERACTION OF GRAVITY AND EXTRAVASCULAR PRESSURE: THE ZONES OF THE LUNG

Blood flow/alveolus ( %)

150 TLC

100

50

rib 2

bottom 0 20

347

15 10 5 Lung distance (cm below rib 2)

0

FIGURE 34–6 Relative blood flow per alveolus (100% = perfusion of each alveolus if all were perfused equally) versus distance from the bottom of the lung in a human seated upright. Measurement of regional blood flow was determined using an intravenous injection of 133Xe. TLC, total lung capacity. (Modified with permission from Hughes JM, Glazier JB, Maloney JE, West JB. Effect of lung volume on the distribution of pulmonary blood flow in man. Respir Physiol. 1968;4(1):58–72.)

If the subject lies down, this pattern of regional perfusion is altered so that perfusion to the anatomically upper and lower portions of the lung is roughly evenly distributed, but blood flow per unit volume is still greater in the more gravitydependent regions of the lung. For example, if the subject were to lie down on the left side, the left lung would receive more blood flow per unit volume than would the right lung. Exercise, which increases the cardiac output, increases the blood flow per unit volume to all regions of the lung, but the perfusion gradient persists so that there is still relatively greater blood flow per unit volume in more gravity-dependent regions of the lung. The reason for this gradient of regional perfusion of the lung is gravity. The pressure at the bottom of a column of a liquid is proportional to the height of the column times the density of the liquid times gravity, so the intravascular pressures in more gravity-dependent portions of the lung are greater than those in upper regions. Because the pressures are greater in the more gravity-dependent regions of the lung, the resistance to blood flow is lower in lower regions of the lung owing to more recruitment or distention of vessels in these regions. It is therefore not only gravity, but also the characteristics of the pulmonary circulation that cause the increased blood flow to more gravity-dependent regions of the lung. After all, the same hydrostatic effects occur to an even greater extent in the systemic circulation, but the thick walls of the systemic arteries are not affected. There is also considerable heterogeneity in pulmonary blood flow at any vertical distance up the lung, that is, there may be significant variations in pulmonary blood flow within a given horizontal plane of the lung. These variations are caused by local factors and mechanical stresses.

When the pulmonary artery pressure is low, the uppermost regions of the lung receive no blood flow. Perfusion of the lung ceases at the point at which alveolar pressure (PA) is just equal to pulmonary artery pressure (Pa). Above this point, there is no perfusion because alveolar pressure exceeds pulmonary artery pressure, and the transmural pressure across capillary walls is negative. Below this point, perfusion per unit volume increases steadily with increased distance down the lung. Thus, under circumstances in which alveolar pressure is greater than pulmonary artery pressure in the upper parts of the lung, no blood flow occurs in that region, and the region is referred to as being in zone 1, as shown in Figure 34–7. (Note that in this figure blood flow is on the x-axis and that distance up the lung is on the y-axis.) Any zone 1, then, is alveoli that are ventilated but not perfused. It is alveolar dead space. Fortunately, during normal, quiet breathing in a person with a normal cardiac output, pulmonary artery pressure, even in the uppermost regions of the lung, is greater than alveolar pressure, so there is no zone 1. The lower portion of the lung in Figure 34–7 is said to be in zone 3. In this region, the pulmonary artery pressure and the pulmonary vein pressure (Pv) are both greater than alveolar pressure. The driving pressure (ΔP) for blood flow through the lung in this region is pulmonary artery pressure minus pulmonary vein pressure. Note that this driving pressure stays constant as one moves further down the lung in zone 3 because the hydrostatic pressure effects are the same for both the arteries and the veins.

Zone 1 PA>Pa>Pv

Pa

PA

Zone 2 Pa>PA>Pv Pv Distance

Zone 3 Pa>Pv>PA

Blood flow

FIGURE 34–7 The zones of the lung. The effects of gravity and alveolar pressure on the perfusion of the lung. Described in text. (Modified with permission from West, J.B., Dollery, C.T., Naimark, A.: Distribution of blood flow in isolated lung: Relation to vascular and alveolar pressures. J Appl Physiol 1964;19:713–724.)

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The middle portion of the lung in Figure 34–7 is in zone 2. In zone 2, pulmonary artery pressure is greater than alveolar pressure, so blood flow does occur. Nevertheless, because alveolar pressure is greater than pulmonary vein pressure, the effective driving pressure for blood flow is pulmonary artery pressure minus alveolar pressure in zone 2. (This is analogous to the situation described in Chapter 32: during a forced expiration, the driving pressure for airflow is equal to alveolar pressure minus intrapleural pressure.) Notice that in zone 2 (at right in Figure 34–7), the increase in blood flow per distance down the lung is greater than it is in zone 3. This is because the upstream driving pressure, the pulmonary artery pressure, increases according to the hydrostatic pressure increase, but the effective downstream pressure, alveolar pressure, is constant throughout the lung at any instant. To summarize: in zone 1, PA > Pa > Pv , and there is no blood flow; in zone 2, Pa > PA > Pv, and the effective driving pressure for blood flow is Pa – PA; in zone 3, Pa > Pv > PA, and the driving pressure for blood flow is Pa – Pv. It is important to realize that the boundaries between the zones are dependent on physiologic conditions—they are not fixed anatomic landmarks. Alveolar pressure changes during the course of each breath. During eupneic breathing these changes are only a few centimeters of water, but they may be much greater during speech, exercise, and other conditions. A patient on a positive-pressure ventilator with positive endexpiratory pressure (PEEP) may have substantial amounts of zone 1 because alveolar pressure is always high. After a hemorrhage or during general anesthesia, pulmonary blood flow and pulmonary artery pressure are low and zone 1 conditions are also likely. During exercise, cardiac output and pulmonary artery pressure increase and any existing zone 1 will be recruited to zone 2. The boundary between zones 2 and 3 will move upward as well. Changes in lung volume also affect the regional distribution of pulmonary blood flow and will therefore affect the boundaries between zones. Finally, changes in body position alter the orientation of the zones with respect to the anatomic locations in the lung, but the same relationships exist with respect to gravity and alveolar pressure.

smooth muscle cells to depolarize, allowing calcium to enter the cells. This, in turn, causes them to contract. The hypoxic pulmonary vasoconstriction response is graded—constriction begins to occur at alveolar Po2’s of approximately 100 mm Hg and increases until PAo2 decreases to about 20–30 mm Hg. If an area of the lung becomes hypoxic because of airway obstruction or if localized atelectasis occurs, any mixed venous blood flowing to that area will undergo little or no gas exchange (Figure 34–8) and will mix with blood draining well-ventilated areas of the lung as it enters the left atrium. This mixing will lower the overall arterial Po2. The hypoxic pulmonary vasoconstriction diverts mixed venous blood flow away from poorly ventilated areas of the lung by locally increasing vascular resistance, as shown in Figure 34–8C. Therefore, mixed venous blood is sent to better-ventilated areas of the lung (Figure 34–8D). The problem with hypoxic pulmonary vasoconstriction is that it is not a very strong response because there is so little smooth muscle in the pulmonary vasculature. Very high pulmonary artery pressures can interfere with hypoxic pulmonary vasoconstriction, as can other physiologic disturbances, such as alkalosis. In hypoxia of the whole lung, such as might be encountered at high altitude or in hypoventilation, hypoxic pulmonary vasoconstriction occurs throughout the lung. Even this may be useful in increasing gas exchange because greatly increasing the pulmonary artery pressure recruits previously unperfused pulmonary capillaries. This increases the surface area available for gas diffusion and improves the matching of ventilation and perfusion, as will be discussed in the next chapter. On the other hand, such a whole-lung hypoxic pulmonary vasoconstriction increases the workload on the right ventricle, and the high pulmonary artery pressure may overwhelm hypoxic pulmonary vasoconstriction in some parts of the lung, increase the capillary hydrostatic pressure in those vessels, and lead to pulmonary edema (see the next section of this chapter). Alveolar hypercapnia (increased carbon dioxide) also causes pulmonary vasoconstriction. Note that both hypoxic and hypercapnic pulmonary vasoconstriction are opposite to what occurs in the systemic circulation.

PULMONARY EDEMA HYPOXIC PULMONARY VASOCONSTRICTION Alveolar hypoxia (low alveolar Po2) or atelectasis (collapsed alveoli) causes an active vasoconstriction in the pulmonary circulation. The site of vascular smooth muscle constriction appears to be in the arterial (precapillary) vessels very close to the alveoli. The mechanism of hypoxic pulmonary vasoconstriction is not completely understood. The response occurs locally, that is, only in the area of the alveolar hypoxia. Connections to the central nervous system are not necessary. Hypoxia may act directly on pulmonary vascular smooth muscle to produce hypoxic pulmonary vasoconstriction. Hypoxia inhibits an outward potassium current, which causes pulmonary vascular

Pulmonary edema is the extravascular accumulation of fluid in the lung. This pathologic condition may be caused by one or more physiologic abnormalities, but the result is inevitably impaired gas transfer. As the edema fluid builds up, first in the interstitium and later in alveoli, diffusion of gases—particularly oxygen—decreases. The capillary endothelium is much more permeable to water and solutes than is the alveolar epithelium. Edema fluid therefore accumulates in the interstitium before it accumulates in the alveoli. As discussed in Chapter 26, the Starling equation describes the movement of liquid across the capillary endothelium: ˙ f = Kf [(Pc – Pis) – σ(πpl – πis)] Q

(1)

CHAPTER 34 Pulmonary Perfusion

O2 ⴝ 150 mm Hg CO2 ⴝ 0 mm Hg

O2 ⴝ 150 mm Hg CO2 ⴝ 0 mm Hg

O2 ⴝ 100 mm Hg CO2 ⴝ 40 mm Hg O2 ⴝ 40 mm Hg CO2 ⴝ 45 mm Hg

349

Decreased O2 Increased CO2 O2 ⴝ 40 mm Hg CO2 ⴝ 45 mm Hg

O2 ⴝ 100 mm Hg CO2 ⴝ 40 mm Hg

A

Decreased O2 Increased CO2

C O2 ⴝ 150 mm Hg CO2 ⴝ 0 mm Hg

O2 ⴝ 100 mm Hg CO2 ⴝ 40 mm Hg

Decreased O2 Increased CO2

Decreased O2 Increased CO2 O2 ⴝ 40 mm Hg CO2 ⴝ 45 mm Hg

Decreased O2 Increased CO2

B

D

FIGURE 34–8 Illustration of the physiologic function of hypoxic pulmonary vasoconstriction (HPV). A) Normal alveolar–capillary unit. B) Perfusion of a hypoventilated alveolus results in blood with a decreased Po and an increased Pco entering the left atrium. C) HPV 2 2 increases the resistance to blood flow to the hypoventilated alveolus. D) This diverts blood flow away from the hypoventilated alveolus to ˙/Q ˙ matching. HPV, hypoxic pulmonary vasoconstriction; V˙/Q ˙ = ventilation–perfusion ratio. better-ventilated alveoli, thus helping to maintainV (Modified with permission from Levitzky MG: Pulmonary Physiology, 7th ed. New York: McGraw-Hill Medical, 2007.)

˙ f is the net flow of fluid, Kf the capillary filtration where Q coefficient (this describes the permeability characteristics of the membrane to fluids), Pc the capillary hydrostatic pressure, Pis the hydrostatic pressure of the interstitial fluid, σ the reflection coefficient (this describes the ability of the membrane to prevent extravasation of solute particles), πpl the colloid osmotic (oncotic) pressure of the plasma, and πis the colloid osmotic pressure of the interstitial fluid. The components of the Starling equation are very useful in understanding the potential causes of pulmonary edema, even though only the plasma colloid osmotic pressure (πpl) can be measured clinically.

CONDITIONS THAT MAY LEAD TO PULMONARY EDEMA Infections, circulating or inhaled toxins, oxygen toxicity, and other factors that destroy the integrity of the capillary endothelium and increase its permeability lead to localized or generalized pulmonary edema. The pulmonary capillary hydrostatic pressure is estimated to be about 10 mm Hg under normal conditions. If the capillary hydrostatic pressure increases dramatically, the filtration of fluid across the capillary endothelium will increase greatly, and enough fluid may leave the capillaries to exceed the lym-

phatic drainage. The pulmonary capillary hydrostatic pressure often increases as a result of problems in the left side of the circulation, such as infarction of the left ventricle, left ventricular failure, or mitral stenosis. As left atrial pressure and pulmonary venous pressure increase because of accumulating blood, the pulmonary capillary hydrostatic pressure also increases. Other causes of increased pulmonary capillary hydrostatic pressure include overzealous administration of intravenous fluids and diseases that occlude the pulmonary veins. The interstitial hydrostatic pressure of the lung is in the range of –5 to –7 mm Hg when a healthy person is at FRC. Conditions that would decrease (i.e., make it more negative) the interstitial pressure would increase the tendency for pulmonary edema to develop. These appear to be limited mainly to potential actions of the health care worker, such as rapid evacuation of chest fluids or treatment of a pneumothorax. Situations that increase alveolar surface tension, for example, when decreased amounts of pulmonary surfactant are present, could also make the interstitial hydrostatic pressure more negative and increase the tendency for the formation of pulmonary edema. Note that as fluid accumulates in the interstitium, the interstitial hydrostatic pressure increases, which helps limit further fluid extravasation. Any situation that permits more solute to leave the capillaries, such as a decreased reflection coefficient, will lead to more fluid movement out of the vascular space.

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Decreases in the colloid osmotic pressure of the plasma, which helps retain fluid in the capillaries, may lead to pulmonary edema. Plasma colloid osmotic pressure, normally in the range of 25–28 mm Hg, decreases with low plasma protein concentration or overadministration of certain intravenous solutions. On the other hand, increased colloid osmotic pressure in the interstitium will pull fluid from the capillaries. Any fluid that makes its way into the pulmonary interstitium must be removed by the lymphatic drainage of the lung. The volume of lymph flow from the human lung is capable of increasing as much as 10-fold under pathologic conditions. It is only when this large safety factor is overwhelmed that pulmonary edema occurs. Conditions that block the lymphatic drainage of the lung, such as tumors or scars, may predispose patients to pulmonary edema. Pulmonary edema can be associated with head injury, heroin overdose, and high altitude. The causes of the edema formation in these conditions are not known, although high-altitude pulmonary edema may be caused by high pulmonary artery pressures secondary to the hypoxic pulmonary vasoconstriction.

NONRESPIRATORY FUNCTIONS OF THE PULMONARY CIRCULATION The pulmonary circulation, strategically located between the systemic veins and arteries, is well suited for several functions not directly related to gas exchange. The entire cardiac output passes over the very large surface area of the pulmonary capillary bed, allowing the lungs to act as a site of blood filtration and storage, as well as for the metabolism of vasoactive constituents of the blood, as was discussed in Chapter 31. A typical adult male has a pulmonary blood volume of about 500 mL, which allows the pulmonary circulation to act as a reservoir for the left ventricle. If left ventricular output is transiently greater than systemic venous return, left ventricular output can be maintained for a few strokes by drawing on blood stored in the pulmonary circulation. Because virtually all mixed venous blood must pass through the pulmonary capillaries, the pulmonary circulation acts as a filter, protecting the systemic circulation from materials that enter the blood. The particles filtered, which may enter the circulation as a result of natural processes, trauma, or therapeutic measures, may include small fibrin or blood clots, fat cells, bone marrow, detached cancer cells, gas bubbles, agglutinated erythrocytes (especially in sickle cell disease), masses of platelets or leukocytes, and debris from stored blood or intravenous solutions. If these particles were to enter the arterial side of the systemic circulation, they might occlude vascular beds with no other source of blood flow. This occlusion would be particularly disastrous if it occurred in the blood supply to the central nervous system or the heart. The lung can perform this very valuable service because there are many more pulmonary capillaries present in the lung

than are necessary for gas exchange at rest: previously unopened capillaries will be recruited. Obviously, no gas exchange can occur distal to a particle embedded in and obstructing a capillary, so this mechanism is limited by the ability of the lung to remove such filtered material. If particles are experimentally suspended in venous blood and are then trapped in the pulmonary circulation, the diffusing capacity (see Chapter 35) usually decreases for 4–5 days and then returns to normal. The mechanisms for removal of material trapped in the pulmonary capillary bed include lytic enzymes in the vascular endothelium, ingestion by macrophages, and penetration to the lymphatic system. Patients on cardiopulmonary bypass do not have the benefit of this pulmonary capillary filtration, and blood administered to these patients must be filtered for them. The colloid osmotic pressure of the plasma proteins normally exceeds the pulmonary capillary hydrostatic pressure. This tends to pull fluid from the alveoli into the pulmonary capillaries and keep the alveolar surface free of liquids other than pulmonary surfactant. Water taken into the lungs is rapidly absorbed into the blood. This protects the gas exchange function of the lungs and opposes transudation of fluid from the capillaries to the alveoli. As noted in Chapter 31, type II alveolar epithelial cells may also actively pump sodium and water from the alveolar surface into the interstitium. Drugs or chemical substances that readily pass through the alveolar–capillary barrier by diffusion or by other means rapidly enter the systemic circulation. The lungs are frequently used as a route of administration of drugs and for anesthetic gases, such as halothane and nitrous oxide. Aerosolized drugs intended for the airways only, such as the bronchodilator isoproterenol and anti-inflammatory corticosteroids, may rapidly pass into the systemic circulation, where they may have clinically significant effects. The effects of isoproterenol, for example, could include cardiac stimulation and vasodilation.

CLINICAL CORRELATION A 60-year-old man who had a left ventricular myocardial infarction 3 months ago returns to the cardiologist because of dyspnea on exertion but not at rest, a cough productive of frothy fluid after exercise, and orthopnea (easier breathing in the upright than recumbent position). At rest, his heart rate is 105/min, blood pressure is 120/90 mm Hg, and his respiratory rate is increased at 20/min. His chest radiograph shows evidence of edema in gravity-dependent lung regions. The patient does not have dyspnea (the feeling of difficult breathing or “shortness of breath”) at rest and his blood pressure is within the normal range. His heart rate at rest is slightly above the normal range (50–100/min; tachycardia) and his respiratory rate is high (normally 12–15/min; tachypnea). He does have orthopnea.

CHAPTER 34 Pulmonary Perfusion ■

He had a left ventricular myocardial infarction 3 months ago and the damaged heart muscle has been replaced with scar tissue that cannot contract. Although his left ventricle can generate a sufficient stroke volume at rest, it cannot match the increased right ventricular output during exercise, leading to increased left atrial pressure. Because there are no valves between the left atrium and the pulmonary veins and capillaries, pulmonary capillary hydrostatic pressure increases. Filtration of fluid from the capillaries into the pulmonary interstitium increases sufficiently to exceed the ability of the pulmonary lymphatic drainage to remove it, resulting in interstitial edema and then alveolar edema. The dyspnea results from several factors. Pulmonary vascular congestion (excess blood in the pulmonary blood vessels) decreases the compliance of the lungs. Interstitial and alveolar edema increases the alveolar– capillary barrier for gas diffusion. This is particularly a problem for oxygen diffusion, as will be discussed in the next chapter. Stretch receptors in the pulmonary circulation respond to pulmonary vascular congestion and the arterial chemoreceptors respond to low arterial Po2, both contributing to the sensation of dyspnea, as will be discussed in Chapter 38. He breathes more easily in the upright position because the edema fluid collects in lower regions of the lungs, allowing better gas exchange in upper parts of the lungs.

CHAPTER SUMMARY ■

■

■ ■

Compared with the systemic arteries, the pulmonary arteries have much less vascular smooth muscle and therefore offer much less resistance to blood flow. Pulmonary arteries are more distensible, and because their intravascular pressures are lower, more compressible than systemic arteries. The vascular transmural pressure gradient is therefore an important determinant of PVR. Although pulmonary vascular smooth muscle can actively contract or relax in response to neural and humoral influences, passive factors play a more important role in determining PVR than they do in determining SVR. PVR is usually lowest at the functional residual capacity and increases at higher and at lower lung volumes. PVR usually decreases with increases in pulmonary blood flow, pulmonary artery pressure, left atrial pressure, or pulmonary capillary blood volume because of distention of already open blood vessels, recruitment of previously unopened vessels, or both.

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There is more blood flow in lower regions of the lung than in upper regions. The effects of pulmonary artery pressure, pulmonary vein pressure, and alveolar pressure on pulmonary blood flow are described as the zones of the lung. Alveolar hypoxia can cause constriction of precapillary pulmonary vessels, diverting blood flow away from poorly ventilated or unventilated alveoli.

STUDY QUESTIONS 1. Compared to the systemic circulation, the pulmonary circulation has A) greater arterial pressure. B) less distensible vessels. C) a more evenly distributed vascular resistance to blood flow among its arteries, capillaries, and veins. D) greater control of vascular resistance by the autonomic nervous system. E) greater total vascular resistance. 2. Which of the following would likely increase pulmonary vascular resistance? A) inhaling from the FRC to the TLC B) exhaling from the FRC to the RV C) breathing 10% O2–90% N2 for 10 minutes D) decreasing the cardiac output from 5 to 2.5 L/min E) all of the above 3. In zone 2 of the lung A) alveolar pressure > pulmonary arterial pressure > pulmonary venous pressure. B) pulmonary arterial pressure > alveolar pressure > pulmonary venous pressure. C) pulmonary arterial pressure > pulmonary venous pressure > alveolar pressure. D) the effective pressure gradient for blood flow is pulmonary arterial pressure minus pulmonary venous pressure. E) there is no blood flow. 4. Compared to the pulmonary circulation, the bronchial circulation has A) more total blood flow. B) higher mean arterial pressure. C) more distensible arteries. D) more even distribution of vascular resistance among the arteries, capillaries, and veins. E) lower arterial Po2. 5. Which of the following is least likely to cause pulmonary edema? A) mitral stenosis B) two liters of rapidly administered intravenous saline solution C) increased left atrial pressure D) rapid administration of very negative intrapleural pressure to alleviate a pneumothorax E) positive pressure ventilation

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35 C

Ventilation–Perfusion Relationships and Respiratory Gas Exchange Michael Levitzky

H A

P

T

E

R

O B J E C T I V E S ■ ■ ■ ■ ■ ■ ■ ■

Predict the consequences of mismatched ventilation and perfusion. Explain the regional differences in the matching of ventilation and perfusion of the normal upright lung. Predict the consequences of the regional differences in the ventilation and perfusion of the normal upright lung. Define diffusion, and distinguish it from bulk flow. State Fick’s law for diffusion. Distinguish between perfusion limitation and diffusion limitation of gas transfer in the lung. Describe the diffusion of oxygen from the alveoli into the blood, and carbon dioxide from the blood to the alveoli. Define the diffusing capacity and discuss its measurement.

Alveolar ventilation and pulmonary perfusion have been discussed in the previous chapters in this section. The respiratory gases must diffuse through the alveolar–capillary barrier for gas exchange to occur. For optimal diffusion, the alveolar ventilation must be matched to the pulmonary perfusion.

VENTILATION–PERFUSION RELATIONSHIPS Alveolar ventilation brings oxygen into the lung and removes carbon dioxide from it. Similarly, the mixed venous blood brings carbon dioxide into the lung and takes up alveolar oxygen. The alveolar Po2 and Pco2 are thus determined by the relationship between alveolar ventilation and perfusion. Alterations in the ratio of ventilation to perfusion, called the V·a /Q· c for alveolar ventilation/pulmonary capillary blood flow (or just V· /Q· ), will result in changes in the alveolar Po2 and Pco2, as well as in gas delivery to or removal from the lung. Alveolar ventilation is normally about 4–6 L/min and pulmonary blood flow (which is equal to cardiac output) has a similar range, so the V· /Q· for the whole lung is in the range of

Ch35_353-362.indd 353

0.8–1.2. However, ventilation and perfusion must be matched on the alveolar–capillary level for optimal gas exchange to occur and the V· /Q· for the whole lung is really of interest only as an approximation of the situation in all the alveolar– capillary units of the lung.

CONSEQUENCES OF HIGH AND LOW VENTILATION–PERFUSION RATIOS Oxygen is delivered to the alveolus by alveolar ventilation, is removed from the alveolus as it diffuses into the pulmonary capillary blood, and is carried away by blood flow. Similarly, carbon dioxide is delivered to the alveolus in the mixed venous blood and diffuses into the alveolus in the pulmonary capillary. It is removed from the alveolus by alveolar ventilation. As will be discussed later in this chapter, at resting cardiac outputs, the diffusion of both oxygen and carbon dioxide is normally limited by pulmonary perfusion. The alveolar partial pressures of both oxygen and carbon dioxide are therefore determined by the V· /Q· . If the V· /Q· in an alveolar–capillary unit increases, the delivery of oxygen relative to its removal will increase, as will the removal of carbon dioxide relative to its delivery. Alveolar

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SECTION VI Pulmonary Physiology O2  150 mm Hg CO2  0 mm Hg B.

O2  150 mm Hg CO2  0 mm Hg

A.

O2  40 mm Hg CO2  45 mm Hg

C.

O2  100 mm Hg CO2  40 mm Hg

O2  150 mm Hg CO2  0 mm Hg

O2  40 mm Hg

O2  40 mm Hg

O2  40 mm Hg

O2  100 mm Hg

CO2  45 mm Hg

CO2  45 mm Hg

CO2  45 mm Hg

CO2  40 mm Hg

Mixed venous blood 0

Decreasing VA/QC

Normal

Increasing VA/QC



Inspired air

· · · · The effect of changes in the ventilation–perfusion ratio on the alveolar PO2 and PCO2. A) Normal VA / QC. B) VA / QC = 0. · · C) VA / QC is infinite. Curved arrows denote direction of blood flow. (Modified with permission from West JB. Ventilation/Blood Flow and Gas Exchange. 5th ed.

FIGURE 35–1

Oxford: Blackwell; 1990.)

Units B and C represent the two extremes of a continuum of ventilation–perfusion ratios. The V· /Q· ratio of a particular alveolar–capillary unit can fall anywhere along this continuum, as shown at the bottom of Figure 35–1. The alveolar Po2 and Pco2 of such units will therefore fall between the two extremes shown in the figure: units with low V· /Q· ratios will have relatively low Po2 and high Pco2; units with high V·/Q· ratios will have relatively high Po2 and low Pco2. This is demonstrated graphi-

• •

Shunt [V/Q = 0] Alveolar PO2 = Venous PO2 = 40 50

• •

Decreasing V/Q

40 Alveolar PCO2 (mm Hg)

Po2 will therefore increase, and alveolar Pco2 will decrease. If the V·/Q· in an alveolar–capillary unit decreases, the removal of oxygen relative to its delivery will increase and the delivery of carbon dioxide relative to its removal will increase. Alveolar Po2 will therefore decrease, and alveolar Pco2 will increase. Figure 35–1 shows the consequences of alterations in the relationship of ventilation and perfusion on hypothetical alveolar– capillary units. Unit A has a normal V·/Q· . Inspired air enters the alveolus with a Po2 of about 150 mm Hg and a Pco2 of nearly 0 mm Hg. Mixed venous blood enters the pulmonary capillary with a Po2 of about 40 mm Hg and a Pco2 of about 45 mm Hg. This results in an alveolar Po2 of about 100 mm Hg and an alveolar Pco2 of 40 mm Hg. The partial pressure gradient for oxygen diffusion from alveolus to pulmonary capillary is thus about 100 – 40, or 60 mm Hg; the partial pressure gradient for CO2 diffusion from pulmonary capillary to alveolus is about 45 – 40, or 5 mm Hg. The airway supplying unit B has become completely occluded. Its V· /Q· is zero. As time goes on, the air trapped in the alveolus equilibrates by diffusion with the gas dissolved in the mixed venous blood entering the alveolar–capillary unit. No gas exchange can occur, and any blood perfusing this alveolus will leave it exactly as it entered it. Unit B is therefore acting as a right-to-left shunt. The blood flow to unit C is blocked by a pulmonary embolus, and unit C is therefore completely unperfused. It has an infinite V·/Q· . Because no oxygen can diffuse from the alveolus into pulmonary capillary blood and because no carbon dioxide can enter the alveolus from the blood, the Po2 of the alveolus is approximately 150 mm Hg and its Pco2 is approximately zero; that is, the gas composition of this unperfused alveolus is the same as that of inspired air. Unit C is alveolar dead space. If unit C were unperfused because its alveolar pressure exceeded its precapillary pressure (rather than because of an embolus), then it would also correspond to part of zone 1, as discussed in Chapter 34.

Normal values PO2 = 100 PCO2 = 40

30 Increasing • • V/Q

20

10

• •

Deadspace [V/Q = ∞] Alveolar PO2 = inspired PO2 = 150

0 0 10 20 30 40 50 60 70 80 90 100 110120 130 140 150

Alveolar PO2 (mm Hg)

FIGURE 35–2 The ventilation–perfusion ratio line on an · · O2–CO2 diagram. Unit with a VA / QC of zero has the PO2 and PCO2 of · · mixed venous blood; a unit with an infinite VA / QC has the PO2 and PCO2 of inspired air. (Reproduced with permission from Kibble J, Halsey CR: The Big Picture, Medical Physiology. New York: McGraw-Hill, 2009.)

CHAPTER 35 Ventilation–Perfusion Relationships and Respiratory Gas Exchange cally in an O2–CO2 diagram such as that seen in Figure 35–2. The diagram shows the results of mathematical calculations of alveolar Po2 and Pco2 for V· /Q· ratios between zero (for mixed venous blood) and infinity (for inspired air). The resulting curve is known as the ventilation–perfusion ratio line. This simple O2–CO2 diagram can be modified to include correction lines for other factors, such as the respiratory exchange ratios of the alveoli and the blood or the dead space. The position of the V· /Q· ratio line is altered if the partial pressures of the inspired gas or mixed venous blood are altered.

TESTING FOR MISMATCHED VENTILATION & PERFUSION Several methods can demonstrate the presence or location of areas of the lung with mismatched ventilation and perfusion. These methods include calculations of the physiologic shunt, and the physiologic dead space, differences between the alveolar and arterial Po2 and Pco2, and lung scans after inhaled and intravenously administered 133Xe or 99mTc.

Physiologic Shunts and the Shunt Equation A right-to-left shunt is the mixing of venous blood that has not been oxygenated (or not fully oxygenated) into the arterial blood. The physiologic shunt, which corresponds to the physiologic dead space, consists of the anatomic shunts plus the intrapulmonary shunts. The intrapulmonary shunts can be absolute shunts, or they can be “shuntlike states,” that is, areas of low ventilation–perfusion ratios in which alveoli are underventilated and/or overperfused. Anatomic shunts consist of systemic venous blood entering the left ventricle without having entered the pulmonary vasculature. In a healthy adult, about 2–5% of the cardiac output, including venous blood from the bronchial veins, the thebesian veins, and the pleural veins, enters the left side of the circulation directly without passing through the pulmonary capillaries. Pathologic anatomic shunts such as right-to-left intracardiac shunts can also occur. Mixed venous blood perfusing pulmonary capillaries associated with totally unventilated or collapsed alveoli constitutes an absolute shunt (like the anatomic shunts) because no gas exchange occurs as the blood passes through the lung. Alveolar– capillary units with low V·a / Q·c also act to lower the arterial oxygen content because blood draining these units has a lower Po2 than blood from units with well-matched ventilation and perfusion. Increasing the percentage of inspired oxygen (FIO2) does not significantly increase the arterial Po2 of patients with absolute intrapulmonary shunts or “shuntlike areas” because the pulmonary capillary blood that flows to unventilated or very poorly ventilated alveoli is not exposed to alveolar air. The shunt equation conceptually divides all alveolar– capillary units into two groups: those with well-matched ventilation and perfusion and those with ventilation– perfusion ratios of zero. Thus, the shunt equation combines

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the areas of absolute shunt (including the anatomic shunts) and the shuntlike areas into a single conceptual group. The resulting ratio of shunt flow to the cardiac output, often referred to as the venous admixture, is the part of the cardiac output that would have to be perfusing absolutely unventilated alveoli to cause the systemic arterial oxygen content obtained from a patient. A much larger portion of the cardiac output could be overperfusing poorly ventilated alveoli and yields the same ratio: Q· s _______ Ccʹ –Ca __ = o2 o2 Q· t Ccʹo2 –C –V o2

(1)

where Q·t represents the total pulmonary blood flow per minute (i.e., the cardiac output), Q· S represents the amount of blood flow per minute entering the systemic arterial blood without receiving any oxygen (the “shunt flow”), Cao2 equals oxygen content of arterial blood (see Chapter 36) in milliliters of oxygen per 100 mL of blood, and C–V o and Ccʹo equal the oxygen content of the mixed venous blood and the end-capillary oxygen content (the oxygen content in the blood at the end of the ventilated and perfused pulmonary capillaries), respectively. The shunt fraction is usually multiplied by 100% so that the shunt flow is expressed as a percentage of the cardiac output. The arterial and mixed venous oxygen contents can be determined if blood samples are obtained from a systemic artery and from the pulmonary artery (for mixed venous blood), but the oxygen content of the blood at the end of the pulmonary capillaries with well-matched ventilation and perfusion is, of course, impossible to measure directly. This must be calculated from the alveolar air equation and the patient’s hemoglobin concentration. 2

2

Physiologic Dead Space The use of the Bohr equation to determine the physiologic dead space was discussed in Chapter 33. If the anatomic dead space is subtracted from the physiologic dead space, the result (if there is a difference) is alveolar dead space, or areas of infinite V· /Q·. Alveolar dead space also results in an arterial– alveolar CO2 difference (or arterial–end-tidal CO2 difference), that is, the end-tidal Pco2 is normally equal to the arterial Pco2. An arterial Pco2 greater than the end-tidal Pco2 usually indicates the presence of alveolar dead space.

ALVEOLAR–ARTERIAL OXYGEN DIFFERENCE The alveolar and arterial Po2 are often treated as though they are equal. However, the arterial Po2 is usually a few mm Hg less than the alveolar Do2. This normal alveolar–arterial oxygen difference, the (A –a)Do2, is caused by the normal anatomic shunt, some degree of ventilation–perfusion mismatch (see later in this chapter), and diffusion limitation in some parts of the lung. Of these, V· /Q· mismatch is usually the most important, with a small contribution from shunts and very little from diffusion

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TABLE 35–1 Causes of increased alveolar–arterial oxygen difference. Increased right-to-left shunt Anatomic Intrapulmonary

average alveolar Po2 that represents what alveolar Po2 should be, not necessarily what it is.

REGIONAL DIFFERENCES IN VENTILATION–PERFUSION RATIOS AND THEIR CONSEQUENCES

Increased ventilation–perfusion mismatch Impaired diffusion Increased inspired partial pressure of oxygen Decreased mixed venous partial pressure of oxygen Shift of oxyhemoglobin dissociation curve Adapted with permission from Marshall BE, Wyche MQ, Jr. Hypoxemia during and after anesthesia. Anesthesiology. 1972;37(2):178–209.

limitation. Larger-than-normal differences between the alveolar and arterial Po2 may indicate significant ventilation–perfusion mismatch; however, increased alveolar–arterial oxygen differences (Table 35–1) can also be caused by anatomic or intrapulmonary shunts, diffusion block, low mixed venous Po2, breathing higher-than-normal oxygen concentrations, or shifts of the oxyhemoglobin dissociation curve (also see Table 37–7). The alveolar–arterial Po2 difference is normally about 5–15 mm Hg in a young healthy person breathing room air at sea level. It increases with age because of the progressive decrease in arterial Po2 that occurs with aging (Chapter 73). The normal alveolar–arterial Po2 difference increases by about 20 mm Hg between the ages of 20 and 70. Note that the “alveolar” Po2 used in determining the alveolar–arterial oxygen difference is the PAo calculated using the alveolar air equation. As noted in Chapter 33, it is an idealized 2

The regional variations in ventilation in the normal upright lung were discussed in Chapter 33. They are summarized on the left side of Figure 35–3. The right side of Figure 35–3 shows that the more gravity-dependent regions of the lung also receive more blood flow per unit volume than do the upper regions of the lung, as discussed in Chapter 34.

REGIONAL DIFFERENCES IN THE VENTILATION–PERFUSION RATIOS IN THE UPRIGHT LUNG Simplified graphs of the gradients of ventilation and perfusion from the bottom to the top of normal upright lungs are shown plotted on the same axes in Figure 35–4. The ventilation– perfusion ratio was then calculated for several locations. Figure 35–4 shows that even though the lower regions of the lung receive both better ventilation and better perfusion than do the upper portions of the lung, the gradient of perfusion from the bottom of the lung to the top is greater than the gradient of ventilation. Because of this, the ventilation–perfusion

Ventilation Intrapleural pressure more negative Greater transmural pressure gradient Alveoli larger, less compliant Less ventilation

FIGURE 35–3

Summary of regional differences in ventilation (left) and perfusion (right) in the normal upright lung. (Modified with permission from Levitzky MG: Pulmonary Physiology, 7th ed. New York: McGraw-Hill Medical, 2007.)

Intrapleural pressure less negative Smaller transmural pressure gradient Alveoli smaller, more compliant More ventilation

Perfusion Lower intravascular pressures Less recruitment, distention Higher resistance Less blood flow

Greater vascular pressures More recruitment, distention Lower resistance Greater blood flow

CHAPTER 35 Ventilation–Perfusion Relationships and Respiratory Gas Exchange

3.0 • •

V/Q Perfusion

V/Q ratio

Ventilation or perfusion

2.0

• •

Ventilation

1.0 • •

Low V/Q at lung bases

physiologic P(A–a)O2 gradient

0 Base

Distance up the lung (from base to apex)

Apex

FIGURE 35–4 Distribution of ventilation and perfusion and ventilation–perfusion ratio down the upright lung. (Reproduced with permission from Kibble J, Halsey CR: The Big Picture, Medical Physiology. New York: McGraw-Hill, 2009.)

ratio is relatively low in more gravity-dependent regions of the lung and higher in upper regions of the lung. The effects of the regional differences in V· /Q· on the alveolar Po2 and Pco2 can be predicted from Figure 35–2: the upper regions should have a relatively high Po2 and a low Pco2; the lower regions should have a relatively low Po2 and a high Pco2. This means that the oxygen content of the blood draining the upper regions is higher and the carbon dioxide content is lower than that of the blood draining the lower regions. However, these contents are based on milliliters of blood (see Chapter 36), and there is much less blood flow to the uppermost sections than there is to the bottom sections. Therefore, even though the uppermost sections have the highest V·/Q· and Po2 and the lowest Pco2, there is more gas exchange in the more basal sections.

DIFFUSION OF GASES Diffusion of a gas occurs when there is a net movement of molecules from an area in which that particular gas exerts a high partial pressure to an area in which it exerts a lower partial pressure. Movement of a gas by diffusion is therefore different from the movement of gases through the conducting airways, which occurs by “bulk flow” (mass movement or convection). In bulk flow, gas movement results from differences in total pressure, and molecules of different gases move together along the total pressure gradient. In diffusion, each of the different gases moves according to its own individual partial pressure gradient. Gas transfer during diffusion occurs by random molecular movement. It is therefore dependent on temperature because molecular movement increases at higher

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temperatures. Gases move in both directions during diffusion, but the area of higher partial pressure, because of its greater number of molecules per unit volume, has proportionately more random “departures.” Thus, the net movement of gas is dependent on the partial pressure difference between the two areas. In a static situation, diffusion continues until no partial pressure differences exist for any gases in the two areas; in the lungs, oxygen and carbon dioxide continuously enter and leave the alveoli, so such an equilibrium does not take place.

FICK’S LAW FOR DIFFUSION Oxygen is brought into the alveoli by bulk flow through the conducting airways. When air flows through the conducting airways during inspiration, the linear velocity of the bulk flow decreases as the air approaches the alveoli. This is because the total cross-sectional area increases dramatically in the distal portions of the tracheobronchial tree. By the time the air reaches the alveoli, bulk flow probably ceases, and further gas movement occurs by diffusion. Oxygen then moves through the gas phase in the alveoli according to its own partial pressure gradient. The distance from the alveolar duct to the alveolar–capillary interface is usually less than 1 mm. Oxygen then diffuses through the alveolar–capillary interface. It must first, therefore, move from the gas phase to the liquid phase, according to Henry’s law, which states that the amount of a gas absorbed by a liquid with which it does not combine chemically is directly proportional to the partial pressure of the gas to which the liquid is exposed and the solubility of the gas in the liquid. Oxygen must dissolve in and diffuse through the thin layer of pulmonary surfactant, the alveolar epithelium, the interstitium, and the capillary endothelium, as was shown in Figure 31–6 (step 2, near the arrow). It must then diffuse through the plasma (step 3), where some remains dissolved and the majority enters the erythrocyte and combines with hemoglobin (step 4). The blood then carries the oxygen out of the lung by bulk flow and distributes it to the other tissues of the body, as was shown in Figure 31–1. At the tissues, oxygen diffuses from the erythrocyte through the plasma, capillary endothelium, interstitium, tissue cell membrane, and cell interior and into the mitochondrial membrane. The process is almost entirely reversed for carbon dioxide. The factors that determine the rate of diffusion of gas through the alveolar–capillary barrier are described by Fick’s law for diffusion, shown as follows in a simplified form: AD(P1 – P2) V·gas = _________ T

(2)

where V· gas is the volume of gas diffusing through the tissue barrier per time (mL/min), A the surface area of the barrier available for diffusion, D the diffusion coefficient, or diffusivity, of the particular gas in the barrier, T the thickness of the barrier or the diffusion distance, and P1 – P2 the partial pressure difference of the gas across the barrier. That is, the volume of gas per unit of time moving across the alveolar–capillary barrier is directly proportional to the area of

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the barrier, the diffusivity, and the difference in concentration between the two sides, but is inversely proportional to the barrier thickness. The surface area of the blood–gas barrier is believed to be at least 70 m2 in a healthy average-sized adult at rest. That is, about 70 m2 of the potential surface area is both ventilated and perfused at rest. If more capillaries are recruited, as in exercise, the surface area available for diffusion increases; if venous return decreases, for example, because of hemorrhage, or if alveolar pressure is increased by positive-pressure ventilation, then capillaries may be derecruited and the surface area available for diffusion may decrease. The thickness of the alveolar–capillary diffusion barrier is only about 0.2–0.5 μm. This barrier thickness can increase in interstitial fibrosis or interstitial edema, thus interfering with diffusion. Diffusion probably increases at higher lung volumes because as alveoli are stretched, the diffusion distance decreases slightly (and also because small airways subject to closure may be open at higher lung volumes). The diffusivity, or diffusion constant, for a gas is directly proportional to the solubility of the gas in the diffusion barrier and is inversely proportional to the square root of the molecular weight (MW) of the gas: Solubility √MW

____ D α _______

through the alveolar–capillary barrier before carbon dioxide retention due to diffusion impairment occurs. The factors that limit the movement of a gas through the alveolar–capillary barrier, as described by Fick’s law for diffusion, can be arbitrarily divided into three components: the diffusion coefficient, the surface area and thickness of the alveolar–capillary membrane, and the partial pressure gradient across the barrier for each particular gas. The diffusion coefficient, as discussed in the previous section, is dependent on the physical properties of the gases and the alveolar– capillary membrane. The surface area and thickness of the membrane are physical properties of the barrier, but they can be altered by changes in the pulmonary capillary blood volume, the cardiac output or the pulmonary artery pressure, or changes in lung volume. The partial pressure gradient of a gas (across the barrier) is the final major determinant of its rate of diffusion. The partial pressure of a gas in the mixed venous blood and in the pulmonary capillaries is just as important a factor as its alveolar partial pressure in determining its rate of diffusion.

Diffusion Limitation An erythrocyte and its attendant plasma spend an average of about 0.75–1.2 seconds inside the pulmonary capillaries at resting cardiac outputs. Figure 35–5 shows the calculated change with time in the partial pressures in the blood of three gases: oxygen, carbon monoxide, and nitrous oxide. These are shown in comparison to the alveolar partial pressures for each gas, as indicated by the dotted line. This alveolar partial pressure is different for each of the three gases, and it depends on its concentration in the inspired gas mixture and on how rap-

(3)

Because oxygen is less dense than carbon dioxide, it should diffuse 1.2 times as fast as carbon dioxide, but the solubility of carbon dioxide in the liquid phase is about 24 times that of oxygen, so carbon dioxide diffuses 20 times more rapidly through the alveolar–capillary barrier than does oxygen. For this reason, patients develop problems in oxygen diffusion

Alveolar partial pressure

FIGURE 35–5 Calculated changes in the partial pressures of carbon monoxide, nitrous oxide, and oxygen in the blood as it passes through a functional pulmonary capillary. There are no units on the ordinate because the scale is different for each of the three gases, depending on the alveolar partial pressure of each gas. The abscissa is in seconds, indicating the time the blood has spent in the capillary. At resting cardiac outputs, blood spends an average of 0.75 of a second in a pulmonary capillary. The alveolar partial pressure of each gas is indicated by the dotted line. Note that the partial pressures of nitrous oxide and oxygen equilibrate rapidly with their alveolar partial pressure. (Modified with permission from Comroe JH: The

Partial pressure in plasma

N2O

O2

CO 0

0

0.25

0.50 Time in capillary (s)

0.75

Lung; Clinical Physiology and Pulmonary Function Tests, 2nd ed. Chicago: Year Book Medical Publishers, 1962.)

Enter capillary

Leave capillary

CHAPTER 35 Ventilation–Perfusion Relationships and Respiratory Gas Exchange idly it is removed by the pulmonary capillary blood. The schematic is drawn as though all three gases were administered simultaneously, but this is not necessarily the case. Consider each gas as though it were acting independently of the others. The partial pressure of carbon monoxide in the pulmonary capillary blood rises very slowly compared with that of the other two gases in the figure if a low inspired concentration of carbon monoxide is used for a very short time. However, if the content of carbon monoxide (in milliliters of carbon monoxide per milliliter of blood) were measured simultaneously, it would be rising very rapidly. The reason for this rapid rise is that carbon monoxide combines chemically with the hemoglobin in the erythrocytes. The affinity of carbon monoxide for hemoglobin is about 210 times that of oxygen for hemoglobin. The carbon monoxide that is chemically combined with hemoglobin does not contribute to the partial pressure of carbon monoxide in the blood because it is no longer physically dissolved in it. Therefore, the partial pressure of carbon monoxide in the pulmonary capillary blood does not come close to the partial pressure of carbon monoxide in the alveoli during the time that the blood is exposed to the alveolar carbon monoxide. The partial pressure gradient across the alveolar–capillary barrier for carbon monoxide is thus well maintained for the entire time the blood spends in the pulmonary capillary. The diffusion of carbon monoxide is therefore limited only by its diffusivity in the barrier and by the surface area and thickness of the barrier. Carbon monoxide transfer from the alveolus to the pulmonary capillary blood is referred to as diffusion-limited rather than perfusion-limited.

Perfusion Limitation The partial pressure of nitrous oxide in the pulmonary capillary blood equilibrates very rapidly with the partial pressure of nitrous oxide in the alveolus because nitrous oxide moves through the alveolar–capillary barrier very easily and because it does not combine chemically with the hemoglobin in the erythrocytes. After only about 0.1 of a second of exposure of the pulmonary capillary blood to the alveolar nitrous oxide, the partial pressure gradient across the alveolar–capillary barrier has been abolished. From this point on, no further nitrous oxide transfer occurs from the alveolus to the blood in the capillary that has already equilibrated with the alveolar nitrous oxide partial pressure; during the last 0.6–0.7 of a second, no net diffusion occurs between the alveolus and the blood as it travels through the pulmonary capillary. Blood just entering the capillary at the arterial end will not be equilibrated with the alveolar partial pressure of nitrous oxide, so nitrous oxide can diffuse into the blood at the arterial end. The transfer of nitrous oxide is therefore perfusion-limited. Nitrous oxide transfer from a particular alveolus to one of its pulmonary capillaries can be increased by increasing the cardiac output and thus reducing the amount of time the blood stays in the pulmonary capillary after equilibration with the alveolar partial pressure of nitrous oxide has occurred. (Because increasing the cardiac output may recruit previously unperfused capillaries, the total

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diffusion of both carbon monoxide and nitrous oxide may increase as the surface area for diffusion increases.)

Diffusion of Oxygen As can be seen in Figure 35–5, the time course for oxygen transfer falls between those for carbon monoxide and nitrous oxide. The partial pressure of oxygen rises fairly rapidly (it starts at the Po2 of the mixed venous blood, about 40 mm Hg, rather than at zero), and equilibration with the alveolar Po2 of about 100 mm Hg occurs within about 0.25 of a second, or about one third of the time the blood is in the pulmonary capillary at typical resting cardiac outputs. Oxygen moves easily through the alveolar– capillary barrier and into the erythrocytes, where it combines chemically with hemoglobin. The partial pressure of oxygen rises more rapidly than the partial pressure of carbon monoxide. Nonetheless, the oxygen chemically bound to hemoglobin (and therefore no longer physically dissolved) exerts no partial pressure, so the partial pressure gradient across the alveolar– capillary membrane is initially well maintained and oxygen transfer occurs. The chemical combination of oxygen and hemoglobin, however, occurs rapidly (within hundredths of a second), and at the normal alveolar partial pressure of oxygen, the hemoglobin becomes nearly saturated with oxygen very quickly, as will be discussed in the next chapter. As this happens, the partial pressure of oxygen in the blood rises rapidly to that in the alveolus, and from that point, no further oxygen transfer from the alveolus to the equilibrated blood can occur. Therefore, under the conditions of normal alveolar Po2 and resting cardiac output, oxygen transfer from alveolus to pulmonary capillary is perfusion-limited. During exercise, blood moves through the pulmonary capillary much more rapidly than it does at resting cardiac outputs. In fact, the blood may stay in the pulmonary capillary an average of only about 0.25 of a second during strenuous exercise. Oxygen transfer into the blood per time will be greatly increased because there is little or no perfusion limitation of oxygen transfer. (Indeed, that part of the blood that stays in the capillary less than the average may be subjected to diffusion limitation of oxygen transfer.) Of course, total oxygen transfer is also increased during exercise because of recruitment of previously unperfused capillaries, which increases the surface area for diffusion, and because of better matching of ventilation and perfusion. A person with an abnormal alveolar–capillary barrier due to a fibrotic thickening or interstitial edema may approach diffusion limitation of oxygen transfer at rest and may have a serious diffusion limitation of oxygen transfer during strenuous exercise. A person with an extremely abnormal alveolar–capillary barrier might have diffusion limitation of oxygen transfer even at rest.

Diffusion of Carbon Dioxide The equilibration of the partial pressure of carbon dioxide in the pulmonary capillary blood with that of the alveolus in a healthy person with a mixed venous partial pressure of carbon dioxide of 45 mm Hg and an alveolar partial pressure of

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carbon dioxide of 40 mm Hg is about 0.25 of a second, or about the same as that for oxygen. This may seem surprising, considering that the diffusivity of carbon dioxide is about 20 times that of oxygen, but the partial pressure gradient is normally only about 5 mm Hg for carbon dioxide, whereas it is about 60 mm Hg for oxygen. Carbon dioxide transfer is therefore also normally perfusion-limited, although it may be diffusion-limited in a person with an abnormal alveolar– capillary barrier.

MEASUREMENT OF DIFFUSING CAPACITY It is often useful to determine the diffusion characteristics of a patient’s lungs during their assessment in the pulmonary function laboratory. It may be particularly important to determine whether an apparent impairment in diffusion is a result of perfusion limitation or diffusion limitation. The diffusing capacity is the rate at which oxygen or carbon monoxide is absorbed from the alveolar gas into the pulmonary capillaries (in milliliters per minute) per unit of partial pressure gradient (in millimeters of mercury). It is usually measured with very low concentrations of carbon monoxide because carbon monoxide transfer from alveolus to capillary is diffusion-limited as was discussed previously in this chapter. The mean partial pressure of oxygen or carbon monoxide is, as already discussed, affected by their chemical reactions with hemoglobin, as well as by their transfer through the alveolar– capillary barrier. For this reason, the diffusing capacity of the lung is influenced by both the diffusing capacity of the membrane and the reaction with hemoglobin. The amount of hemoglobin in the lung is dependent on the hemoglobin concentration in the blood and the amount of blood in the pulmonary capillaries—the pulmonary capillary blood volume. Diffusion through the alveolus is normally very rapid and usually can be disregarded, although it could be a major factor in a person with pulmonary edema. Several different methods are used clinically to measure the carbon monoxide diffusing capacity (the DLCO) and involve both single-breath and steady-state techniques, sometimes during exercise. The DLCO is decreased in diseases associated with interstitial or alveolar fibrosis, such as sarcoidosis, scleroderma, and asbestosis, or with conditions causing interstitial or alveolar pulmonary edema, as indicated in Table 35–2. It is also decreased in conditions causing a decrease in the surface area available for diffusion, such as emphysema, tumors, a low cardiac output, or a low pulmonary capillary blood volume, as well as in conditions leading to ventilation–perfusion mismatch, which effectively decreases the surface area available for diffusion. The carbon monoxide diffusing capacity can be very useful in assessing patients with chronic obstructive pulmonary disease (COPD). A low DLCO distinguishes patients whose disorder is primarily emphysema from those whose disorder is primarily chronic bronchitis. The DLCO can also be helpful in assessing patients with restrictive diseases.

TABLE 35–2 Conditions that decrease the diffusing capacity. Thickening of the barrier Interstitial or alveolar edema Interstitial or alveolar fibrosis Sarcoidosis Scleroderma Decreased surface area Emphysema Tumors Low cardiac output Low pulmonary capillary blood volume Decreased uptake by erythrocytes Anemia Low pulmonary capillary blood volume Ventilation–perfusion mismatch Reproduced with permission from Levitzky MG: Pulmonary Physiology, 7th ed. New York: McGraw-Hill Medical, 2007.

CLINICAL CORRELATION A 40-year-old man with a broken leg in a cast because of a skiing injury and no history of respiratory problems suddenly has difficulty breathing and complains of chest pain. He is brought to the hospital. In the emergency department, his breathing is observed to be rapid and shallow. His heart rate is 120/min and his arterial blood pressure is 80/60 mm Hg. His respiratory rate is 25/min. A chest x-ray and an electrocardiogram (ECG) are performed on the patient to help determine the cause of his chest pain and dyspnea. The ECG shows no abnormalities indicative of myocardial ischemia (insufficient blood flow to the heart muscle) or myocardial infarction (injury of the heart muscle) such as ST segment or T-wave abnormalities (see Chapter 23). The chest x-ray shows no abnormalities indicative of pneumonia, atelectasis (collapsed alveoli), or pneumothorax (air between the inside of the chest wall and the outside of the lung). An arterial blood sample is obtained from the patient while he was breathing room air to determine his arterial blood gases (arterial Po2, arterial Pco2, and arterial pH). His arterial Po2 was 70 mm Hg (normal >90); his arterial Pco2 was 30 mm Hg (normal range is 35–45); his pH was 7.50 (normal range is 7.35–7.45). The patient has a pulmonary embolus, most likely as a result of blood clotting in his immobilized leg. Flow of venous blood in the broken leg is impaired by the cast and the lack of muscle contraction to enhance venous return from his leg to his heart. Stasis (low or absent flow) of blood often leads to clotting (thrombosis). When thrombosis occurs in nonsuperficial veins such as those in the leg, it is called deep venous thrombosis (DVT). The thrombus can break loose and be carried to the right side of the heart and enter the pulmonary arterial tree,

CHAPTER 35 Ventilation–Perfusion Relationships and Respiratory Gas Exchange

where it can block blood flow to part of the lung. This is called a pulmonary embolus, in this case a thromboembolus. Pulmonary emboli can be life-threatening if they occlude a significant fraction of the pulmonary vascular bed. The region of the lung with occluded blood flow creates alveolar dead space (ventilated but not perfused) that contributes nothing to gas exchange. The patient’s end-tidal Pco2 decreases because it contains air coming from unperfused alveoli that contribute no carbon dioxide to the exhaled air. The arterial Pco2 is therefore greater than the end-tidal (“alveolar”) Pco2. The diffusing capacity of the patient is decreased because of decreased surface area for gas exchange. Occlusion of pulmonary vessels is likely to increase pulmonary vascular resistance, increase pulmonary artery pressure, and increase right ventricular work. Blood flow to the left side of the patient’s heart decreases, which explains his low systemic blood pressure. His tachycardia is likely a result of the response of his baroreceptor reflex to his low blood pressure, and the pain and anxiety he is experiencing. His tachypnea is explained by the influence of receptors in his lungs (which will be described in Chapter 38) and the pain and anxiety. The tachypnea resulted in hyperventilation causing his arterial Pco2 to decrease below the normal range and his arterial pH to exceed the normal range (see discussion of uncompensated respiratory alkalosis in Chapter 37). His low arterial Po2 is a result of the occlusion of pulmonary vessels forcing blood flow to poorly ventilated alveoli. Treatment of patients with pulmonary emboli (sometimes called pulmonary embolism) depends on the severity of the disorder. Anticoagulants are used to prevent further clotting, thrombolytic drugs are used to break clots down, intravenous catheters with deployable filters can be used to remove the emboli, and large life-threatening emboli may be removed surgically (embolectomy).

CHAPTER SUMMARY ■ ■

■

■

Ventilation and perfusion must be matched on the alveolar– capillary level for optimal gas exchange. Ventilation–perfusion ratios close to 1.0 result in alveolar Po2 of approximately 100 mm Hg and Pco2 close to 40 mm Hg; ventilation–perfusion ratios greater than 1.0 increase the Po2 and decrease the Pco2; ventilation–perfusion ratios less than 1.0 decrease the Po2 and increase the Pco2. Alveolar dead space and intrapulmonary shunt represent the two extremes of ventilation–perfusion ratios, infinite and zero, respectively. The ventilation–perfusion ratios in lower regions of the normal upright lung are lower than 1.0, resulting in lower Po2 and higher Pco2; the ventilation–perfusion ratios in upper parts of the lung are greater than 1.0, resulting in higher Po2 and lower

■

■

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Pco2; nonetheless, there is normally more gas exchange in lower regions of the lung because they receive more blood flow. The volume of gas per unit of time moving across the alveolar–capillary barrier is directly proportional to the area of the barrier, the diffusivity of the gas in the barrier, and the difference in concentration of the gas between the two sides of the barrier, but is inversely proportional to the barrier thickness. If the partial pressure of a gas in the plasma equilibrates with the alveolar partial pressure of the gas within the amount of time the blood is in the pulmonary capillary, its transfer is perfusion-limited; if equilibration does not occur within the time the blood is in the capillary, its transfer is diffusion-limited.

STUDY QUESTIONS 1. An otherwise normal person is brought to the emergency department after having accidentally aspirated a foreign body into the right main-stem bronchus, partially occluding it. Which of the following is/are likely to occur? A) The right lung’s alveolar Po2 will be lower and its alveolar Pco will be higher than those of the left lung. 2 B) The calculated shunt fraction will increase. C) Blood flow to the right lung will decrease. D) The arterial Po2 will decrease. E) All of the above. 2. A healthy person lies down on her right side and breathes normally. Her right lung, in comparison to her left lung, will be expected to have a A) lower alveolar Po2 and a higher alveolar Pco2. B) lower blood flow per unit volume. C) less ventilation per unit volume. D) higher ventilation–perfusion ratio. E) larger alveoli. 3. Which of the following conditions or circumstances is expected to increase the diffusing capacity (DL) of the lungs? A) changing from the supine to the upright position B) exercise C) emphysema D) anemia E) low cardiac output due to blood loss F) diffuse interstitial fibrosis of the lungs 4. If the pulmonary capillary partial pressure of a gas equilibrates with that in the alveolus before the blood leaves the capillary (assume the gas is diffusing from the alveolus to the pulmonary capillary) A) its transfer is said to be perfusion-limited. B) its transfer is said to be diffusion-limited. C) increasing the cardiac output will not increase the amount of the gas diffusing across the alveolar–capillary barrier. D) increasing the alveolar partial pressure of the gas will not increase the amount of the gas diffusing across the alveolar–capillary barrier. E) recruiting additional pulmonary capillaries will not increase the amount of the gas diffusing across the alveolar–capillary barrier.

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36 C

Transport of Oxygen and Carbon Dioxide Michael Levitzky

H A

P

T

E

R

O B J E C T I V E S ■ ■ ■ ■ ■

■ ■ ■ ■

State the relationship between the partial pressure of oxygen in the blood and the amount of oxygen physically dissolved in the blood. Describe the chemical combination of oxygen with hemoglobin and the oxyhemoglobin dissociation curve. Define hemoglobin saturation, oxygen-carrying capacity, and oxygen content. State the physiologic consequences of the shape of the oxyhemoglobin dissociation curve. List the physiologic factors that can influence the oxyhemoglobin dissociation curve, and predict their effects on oxygen transport by the blood. State the relationship between the partial pressure of carbon dioxide in the blood and the amount of carbon dioxide physically dissolved in the blood. Describe the transport of carbon dioxide as carbamino compounds with blood proteins. Explain how most of the carbon dioxide in the blood is transported as bicarbonate. Describe the carbon dioxide dissociation curve for whole blood.

TRANSPORT OF OXYGEN BY THE BLOOD Oxygen is transported both physically dissolved in blood and chemically combined to the hemoglobin in the erythrocytes. Much more oxygen is normally transported combined with hemoglobin than is physically dissolved in the blood. Without hemoglobin, the cardiovascular system could not supply sufficient oxygen to meet tissue demands.

PHYSICALLY DISSOLVED At a temperature of 37°C, 1 mL of plasma contains 0.00003mL O2/(mm Hg Po2). Whole blood contains a similar amount of dissolved oxygen per milliliter because oxygen dissolves in the fluid of the erythrocytes in about the same amount. Therefore,

Ch36_363-374.indd 363

normal arterial blood with a Po2 of approximately 100 mm Hg contains only about 0.003 mL O2/mL of blood, or 0.3 mL O2/100 mL of blood. (Blood oxygen content is conventionally expressed in milliliters of oxygen per 100 mL of blood, also called volume percent.) The physically dissolved oxygen in the blood therefore cannot meet the metabolic demand for oxygen, even at rest.

CHEMICALLY COMBINED WITH HEMOGLOBIN The Structure of Hemoglobin Hemoglobin is a complex molecule with a tetrameric structure consisting of four linked polypeptide chains (globin), each of which is attached to a protoporphyrin (heme) group. Each heme group has a ferrous (Fe2+) iron atom at its center 363

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and can bind a molecule of oxygen (or carbon monoxide), so the tetrameric hemoglobin molecule can combine chemically with four oxygen molecules (or eight oxygen atoms). Variations in the amino acid sequences of the four globin subunits may have important physiologic consequences. Normal adult hemoglobin (HbA) consists of two alpha (α) chains, each of which has 141 amino acids, and two beta (β) chains, each of which has 146 amino acids. Fetal hemoglobin (HbF), which consists of two α chains and two gamma (γ) chains, has a higher affinity for oxygen than does HbA. Synthesis of β chains normally begins about 6 weeks before birth, and HbA usually replaces almost all the HbF by the time an infant is 4 months old. Other, abnormal hemoglobin molecules may be produced by genetic substitution of a single amino acid for the normal one in an α or β chain or (rarely) by alterations in the structure of heme groups. These alterations may produce changes in the affinity of the hemoglobin for oxygen, change the physical properties of hemoglobin, or alter the interaction of hemoglobin and other substances that affect its combination with oxygen, such as 2,3-bisphosphoglycerate (2,3-BPG) (discussed later in this chapter). More than 120 abnormal variants of normal HbA have been demonstrated in patients. The best known of these, hemoglobin S, is present in sickle cell disease. Hemoglobin S tends to polymerize and crystallize in the cytosol of the erythrocyte when it is not combined with oxygen. This polymerization and crystallization decreases the solubility of hemoglobin S within the erythrocyte and changes the shape of the cell from the normal biconcave disk to a crescent or “sickle” shape. A sickled cell is more fragile than a normal cell. In addition, the cells have a tendency to stick to one another, which increases blood viscosity and also favors thrombosis or blockage of blood vessels.

Chemical Reaction of Oxygen and Hemoglobin Hemoglobin rapidly combines reversibly with oxygen. It is the reversibility of the reaction that allows oxygen to be released to the tissues; if the reaction did not proceed easily in both directions, hemoglobin would be of little use in delivering oxygen to satisfy metabolic needs. The reaction is very fast, with a half-time of 0.01 of a second or less. Each gram of hemoglobin is capable of combining with about 1.39 mL of oxygen under optimal conditions, but under normal circumstances, some hemoglobin exists in forms such as methemoglobin (in which the iron atom is in the ferric state) or is combined with carbon monoxide, in which case the hemoglobin cannot bind oxygen. For this reason, the oxygen-carrying capacity of hemoglobin is conventionally considered to be 1.34 mL O2/(g Hb), that is, each gram of hemoglobin, when fully saturated with oxygen, binds 1.34 mL of oxygen. Therefore, a person with 15 g Hb/ 100 mL of blood has an oxygen-carrying capacity of 20.1 mL O2/100 mL of blood: 1.34 mL O 20.1 mL O2 (1) 15 g Hb __________ × ________2 = __________ 100 mL blood

g Hb

100 mL blood

The reaction of hemoglobin and oxygen is conventionally written as follows: Hb + O2 Deoxyhemoglobin

HbO2 Oxyhemoglobin

(2)

HEMOGLOBIN AND THE PHYSIOLOGIC IMPLICATIONS OF THE OXYHEMOGLOBIN DISSOCIATION CURVE The equilibrium point of the reversible reaction of hemoglobin and oxygen is dependent on how much oxygen the hemoglobin in blood is exposed to. This corresponds directly to the partial pressure of oxygen (Po2) in the plasma under the conditions in the body. Thus, the Po2 of the plasma determines the amount of oxygen that binds to the hemoglobin in the erythrocytes.

THE OXYHEMOGLOBIN DISSOCIATION CURVE One way to express the proportion of oxygen that is bound to hemoglobin is as percent saturation. This is equal to the content of oxygen in the blood (minus that part physically dissolved) divided by the oxygen-carrying capacity of the hemoglobin in the blood times 100%: O bound to Hb O2 capacity of Hb

2 % Hb saturation = _____________ × 100%

(3)

Note that the oxygen-carrying capacity of an individual depends on the amount of hemoglobin in the blood. The blood oxygen content also depends on the amount of hemoglobin present (as well as on the Po2). Both content and capacity are expressed as milliliters of oxygen per 100 mL of blood. On the other hand, the percent hemoglobin saturation expresses only a percentage and not an amount or volume of oxygen; “percent saturation” is not interchangeable with “oxygen content.” For example, two patients might have the same percent of hemoglobin saturation, but if one has a lower blood hemoglobin concentration because of anemia, he or she will have a lower blood oxygen content. The relationship between the Po2 of the plasma and the percent of hemoglobin saturation can be expressed graphically as the oxyhemoglobin dissociation curve. An oxyhemoglobin dissociation curve for normal blood is shown in Figure 36–1. The oxyhemoglobin dissociation curve is really a plot of how the availability of one of the reactants, oxygen (expressed as the Po2 of the plasma), affects the reversible chemical reaction of oxygen and hemoglobin. The product, oxyhemoglobin, is expressed as percent saturation—really a percentage of the maximum for any given amount of hemoglobin. As can be seen in Figure 36–1, the relationship between Po2 and HbO2 is not linear; it is a sigmoid (S-shaped) curve, steep at the lower Po2 and nearly flat when the Po2 is above 70 mm Hg.

CHAPTER 36 Transport of Oxygen and Carbon Dioxide

365

Hemoglobin saturation ( %)

100

80

60 50% 40

20 0 20

0

40

60

80

100

120

140

160

P50 Partial pressure of oxygen (mm Hg)

FIGURE 36–1 A typical “normal” adult oxyhemoglobin dissociation curve for blood at 37°C with a pH of 7.40 and a PCO2 of 40 mm Hg. The P50 is the partial pressure of oxygen at which hemoglobin is 50% saturated with oxygen. (Modified with permission from Levitzky MG: Pulmonary Physiology, 7th ed. New York: McGraw-Hill Medical, 2007.)

It is this S shape that is responsible for several very important physiologic properties of the reaction of oxygen and hemoglobin. The reason that the curve is S-shaped and not linear is that it is actually a plot of four reactions rather than one, that is, each of the four subunits of hemoglobin can combine with one molecule of oxygen. The reactions of the four subunits of hemoglobin with oxygen do not occur simultaneously. Instead they occur sequentially in four steps, with an interaction between the subunits occurring in such a way that during the successive combinations of the subunits with oxygen, each combination facilitates the next. Similarly, dissociation of oxygen from hemoglobin subunits facilitates further dissociations. The dissociation curve for a single monomer of hemoglobin is far different from that for the tetramer (see Figure 36–4C).

Loading Oxygen in the Lung Mixed venous blood entering the pulmonary capillaries normally has a Po2 of about 40 mm Hg. At a Po2 of 40 mm Hg, hemoglobin is about 75% saturated with oxygen, as seen in Figure 36–1. Assuming a blood hemoglobin concentration of 15 g Hb/100 mL of blood, this corresponds to 15.08 mL O2/100 mL of blood bound to hemoglobin plus an additional 0.12 mL O2/100 mL of blood physically dissolved, or a total oxygen content of approximately 15.2 mL O2/100 mL of blood. Oxygen-carrying capacity is given as follows: 1.34 mL O 20.1 mL O2 15 g Hg __________ × ________2 = __________ 100 mL blood g Hb 100 mL blood

(4)

Oxygen bound to hemoglobin at a Po2 of 40 mm Hg (37°C, pH 7.4) is given as follows: 20.1 mL O2 __________ × 100 mL blood Capacity

75% % saturation

15.08 mL O2 = ___________ 100 mL blood Content

(5)

Oxygen physically dissolved at a Po2 of 40 mm Hg is given as follows: 0.003 mL O2 0.12 mL O2 ______________________ × 40 mm Hg = __________ (6) 100 mL blood Po2 (in mm Hg) 100 mL blood

Total blood oxygen content at a Po2 of 40 mm Hg (37°C, pH 7.4) is given as follows: 15.08 mL O2 __________ 100 mL blood Bound to Hb

0.12 mL O2 __________ 100 mL blood

+

=

Physically dissolved

15.2 mL O2 __________ 100 mL blood (7) Total

As the blood passes through the pulmonary capillaries, it equilibrates with the alveolar Po2 of about 100 mm Hg. At a Po2 of 100 mm Hg, hemoglobin is about 97.4% saturated with oxygen, as seen in Figure 36–1. This corresponds to 19.58 mL O2/100 mL of blood bound to hemoglobin plus 0.3 mL O2/100 mL of blood physically dissolved, or a total oxygen content of 19.88 mL O2/100 mL of blood. Oxygen bound to hemoglobin at a Po2 of 100 mm Hg (37°C, pH 7.4) is given as follows: 20.1 mL O2 ___________ × 100 mL blood Capacity

97.4%

19.58 mL O 100 mL blood

2 = __________

% saturation

(8)

Content

Oxygen physically dissolved at a Po2 of 100 mm Hg is given as follows: 0.003 mL O2 0.3 mL O2 ______________________ × 100 mm Hg = __________ (9) 100 mL blood Po2 (in mm Hg) 100 mL blood

Total blood oxygen content at a Po2 of 100 mm Hg (37°C, pH 7.4) is given as follows: 19.58 mL O2 __________ 100 mL blood Bound to Hb

+

0.3 mL O2 __________ 100 mL blood Physically dissolved

=

19.88 mL O2 __________ 100 mL blood (10) Total

Thus, in passing through the lungs, each 100 mL of blood has loaded (19.88 – 15.20) mL O2, or 4.68 mL O2. Assuming a

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cardiac output of 5 L/min, this means that approximately 234 mL O2 is loaded into the blood per minute: 46.8 mL O2 ________ 234 mL O 5 L blood ________ _______ × = min 2 min liter blood

(11)

Note that the oxyhemoglobin dissociation curve is relatively flat when Po2 is greater than approximately 70 mm Hg. This is very important physiologically because it means that there is only a small decrease in the oxygen content of blood equilibrated with a Po2 of 70 mm Hg instead of 100 mm Hg. In fact, the curve shows that at a Po2 of 70 mm Hg, hemoglobin is still approximately 94.1% saturated with oxygen. This constitutes an important safety factor because a patient with a relatively low alveolar or arterial Po2 of 70 mm Hg (owing to hypoventilation or intrapulmonary shunt, for example) is still able to load adequate oxygen into the blood. A quick calculation shows that at 70 mm Hg, the total blood oxygen content is approximately 19.12 mL O2/100 mL of blood compared with the 19.88 mL O2/100 mL of blood at a Po2 of 100 mm Hg. These calculations show that Po2 is often a more sensitive diagnostic indicator of the status of a patient’s respiratory system than the arterial oxygen content. Of course, the oxygen content is more important physiologically to the patient. Because hemoglobin is approximately 97.4% saturated at a Po2 of 100 mm Hg, increasing the alveolar Po2 above 100 mm Hg can add little additional oxygen to hemoglobin (only about 0.52 mL O2/100 mL of blood at a hemoglobin concentration of 15 g/100 mL of blood). Hemoglobin is fully saturated with oxygen at a Po2 of about 250 mm Hg.

Unloading Oxygen at the Tissues As blood passes from the arteries into the systemic capillaries, it is exposed to lower Po2 and oxygen is released by the hemoglobin. The Po2 in the capillaries varies from tissue to tissue, being very low in some (e.g., myocardium) and relatively higher in others (e.g., renal cortex). As can be seen in Figure 36–1, the oxyhemoglobin dissociation curve is very steep in the range of 40–10 mm Hg. This means that a small decrease in Po2 can result in a substantial further dissociation of oxygen and hemoglobin, unloading more oxygen for use by the tissues. At a Po2 of 40 mm Hg, hemoglobin is about 75% saturated with oxygen, with a total blood oxygen content of 15.2 mL O2/100 mL of blood (at 15 g Hb/100 mL of blood). At a Po2 of 20 mm Hg, hemoglobin is only 32% saturated with oxygen. The total blood oxygen content is only 6.49 mL O2/100 mL of blood, a decrease of 8.71 mL O2/100 mL of blood for only a 20-mm Hg decrease in Po2. The unloading of oxygen at the tissues is also facilitated by other physiologic factors that can alter the shape and position of the oxyhemoglobin dissociation curve. These include the pH, Pco2, temperature of the blood, and concentration of 2,3-BPG in the erythrocytes.

INFLUENCES ON THE OXYHEMOGLOBIN DISSOCIATION CURVE Figure 36–2 shows the influence of alterations in temperature, pH, Pco2, and 2,3-BPG on the oxyhemoglobin dissociation

curve. High temperature, low pH, high Pco2, and elevated levels of 2,3-BPG all shift the oxyhemoglobin dissociation curve to the right; that is, for any particular Po2, there is less oxygen chemically combined with hemoglobin at higher temperatures, lower pH, higher Pco2, and elevated levels of 2,3-BPG. The rightward shift represents a decreased affinity of hemoglobin for oxygen. The effects of blood pH and Pco2 on the oxyhemoglobin dissociation curve are shown in Figure 36–2A and B. Low pH and high Pco2 both shift the curve to the right. High pH and low Pco2 both shift the curve to the left. These two effects often occur together. The influence of pH (and Pco2) on the oxyhemoglobin dissociation curve is referred to as the Bohr effect. The Bohr effect will be discussed in greater detail at the end of this chapter. Figure 36–2C shows the effects of blood temperature on the oxyhemoglobin dissociation curve. High temperatures shift the curve to the right; low temperatures shift the curve to the left. At very low blood temperatures, hemoglobin has such a high affinity for oxygen that it does not release the oxygen, even at very low Po2. 2,3-BPG (also called 2,3-diphosphoglycerate, or 2,3-DPG) is produced by erythrocytes during their normal glycolysis and is present in fairly high concentrations within red blood cells (about 15 mmol/(g Hb)). 2,3-BPG binds to the hemoglobin in erythrocytes, which decreases the affinity of hemoglobin for oxygen. Higher concentrations of 2,3-BPG therefore shift the oxyhemoglobin dissociation curve to the right, as shown in Figure 36–2D. It has been demonstrated that more 2,3-BPG is produced during chronic hypoxic conditions, thus shifting the dissociation curve to the right and allowing more oxygen to be released from hemoglobin at a particular Po2. Very low levels of 2,3-BPG shift the curve far to the left, as shown in the figure. This means that blood deficient in 2,3-BPG does not unload much oxygen. Blood stored in blood banks for as little as 1 week has been shown to have very low levels of 2,3-BPG. Use of banked blood in patients may result in decreased oxygen unloading to the tissues unless steps are taken to restore the normal levels of 2,3-BPG. As blood enters metabolically active tissues, it is exposed to an environment different from that found in the arterial tree. The Pco2 is higher, the pH is lower, and the temperature is also higher than that of the arterial blood. The curve shown in Figure 36–1 is for blood at 37°C, with a pH of 7.4 and a Pco2 of 40 mm Hg. Blood in metabolically active tissues and therefore the venous blood draining them are no longer subject to these conditions because they have been exposed to a different environment. Because low pH, high Pco2, increased 2,3-BPG, and higher temperature all shift the oxyhemoglobin dissociation curve to the right, they all can help unload oxygen from hemoglobin at the tissues. On the other hand, as the venous blood returns to the lung and CO2 leaves the blood (which increases the pH), the affinity of hemoglobin for oxygen increases as the curve shifts back to the left, as shown in Figure 36–3. Note that the effects of pH, Pco2, and temperature shown in Figure 36–2 have a more profound effect on enhancing the unloading of oxygen at the tissues than they do interfering with its loading at the lungs.

CHAPTER 36 Transport of Oxygen and Carbon Dioxide 100

100

Hemoglobin saturation (%)

 pH

60

40

20

80

60

40

20

0 A.

20

40

60 PO (mm Hg) 2

80

0

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0 C.

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80

100

80

100

100

PCO  20 mm Hg 2 PCO  40 mm Hg 2

40

PCO2  80 mm Hg 20 0

0 B.

20

40

60 80 100 PO (mm Hg) 2

120

140

160

60

40

20

0

FIGURE 36–2

No

60

No 2 ,3

80

rm al 2 ,3Add BP ed G 2,3 -B PG

-BPG

80 Hemoglobin saturation (%)

Hemoglobin saturation ( %)

37° 43°



 pH

pH

Hemoglobin saturation ( %)

80

7.4 0 7.2 0

7.6 0

20°

0

367

0 D.

20

40

60 PO (mm Hg) 2

The effects of pH (A), PCO2 (B), temperature (C), and 2,3-BPG (D) on the oxyhemoglobin dissociation curve. (Modified with

permission from Levitzky MG: Pulmonary Physiology, 7th ed. New York: McGraw-Hill Medical, 2007.)

A convenient way to discuss shifts in the oxyhemoglobin dissociation curve is the P50, shown in Figures 36–1 and 36–3. The P50 is the Po2 at which 50% of the hemoglobin present in the blood is in the deoxyhemoglobin state and 50% is in the oxyhemoglobin state. At a temperature of 37°C, a pH of 7.4, and a Pco2 of 40 mm Hg, normal human blood has a P50 of 26 or 27 mm Hg. If the oxyhemoglobin dissociation curve is shifted to the right, the P50 increases. If it is shifted to the left, the P50 decreases.

Other Factors Affecting Oxygen Transport Most forms of anemia (low blood hemoglobin concentration or low number of red blood cells) do not affect the oxyhemoglobin dissociation curve if the association of oxygen and hemoglobin is expressed as percent saturation. For

example, anemia secondary to erythrocyte loss does not affect the combination of oxygen and hemoglobin for the remaining erythrocytes. It is the amount of hemoglobin that decreases, not the percent saturation or even the arterial Po2. The arterial content of oxygen, however, in milliliters of oxygen per 100 mL of blood, is reduced, as shown in Figure 36–4A, because the decreased amount of hemoglobin per 100 mL of blood decreases the oxygen-carrying capacity of the blood. Carbon monoxide has a much greater affinity for hemoglobin than does oxygen, as discussed in Chapter 35. It can therefore effectively block the combination of oxygen with hemoglobin because oxygen cannot be bound to iron atoms already combined with carbon monoxide. Carbon monoxide has a second deleterious effect: it shifts the oxyhemoglobin dissociation curve to the left. Thus, carbon monoxide can

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SECTION VI Pulmonary Physiology a

100

Hemoglobin saturation (%)

80

v-

60 50% 40

20

0

0

20

40 P50

60 PO2 (mm Hg)

80

100

FIGURE 36–3 Oxyhemoglobin dissociation curves for arterial and venous blood. The venous curve is shifted to the right because the pH is lower and the PCO2 (and possibly the temperature) is higher. The rightward shift results in a higher P50 for venous blood. a, arterial point (P 2 = 100mm Hg); –v, mixed venous point (P 2 = 40mm Hg). O

O

(Modified with permission from Levitzky MG: Pulmonary Physiology, 7th ed. New York: McGraw-Hill Medical, 2007.)

prevent the loading of oxygen into the blood in the lungs and can also interfere with the unloading of oxygen at the tissues. This can be seen in Figure 36–4A. Carbon monoxide is particularly dangerous for several reasons. A person breathing very low concentrations of carbon monoxide can slowly reach life-threatening levels of carboxyhemoglobin (COHb) in the blood because carbon monoxide has such a high affinity for hemoglobin. The effect is cumulative. What is worse is that a person breathing carbon monoxide is not aware of doing so—the gas is colorless, odorless, and tasteless and does not elicit any reflex coughing or sneezing, increase in ventilation, or feeling of difficulty in breathing. Smoking and living in urban areas cause small amounts of COHb to be present in the blood of healthy adults. A nonsmoker who lives in a rural area may have only about 1% COHb; a smoker who lives in an urban area may have 5–8% COHb in the blood. Hemoglobin within erythrocytes can rapidly scavenge nitric oxide (NO). NO can react with oxyhemoglobin to form methemoglobin and nitrate or react with deoxyhemoglobin to form a hemoglobin–NO complex. In addition, hemoglobin may act as a carrier for NO, in the form of S-nitrosothiol, on the cysteine residues on the β-globin chain. This is called s-nitrosohemoglobin (SNO-Hb). When hemoglobin binds oxygen, the formation of this S-nitrosothiol is enhanced; when hemoglobin releases oxygen, NO could be released. Thus, in regions where the Po2 is low, NO—a potent vasodilator—could be released. Methemoglobin is hemoglobin with iron in the ferric (Fe3+) state. It can be caused by nitrite poisoning or by toxic reactions

to oxidant drugs, or it can be found congenitally in patients with hemoglobin M. Iron atoms in the Fe3+ state will not combine with oxygen. As already discussed in this chapter, variants of the normal HbA may have different affinities for oxygen. HbF in red blood cells has a dissociation curve to the left of that for HbA, as shown in Figure 36–4B. Fetal Po2 is much lower than in the adult; the curve is located properly for its operating range. Furthermore, HbF’s greater affinity for oxygen relative to the maternal hemoglobin promotes transport of oxygen across the placenta by maintaining the diffusion gradient. The shape of the HbF curve in blood appears to be a result of the fact that 2,3-BPG has little effect on the affinity of HbF for oxygen. Myoglobin (Mb), a heme protein that occurs naturally in muscle cells, consists of a single polypeptide chain attached to a heme group. It can therefore combine chemically with a single molecule of oxygen and is similar structurally to a single subunit of hemoglobin. As can be seen in Figure 36–4C, the hyperbolic dissociation curve of Mb (which is similar to that of a single hemoglobin subunit) is far to the left of that of normal HbA; that is, at lower Po2, much more oxygen remains bound to Mb. Mb can therefore store oxygen in skeletal muscle. As blood passes through the muscle, oxygen leaves hemoglobin and binds to Mb. It can be released from the Mb when conditions within muscle cause lower tissue Po2. Cyanosis is not really an influence on the transport of oxygen but rather is a sign of poor transport of oxygen. It occurs when more than 5 g Hb/100 mL of arterial blood is in the deoxy state. It is a bluish purple discoloration of the skin, nail beds, and mucous membranes, and its presence is indicative of an abnormally high concentration of deoxyhemoglobin in the arterial blood. Its absence, however, does not exclude hypoxemia because an anemic patient with hypoxemia may not have sufficient hemoglobin to appear cyanotic.

TRANSPORT OF CARBON DIOXIDE BY THE BLOOD Carbon dioxide is carried in the blood in physical solution, chemically combined to amino acids in blood proteins, and as bicarbonate ions. About 200–250 mL of carbon dioxide is produced by the tissue metabolism each minute in a resting 70-kg person and must be carried by the venous blood to the lung for removal from the body. At a cardiac output of 5 L/min, each 100 mL of blood passing through the lungs must therefore unload 4–5 mL of carbon dioxide.

PHYSICALLY DISSOLVED Carbon dioxide is about 20 times more soluble in the plasma (and inside the erythrocytes) compared to oxygen. As a result, about 5–10% of the total carbon dioxide transported by the blood is carried in physical solution.

CHAPTER 36 Transport of Oxygen and Carbon Dioxide

369

100

20

12

60

50% CO Hb 8

Anemia (6 g Hb/100 mL blood)

Hb su bu nit Hb A

80 Mb

16

Saturation (%)

O2 bound to hemoglobin, mL O2/100 mL

Normal blood

40

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Hemoglobin saturation (%)

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PO2 (mm Hg)

About 0.0006mL CO2/(mm Hg Pco2) will dissolve in 1 mL of plasma at 37°C. One hundred milliliters of plasma or whole blood at a Pco2 of 40 mm Hg, therefore, contains about 2.4 mL CO2 in physical solution. Figure 36–5 shows that the total CO2 content of whole blood is about 48 mL CO2/100 mL of blood at 40 mm Hg, so approximately 5% of the carbon dioxide carried in the arterial blood is in physical solution. Similarly, multiplying 0.06mL CO2/100mL of blood/ (mm Hg Pco2) times a venous Pco2 of 45 mm Hg shows that about 2.7 mL CO2 is physically dissolved in the mixed venous blood. The total carbon dioxide content of venous blood is about 52.5 mL CO2/100 mL of blood; a little more than 5% of the total carbon dioxide content of venous blood is in physical solution.

FIGURE 36–4 Other physiologic factors influencing oxygen transport and storage. A) The effects of carbon monoxide and anemia on the carriage of oxygen by hemoglobin. Note that the ordinate is expressed as the volume of oxygen bound to hemoglobin in milliliters of oxygen per 100 mL of blood. B) A comparison of the oxyhemoglobin dissociation curves for normal adult hemoglobin (HbA) and fetal hemoglobin (HbF). C) Dissociation curves for normal HbA, a single monomeric subunit of hemoglobin (Hb subunit), and myoglobin (Mb). (Modified with permission from Levitzky MG: Pulmonary Physiology, 7th ed. New York: McGraw-Hill Medical, 2007.)

CARBAMINO COMPOUNDS Carbon dioxide can combine chemically with the terminal amine groups in blood proteins, forming carbamino compounds. The reaction occurs rapidly; no enzymes are necessary. Note that a hydrogen ion is released when a carbamino compound is formed: H

H R

+ CO2

N H

Terminal amine group

R

N

+ H+ COO– Carbamino compound

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FIGURE 36–5 Carbon dioxide dissociation curves for whole blood (37°C) at different oxyhemoglobin saturations. Note that the ordinate is whole blood CO2 content in milliliters of CO2 per 100 mL of blood. a, arterial point; –v, mixed venous point. (Modified with permission from Levitzky MG:

Whole blood carbon dioxide content, mL CO2 /100 mL blood

70

60 v50

%H 97.5

bO 2

a 40

30

20

10

Pulmonary Physiology, 7th ed. New York: McGraw-Hill Medical, 2007.)

Because the protein found in greatest concentration in the blood is the globin of hemoglobin, most of the carbon dioxide transported in this manner is bound to amino acids of hemoglobin. Deoxyhemoglobin can bind more carbon dioxide as carbamino groups than can oxyhemoglobin. Therefore, as the hemoglobin in the venous blood enters the lung and combines with oxygen, it releases carbon dioxide from its terminal amine groups. About 5–10% of the total carbon dioxide content of blood is in the form of carbamino compounds.

BICARBONATE The remaining 80–90% of the carbon dioxide transported by the blood is carried as bicarbonate ions. This is made possible by the following reaction: CO2 + H2O Carbonic anhydrase H2CO3

HbO 2 0% HbO 2 70%

H+ + HCO3– (12)

Carbon dioxide can combine with water to form carbonic acid, which then dissociates into a hydrogen ion and a bicarbonate ion. Very little carbonic acid is formed by the association of water and carbon dioxide without the presence of the enzyme carbonic anhydrase because the reaction occurs so slowly. Carbonic anhydrase, which is present in high concentration in erythrocytes (but not in plasma), makes the reaction proceed about 13,000 times faster. (Note that the product of the carbonic anhydrase reaction is actually not carbonic acid, but a bicarbonate ion and a proton—see Chapter 47.) Hemoglobin also plays an integral role in the transport of carbon dioxide because it can accept the hydrogen ion liberated by the

0 0

10

20

30

40 50 PCO (mm Hg) 2

60

70

80

dissociation of carbonic acid, thus allowing the reaction to continue. This will be discussed in detail in the last section of this chapter.

THE CARBON DIOXIDE DISSOCIATION CURVE The carbon dioxide dissociation curve for whole blood is shown in Figure 36–5. Within the normal physiologic range of Pco2, the curve is nearly a straight line, with no steep or flat portions. The carbon dioxide dissociation curve for whole blood is shifted to the right at greater levels of oxyhemoglobin and shifted to the left at greater levels of deoxyhemoglobin. This is known as the Haldane effect. The Haldane effect allows the blood to load more carbon dioxide at the tissues, where there is more deoxyhemoglobin, and unload more carbon dioxide in the lungs, where there is more oxyhemoglobin. The Bohr and Haldane effects are both explained by the fact that deoxyhemoglobin is a weaker acid than oxyhemoglobin; that is, deoxyhemoglobin more readily accepts the hydrogen ion liberated by the dissociation of carbonic acid, thus permitting more carbon dioxide to be transported in the form of bicarbonate ion. This is referred to as the isohydric shift. Conversely, the association of hydrogen ions with the amino acids of hemoglobin lowers the affinity of hemoglobin for oxygen, thus shifting the oxyhemoglobin dissociation curve to the right at low pH or high Pco2. The following relationship can therefore be written: H+Hb + O2

H+ + HbO2

(13)

CHAPTER 36 Transport of Oxygen and Carbon Dioxide

371

A. IN THE TISSUES TISSUE

ERYTHROCYTE

PLASMA Dissolved CO2

CO2

CAPILLARY WALL

H2O

CO2

Dissolved

H2O  CO2 Carbonic anhydrase

CO2

H2CO3 HCO3 

Cl

HCO3  H Cl H  HbO2

O2

O2  HHb

O2

HHb  CO2 Carbamino compounds

B. IN THE LUNG ALVEOLUS

ERYTHROCYTE

PLASMA Dissolved CO2

CAPILLARY WALL

CO2

H2O

CO2

Dissolved

H2O  CO2 Carbonic anhydrase

CO2

H2CO3 HCO3 Cl

HCO3  H Cl H  HbO2

O2

O2

O2  HHb

HHb  CO2 Carbamino compounds

FIGURE 36–6 Schematic representation of uptake and release of carbon dioxide and oxygen at the tissues (A) and in the lung (B). Note that small amounts of carbon dioxide can form carbamino compounds with blood proteins other than hemoglobin and may also be hydrated in trivial amounts in the plasma to form carbonic acid and then bicarbonate (not shown in diagram). The circles represent the bicarbonate–chloride exchange carrier protein. (Modified with permission from Levitzky MG: Pulmonary Physiology, 7th ed. New York: McGraw-Hill Medical, 2007.)

These effects can be seen in the schematic diagrams of oxygen and carbon dioxide transport shown in Figure 36–6. At the tissues, the Po2 is decreased and the Pco2 is increased. Carbon dioxide dissolves in the plasma, and some diffuses into the erythrocyte. Some of this carbon dioxide dissolves in the cytosol, some forms carbamino compounds with hemoglobin, and some is hydrated by carbonic anhydrase to form carbonic acid. At low Po2, there are substantial amounts of

deoxyhemoglobin in the erythrocytes and the deoxyhemoglobin is able to accept the hydrogen ions liberated by the dissociation of carbonic acid and the formation of carbamino compounds. The hydrogen ions released by the dissociation of carbonic acid and the formation of carbamino compounds bind to specific amino acid residues on the globin chains and facilitate the release of oxygen from hemoglobin (the Bohr effect). Bicarbonate ions diffuse out of the erythrocyte

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SECTION VI Pulmonary Physiology

through the cell membrane much more readily than do hydrogen ions. Because more bicarbonate ions than hydrogen ions leave the erythrocyte, electrical neutrality is maintained by the exchange of chloride ions for bicarbonate ions by the bicarbonate–chloride carrier protein. This is the “chloride shift.” Small amounts of water also move into the cell to maintain the osmotic equilibrium. At the lung, the Po2 is increased and the Pco2 is decreased. As oxygen combines with hemoglobin, the hydrogen ions that were taken up when it was in the deoxyhemoglobin state are released. They combine with bicarbonate ions, forming carbonic acid. This breaks down into carbon dioxide and water. At the same time, carbon dioxide is also released from the carbamino compounds. Carbon dioxide then diffuses out of the red blood cells and plasma and into the alveoli. A chloride shift opposite in direction to that in the tissues also occurs to maintain electrical neutrality.

CLINICAL CORRELATION An 18-year-old man is brought by ambulance to the emergency department about 35 minutes after being shot in the leg. He is conscious, although disoriented and in pain, and appears pale. Heart rate is 150/min and his arterial blood pressure is 80/60 mm Hg. He is breathing spontaneously with a high respiratory rate of 26/min. During the trip to hospital, the wound was stabilized and he received 2 L of normal saline (0.9% NaCl in water) solution intravenously. In the emergency department, he continues to lose blood while the physicians attempt to stop the hemorrhage. As his arterial blood pressure continues to decrease to 60/45 mm Hg, he is given 2 additional liters of saline. His hematocrit decreases to 21% (normal range 40–50%), corresponding to a hemoglobin concentration of 7 g/100 mL of blood (normal range 13–18 g/100 mL blood). His respiratory rate increases to 40/min. Results of blood gas analysis (see Chapter 37) from an arterial blood sample show an arterial Po2 of 95 mm Hg, an arterial Pco2 of 28 mm Hg (normal range 35–45 mm Hg), and an arterial pH of 7.30 (normal range 7.35–7.45) despite the hypocapnia. He becomes agitated and loses consciousness. He is intubated (a tube inserted into trachea) and mechanically ventilated via the endotracheal tube. The patient’s decreased blood volume led to decreased venous return, decreased cardiac output, and decreased systemic blood pressure. Decreased firing of the baroreceptors in the carotid sinuses and aortic arch decreased parasympathetic stimulation of the heart and increased sympathetic stimulation of the heart, arterioles, and the veins. This resulted in increased heart rate and myocardial contractility; increased arteriolar tone; and decreased venous compliance to enhance venous return, cardiac

output, and blood pressure. However, all of these responses were not sufficient to increase his blood pressure or his cardiac output to normal levels, as he continued to lose blood. The decreased cardiac output and increased vascular resistance to most vascular beds resulted in decreased tissue perfusion (including his skin, explaining his pale appearance). This ischemia resulted in production of lactic acid causing hydrogen ion stimulation of the arterial chemoreceptors (see Chapters 37 and 38), which explains his tachypnea (high respiratory rate). He was hyperventilating in compensation as demonstrated by the hypocapnia. As he continued to lose blood, his blood pressure was no longer sufficient to provide adequate cerebral blood flow and he lost consciousness and showed signs of circulatory shock. Administration of normal saline temporarily increased blood volume, but diluted his erythrocytes, decreasing his hematocrit, hemoglobin concentration, oxygen-carrying capacity, and arterial oxygen content, even if his alveolar and arterial partial pressures of oxygen were normal. Mixed venous Po2 would decrease as tissues extracted as much oxygen as possible from the arterial blood. Renal and endocrine responses to hemorrhage also would occur, as will be discussed in Sections 7 and 9. In the emergency department, his treatment would be aimed at stopping blood loss and restoring cardiac output and blood pressure with matched packed red blood cells (red blood cells after most of the plasma and other cells have been removed from whole blood) to restore his oxygen carrying capacity.

CHAPTER SUMMARY ■

■

■

■

■

Blood normally carries a small amount of oxygen physically dissolved in the plasma and a large amount chemically combined to hemoglobin: only the physically dissolved oxygen contributes to the partial pressure, but the partial pressure of oxygen determines how much combines chemically with hemoglobin. The oxyhemoglobin dissociation curve describes the reversible reaction of oxygen and hemoglobin to form oxyhemoglobin; it is relatively flat at a Po2 above approximately 70 mm Hg and is very steep at a Po2 in the range of 20–40 mm Hg. Decreased pH, increased Pco2, increased temperature, and increased 2,3-BPG concentration of the blood all shift the oxyhemoglobin dissociation curve to the right. Blood normally carries small amounts of carbon dioxide physically dissolved in the plasma and chemically combined to blood proteins as carbamino compounds and a large amount in the form of bicarbonate ions. Deoxyhemoglobin favors the formation of carbamino compounds, and it promotes the transport of carbon dioxide as bicarbonate ions by buffering hydrogen ions formed by the dissociation of carbonic acid.

CHAPTER 36 Transport of Oxygen and Carbon Dioxide

STUDY QUESTIONS 1. An otherwise healthy person has lost enough blood to decrease the hemoglobin concentration from 15 to 12 g/100 mL blood. Which of the following would be expected to decrease? A) arterial Po2 B) blood oxygen-carrying capacity C) arterial hemoglobin saturation D) arterial oxygen content E) B and D. 2. A woman’s hemoglobin concentration is 10 g of hemoglobin per 100 mL of blood. If her hemoglobin is 90% saturated with oxygen at an arterial Po2 of 80 mm Hg, what is her total arterial oxygen content, including physically dissolved oxygen? A) 10.72 mL O2/100 mL blood B) 10.96 mL O2/100 mL blood C) 12.06 mL O2/100 mL blood D) 12.30 mL O2/100 mL blood E) 13.40 mL O2/100 mL blood

3. Which of the following should increase the P50 of the oxyhemoglobin dissociation curve? A) hypercapnia B) acidosis C) increased blood levels of 2,3-BPG D) increased body temperature E) all of the above 4. Most of the carbon dioxide in the blood is transported A) as bicarbonate. B) as carbamino compounds. C) physically dissolved in the plasma. D) physically dissolved inside erythrocytes.

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37 C

Acid–Base Regulation and Causes of Hypoxia Michael Levitzky

H A

P

T

E

R

O B J E C T I V E S ■ ■ ■ ■ ■ ■ ■

Define acids, bases, and buffers. List the buffer systems available in the human body. State the normal ranges of arterial pH, PCO2, and bicarbonate concentration, and define alkalosis and acidosis. List the potential causes of respiratory acidosis and alkalosis and metabolic acidosis and alkalosis. Discuss the respiratory mechanisms that help compensate for acidosis and alkalosis. Evaluate blood gas data to determine acid–base status. Classify and explain the causes of tissue hypoxia.

The respiratory and renal systems maintain the balance of acids and bases in the body. This chapter will introduce the major concepts of the respiratory system’s contribution to acid–base balance; Chapter 47 addresses the renal system contribution to acid–base balance and includes a more detailed discussion of the basic chemistry of acid–base physiology, buffers, and the chemistry of the CO2–bicarbonate system.

INTRODUCTION TO ACID–BASE CHEMISTRY An acid can be simply defined as a substance that can donate a hydrogen ion (a proton) to another substance and a base as a substance that can accept a hydrogen ion from another substance. A strong acid is a substance that is completely or almost completely dissociated into a hydrogen ion and its corresponding or conjugate base in dilute aqueous solution; a weak acid is only slightly ionized in aqueous solution. In general, a strong acid has a weak conjugate base and a weak acid has a strong conjugate base. The strength of an acid or a base should not be confused with its concentration. A buffer is a mixture of substances in aqueous solution (usually a combination of a weak acid and its conjugate base) that can resist changes in hydrogen ion concentration when

Ch37_375-384.indd 375

strong acids or bases are added; that is, the changes in hydrogen ion concentration that occur when a strong acid or base is added to a buffer system are much smaller than those that would occur if the same amount of acid or base were added to pure water or another nonbuffer solution. The hydrogen ion activity of pure water is about 1.0 × 10–7 mol/L. By convention, solutions with hydrogen ion activities above 10–7 mol/L are considered to be acid; those with hydrogen ion activities below 10–7 are considered to be alkaline. The range of hydrogen ion concentrations or activities in the body is normally from about 10–1 for gastric acid to about 10–8 for the most alkaline pancreatic secretion. This wide range of hydrogen ion activities necessitates the use of the more convenient pH scale. The pH of a solution is the negative logarithm of its hydrogen ion activity. With the exception of the highly concentrated gastric acid, in most instances in the body, the hydrogen ion activity is about equal to the hydrogen ion concentration. The pH of arterial blood is normally close to 7.40, with a normal range considered to be about 7.35–7.45. An arterial pH (pHa) less than 7.35 is considered acidemia; a pHa greater than 7.45 is considered alkalemia. The underlying condition characterized by hydrogen ion retention or by loss of bicarbonate or other bases is referred to as acidosis; the underlying condition characterized by hydrogen ion loss or retention of

375

11/29/10 4:40:09 PM

376

SECTION VI Pulmonary Physiology

TABLE 37–1 The pH scale. pH

Concentration (nmol/L)

6.90

126

7.00

100

7.10

79

7.20

63

7.30

50

7.40

40

7.50

32

7.60

25

7.70

20

7.80

16

Reproduced with permission from Levitzky MG: Pulmonary Physiology, 7th ed. New York: McGraw-Hill Medical, 2007.

base is referred to as alkalosis. Under pathologic conditions, the extremes of arterial blood pH have been noted to range as high as 7.8 and as low as 6.9. These correspond to hydrogen ion concentrations as seen in Table 37–1 (hydrogen ion concentrations are expressed as nanomoles [10–9 mol/L] for convenience). Note that the pH scale is “inverted” by the negative sign and is also logarithmic as it is defined. An increase in pH represents a decrease in hydrogen ion concentration. In fact, an increase of only 0.3 pH units indicates that the hydrogen ion concentration was cut in half. Hydrogen ions are the most reactive cations in body fluids, and they interact with negatively charged regions of other molecules, such as those of body proteins. Interactions of hydrogen ions with negatively charged functional groups of proteins can lead to marked changes in protein structural conformations with resulting alterations in the behavior of the proteins. An example of this was already seen in Chapter 36, where hemoglobin was noted to combine with less oxygen at a lower pH (the Bohr effect). Alterations in the structural conformations and charges of protein enzymes affect their activities, with resulting alterations in the functions of body tissues. Extreme changes in the hydrogen ion concentration of the body can result in loss of organ system function and may be fatal. Under normal circumstances, cellular metabolism is the main source of acids in the body. These acids are the waste products of substances ingested as foodstuffs. The greatest source of hydrogen ions is the carbon dioxide produced as one of the end products of the oxidation of glucose and fatty acids during aerobic metabolism. The hydration of carbon dioxide results in the formation of carbonic acid, which then can dissociate into a hydrogen ion and a bicarbonate ion, as discussed in Chapter 36. This process is reversed in the pulmonary capillaries, and CO2 then diffuses through the alveolar–capillary barrier into the alveoli, from which it is removed by alveolar

ventilation. Carbonic acid is therefore said to be a volatile acid because it can be converted into a gas and then removed from an open system such as the body. Very great amounts of carbon dioxide can be removed from the lungs by alveolar ventilation: under normal circumstances, about 15,000–25,000 mmol of carbon dioxide is removed via the lungs daily. A much smaller quantity of fixed or nonvolatile acids is also normally produced during the course of the metabolism of foodstuffs. The fixed acids produced by the body include sulfuric acid, which originates from the oxidation of sulfurcontaining amino acids such as cysteine; phosphoric acid from the oxidation of phospholipids and phosphoproteins; hydrochloric acid, which is produced during the conversion of ingested ammonium chloride to urea and by other reactions; and lactic acid from the anaerobic metabolism of glucose. Other fixed acids may be ingested accidentally or formed in abnormally large quantities by disease processes, such as the acetoacetic and butyric acid formed during diabetic ketoacidosis (see Chapter 66). About 70 mEq of fixed acids is normally removed from the body each day (about 1 mEq/kg/body weight per day); the range is 50–100 mEq. A vegetarian diet may produce significantly less fixed acid and may even result in no net production of fixed acids. The removal of fixed acids is accomplished mainly by the kidneys, as will be discussed in Chapter 47. Some may also be removed via the gastrointestinal tract. Fixed acids normally represent only about 0.2% of the total body acid production. The body contains a variety of substances that can act as buffers in the physiologic pH range. These include bicarbonate, phosphate, and proteins in the blood, the interstitial fluid, and inside cells (discussed in greater detail in Chapter 47). The isohydric principle states that all the buffer pairs in a homogeneous solution are in equilibrium with the same hydrogen ion concentration. For this reason, all the buffer pairs in the plasma behave similarly, so that the detailed analysis of a single buffer pair, like the bicarbonate buffer system, can reveal a great deal about the chemistry of all the plasma buffers. The main buffers of the blood are bicarbonate, phosphate, and proteins. The bicarbonate buffer system consists of the buffer pair of the weak acid, carbonic acid, and its conjugate base, bicarbonate. The ability of the bicarbonate system to function as a buffer of fixed acids in the body is largely due to the ability of the lungs to remove carbon dioxide from the body. In a closed system, bicarbonate would not be nearly as effective. At a temperature of 37°C, about 0.03 mmol of carbon dioxide per mm Hg of Pco2 will dissolve in a liter of plasma. (Note that the solubility of CO2 was expressed as milliliters of CO2 per 100 mL of plasma in Chapter 36.) Therefore, the carbon dioxide dissolved in the plasma, expressed as millimoles per liter, is equal to 0.03 x Pco2 . At body temperature in the plasma, the equilibrium of the reaction is such that there is roughly 1,000 times more carbon dioxide physically dissolved in the plasma than there is in the form of carbonic acid. The dissolved carbon dioxide is in equilibrium with the carbonic acid, though, so both the dissolved carbon dioxide and the carbonic

CHAPTER 37 Acid–Base Regulation and Causes of Hypoxia acid are considered as the undissociated HA in the Henderson–Hasselbalch equation (see Chapter 47) for the bicarbonate system: [HCO3–]p

pH = pK + log ___________ [CO + H CO ] 2

2

(1)

3

where [HCO3−]p stands for plasma bicarbonate concentration. The concentration of carbonic acid is negligible, so we have: [HCO3–]p

pH = pK′ + log _______ 0.03 P

(2)

co2

where pK′ is the pK of the HCO3−–CO2 system in blood. The pK′ of this system at physiologic pH values and at 37°C is 6.1. Therefore, at a pHa of 7.40 and an arterial Pco2 of 40 mm Hg, we have: [HCO3–]p

7.40 = 6.1 + log _________

(3)

1.2 mmol/L

Therefore, the arterial plasma bicarbonate concentration is about 24 mmol/L (the normal range is 23–28 mmol/L) because the logarithm of 20 is equal to 1.3. Note that the term total CO2 refers to the dissolved carbon dioxide (including carbonic acid) plus the carbon dioxide present as bicarbonate. A useful way to display the interrelationships among the variables of pH, Pco2, and bicarbonate concentration of the plasma, as expressed by the Henderson–Hasselbalch equation, is the pH–bicarbonate diagram shown in Figure 37–1. As can be seen from Figure 37–1, pH is on the abscissa of the pH–bicarbonate diagram, and the plasma bicarbonate concentration in millimoles per liter is on the ordinate. For

100 40

80

70

[H ] (nmol/L) 50 40

60

30

20

16

ba

r

A

iso ba

B

Hg

m m 

40 m

m

60

 CO 2



CO 2

r

ba

C

P

CO 2

P

25

r

iso Hg

mm 80

30 P

[HCO3]p (mmol/L)

Hg

ba

r

iso

35

20

D



P CO

E

15 10 7.0

m

7.1

7.2

7.3

7.4 pH

Hg

iso

0m

2

2

7.5

Normal buffer line

7.6

7.7

FIGURE 37–1

2

Acid–Base Chemistry, 6th ed. 1974.)

each value of pH and bicarbonate ion concentration, there is a single corresponding Pco2 on the graph. Conversely, for any particular pH and Pco2, only one bicarbonate ion concentration will satisfy the Henderson–Hasselbalch equation. If the Pco2 is held constant, for example, at 40 mm Hg, an isobar line can be constructed, connecting the resulting points as the pH is varied. The representative isobars shown in Figure 37–1 give an indication of the potential alterations of acid–base status when alveolar ventilation is increased or decreased. If everything else remains constant, hypoventilation leads to acidosis; hyperventilation leads to alkalosis. The bicarbonate buffer system is a poor buffer for carbonic acid. The presence of hemoglobin makes blood a much better buffer. The buffer value of plasma in the presence of hemoglobin is four to five times that of plasma separated from erythrocytes. Therefore, the slope of the normal in vivo buffer line shown in Figures 37–1 is mainly determined by the nonbicarbonate buffers present in the body. The phosphate buffer system mainly consists of the buffer pair of the dihydrogen phosphate (H2PO4−) and the monohydrogen phosphate (HPO42−) anions. Although several potential buffering groups are found on proteins, only one large group has pK in the pH range encountered in the blood. These are the imidazole groups in the histidine residues of the peptide chains. The protein present in the greatest quantity in the blood is hemoglobin. As already noted, deoxyhemoglobin is a weaker acid than is oxyhemoglobin. Thus, as oxygen leaves hemoglobin in the tissue capillaries, the imidazole group removes hydrogen ions from the erythrocyte interior, allowing more carbon dioxide to be transported as bicarbonate. This process is reversed in the lungs. The bicarbonate buffer system is the major buffer found in the interstitial fluid, including the lymph. The phosphate buffer pair is also found in the interstitial fluid. The volume of the interstitial compartment is much larger than that of the plasma, so the interstitial fluid may play an important role in buffering. The extracellular portion of bone contains very large deposits of calcium and phosphate salts, mainly in the form of hydroxyapatite. In an otherwise healthy adult, where bone growth and resorption are in a steady state, bone salts can buffer hydrogen ions in chronic acidosis. Chronic buffering of hydrogen ions by the bone salts may therefore lead to demineralization of bone. The intracellular proteins and organic phosphates of most cells can function to buffer both fixed acids and carbonic acid. Of course, buffering by the hemoglobin in erythrocytes is intracellular.

7.8

The pH–bicarbonate diagram with PCO isobars. 2 Note the hydrogen ion concentration in nanomoles per liter at the top of the figure corresponding to the pH values on the abscissa. Points A to E correspond to different pH values and bicarbonate concentrations all falling on the same PCO isobar. (Modified with

permission of the University of Chicago Press from Davenport HW: The ABC of

377

ACIDOSIS AND ALKALOSIS Acid–base disorders can be divided into four major categories: respiratory acidosis, respiratory alkalosis, metabolic acidosis, and metabolic alkalosis. These primary acid–base disorders may occur singly (“simple”) or in combination (“mixed”) or may be altered by compensatory mechanisms.

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SECTION VI Pulmonary Physiology

RESPIRATORY ACIDOSIS

TABLE 37–2 Common causes of respiratory acidosis.

The arterial Pco2 is normally maintained at or near 40 mm Hg (normal range is 35–45 mm Hg) by the mechanisms that regulate breathing. Sensors exposed to the arterial blood and to the cerebrospinal fluid provide the central controllers of breathing with the information necessary to regulate the arterial Pco2 at or near 40 mm Hg (see Chapter 38). Any short-term alterations (i.e., those which occur without renal compensation) in alveolar ventilation that result in an increase in alveolar and therefore also in arterial Pco2 tend to lower the pHa, resulting in respiratory acidosis. This can be appreciated by examining the Pco2 = 60 and 80 mm Hg isobars in Figure 37–1. The pHa at any Paco2 depends on the bicarbonate and other buffers present in the blood. Pure changes in arterial Pco2 caused by changes in ventilation travel along the normal in vivo buffer line (Figures 37–1 and 37–2). Pure uncompensated respiratory acidosis would correspond with point C in Figure 37–2 (at the intersection of an elevated Pco2 isobar and the normal buffer line). In respiratory acidosis, the ratio of bicarbonate to CO2 decreases. Yet, as can be seen at point C in Figure 37–2, in uncompensated primary (simple) respiratory acidosis, the absolute plasma bicarbonate concentration does increase somewhat because of the buffering of some of the hydrogen ions liberated by the dissociation of carbonic acid by nonbicarbonate buffers. Any impairment of alveolar ventilation can cause respiratory acidosis. As shown in Table 37–2, depression of the respiratory centers in the medulla (see Chapter 38) by anesthetic agents, narcotics, hypoxia, central nervous system disease or trauma, or even greatly increased PaCo2 itself results in hypoventilation and respiratory acidosis. Interference with the neural transmission to the respiratory muscles by disease

Metabolic alkalosis and respiratory acidosis F 35

[HCO3]p (mmol/L)

D

25

20

15

Uncompensated metabolic alkalosis

Metabolic alkalosis Uncompensated E respiratory acidosis Metabolic alkalosis C and respiratory alkalosis Metabolic acidosis A and respiratory acidosis Normal buffer line I Metabolic G acidosis B Uncompensated Uncompensated metabolic acidosis respiratory alkalosis Metabolic acidosis H and respiratory alkalosis

10 7.0

7.1

FIGURE 37–2

7.2

7.3

7.4 pH

7.5

7.6

7.7

7.8

Acid–base paths in vivo. (Modified with permission of

the University of Chicago Press from Davenport HW: The ABC of Acid–Base Chemistry, 6th ed. 1974.)

Neuromuscular disorders Spinal cord injury Phrenic nerve injury Poliomyelitis, Guillain–Barré syndrome, etc. Botulism, tetanus Myasthenia gravis Administration of curarelike drugs Diseases affecting the respiratory muscles Chest wall restriction Kyphoscoliosis Extreme obesity Lung restriction Pulmonary fibrosis Sarcoidosis Pneumothorax, pleural effusions, etc. Pulmonary parenchymal diseases Pneumonia, etc. Pulmonary edema Airway obstruction Chronic obstructive pulmonary disease Upper airway obstruction Reproduced with permission from Levitzky MG: Pulmonary Physiology, 7th ed. New York: McGraw-Hill Medical, 2007.

processes, drugs or toxins, or dysfunctions or deformities of the respiratory muscles or the chest wall can result in respiratory acidosis. Restrictive, obstructive, and obliterative diseases of the lungs can also result in respiratory acidosis.

RESPIRATORY ALKALOSIS

40

30

Depression of the respiratory control centers Anesthetics Sedatives Opiates Brain injury or disease Severe hypercapnia, hypoxia

Alveolar ventilation in excess of that needed to keep pace with body’s carbon dioxide production results in alveolar and arterial Pco2 below 35 mm Hg. Such hyperventilation leads to respiratory alkalosis. Uncompensated primary respiratory alkalosis results in movement to a lower Pco2 isobar along the normal buffer line, as seen at point B in Figure 37–2. The decreased Paco2 shifts the equilibrium of the series of reactions describing carbon dioxide hydration and carbonic acid dissociation to the left. This results in a decreased arterial hydrogen ion concentration, increased pH, and a decreased plasma bicarbonate concentration. The ratio of bicarbonate to carbon dioxide increases. The causes of respiratory alkalosis include anything leading to hyperventilation. As shown in Table 37–3, hyperventilation syndrome, a psychological dysfunction of unknown cause, results in chronic or recurrent episodes of hyperventilation and respiratory alkalosis. Drugs, hormones (such as progesterone), toxic substances, central nervous system diseases or disorders,

CHAPTER 37 Acid–Base Regulation and Causes of Hypoxia

TABLE 37–3 Common causes of respiratory alkalosis.

379

TABLE 37–4 Common causes of metabolic acidosis.

Central nervous system Anxiety Hyperventilation syndrome Inflammation (encephalitis, meningitis) Cerebrovascular disease Tumors

Ingested drugs or toxic substances Methanol Ethanol Salicylates Ethylene glycol Ammonium chloride

Drugs or hormones Salicylates Progesterone

Loss of bicarbonate ions Diarrhea Pancreatic fistulas Renal dysfunction

Bacteremias, fever Pulmonary diseases Acute asthma Pulmonary vascular diseases (pulmonary embolism) Overventilation with mechanical ventilators Hypoxia; high altitude Reproduced with permission from Levitzky MG: Pulmonary Physiology, 7th ed. New York: McGraw-Hill Medical, 2007.

bacteremias, fever, overventilation by mechanical ventilators (or the clinician), or ascent to high altitude may all result in respiratory alkalosis.

Lactic acidosis Hypoxemia Anemia, carbon monoxide Shock (hypovolemic, cardiogenic, septic, etc.) Severe exercise Acute respiratory distress syndrome (ARDS) Ketoacidosis Diabetes mellitus Alcoholism Starvation Inability to excrete hydrogen ions Renal dysfunction Reproduced with permission from Levitzky MG: Pulmonary Physiology, 7th ed. New York: McGraw-Hill Medical, 2007.

METABOLIC ACIDOSIS Metabolic acidosis may be thought of as nonrespiratory acidosis. It can be caused by the ingestion, infusion, or production of a fixed acid; decreased renal excretion of hydrogen ions; the movement of hydrogen ions from the intracellular to the extracellular compartment; or the loss of bicarbonate or other bases from the extracellular compartment. As can be seen in Figure 37–2, primary uncompensated metabolic acidosis results in a downward movement along the Pco2 = 40 mm Hg isobar to point G, that is, a net loss of buffer establishes a new blood–buffer line lower than and parallel to the normal blood–buffer line. Pco2 is unchanged, hydrogen ion concentration is increased, and the ratio of bicarbonate concentration to CO2 is decreased. As shown in Table 37–4, ingestion of methyl alcohol or salicylates can cause metabolic acidosis by increasing the fixed acids in the blood. (Salicylate poisoning—for example, aspirin overdose—causes both metabolic acidosis and later respiratory alkalosis.) Diarrhea can cause significant bicarbonate losses, resulting in metabolic acidosis. Renal dysfunction can lead to an inability to excrete hydrogen ions, as well as an inability to reabsorb bicarbonate ions, as will be discussed in the next section. True “metabolic” acidosis may be caused by an accumulation of lactic acid in severe hypoxemia or shock and by diabetic ketoacidosis.

METABOLIC ALKALOSIS Metabolic, or nonrespiratory, alkalosis occurs when there is an excessive loss of fixed acids from the body, or it may occur

as a consequence of the ingestion, infusion, or excessive renal reabsorption of bases such as bicarbonate. Figure 37–2 shows that primary uncompensated metabolic alkalosis results in an upward movement along the Pco2 = 40 mm Hg isobar to point D, that is, a net gain of buffer establishes a new blood–buffer line higher than and parallel to the normal blood–buffer line. Pco2 is unchanged, hydrogen ion concentration is decreased, and the ratio of bicarbonate concentration to carbon dioxide is increased. As shown in Table 37–5, loss of gastric juice by vomiting results in a loss of hydrogen ions and may cause metabolic alkalosis. Excessive ingestion of bicarbonate or other bases (e.g., stomach antacids) or overinfusion of bicarbonate by the clinician may cause metabolic alkalosis. In addition,

TABLE 37–5 Common causes of metabolic alkalosis. Loss of hydrogen ions Vomiting Gastric fistulas Diuretic therapy Treatment with or overproduction of steroids (aldosterone or other mineralocorticoids) Ingestion or administration of excess bicarbonate or other bases Intravenous bicarbonate Ingestion of bicarbonate or other bases (e.g., antacids) Reproduced with permission from Levitzky MG: Pulmonary Physiology, 7th ed. New York: McGraw-Hill Medical, 2007.

380

SECTION VI Pulmonary Physiology

diuretic therapy, treatment with steroids (or the overproduction of endogenous steroids), and conditions leading to severe potassium depletion may also cause metabolic alkalosis.

mechanism or the breathing apparatus itself. Compensation for acidosis or alkalosis in these conditions must therefore come from outside the respiratory system. The respiratory compensatory mechanism can operate very rapidly (within minutes) to partially correct metabolic acidosis or alkalosis.

COMPENSATORY MECHANISMS Uncompensated primary acid–base disturbances, such as those indicated by points B–D and G in Figure 37–2, seldom occur because respiratory and renal compensatory mechanisms are called into play to offset these disturbances. The two main compensatory mechanisms are functions of the respiratory and renal systems.

RESPIRATORY COMPENSATORY MECHANISMS The respiratory system can compensate for metabolic acidosis or alkalosis by altering alveolar ventilation. As discussed in Chapter 33, if carbon dioxide production is constant, the alveolar Pco2 is inversely proportional to the alveolar ventilation. In metabolic acidosis, the increased blood hydrogen ion concentration stimulates chemoreceptors, which, in turn, increase alveolar ventilation, thus decreasing arterial Pco2. This causes an increase in pHa, returning it toward normal. (The mechanisms by which ventilation is regulated are discussed in detail in Chapter 38.) These events can be better understood by looking at Figure 37–2. Point G represents uncompensated metabolic acidosis. As the respiratory compensation for the metabolic acidosis occurs, in the form of an increase in ventilation, the arterial Pco2 decreases. The point representing blood pHa, Paco2, and bicarbonate concentration would then move a short distance along the lower-than-normal buffer line (from point G toward point H) until a new lower Paco2 is attained. This returns the pHa toward normal; complete compensation does not occur. The respiratory compensation for metabolic acidosis occurs almost simultaneously with the development of the acidosis. The blood pH, Pco2, and bicarbonate concentration point does not really move first from the normal (point A) to point G and then move a short distance along line GH; instead, the compensation begins to occur as the acidosis develops, so the point takes an intermediate pathway between the two lines. The respiratory compensation for metabolic alkalosis is to decrease alveolar ventilation, thus increasing Paco2. This decreases pHa toward normal, as can be seen in Figure 37–2. Point D represents uncompensated metabolic alkalosis; respiratory compensation would move the blood pHa, PaCo2, and bicarbonate concentration point a short distance along the new higher-than-normal blood–buffer line toward point F. Again the compensation occurs as the alkalosis develops, with the point moving along an intermediate course. Under most circumstances, the cause of respiratory acidosis or alkalosis is a dysfunction in the ventilatory control

RENAL COMPENSATORY MECHANISMS The kidneys can compensate for respiratory acidosis and metabolic acidosis of nonrenal origin by excreting fixed acids and by retaining filtered bicarbonate. They can also compensate for respiratory alkalosis or metabolic alkalosis of nonrenal origin by decreasing hydrogen ion excretion and by decreasing the retention of filtered bicarbonate. These mechanisms are discussed in Chapter 47. Renal compensatory mechanisms for acid–base disturbances operate much more slowly than respiratory compensatory mechanisms. For example, the renal compensatory responses to sustained respiratory acidosis or alkalosis may take 3–6 days. The kidneys help regulate acid–base balance by altering the excretion of fixed acids and the retention of the filtered bicarbonate; the respiratory system helps regulate body acid–base balance by adjusting alveolar ventilation to alter alveolar Pco2. For these reasons, the Henderson–Hasselbalch equation is in effect: Kidneys

pH = Constant + ______ Lungs

(4)

CLINICAL INTERPRETATION OF ARTERIAL BLOOD GASES Samples of arterial blood are usually analyzed clinically to determine the “arterial blood gases”: the arterial Po2, Pco2, and pH. The plasma bicarbonate can then be calculated from the pH and Pco2 by using the Henderson–Hasselbalch equation. This can be done directly, or by using a nomogram, or by graphical analysis such as the pH–bicarbonate diagram (the “Davenport plot,” after its popularizer), the pH– Pco2 diagram (the “Siggaard-Andersen”), or the composite acid–base diagram. Blood gas analyzers perform these calculations automatically. Table 37–6 summarizes the changes in pHa, Paco2, and plasma bicarbonate concentration that occur in simple, mixed, and partially compensated acid–base disturbances. It contains the same information shown in Figure 37–2, depicted differently. A thorough understanding of the patterns shown in Table 37–6 coupled with knowledge of a patient’s Pco2 and other clinical findings can reveal a great deal about the underlying pathophysiologic processes in progress. A simple approach to interpreting a blood gas set is to first look at the pH to determine whether the predominant problem is acidosis or alkalosis. (Note that an acidemia could represent more than one cause of acidosis, an acidosis with some compensation, or even an acidosis and a separate underlying

CHAPTER 37 Acid–Base Regulation and Causes of Hypoxia

TABLE 37–6 Acid–base disturbances. pH

PCO2

HCO3−

Uncompensated respiratory acidosis

↓↓

↑↑

↑

Uncompensated respiratory alkalosis

↑↑

↓↓

↓

Uncompensated metabolic acidosis

↓↓

↔

↓↓

Uncompensated metabolic alkalosis

↑↑

↔

↑↑

Partially compensated respiratory acidosis

↓

↑↑

↑↑

Partially compensated respiratory alkalosis

↑

↓↓

↓↓

Partially compensated metabolic acidosis

↓

↓↓

↓↓

Partially compensated metabolic alkalosis

↑

↑↑

↑↑

Respiratory and metabolic acidosis

↓↓

↑↑

↓

Respiratory and metabolic alkalosis

↑↑

↓↓

↑

Reproduced with permission from Levitzky MG: Pulmonary Physiology, 7th ed. New York: McGraw-Hill Medical, 2007.

alkalosis. Similarly, an alkalemia could represent more than one cause of alkalosis, an alkalosis with some compensation, or even an alkalosis and a separate underlying acidosis.) After evaluating the pH, look at the arterial Pco2 to see if it explains the pH. For example, if the pH is low and the Pco2 is increased, then the primary problem is respiratory acidosis. If the pH is low and the Pco2 is near 40 mm Hg, then the primary problem is metabolic acidosis with little or no compensation. If both the pH and the Pco2 are low, there is metabolic acidosis with respiratory compensation. Then look at the bicarbonate concentration to confirm your diagnosis. It should be slightly increased in uncompensated respiratory acidosis, high in partially compensated respiratory acidosis, and low in metabolic acidosis. If the pH is high and the Pco2 is low, then the primary problem is respiratory alkalosis. If the pH is high and the Pco2 is near 40 mm Hg, then the problem is uncompensated metabolic alkalosis. If both the pH and the Pco2 are high, then there is partially compensated metabolic alkalosis. The bicarbonate should be slightly decreased in respiratory alkalosis, decreased in partially compensated respiratory alkalosis, and increased in metabolic alkalosis.

BASE EXCESS Calculation of the base excess or base deficit may be very useful in determining the therapeutic measures to be admin-

381

istered to a patient. The base excess or base deficit is the number of milliequivalents of acid or base needed to titrate 1 L of blood to pH 7.4 at 37°C if the Paco2 were held constant at 40 mm Hg. It is not, therefore, just the difference between the plasma bicarbonate concentration of the sample in question and the normal plasma bicarbonate concentration because respiratory adjustments also cause a change in bicarbonate concentration: the arterial Pco2 must be considered, although in most cases the vertical deviation of the bicarbonate level above or below the blood–buffer line on the Davenport diagram at the pH of the sample is a reasonable estimate. Base excess can be determined by actually titrating a sample or by using a nomogram, diagram, or calculator program. Most blood gas analyzers calculate the base excess automatically. The base excess is expressed in milliequivalents per liter above or below the normal buffer-base range—it therefore has a normal value of 0 ± 2 mEq/L. A base deficit is also called a negative base excess. The base deficit can be used to estimate how much sodium bicarbonate (in mEq) should be given to a patient by multiplying the base deficit (in mEq/L) times the patient’s estimated extracellular fluid (ECF) space (in liters), which is the distribution space for the bicarbonate. The ECF is usually estimated to be 0.3 times the lean body mass in kilograms.

ANION GAP Calculation of the anion gap can be helpful in determining the cause of a patient’s metabolic acidosis. It is determined by subtracting the sum of a patient’s plasma chloride and bicarbonate concentrations (in mEq/L) from his or her plasma sodium concentration: Anion gap =[Na+]–([C1–]+[HCO3–])

(5)

The anion gap is normally 12 ± 4 mEq/L. The sum of all of the plasma cations must equal the sum of all of the plasma anions, so the anion gap exists only because all of the plasma cations and anions are not measured when standard blood chemistry is done. Sodium, chloride, and bicarbonate concentrations are almost always reported. The normal anion gap is a result of the presence of more unmeasured anions than unmeasured cations in normal blood: [Na+]+[Unmeasured cations]= [ C1 ]+[HCO3–]+[Unmeasured anions]

(6)

[Na+]–([ C1–]+[HCO3–])= [Unmeasured anions]–[Unmeasured cations]

(7)

–

The anion gap is therefore the difference between the unmeasured anions and the unmeasured cations. The negative charges on the plasma proteins probably make up most of the normal anion gap, because the total charges of the other plasma cations (K+, Ca2+, Mg2+) are approximately equal to the total charges of the other anions (PO43−, SO42−, organic anions).

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An increased anion gap usually indicates an increased number of unmeasured anions (those other than C1– and HCO3−) or a decreased number of unmeasured cations (K+, Ca2+, or Mg2+), or both. This is most likely to happen when the measured anions, [HCO3−] or [Cl–], are lost and replaced by unmeasured anions. For example, the buffering by HCO3− of H+ from ingested or metabolically produced acids produces an increased anion gap. Thus, metabolic acidosis with an abnormally great anion gap (i.e., greater than 16 mEq/L) would probably be caused by lactic acidosis or ketoacidosis; ingestion of organic anions such as salicylate, methanol, and ethylene glycol; or renal retention of anions such as sulfate, phosphate, and urate.

THE CAUSES OF HYPOXIA Thus far, only two of the three variables referred to as the arterial blood gases, the arterial Pco2, and pH have been discussed. Many abnormal conditions or diseases can cause a low arterial Po2. They are discussed in the following section about the causes of tissue hypoxia in the discussion of hypoxic hypoxia. The causes of tissue hypoxia can be classified (in some cases rather arbitrarily) into four or five major groups (Table 37–7). The underlying physiology of most of these types of hypoxia has already been discussed in this or previous chapters.

HYPOXIC HYPOXIA Hypoxic hypoxia refers to conditions in which the arterial Po2 is abnormally low. Because the amount of oxygen that will combine with hemoglobin is mainly determined by the Po2, such conditions may lead to decreased oxygen delivery to the tissues if reflexes or other responses cannot adequately increase the cardiac output or hemoglobin concentration of the blood.

Low Alveolar PO2 Conditions causing low alveolar Po2 inevitably lead to low arterial Po2 and oxygen contents because the alveolar Po2 determines the upper limit of arterial Po2. Hypoventilation leads to both alveolar hypoxia and hypercapnia (high CO2), as discussed in Chapter 33. Hypoventilation can be caused by depression or injury of the respiratory centers in the brain (discussed in Chapter 38), interference with the nerves supplying the respiratory muscles, as in spinal cord injury, neuromuscular junction diseases such as myasthenia gravis, and altered mechanics of the lung or chest wall, as in noncompliant lungs due to sarcoidosis, reduced chest wall mobility because of kyphoscoliosis or obesity, and airway obstruction. Ascent to high altitude causes alveolar hypoxia because of the reduced total barometric pressure encountered above sea level. Reduced FIo2 (fractional concentration of inspired oxygen) has a similar effect. Alveolar carbon dioxide is decreased because of the reflex increase in ventilation caused by hypoxic stimulation, as will be discussed in Chapter 71. Hypoventilation and ascent to high altitude lead to decreased venous Po2 and oxygen content as oxygen is extracted from the already hypoxic arterial blood. Administration of increased oxygen concentrations in the inspired gas can alleviate the alveolar and arterial hypoxia in hypoventilation and in ascent to high altitude, but it cannot reverse the hypercapnia of hypoventilation. In fact, administration of increased FIo2 to spontaneously breathing patients hypoventilating because of a depressed central response to carbon dioxide (see Chapter 38) can further depress ventilation.

Diffusion Impairment Alveolar–capillary diffusion is discussed in greater detail in Chapter 35. Conditions such as interstitial fibrosis and interstitial or alveolar edema can lead to low arterial Po2 and contents with normal or elevated alveolar Po2. High FIo2 that increases the alveolar Po2 to very high levels may increase the

TABLE 37–7 A classification of the causes of hypoxia. PAO2

PaO2

CaO2

P –V O2

C–V O2

Increased FIO2 Helpful?

Low

Low

Low

Low

Low

Yes

Diffusion impairment

N

Low

Low

Low

Low

Yes

Right-to-left shunts

N

Low

Low

Low

Low

No

˙V/ Q ˙ mismatch

N

Low

Low

Low

Low

Yes

Anemic hypoxia

N

N

Low

Low

Low

No

CO poisoning

N

N

Low

Low

Low

Possibly

Hypoperfusion hypoxia

N

N

N

Low

Low

No

Histotoxic hypoxia

N

N

N

High

High

No

Classification Hypoxic hypoxia Low alveolar PO

2

N, normal. Reproduced with permission from Levitzky MG: Pulmonary Physiology, 7th ed. New York: McGraw-Hill Medical, 2007.

CHAPTER 37 Acid–Base Regulation and Causes of Hypoxia arterial Po2 by increasing the partial pressure gradient for oxygen diffusion.

Shunts True right-to-left shunts, such as anatomic shunts and absolute intrapulmonary shunts, can cause decreased arterial Po2 with normal or even increased alveolar Po2. Patients with intrapulmonary shunts have low arterial Po2, but may not have significantly increased Pco2 if they are able to increase their alveolar ventilation or if they are mechanically ventilated. This is a result of the different shapes of the oxyhemoglobin dissociation curve (see Figure 36–1) and the carbon dioxide dissociation curve (see Figure 36–5). The carbon dioxide dissociation curve is almost linear in the normal range of arterial Pco2, and arterial Pco2 is very tightly regulated by the respiratory control system (see Chapter 38). Carbon dioxide retained in the shunted blood stimulates increased alveolar ventilation, and because the carbon dioxide dissociation curve is nearly linear, increased ventilation will allow more carbon dioxide to diffuse from the nonshunted blood into well-ventilated alveoli and be exhaled. On the other hand, increasing alveolar ventilation will not get any more oxygen into the shunted blood and, because of the shape of the oxyhemoglobin dissociation curve, very little more into the unshunted blood. This is because the hemoglobin of well-ventilated and perfused alveoli is nearly saturated with oxygen, and little more will dissolve in the plasma. Similarly, arterial hypoxemia caused by true shunts is not relieved by high FIo2 because the shunted blood does not come into contact with the high levels of oxygen. The hemoglobin of the unshunted blood is nearly completely saturated with oxygen at a normal FIo2 of 0.21, and the small additional volume of oxygen dissolved in the blood at high FIo2 cannot make up for the low hemoglobin saturation of the shunted blood.

VENTILATION–PERFUSION MISMATCH ˙ /Q ˙) Alveolar–capillary units with low ventilation–perfusion (V ratios contribute to arterial hypoxia, as already discussed. Units ˙ /Q ˙ do not by themselves lead to arterial hypoxia, of with high V course, but large lung areas that are underperfused are usually associated either with overperfusion of other units or with low cardiac outputs (see the section “Hypoperfusion Hypoxia”). Hypoxic pulmonary vasoconstriction (discussed in Chapter 34) and local airway responses (discussed in Chapter 32) nor˙/Q ˙ mismatch. mally help minimize V ˙/Q ˙ mismatch Note that diffusion impairment, shunts, and V increase the alveolar–arterial Po2 difference (see Table 35–1 and the first two columns in Table 37–7).

ANEMIC HYPOXIA Anemic hypoxia is caused by a decrease in the amount of functioning hemoglobin, which can be a result of decreased hemoglobin or erythrocyte production, the production of abnormal hemoglobin or red blood cells, pathologic destruction of eryth-

383

rocytes, or interference with the chemical combination of oxygen and hemoglobin. Carbon monoxide poisoning, for example, results from the greater affinity of hemoglobin for carbon monoxide than for oxygen. Methemoglobinemia is a condition in which the iron in hemoglobin has been altered from the Fe2+ to the Fe3+ form, which does not combine with oxygen. Anemic hypoxia results in a decreased oxygen content when both alveolar and arterial Po2 are normal. Standard analysis of arterial blood gases could therefore give normal values unless blood oxygen content is measured independently. Venous Po2 and oxygen content are both decreased. Administration of high FIo2 is not effective in greatly increasing the arterial oxygen content (except possibly in carbon monoxide poisoning).

HYPOPERFUSION HYPOXIA Hypoperfusion hypoxia (sometimes called stagnant hypoxia) results from low blood flow. This can occur either locally, in a particular vascular bed, or systemically, in the case of a low cardiac output. The alveolar Po2 and the arterial Po2 and oxygen content may be normal, but the reduced oxygen delivery to the tissues may result in tissue hypoxia. Venous Po2 and oxygen content are low. Increasing the FIo2 is of little value in hypoperfusion hypoxia (unless it directly increases the perfusion) because the blood flowing to the tissues is already oxygenated normally.

HISTOTOXIC HYPOXIA Histotoxic hypoxia refers to a poisoning of the cellular machinery that uses oxygen to produce energy. Cyanide, for example, binds to cytochrome oxidase in the respiratory chain and effectively blocks oxidative phosphorylation. Alveolar Po2 and arterial Po2 and oxygen content may be normal (or even increased, because low doses of cyanide increase ventilation by stimulating the arterial chemoreceptors). Venous Po2 and oxygen content are increased because oxygen is not utilized in the tissues.

THE EFFECTS OF HYPOXIA Hypoxia can result in reversible tissue injury or even tissue death. The outcome of an hypoxic episode depends on whether the tissue hypoxia is generalized or localized, how severe the hypoxia is, the rate of development of the hypoxia (see Chapter 71), and the duration of the hypoxia. Different cell types have different susceptibilities to hypoxia; unfortunately, brain cells and heart cells are the most susceptible.

CLINICAL CORRELATION A 15-year-old adolescent entered the emergency department with dyspnea (shortness of breath), a feeling of chest tightness, coughing, wheezing, and anxiety. His nail beds and lips were blue (cyanosis).

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He has had frequent episodes of dyspnea and wheezing for several years, especially in the spring, and has been diagnosed with asthma. Pulmonary function tests done at the time of his diagnosis showed lower-than-predicted forced expiratory volume in the first second (FEV1), forced vital capacity (FVC), FEV1/FVC, and peak expiratory flow (PEF). Inhaling a bronchodilator improved all of these. An arterial blood gas was obtained to help determine the severity of the episode. The arterial Po2 was 55 mm Hg, the arterial Pco2 was 32 mm Hg, the arterial pH was 7.52, and the bicarbonate was 25 mEq/L, indicating hypoxemia and uncompensated respiratory alkalosis. Asthma is an episodic obstructive disease and it is reasonable to assume that it would cause CO2 retention and therefore respiratory acidosis during attacks. This is true in very severe asthma attacks, but most asthma attacks result in hypocapnia and respiratory alkalosis. As the asthma attack occurs, bronchial smooth muscle spasm and mucus secretion obstruct the ventilation to some alveoli. Although some hypoxic pulmonary vasoconstriction may occur, it is not sufficient to divert all of the mixed venous blood flow away from these poorly ventilated alveoli. This results in a right-to-left shunt or shuntlike state (Chapter 35), which would therefore be expected to cause the arterial Po2 to decrease and the arterial Pco2 to increase. However, the Pco2 decreases because the patient increases alveolar ventilation if he or she is able to. Irritant receptors in the airways are stimulated by the mucus and by chemical mediators released during the attack. Hypoxia caused by the shunt stimulates the arterial chemoreceptors; the patient also has the feeling of dyspnea (many asthma attacks have an emotional component). All of these factors cause increased breathing and therefore increased alveolar ventilation. Increasing ventilation will get more CO2 out of the blood perfusing ventilated alveoli (and therefore out of the body) but it will not get much oxygen into alveoli supplied by obstructed airways, nor will it get much more oxygen into the blood of the unobstructed alveoli because of the shape of the oxyhemoglobin dissociation curve. Remember that the hemoglobin is already 97.4% saturated with oxygen and not much more will dissolve in the plasma. Therefore, during the attack the patient has hypoxemia, hypocapnia, and respiratory alkalosis. It is only when the attack is so severe that the patient cannot do the additional work of breathing that hypercapnia and respiratory acidosis occur. Acute treatment of asthma is aimed at dilating the airways with a bronchodilator, such as a β2-adrenergic agonist, and relieving the hypoxemia with oxygen. Mechanical ventilation may be used in more severe cases. Chronic treatment includes bronchodilators such as β2-adrenergic agonists; anticholinergics, to block parasympathetically mediated constriction and mucus production; antileukotriene drugs and inhaled corticosteroids, to prevent inflammation; and inhibition of mast cells to prevent them from releasing cytokines.

CHAPTER SUMMARY ■

■

■

■

■

■

Hypoventilation causes respiratory acidosis; the compensation for respiratory acidosis is renal retention of base and excretion of hydrogen ions. Hyperventilation causes respiratory alkalosis; the compensation for respiratory alkalosis is renal excretion of base and retention of hydrogen ions. Ingestion, infusion, overproduction, or decreased renal excretion of hydrogen ions, or loss of bicarbonate ions, can cause metabolic acidosis; the compensation for metabolic acidosis is increased alveolar ventilation. Ingestion, infusion, or excessive renal reabsorption of bases, or loss of hydrogen ions, can cause metabolic alkalosis; the compensation for metabolic alkalosis is decreased alveolar ventilation. Metabolic acidosis with an abnormally elevated anion gap indicates an increased plasma concentration of anions other than chloride and bicarbonate or a decreased plasma concentration of potassium, calcium, or magnesium ions. Tissue hypoxia can be a result of low alveolar Po2, diffusion impairment, right-to-left shunts, or ventilation–perfusion mismatch (hypoxic hypoxia), decreased functional hemoglobin (anemic hypoxia), low blood flow (hypoperfusion hypoxia), or an inability of the mitochondria to use oxygen (histotoxic hypoxia).

STUDY QUESTIONS 1–4. Match each of the following sets of blood gas data to one of the underlying problems listed below. Assume the body temperature to be 37°C, and the hemoglobin concentration to be 15 g Hb/100 mL blood. FIo2 is 0.21 (room air). A) acute methanol ingestion B) diarrhea C) accidental hypoventilation of a patient on a mechanical ventilator for 10 minutes D) chronic obstructive pulmonary disease 1. pHa = 7.25, Paco2 = 50 mm Hg , [HCO3−] = 26 mEq/L, Pao2 = 70 mm Hg, anion gap = 11 mEq/L. 2. pHa = 7.34, Paco2 = 65 mm Hg, [HCO3−] = 40 mEq/L, Pao2 = 65 mm Hg, anion gap = 11 mEq/L. 3. pHa = 7.25, Paco2 = 30 mm Hg, [HCO3−] = 15 mEq/L, Pao2 = 95 mm Hg, anion gap = 10 mEq/L. 4. pHa = 7.25, Paco2 = 30 mm Hg, [HCO3−] = 15 mEq/L, Pao2 = 95 mm Hg, anion gap = 25mEq/L.

38 C

Control of Breathing Michael Levitzky

H A

P

T

E

R

O B J E C T I V E S ■ ■ ■ ■ ■ ■ ■ ■

Describe the general organization of the respiratory control system. Localize the centers that generate the spontaneous rhythm of breathing. Describe the groups of neurons that effect inspiration and expiration. Describe the other centers in the brainstem that may influence the spontaneous rhythm of breathing. List the cardiopulmonary and other reflexes that influence the breathing pattern. State the ability of the brain cortex to override the normal pattern of inspiration and expiration temporarily. Describe the effects of alterations in body oxygen, carbon dioxide, and hydrogen ion levels on the control of breathing. Describe the sensors of the respiratory system for oxygen, carbon dioxide, and hydrogen ion concentration.

ORGANIZATION OF THE RESPIRATORY CONTROL SYSTEM Breathing is spontaneously initiated in the central nervous system. A cycle of inspiration and expiration is automatically generated by neurons located in the brainstem. Usually, breathing occurs without a conscious initiation of inspiration and expiration. This spontaneously generated cycle of inspiration and expiration can be modified, altered, or even temporarily suppressed by a number of mechanisms. As shown in Figure 38–1, these include reflexes arising in the lungs, the airways, and the cardiovascular system; information from receptors in contact with the cerebrospinal fluid; and commands from higher centers of the brain such as the hypothalamus, the centers of speech, or other areas in the cerebral cortex. The centers that are responsible for the generation of the spontaneous rhythm of inspiration and expiration are, therefore, able to alter their activity to meet the increased metabolic demand on the respi-

Ch38_385-396.indd 385

ratory system during exercise or may even be temporarily superseded or suppressed during speech or breath holding. The respiratory control centers in the brainstem affect the automatic rhythmic control of breathing via a final common pathway consisting of the spinal cord, the innervation of the muscles of respiration such as the phrenic nerves, and the muscles of respiration themselves. Alveolar ventilation is therefore determined by the interval between successive groups of discharges of the respiratory neurons and the innervation of the muscles of respiration, which determines the respiratory rate or breathing frequency; and by the frequency of neural discharges transmitted by individual nerve fibers to their motor units, the duration of these discharges, and the number of motor units activated during each inspiration or expiration, which determine the depth of respiration or the tidal volume. Note that some pathways from the cerebral cortex to the muscles of respiration, such as those involved in voluntary breathing, bypass the medullary respiratory center described below and travel directly to the spinal α motor neurons. These are represented by the dashed line in Figure 38–1.

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SECTION VI Pulmonary Physiology

Influences from higher centers

Reflexes from: Lungs Airways Cardiovascular system Muscles and joints Skin

Cycle of inspiration and expiration

Reflexes from: Arterial chemoreceptors Central chemoreceptors

Muscles of breathing

FIGURE 38–1 Schematic representation of the organization of the respiratory control system. A cycle of inspiration and expiration is automatically established in the medullary respiratory center. Its output represents a final common pathway to the respiratory muscles, except for some voluntary pathways that may go directly from higher centers to the respiratory muscles (dashed line). Reflex responses from chemoreceptors and other sensors may modify the cycle of inspiration and expiration established by the medullary respiratory center. (Modified with permission from Levitzky MG: Pulmonary Physiology, 7th ed. New York: McGraw-Hill Medical, 2007.)

THE GENERATION OF SPONTANEOUS RHYTHMICITY The centers that initiate breathing are located in the reticular formation of the medulla, beneath the floor of the fourth ventricle. This area, known as the medullary respiratory center, consists of inspiratory neurons, that fire during inspiration to stimulate inspiratory muscles to contract, and expiratory neurons, that fire during expiration to stimulate expiratory muscles to contract. Because expiration is passive in normal quiet breathing, the expiratory neurons may not discharge unless expiration is active. There are two dense bilateral aggregations of respiratory neurons in the medullary respiratory center known as the dorsal respiratory groups (DRG) and the ventral respiratory groups (VRG) (Figure 38–2). Inspiratory and expiratory neurons are anatomically intermingled to a greater or lesser extent within these areas. The dorsal respiratory groups are located bilaterally in the nucleus of the tractus solitarius (NTS). They consist mainly of inspiratory neurons that project primarily to the contralateral spinal cord. They serve as the principal initiators of the activity of the phrenic nerves and maintain the activity of the diaphragm. Dorsal respiratory group neurons send many collateral fibers to those in the ventral respiratory group, but the ventral respiratory group sends only a few collateral fibers to the dorsal respiratory group. The NTS receives visceral afferent fibers of the 9th cranial nerve (the glossopha-

ryngeal) and the 10th cranial nerve (the vagus). These nerves carry information about the arterial Po2, Pco2, and pH from the carotid and aortic arterial chemoreceptors (Figure 38–3) and information concerning the systemic arterial blood pressure from the carotid and aortic baroreceptors (see Chapter 29). In addition, the vagus carries information from stretch receptors and other sensors in the lungs that may also exert profound influences on the control of breathing. The effects of information from these sensors on the control of breathing will be discussed later in this chapter. The location of the DRG within the NTS suggests that it may be the site of integration of various inputs that can reflexly alter the spontaneous pattern of inspiration and expiration. The ventral respiratory groups are located bilaterally in the retrofacial nucleus, the nucleus ambiguus, the nucleus para-ambigualis, and the nucleus retroambigualis. They consist of both inspiratory and expiratory neurons. The neurons in the nucleus ambiguus are primarily vagal motor neurons that innervate the ipsilateral laryngeal, pharyngeal, and tongue muscles involved in breathing and in maintaining the patency of the upper airway. They are both inspiratory and expiratory neurons. Other neurons from the ventral respiratory groups mainly project contralaterally to innervate inspiratory muscles and the expiratory muscles. The retrofacial nucleus, located most rostrally in the ventral respiratory groups, mainly contains expiratory neurons in a group of cells called the Bötzinger complex. Neurons in the area called the pre-Bötzinger complex have been identified as the

CHAPTER 38 Control of Breathing

387

Pons Pneumotaxic center Apneustic center

Medulla

Dorsal respiratory group (DRG) Inspiratory neurons

Ventral respiratory group (VRG) Pre-Bötzinger complex (rhythm-generating neurons) Inspiratory neurons

FIGURE 38–2 Brainstem respiratory control centers responsible for respiratory rhythm generation, activation of inspiratory and expiratory neuron and muscle activation, and monitoring lung inflation via pulmonary stretch receptors and alveolar ventilation via changes in arterial blood gas partial pressures. Input from the central chemoreceptors was omitted for clarity.

Expiratory neurons

Inspiratory Expiratory Spinal motor neurons

Inspiratory Expiratory Muscles

Lung stretch receptors

Ventilation Lung

(Reproduced with permission from Widmaier EP, Raff H, Strang KT: Vander’s Human Physiology, 11th ed. McGraw-Hill, 2008.)

Arterial chemoreceptors

pacemakers of the respiratory rhythm—the respiratory rhythm generator. An area in the in the pons (the part of the brainstem just rostral to the medulla) called the apneustic center appears to be an integration site for afferent information that can terminate inspiration. The specific group of neurons that function as the apneustic center has not been identified. A group of respiratory neurons rostral to the apneustic center known as the pontine respiratory groups (also called the pneumotaxic center, as in Figure 38–2) functions to modulate the activity of the apneustic center. These cells, located in the upper pons in the nucleus parabrachialis medialis and the Kölliker-Fuse nucleus, probably function to “fine-tune” the breathing pattern and smooth the transitions between inspiration and expiration. The pontine respiratory groups may also modulate the respiratory control system response to stimuli such as lung inflation, hypercapnia, and hypoxia. In the spinal cord axons projecting from the DRG, the VRG, the cortex, and other supraspinal sites descend in the spinal white matter to influence the diaphragm and the intercostal and abdominal muscles of respiration, as already discussed. There is integration of descending influences as well as the presence of local spinal reflexes that can affect these motor

Blood gas partial pressures

neurons. Descending axons with inspiratory activity excite phrenic and external intercostal motor neurons and also inhibit internal intercostal motor neurons by exciting spinal inhibitory interneurons. They are actively inhibited during expiratory phases of the respiratory cycle. Ascending pathways in the spinal cord, carrying information from pain, touch, and temperature receptors, as well as from proprioceptors, can also influence breathing, as will be discussed in the next section. Inspiratory and expiratory fibers appear to be separated in the spinal cord. The spontaneous rhythmicity generated in the medullary respiratory center can be completely overridden (at least temporarily) by influences from higher brain centers. In fact, the greatest minute ventilations obtainable from healthy conscious human subjects can be attained voluntarily, exceeding those obtained with the stimuli of severe exercise, hypercapnia, or hypoxia. This is the underlying concept of the maximum voluntary ventilation (MVV) test often used to assess respiratory function. Conversely, the respiratory rhythm can be completely suppressed for several minutes by voluntary breath holding, until the chemical drive to breath (high Pco2 and low Po2 and pH) overrides the voluntary suppression of breathing at the breakpoint. During speech, singing, or playing a wind

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SECTION VI Pulmonary Physiology

Sensory nerves Sensory nerves Carotid bodies

Common carotid artery

Aortic bodies

Aorta

Heart

FIGURE 38–3 Location of the carotid and aortic bodies. Note that the carotid bodies are close to the carotid sinuses, the location of the major arterial baroreceptors. (Reproduced with permission from Widmaier EP, Raff H, Strang KT: Vander’s Human Physiology, 11th ed. McGraw-Hill, 2008.)

instrument, the normal cycle of inspiration and expiration is automatically modified by higher brain centers. In certain emotional states, chronic hyperventilation severe enough to cause respiratory alkalosis may occur.

RESPIRATORY REFLEXES A large number of sensors located in the lungs, the cardiovascular system, the muscles and tendons, and the skin and viscera can elicit reflexes in the control of breathing. They are summarized in Table 38–1, which lists the stimulus, receptor, afferent pathway, and effects for each reflex.

PULMONARY STRETCH RECEPTORS Three respiratory reflexes can be elicited by the activity of pulmonary stretch receptors: the Hering–Breuer inflation reflex, the Hering–Breuer deflation reflex, and the “paradoxical” reflex.

Inflation of the lungs of anesthetized spontaneously breathing animals decreases the frequency of the inspiratory effort or causes a transient apnea (cessation of breathing). The stimulus for this reflex is pulmonary inflation. The sensors are stretch receptors located within the smooth muscle of large and small airways. They are sometimes referred to as slowly adapting pulmonary stretch receptors because their activity is maintained with sustained stretches. The afferent pathway consists of large myelinated fibers in the vagus, which enter the brainstem and project to the DRGs, the apneustic center, and the pontine respiratory groups. The Hering–Breuer inflation reflex was originally believed to be an important determinant of the rate and depth of ventilation, but recent studies have cast doubt on this conclusion because the threshold of the reflex is much higher than the normal tidal volume during eupneic breathing. Tidal volumes of 800–1,500 mL are generally required to elicit this reflex in conscious eupneic adults. The Hering–Breuer inflation reflex may help minimize the work of breathing by inhibiting large tidal volumes as well as prevent overdistention of the alveoli. It may also be important in the control of breathing in neonates. Neonates have Hering–Breuer inflation reflex thresholds within their normal tidal volume ranges, and the reflex may be an important influence on their tidal volumes and respiratory rates. Deflation of the lungs increases the ventilatory rate. This could be a result of decreased stretch receptor activity or of stimulation of other pulmonary receptors, or rapidly adapting receptors such as the irritant receptors and J receptors, which will be discussed later in this chapter. The afferent pathway is the vagus, and the effect is increased minute ventilation (hyperpnea). This reflex may be responsible for the increased ventilation elicited when the lungs are deflated abnormally, as in pneumothorax, or it may play a role in the periodic spontaneous deep breaths (sighs) that help prevent atelectasis. These sighs occur occasionally and irregularly during the course of normal, quiet, spontaneous breathing. They consist of a slow deep inspiration (larger than a normal tidal volume) followed by a slow deep expiration. This response appears to be very important because patients maintained on mechanical ventilators must be given large tidal volumes or periodic deep breaths or they develop diffuse atelectasis, which may lead to arterial hypoxemia. The Hering–Breuer deflation reflex may be very important in helping to actively maintain functional residual capacities (FRCs) in infants. It is very unlikely that infants’ FRCs are determined passively like those of adults because the inward recoil of their lungs is considerably greater than the outward recoil of their very compliant chest walls. After partly blocking the vagus nerves with cold temperatures, lung inflation causes a further inspiration instead of the apnea expected when the vagus nerves are completely functional. The receptors for this paradoxical reflex are located in the lungs, but their precise location is not known. Afferent information travels in the vagus; the effect is very deep inspirations. This reflex may also be involved in the sigh response,

CHAPTER 38 Control of Breathing

389

TABLE 38–1 Respiratory reflexes. Stimulus

Reflex Name

Receptor

Afferent Pathway

Effects

Lung inflation

Hering–Breuer inflation reflex

Stretch receptors within smooth muscle of large and small airways

Vagus

Respiratory Cessation of inspiratory effort, apnea, or decreased breathing frequency; bronchodilation Cardiovascular Increased heart rate, slight vasoconstriction

Lung deflation

Hering–Breuer deflation reflex

Possibly J receptors, irritant receptors in lungs, or stretch receptors in airways

Vagus

Respiratory Hyperpnea

Lung inflation

Paradoxical reflex

Stretch receptors in lungs

Vagus

Respiratory Inspiration

Negative pressure in the upper airway

Pharyngeal dilator reflex

Receptors in nose, mouth, upper airways

Trigeminal, laryngeal, glossopharyngeal

Respiratory Contraction of pharyngeal dilator muscles

Mechanical or chemical irritation of airways

Cough

Receptors in upper airways, tracheobronchial tree

Vagus

Respiratory Cough; bronchoconstriction

Sneeze

Receptors in nasal mucosa

Trigeminal, olfactory

Sneeze; bronchoconstriction

Receptors in nasal mucosa and face

Trigeminal

Face immersiona

Diving reflex

Cardiovascular Increased blood pressure Respiratory Apnea Cardiovascular Decreased heart rate; vasoconstriction

Pulmonary embolism

J receptors in pulmonary vessels

Vagus

Respiratory Apnea or tachypnea

Pulmonary vascular congestion

J receptors in pulmonary vessels

Vagus

Respiratory Tachypnea, possibly sensation of dyspnea

Specific chemicals in the pulmonary circulation

Pulmonary chemoreflex

J receptors in pulmonary vessels

Vagus

Respiratory Apnea or tachypnea; bronchoconstriction

Low PaO , high 2 PaCO , low pHa

Arterial chemoreceptor reflex

Carotid bodies, aortic bodies

Glossopharyngeal, vagus

Respiratory Hyperpnea; bronchoconstriction, dilation of upper airway

2

Cardiovascular Decreased heart rate (direct effect), vasoconstriction Increased systemic arterial blood pressure

Arterial baroreceptor reflex

Carotid sinus stretch receptors

Glossopharyngeal, vagus

Respiratory Apnea, bronchodilation Cardiovascular Decreased heart rate, vasodilation etc.

Aortic arch stretch receptors Stretch of muscles, tendons, movement of joints

Muscle spindles, tendon organs, proprioreceptors

Various spinal pathways

Respiratory Provide respiratory controller with feedback about work of breathing, stimulation of proprioreceptors in joints causes hyperpnea

Somatic pain

Pain receptors

Various spinal pathways

Respiratory Hyperpnea Cardiovascular Increased heart rate, vasoconstriction, etc.

a

Discussed in Chapter 71.

Reproduced with permission from Levitzky MG: Pulmonary Physiology, 7th ed. New York: McGraw-Hill Medical, 2007.

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or it may be involved in generating the first breath of the newborn baby; very great inspiratory efforts must be generated to inflate the fluid-filled lungs.

RECEPTORS IN THE AIRWAYS AND THE LUNGS Negative pressure in the upper airway causes reflex contraction of the pharyngeal dilator muscles. The receptors for the pharyngeal dilator reflex appear to be located in the nose, mouth, and upper airways; the afferent pathways appear to be in the trigeminal, laryngeal, and glossopharyngeal nerves. This reflex may be very important in maintaining the patency of the upper airway during strong inspiratory efforts and during sleep. Mechanical or chemical irritation of the airways (and possibly the alveoli) can elicit a reflex cough or sneeze, or it can cause hyperpnea, bronchoconstriction, and increased blood pressure. The receptors are located in the nasal mucosa, upper airways, tracheobronchial tree, and possibly the alveoli themselves. Those in the larger airways of the tracheobronchial tree, which also respond to stretch, are sometimes referred to as rapidly adapting pulmonary stretch receptors because their activity decreases rapidly during a sustained stimulus. The afferent pathways are the vagus nerves for all but the receptors located in the nasal mucosa, which send information centrally via the trigeminal and olfactory tracts. The cough and the sneeze reflexes were discussed in Chapter 32.

PULMONARY VASCULAR RECEPTORS (J RECEPTORS) Pulmonary embolism causes rapid shallow breathing (tachypnea) or apnea; pulmonary vascular congestion also causes tachypnea. The receptors responsible for initiating these responses are located in the walls of the pulmonary capillaries or in the interstitium; therefore, they are called J (for juxtapulmonary capillary) receptors. These receptors may also be responsible for the dyspnea (a feeling of difficult or labored breathing) encountered during the pulmonary vascular congestion and edema secondary to left ventricular failure or even the dyspnea that healthy people feel at the onset of exercise. The afferent pathway of these reflexes is slow-conducting nonmyelinated vagal fibers. Other receptors that may contribute to the sensation of dyspnea include the arterial chemoreceptors, stretch receptors in the heart and blood vessels, and receptors in the respiratory muscles.

OTHER CARDIOVASCULAR RECEPTORS The arterial chemoreceptors are located bilaterally in the carotid bodies, which are situated near the bifurcations of the common carotid arteries, and in the aortic bodies, which are located in the arch of the aorta as shown in Figure 38–3. They

respond to low arterial Po2, high arterial Pco2, and low arterial pH (as will be discussed later in this chapter), with the carotid bodies generally capable of a greater response than the aortic bodies. The afferent pathway from the carotid body is Hering’s nerve, a branch of the glossopharyngeal nerve; the afferent pathway from the aortic body is the vagus. The reflex effects of stimulation of the arterial chemoreceptors are hyperpnea, bronchoconstriction, dilation of the upper airway, and increased blood pressure. The direct effect of arterial chemoreceptor stimulation is a decrease in heart rate; however, this is usually masked by an increase in heart rate secondary to the increase in lung inflation. The arterial baroreceptors exert a very minor influence on the control of ventilation. Low blood pressure may stimulate breathing.

OTHER RECEPTORS IN MUSCLE, TENDONS, SKIN, AND VISCERA Stimulation of receptors located in the muscles, the tendons, and the joints can increase ventilation. Included are receptors in the muscles of respiration (e.g., muscle spindles) and rib cage as well as other skeletal muscles, joints, and tendons. These receptors may play an important role in adjusting the ventilatory effort to elevated workloads and may help minimize the work of breathing. They may also participate in initiating and maintaining the elevated ventilation that occurs during exercise, as will be discussed in Chapter 72. Somatic pain generally causes hyperpnea; visceral pain generally causes apnea or decreased ventilation.

THE RESPONSE TO CARBON DIOXIDE The respiratory control system normally reacts very effectively to alterations in the internal “chemical” environment of the body. Changes in the Pco2, pH, and Po2 result in alterations in alveolar ventilation designed to return these variables to their normal values. Chemoreceptors alter their activity when their own local chemical environment changes and can therefore supply the central respiratory controller with the afferent information necessary to make the appropriate adjustments in alveolar ventilation to change the whole-body Pco2, pH, and Po2. The respiratory control system therefore functions as a negative-feedback system as discussed in Chapter 1. The arterial and cerebrospinal fluid partial pressures of carbon dioxide are probably the most important inputs to the ventilatory control system in establishing the breath-to-breath levels of tidal volume and ventilatory frequency. (Of course, changes in carbon dioxide lead to changes in hydrogen ion concentration, so the effects of these two stimuli are complementary.) An increase in carbon dioxide is a very powerful stimulus to ventilation: only voluntary hyperventilation and the hyperpnea of exercise can surpass the minute ventilations obtained with hypercapnia. However, the arterial Pco2 is so

CHAPTER 38 Control of Breathing

20

PaO  35 mm Hg 2 PaO  50 mm Hg

Alveolar ventilation (L/min)

2

15

10

5 PaO  100 mm Hg 2

0

30

35 40 45 PaCO2 (mm Hg)

50

FIGURE 38–4 Ventilatory carbon dioxide response curves at three different levels of arterial PO . (Modified with permission from 2

Levitzky MG: Pulmonary Physiology, 7th ed. New York: McGraw-Hill Medical, 2007.)

precisely controlled that it changes little (<1 mm Hg) during exercise severe enough to increase metabolic carbon dioxide production 10-fold. Acutely increasing the level of carbon dioxide in the inspired air (the Fico2) increases minute ventilation. The effect is most pronounced in Fico2 in the range of 0.05–0.10 (5–10% CO2 in inspired gas), which produces alveolar Pco2 between about 40 and 70 mm Hg. Above 10–15% CO2 in inspired air, there is little further increase in alveolar ventilation: very high arterial Pco2 (>70–80 mm Hg) may directly produce respiratory depression. (Very low arterial Pco2 caused by hyperventilation may temporarily cause apnea because of decreased ventilatory

15

Metabolic acidosis

391

drive. Metabolically produced carbon dioxide will then build up and restore breathing.) The ventilatory response of a normal conscious person to physiologic levels of carbon dioxide is shown in Figure 38–4. Alveolar (and arterial) Pco2 in the range of 38–50 mm Hg increase alveolar ventilation linearly. The slope of the line is quite steep and varies from person to person. It decreases with age. The figure also shows that hypoxia potentiates the ventilatory response to carbon dioxide. At lower arterial Po2 (e.g., 35 and 50 mm Hg), the response curve is shifted to the left and the slope is steeper; that is, for any particular arterial Pco2, the ventilatory response is greater at a lower arterial Po2. This may be caused by the effects of hypoxia at the chemoreceptor itself or at higher integrating sites; changes in the central acid–base status secondary to hypoxia may also contribute to the enhanced response. Other influences on the carbon dioxide response curve are illustrated in Figure 38–5. Sleep shifts the curve slightly to the right. The arterial Pco2 normally increases during slowwave sleep, increasing as much as 5–6 mm Hg during deep sleep. Because of this rightward shift in the CO2 response curve during non-REM sleep, it is possible that there is a “wakefulness” component of respiratory drive. A depressed response to carbon dioxide during sleep may be involved in central sleep apnea, a condition characterized by abnormally long periods (1–2 minutes) between breaths during sleep. This lack of central respiratory drive is a potentially dangerous condition in both infants and adults. (In obstructive sleep apnea, the central respiratory controller does issue the command to breathe, but the upper airway is obstructed because the pharyngeal muscles do not contract properly, there is too much fat around the pharynx, or the tongue blocks the airway.) Narcotics and anesthetics may profoundly depress the ventilatory response to carbon dioxide. Indeed, respiratory depression is

Awake normal

Alveolar ventilation (L/min)

Sleep

10

Narcotics, chronic obstruction

5 Deep anesthesia

0 25

35

45 PaCO (mm Hg) 2

55

65

FIGURE 38–5 The effects of sleep, narcotics, chronic obstructive pulmonary disease, deep anesthesia, and metabolic acidosis on the ventilatory response to carbon dioxide. (Modified with permission from Levitzky MG: Pulmonary Physiology, 7th ed. New York: McGraw-Hill Medical, 2007.)

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the most common cause of death in cases of overdose of opiate alkaloids and their derivatives, barbiturates, and most anesthetics. Chronic obstructive pulmonary diseases (COPD) depress the ventilatory response to hypercapnia, in part because of depressed ventilatory drive secondary to central acid–base changes, and because the work of breathing may be so great that ventilation cannot be increased normally. Metabolic acidosis displaces the carbon dioxide response curve to the left, indicating that for any particular Paco2, ventilation is increased during metabolic acidosis because of hydrogen ion stimulation of the arterial chemoreceptors. As already discussed, the respiratory control system constitutes a negative-feedback system. This is exemplified by the response to carbon dioxide. Increased metabolic production of carbon dioxide increases the carbon dioxide brought to the lung. If alveolar ventilation stayed constant, the alveolar Pco2 would increase, as would arterial and cerebrospinal Pco2. This stimulates alveolar ventilation by stimulating the arterial and central chemoreceptors (described later in this chapter). Increased alveolar ventilation decreases alveolar and arterial Pco2, as was discussed in Chapter 33, returning the Pco2 to the original value. The Pco2, pH, and Po2 are the principal controlled variables in the respiratory control system. To act as a negative-feedback system, the respiratory controller must receive information concerning the levels of the controlled variables from sensors in the system. The sensors are the arterial chemoreceptors (peripheral chemoreceptors) and the central chemoreceptors located bilaterally near the ventrolateral surface of the medulla in the brainstem and other sites. The arterial chemoreceptors are exposed to arterial blood; the central chemoreceptors are exposed to cerebrospinal fluid. The central chemoreceptors are therefore on the brain side of the blood– brain barrier. Both the peripheral and central chemoreceptors respond to increases in the partial pressure of carbon dioxide, although the response may be related to the local increase in hydrogen ion concentration that occurs with increased Pco2; that is, the sensors may be responding to the increased carbon dioxide concentration, the subsequent increase in hydrogen ion concentration, or both. The arterial chemoreceptors increase their firing rate in response to increased arterial Pco2, decreased arterial Po2, or decreased arterial pH. The response of the receptors is both rapid enough and sensitive enough that they can relay information concerning breath-to-breath alterations in the composition of the arterial blood to the medullary respiratory center. The response of the arterial chemoreceptors changes nearly linearly with the arterial Pco2 over the range of 20–60 mm Hg. The central chemoreceptors are exposed to the cerebrospinal fluid and are not in direct contact with the arterial blood. As shown in Figure 38–6, the cerebrospinal fluid is separated from the arterial blood by the blood–brain barrier. Carbon dioxide can easily diffuse through the blood–brain barrier, but hydrogen ions and bicarbonate ions do not. Because of this, alterations in the arterial Pco2 are rapidly transmitted to the cerebrospinal fluid in about 60 seconds. Changes in arterial pH that are not caused by changes in Pco2 take much longer to

influence the cerebrospinal fluid; in fact, the cerebrospinal fluid may have changes in hydrogen ion concentration opposite to those seen in the blood in certain circumstances, as will be discussed later in this chapter. The composition of the cerebrospinal fluid is considerably different from that of the blood. The pH of the cerebrospinal fluid is normally about 7.32, compared with the pH of 7.40 of arterial blood. The Pco2 of the cerebrospinal fluid is about 50 mm Hg—about 10 mm Hg higher than the normal arterial Pco2 of 40 mm Hg. The concentration of proteins in the cerebrospinal fluid is only in the range of 0.02-0.05 g/100 mL, whereas the concentration of proteins in the plasma normally ranges from 6.6 to 8.6 g/100 mL. This does not even include the hemoglobin in the erythrocytes. As a result, bicarbonate is the main buffer in the cerebrospinal fluid. Arterial hypercapnia will therefore lead to greater changes in cerebrospinal fluid hydrogen ion concentration than it does in the arterial blood. The brain produces carbon dioxide as an end product of metabolism. Brain carbon dioxide levels are higher than those of the arterial blood, which explains the high Pco2 of the cerebrospinal fluid. The central chemoreceptors respond to local increases in hydrogen ion concentration or Pco2, or both. They do not respond to hypoxia. About 80–90% of the normal total steady-state response to increased inspired carbon dioxide concentrations comes from the central chemoreceptors; the arterial chemoreceptors contribute only 10–20% of the steady-state response. However, the response comes from the arterial chemoreceptors when rapid changes in arterial Pco2 occur, that is, the central chemoreceptors may be mainly responsible for establishing the resting ventilatory level but the arterial chemoreceptors are more important in short-term transient responses to carbon dioxide. Both the arterial and central chemoreceptors likely respond to hydrogen ion concentration, not Pco2. Of course, they are usually very closely related in the body, so it is difficult to distinguish their effects. There may be other sensors for carbon dioxide in the body that may influence the control of ventilation. Chemoreceptors within the pulmonary circulation or airways have been proposed but have not as yet been substantiated or localized.

THE RESPONSE TO HYDROGEN IONS Ventilation increases nearly linearly with changes in hydrogen ion concentration over the range of 20–60 nEq/L (nmol/L), as shown in Figure 38–7. A metabolic acidosis of nonbrain origin results in hyperpnea coming entirely from the peripheral chemoreceptors. Hydrogen ions cross the blood–brain barrier too slowly to affect the central chemoreceptors initially. Acidotic stimulation of the peripheral chemoreceptors increases alveolar ventilation, and the arterial Pco2 decreases. Because the cerebrospinal fluid Pco2 is in a sort of dynamic equilibrium

CHAPTER 38 Control of Breathing

BRAIN TISSUE

BRAIN TISSUE

393

CSF

Venous blood

CO2

H

CO2

barrier

Metabolic CO2 production

Blood-brain

Blood-brain

barrier

CO2

CO2

Dilates

Central Chemoreceptor

CO2 HCO3 Dilates

CO2 Arterial blood: pH  7.40 PCO  40 mm Hg 2 Protein Buffers

H

CO2 HCO3

Slow (h) Smooth muscle

Smooth muscle

CO2

CSF: pH  7.32 PCO  50 mm Hg 2 Little protein

FIGURE 38–6

Representation of the central chemoreceptor showing its relationship to carbon dioxide (CO2), hydrogen (H+), and bicarbonate (HCO3−) ions in the arterial blood and cerebrospinal fluid (CSF). CO2 crosses the blood–brain barrier easily; H+ and HCO3− do not.

(Modified with permission from Levitzky MG: Pulmonary Physiology, 7th ed. New York: McGraw-Hill Medical, 2007.)

15

VE (L/min)

12

9

6

40

41

42

43

44

45

46



Plasma [H ], nEq/L

FIGURE 38–7 The ventilatory response to increased plasma hydrogen ion concentration. (Modified with permission from Levitzky MG: Pulmonary Physiology, 7th ed. New York: McGraw-Hill Medical, 2007.)

with the arterial Pco2, carbon dioxide diffuses out of the cerebrospinal fluid and the pH of the cerebrospinal fluid increases, thus decreasing stimulation of the central chemoreceptor. If the situation lasts a long time (hours to days), the bicarbonate concentration of the cerebrospinal fluid decreases slowly, returning the pH of the cerebrospinal fluid toward the normal 7.32. The mechanism by which this occurs is not completely agreed on. It may represent the slow diffusion of bicarbonate ions across the blood–brain barrier, active transport of bicarbonate ions out of the cerebrospinal fluid, or decreased formation of bicarbonate ions by carbonic anhydrase as the cerebrospinal fluid is formed. Similar mechanisms must alter the bicarbonate concentration in the cerebrospinal fluid in the chronic respiratory acidosis of chronic obstructive lung disease because the pH of the cerebrospinal fluid is nearly normal. In this case, the cerebrospinal fluid concentration of bicarbonate increases nearly proportionately to its increased concentration of carbon dioxide.

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70

Alveolar ventilation (L/min)

60

50

40 PaCO2 50 mm Hg 30 PaCO2 45 mm Hg 20 PaCO  38 mm Hg 2

10 0 20

40

60

80 100 PaO (mm Hg) 2

120

140

FIGURE 38–8 The ventilatory responses to hypoxia at three different levels of arterial PCO . (Modified with permission from Levitzky MG: 2

Pulmonary Physiology, 7th ed. New York: McGraw-Hill Medical, 2007.)

THE RESPONSE TO HYPOXIA The ventilatory response to hypoxia arises solely from the peripheral chemoreceptors. The carotid bodies are much more important in this response than are the aortic bodies. In the absence of the peripheral chemoreceptors, the effect of increasing degrees of hypoxia is a progressive direct depression of the central respiratory controller. Therefore, when the peripheral chemoreceptors are intact, their excitatory influence on the central respiratory controller must offset the direct depressant effect of hypoxia. The response of the respiratory system to hypoxia is shown in Figure 38–8. The figure shows that at a normal arterial Pco2 of about 38–40 mm Hg, there is very little increase in ventilation until the arterial Po2 decreases below about 50–60 mm Hg. The response to hypoxia is potentiated at higher arterial Pco2. Experiments have shown that the respiratory response to hypoxia is related to the change in Po2 rather than the change in oxygen content. Hypoxia alone, by stimulating alveolar ventilation, causes a decrease in arterial Pco2, which may lead to respiratory alkalosis. This will be discussed in Chapter 71.

ented. She has vomited twice and says she is thirsty and her stomach hurts. The symptoms developed gradually overnight. Her heart rate is 110/min, her blood pressure is 95/75 mm Hg, and her respiratory rate is 22/min with obvious large tidal volumes. Her blood glucose is very high at 450 mg/dL, her arterial Po2 is slightly increased at 105 mm Hg, her arterial Pco2 is 20 mm Hg (normal range 35–45 mm Hg), and her arterial pH is 7.15 (normal range 7.35–7.45). Her bicarbonate concentration is 15 mEq/L (normal range 22–26 mEq/L) and her anion gap is 22 mEq/L (normal range 8–16 mEq/L). The patient has type 1 diabetes mellitus; she is in diabetic ketoacidosis (see Chapter 66). The drug she did not bring with her is insulin; as a result, her blood glucose concentration is very high and she is producing ketone bodies (see Chapter 66). Nausea, vomiting, abdominal pain, and confusion are common symptoms and signs of diabetes mellitus, as will be discussed in Sections 7 and 9. Hydrogen ions from the ketone bodies, which are acids, have been buffered by bicarbonate and have been exhaled as carbon dioxide, explaining the low bicarbonate concentration and the elevated anion gap (see Chapter 37). The hydrogen ions are stimulating her arterial chemoreceptors causing her to hyperventilate, as shown by her low arterial Pco2. Her central chemoreceptors are not contributing to the hyperventilation because the hydrogen ions do not cross her blood–brain barrier and therefore cannot stimulate them (Figure 38–6); it is likely that her central chemoreceptors have decreased activity because as she hyperventilates her cerebrospinal fluid Pco2 decreases and her cerebrospinal fluid pH increases. Her acid–base disorder can be described as a primary metabolic acidosis, with increased anion gap, with a secondary respiratory alkalosis.

CHAPTER SUMMARY ■

■

A cycle of inspiration and expiration is automatically generated by neurons in the medulla; this cycle can be modified or temporarily suppressed by reflexes or influences from higher brain centers. The respiratory control system functions as a negative-feedback system; arterial Po , Pco , and pH and cerebrospinal fluid Pco and pH are the regulated variables. The increases in alveolar ventilation in response to increases in arterial Pco and hydrogen ion concentrations are nearly linear within their normal ranges; the increase in alveolar ventilation in response to decreases in arterial Po is small near the normal range and very large when the Po falls below 50–60 mm Hg. The arterial chemoreceptors rapidly respond to changes in arterial Po , Pco , and pH; the central chemoreceptors are on the brain side of the blood–brain barrier and respond to changes in cerebrospinal fluid Pco and pH. 2

■

2

2

2

2

CLINICAL CORRELATION A 14-year-old girl forgot her prescription drug on a weekend sleepover party at her friend’s house. She arrives in the emergency department lethargic, confused, and disori-

2

■

2

2

2

CHAPTER 38 Control of Breathing

STUDY QUESTIONS 1. The ventral respiratory groups A) are located in the nucleus of the tractus solitarius. B) include the pacemaker for breathing. C) consist solely of inspiratory neurons. D) consist solely of expiratory neurons. E) all of the above. 2. Which of the following conditions would be expected to stimulate the central chemoreceptors? A) mild anemia B) severe exercise C) hypoxia due to ascent to high altitude D) acute airway obstruction E) all of the above

395

3. Stimulation of which of the following receptors should result in decreased ventilation? A) aortic chemoreceptors B) carotid chemoreceptors C) central chemoreceptors D) Hering–Breuer inflation (stretch) receptors E) all of the above 4. Which of the following would be expected to increase the ventilatory response to carbon dioxide, shifting the CO2 response curve to the left? A) barbiturates B) hypoxia C) slow-wave sleep D) deep anesthesia E) all of the above

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SECTION VII RENAL PHYSIOLOGY

39 C

Renal Functions, Basic Processes, and Anatomy Douglas C. Eaton and John P. Pooler

H A

P

T

E

R

O B J E C T I V E S ■ ■ ■

■

■ ■ ■

■ ■

State the seven major functions of the kidneys. Define the balance concept. Define the gross structures and their interrelationships: renal pelvis, calyces, renal pyramids, renal medulla (inner and outer zones), renal cortex, and papilla. Define the components of the nephron–collecting duct system and their interrelationships: renal corpuscle, glomerulus, tubule, and collecting duct system. Draw the relationship between glomerulus, Bowman’s capsule, and the proximal tubule. Define juxtaglomerular apparatus and describe its three cell types; state the function of the granular cells. List the individual tubular segments in order; state the segments that comprise the proximal tubule, Henle’s loop, and the collecting duct system; define principal cells and intercalated cells. Define the basic renal processes: glomerular filtration, tubular reabsorption, and tubular secretion. Define renal metabolism of a substance and give examples.

FUNCTIONS The kidneys perform a number of essential functions that go far beyond their well-known role of eliminating waste. This chapter describes these functions and presents an overview of how the kidneys perform them. Ensuing chapters develop more detail of the mechanisms involved.

Ch39_397-408.indd 397

FUNCTION 1: REGULATION OF WATER AND ELECTROLYTE BALANCE The balance concept states that our bodies are in balance for any substance when the inputs and outputs of that substance are matched (see Figure 1–4). The kidneys vary the output of water and an array of electrolytes and other substances in close pace with their input, thereby keeping the body content of those substances nearly constant, that is, in balance. As an example, our input of water is enormously variable and is only sometimes 397

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driven in response to body needs. We drink water when thirsty, but we also drink water because it is a component of beverages that we consume for reasons other than hydration. In addition, solid food often contains large amounts of water. The kidneys respond by varying the output of water in the urine, thereby maintaining balance for water (i.e., constant total body water content). Similarly, electrolytes such as sodium, potassium, and magnesium are components of foods and generally present far in excess of body needs. As with water, the kidneys excrete electrolytes at a highly variable rate that, in the aggregate, matches input. One of the amazing feats of the kidneys is their ability to regulate each of these minerals independently (i.e., we can be on a high-sodium, low-potassium diet or low-sodium, highpotassium diet, and the kidneys adjust excretion of each of these substances appropriately). The reader should be aware that being in balance does not by itself imply a normal state or good health. A person may have an excess or deficit of a substance, yet still be in balance so long as output matches input. This is often the case in chronic disorders of renal function or metabolism.

FUNCTION 2: REGULATION OF ACID–BASE BALANCE Acids and bases enter the body fluids via ingestion and from metabolic processes. The body has to excrete acids and bases to maintain balance, and it also has to regulate the concentration of free hydrogen ions (pH) within a limited range. The kidneys accomplish both tasks by a combination of elimination and synthesis. These interrelated tasks are among the most complicated aspects of renal function and will be explored thoroughly in Chapter 47.

FUNCTION 3: EXCRETION OF METABOLIC WASTE AND BIOACTIVE SUBSTANCES Our bodies continuously form the end products of metabolic processes that for the most part serve no function and are harmful at high concentrations; thus, they must be excreted at the same rate they are produced. These include urea (from protein), uric acid (from nucleic acids), creatinine (from muscle creatine), and the end products of hemoglobin breakdown (which give urine much of its color). In addition, the kidneys participate with the liver in removing drugs, hormones, and foreign substances. Clinicians have to be mindful of how fast drugs are excreted in order to prescribe a dose that achieves the appropriate body levels.

FUNCTION 4: REGULATION OF ARTERIAL BLOOD PRESSURE Although most people appreciate that the kidneys excrete waste substances such as urea (hence the name urine) and salts, few

realize the kidneys’ crucial role in controlling blood pressure (BP). BP ultimately depends on blood volume, and the kidneys’ maintenance of sodium and water balance achieves regulation of blood volume. Thus, through volume control, the kidneys participate in BP control. They also participate in direct regulation of BP via the generation of vasoactive substances that regulate smooth muscle in the peripheral vasculature.

FUNCTION 5: REGULATION OF RED BLOOD CELL PRODUCTION Erythropoietin is a peptide hormone that is involved in the control of erythrocyte (red blood cell) production by the bone marrow. Its major source is the kidneys, although the liver also secretes small amounts. The renal cells that secrete it are a particular group of cells in the interstitium. The stimulus for its secretion is a reduction in the partial pressure of oxygen in the kidneys, as occurs, for example, in anemia, arterial hypoxia (see Chapter 71), and inadequate renal blood flow. Erythropoietin stimulates the bone marrow to increase its production of erythrocytes. Renal disease may result in diminished erythropoietin secretion, and the ensuing decrease in bone marrow activity is one important causal factor of the anemia of chronic renal disease.

FUNCTION 6: REGULATION OF VITAMIN D PRODUCTION When we think of vitamin D, we often think of sunlight or additives to milk. In vivo vitamin D synthesis involves a series of biochemical transformations, the last of which occurs in the kidneys. The active form of vitamin D (1,25-dihydroxyvitamin D) is actually made in the kidneys, and its rate of synthesis is regulated by hormones that control calcium and phosphate balance that will be discussed in detail in Chapter 64.

FUNCTION 7: GLUCONEOGENESIS Our central nervous system is an obligate user of blood glucose regardless of whether we have just eaten sugary doughnuts or gone without food for a week. Whenever the intake of carbohydrate is stopped for much more than half a day, our body begins to synthesize new glucose (the process of gluconeogenesis) from noncarbohydrate sources (amino acids from protein and glycerol from triglycerides). Most gluconeogenesis occurs in the liver (see Chapters 66 and 69), but a substantial fraction occurs in the kidneys, particularly during a prolonged fast.

OVERVIEW OF RENAL PROCESSES Most of what the kidneys do to perform these various functions is, at least conceptually, fairly straightforward. Of the considerable volume of plasma entering the kidneys each minute, they

CHAPTER 39 Renal Functions, Basic Processes, and Anatomy

399

Cortex

Diaphragm

Medulla Papilla

Kidney

Renal vein Renal artery

Calyx Ureter Pelvis

Ureter Capsule Bladder

FIGURE 39–2 Urethra

FIGURE 39–1 Urinary system in a female, indicating the location of the kidneys below the diaphragm and well above the bladder, which is connected to the kidneys via the ureters. (Reproduced with permission from Widmaier EP, Raff H, Strang KT: Vander’s Human Physiology, 11th ed. McGraw-Hill, 2008.)

transfer (by filtration) about one fifth of it, minus the larger proteins, into the renal tubules and then selectively reabsorb varying fractions of the filtered substances back into the blood, leaving the unreabsorbed portions to be excreted. In some cases additional amounts are added by secretion or synthesis. In essence, the renal tubules operate like assembly lines; they accept the fluid coming into them, perform some segment-specific modification of the fluid, and send it on to the next segment.

ANATOMY OF THE KIDNEYS AND URINARY SYSTEM The kidneys lie just under the rib cage on each side of the vertebral column, behind the peritoneal cavity and in front of the major back muscles (Figure 39–1). Each of the two kidneys is a bean-shaped structure about the size of a fist, with the rounded, outer convex surface of each kidney facing the side of the body, and the indented surface, called the hilum, facing the spine. Each hilum is penetrated by blood vessels, nerves, and a ureter, which carries urine out of the kidney to the bladder. Each ureter is formed from funnel-like structures called major calyces, which, in turn, are formed from minor calyces (Figure 39–2). The minor calyces fit over underlying coneshaped renal tissue called pyramids. The tip of each pyramid is called a papilla and projects into a minor calyx. The calyces act as collecting cups for the urine formed by the renal tissue in the pyramids. The pyramids are arranged radially around the hilum, with the papillae pointing toward the hilum and the

Major structural components of the kidney.

(Reproduced with permission from Kibble J, Halsey CR: The Big Picture, Medical Physiology. New York: McGraw-Hill, 2009.)

broad bases of the pyramids facing the outside, top, and bottom of the kidney. The pyramids constitute the medulla of the kidney. Overlying the medullary tissue is a cortex, and covering the cortical tissue on the very external surface of the kidney is a thin connective tissue capsule. The working tissue mass of both the cortex and medulla is constructed almost entirely of tubules (nephrons and collecting tubules) and blood vessels (mostly capillaries and capillarylike vessels). In the cortex, tubules and blood vessels are intertwined randomly, something like a plateful of spaghetti. In the medulla, they are arranged in parallel arrays like bundles of sticks. In both cases, blood vessels and tubules are always close to each other. Between the tubules and blood vessels lies the interstitium, which comprises less than 10% of the renal volume. The interstitium contains a small amount of fluid and scattered interstitial cells (fibroblasts and others) that synthesize an extracellular matrix of collagen, proteoglycans, and glycoproteins. It is important to realize that the cortex and medulla have very different properties both structurally and functionally. On close examination, we see that (1) the cortex has a highly granular appearance, absent in the medulla, and (2) each medullary pyramid is divisible into an outer zone (adjacent to the cortex) and an inner zone, which includes the papilla. All these distinctions reflect the different arrangement of the various tubules and blood vessels in the different regions of the kidney.

THE NEPHRON Each kidney contains approximately 1 million nephrons, one of which is shown diagrammatically in Figure 39–3. Each nephron begins with a spherical filtering component, called the renal corpuscle, followed by a long tubule leading out of it that continues until it merges with the tubules of other nephrons to form collecting ducts, which are themselves long

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Afferent arteriole Bowman’s capsule

TABLE 39–1 Terminology for the tubular segments. Macula densa

Distal tubule Sequence of Segments

Proximal tubule Cortical collecting duct Thick ascending limb Thin descending limb Thin ascending limb

FIGURE 39–3

Combination Terms Used in Text

Proximal convoluted tubule Proximal straight tubule

Proximal tubule

Descending thin limb of Henle’s loop Ascending thin limb of Henle’s loop Thick ascending limb of Henle’s loop (contains macula densa near end)

Henle’s loop

Distal convoluted tubule

Medullary collecting duct

Components of the nephron. (Reproduced with

Connecting tubule Cortical collecting duct Outer medullary collecting duct Inner medullary collecting duct (last portion is papillary duct)

Collecting duct system

Reproduced with permission from Eaton DC, Pooler JP: Vander’s Renal Physiology, 7th ed. New York, NY: Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2009.

permission from Kibble J, Halsey CR: The Big Picture, Medical Physiology. New York: McGraw-Hill, 2009.)

THE TUBULE tubes. Collecting ducts eventually merge with others in the renal papilla to form a ureter that conveys urine to the bladder (Figure 39–3).

THE RENAL CORPUSCLE The renal corpuscle is a hollow sphere (Bowman’s capsule) filled with a compact tuft of interconnected capillary loops, the glomerulus (plural glomeruli) (Figure 39–4a). Blood enters the capillaries inside Bowman’s capsule through an afferent arteriole that penetrates the surface of the capsule at one side, called the vascular pole. Blood then leaves the capillaries through a nearby efferent arteriole on the same side. The space within Bowman’s capsule not occupied by the glomerulus is called the urinary space or Bowman’s space, and it is into this space that fluid filters from the glomerular capillaries before flowing into the first portion of the tubule, located opposite the vascular pole. The structure and properties of the filtration barrier that separates plasma in the glomerular capillaries from fluid in urinary space are crucial for renal function and will be described thoroughly in the next chapter. For now, we note simply that the functional significance of the filtration barrier is that it permits the filtration of large volumes of fluid from the capillaries into Bowman’s space, but restricts filtration of large plasma proteins such as albumin. Another cell type—the mesangial cell—is found in close association with the capillary loops of the glomerulus. Glomerular mesangial cells act as phagocytes and remove trapped material from the basement membrane. They also contain large numbers of myofilaments and can contract in response to a variety of stimuli in a manner similar to vascular smooth muscle cells. The role of such contraction in influencing filtration by the renal corpuscles is discussed in Chapters 40 and 45.

Throughout its course, the tubule, which begins at and leads out of Bowman’s capsule, is made up of a single layer of epithelial cells resting on a basement membrane and connected by tight junctions that physically link the cells together (like the plastic form that holds a six pack of soft drinks together). Table 39–1 lists the names and sequence of the various tubular segments, as illustrated in Figure 39–5. Physiologists and anatomists have traditionally grouped two or more contiguous tubular segments for purposes of reference, but the terminologies have varied considerably. Table 39–1 also gives the combination terms used in this text. The proximal tubule, which drains Bowman’s capsule, consists of a coiled segment—the proximal convoluted tubule— followed by a straight segment—the proximal straight tubule—which descends toward the medulla, perpendicular to the cortical surface of the kidney. The next segment is the descending thin limb of the loop of Henle (or simply the descending thin limb). The descending thin limbs of different nephrons penetrate into the medulla to varying depths, and then abruptly reverse at a hairpin turn and begin an ascending portion of the loop of Henle parallel to the descending portion. In long loops (depicted on the left side of Figure 39–5) the epithelium of the first portion of the ascending limb remains thin, although different functionally from that of the descending limb. This segment is called the ascending thin limb of Henle’s loop, or simply the ascending thin limb (see Figure 39–5). Further up the ascending portion the epithelium thickens, and this next segment is called the thick ascending limb of Henle’s loop, or simply the thick ascending limb. In short loops (depicted on the right side of Figure 39–5) there is no ascending thin portion, and the thick ascending portion begins right at the hairpin loop. The thick ascending limb rises back into the cortex to the very same Bowman’s capsule from which the tubule originated. Here it passes directly between the afferent and efferent arterioles at

CHAPTER 39 Renal Functions, Basic Processes, and Anatomy

Parietal layer Visceral layer (podocyte)

Bowman's capsule Renal corpuscle

Glomerular capillary (covered by visceral layer)

Proximal tubule

Afferent arteriole

Capillary

Juxtaglomerular cells Macula densa

Juxtaglomerular apparatus

401

a. Blood flows into the glomerulus through the afferent arterioles and leaves the glomerulus through the efferent arterioles. The proximal tubule exits Bowman’s capsule.

Distal tubule Efferent arteriole (a)

Podocyte (visceral layer of Bowman's capsule)

Cell processes Cell body

b. Podocytes of Bowman’s capsule surround the capillaries. Filtration slits between the podocytes allow fluid to pass into Bowman’s capsule. The glomerulus is composed of capillary endothelium that is fenestrated. Surrounding the endothelial cells is a basement membrane.

Filtration slits

Glomerular capillary (cut)

(b)

Fenestrae

Capsular space Foot processes

Filtration slits

c. Substances in the blood are filtered through capillary fenestrae between endothelial cells (single layer). The filtrate then passes across the basement membrane and through slit pores between the foot processes (also called pedicels) and enters the capsular space. From here, the filtrate is transported to the lumen of the proximal convoluted tubule.

Basement membrane

Fenestra

Capillary lumen (c)

Endothelium

Movement of filtrate

FIGURE 39–4 The renal corpuscle. a) Cutaway view of the renal corpuscle. b) Close-up of podocytes surrounding capillaries. c) Transmission EM of the filtration barrier. (Reproduced with permission from Daniel Friend from William Bloom and Don Fawcett, Textbook of Histology, 10th ed. W.B. Saunders Co. 1975.)

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Peritubular capillaries Proximal convoluted tubule

Distal convoluted tubule

Efferent arteriole Afferent arteriole

Artery Vein C o r t e x

Renal corpuscle Bowman’s capsule Glomerulus Macula densa

Cortical collecting duct

Loop of Henie

Vein Artery

Descending limb

Corticomedullary junction

Thick segment of ascending limb

M e d u l l a

Medullary collecting duct

Thin segment of ascending limb

Urine

Vasa recta Juxtamedullary nephron

Cortical nephron

FIGURE 39–5 Basic structure of nephrons and vascular elements as described in the text. Note the difference between a juxtamedullary nephron with its renal corpuscle located just above the corticomedullary border (left side of figure) and a cortical nephron with its renal corpuscle higher in the cortex (right side of figure). Cortical nephrons have efferent arterioles that give rise to peritubular capillaries, and they have short loops of Henle. In contrast, juxtamedullary nephrons have efferent arterioles that descend into the medulla to form vasa recta, and they have long loops of Henle. (Reproduced with permission from Widmaier EP, Raff H, Strang KT: Vander’s Human Physiology, 11th ed. McGraw-Hill, 2008.)

the point where they enter and exit the renal corpuscle at its vascular pole (see Figure 39–4a). The cells in the thick ascending limb closest to Bowman’s capsule (between the afferent and efferent arterioles) are a group of specialized cells known as the macula densa (see Figure 39–6). The macula densa marks the end of the thick ascending limb and the beginning of the distal convoluted tubule. This is followed by the con-

necting tubule, which leads to the cortical collecting tubule, the first portion of which is called the initial collecting tubule. From Bowman’s capsule to the proximal tubule, loop of Henle, distal tubule, and initial collecting tubules, each of the 1 million nephrons in each kidney is completely separate from the others. However, connecting tubules from several nephrons merge to form cortical collecting tubules, and a number of ini-

CHAPTER 39 Renal Functions, Basic Processes, and Anatomy

403

known more commonly as principal cells. Interspersed among the segment-specific cells in each of these three segments are individual cells of the second type, called intercalated cells. The last portion of the medullary collecting duct contains neither principal cells nor intercalated cells but is composed entirely of a distinct cell type called the inner medullary collecting duct cells.

Podocytes

Mesangial cells Efferent arteriole

Sympathetic nerve fiber

Juxtaglomerular cells

Afferent arteriole Smooth muscle cells Distal tubule

Macula densa

FIGURE 39–6 Components of the juxtaglomerular (JG) apparatus. It is made up of (1) juxtaglomerular cells (granular cells), which are specialized smooth muscle cells surrounding the afferent arteriole, (2) extraglomerular mesangial cells, and (3) cells of the macula densa, which are part of the tubule. The close proximity of these components to each other permits chemical mediators released from one cell to easily diffuse to other components. Note that sympathetic nerve fibers innervate the granular cells. (Reproduced with permission from Widmaier EP, Raff H, Strang KT: Vander’s Human Physiology, 11th ed. McGraw-Hill, 2008.)

tial collecting tubules then join end to end or side to side to form larger cortical collecting ducts. All the cortical collecting ducts then run downward to enter the medulla and become outer medullary collecting ducts, and then inner medullary collecting ducts. The latter merge to form several hundred large ducts, the last portions of which are called papillary collecting ducts, each of which empties into a calyx of the renal pelvis. Each renal calyx is continuous with the ureter, which empties into the urinary bladder, where urine is temporarily stored and from which it is intermittently eliminated. The urine is not altered after it enters a calyx. From this point on, the remainder of the urinary system serves only to maintain the composition of the tubular fluid established by the kidney. Up to the distal convoluted tubule, the epithelial cells forming the wall of a nephron in any given segment are homogeneous and distinct for that segment. For example, the thick ascending limb contains only thick ascending limb cells. However, beginning in the second half of the distal convoluted tubule, two cell types are found intermingled in most of the remaining segments. One type constitutes the majority of cells in the particular segment, is considered specific for that segment, and is named accordingly: distal convoluted tubule cells, connecting tubule cells, and collecting duct cells, the last

THE JUXTAGLOMERULAR APPARATUS Reference was made earlier to the macula densa, a portion of the late thick ascending limb at the point where this segment comes between the afferent and efferent arterioles at the vascular pole of the renal corpuscle from which the tubule arose. This entire area is known as the juxtaglomerular apparatus (JG) (see Figure 39–6), which, as will be described later, plays a very important signaling function. (Do not confuse the term JG with juxtamedullary nephron, meaning a nephron with a glomerulus located close to the cortical–medullary border.) Each JG apparatus is made up of the following three cell types: (1) granular cells (called juxtaglomerular cells in Figure 39–6), which are differentiated smooth muscle cells in the walls of the afferent arterioles; (2) extraglomerular mesangial cells; and (3) macula densa cells, which are specialized thick ascending limb epithelial cells. The granular cells are named because they contain secretory vesicles that appear granular in light micrographs. These granules contain the hormone renin (pronounced REE-nin). As we will describe in Chapter 45, renin is a crucial substance for control of renal function and systemic BP. The extraglomerular mesangial cells are morphologically similar to and continuous with the glomerular mesangial cells, but lie outside Bowman’s capsule. The macula densa cells are detectors of the composition of the fluid within the nephron at the very end of the thick ascending limb and contribute to the control of glomerular filtration rate (GFR—see below) and to the control of renin secretion.

BASIC RENAL PROCESSES The working structures of the kidney are the nephrons and collecting tubules into which the nephrons drain. Figure 39–7 illustrates the meaning of several keywords that we use to describe how the kidneys function. It is essential that any student of the kidney grasp their meaning. Filtration is the process by which water and solutes in the blood leave the vascular system through the filtration barrier and enter Bowman’s space (a space that is topologically outside the body). Secretion is the process of moving substances into the tubular lumen from the cytosol of epithelial cells that form the walls of the nephron. Secreted substances may originate by synthesis within the epithelial cells or, more often, by crossing the epithelial layer from the surrounding renal interstitium. Reabsorption is the process of moving substances from the lumen across the epithelial layer into the surrounding interstitium. In most cases, reabsorbed substances then move into surrounding blood vessels, so that

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SECTION VII Renal Physiology

Artery Afferent arteriole

Glomerular capillary

Efferent arteriole

1. Glomerular filtration 2. Tubular secretion 3. Tubular reabsorption

1 Bowman’s space

2

Peritubular capillary

Tubule 3

Vein Urinary excretion

FIGURE 39–7 Fundamental elements of renal function— glomerular filtration, tubular secretion, and tubular reabsorption—and the association between the tubule and vasculature in the cortex. (Reproduced with permission from Widmaier EP,

organics glucose and urea; amino acids; and peptides such as insulin and antidiuretic hormone (ADH). The volume of filtrate formed per unit time is known as the glomerular filtration rate (GFR). In a healthy young adult male, the GFR is an incredible 180 L per day (125 mL/min)! Contrast this value with the net filtration of fluid across all the other capillaries in the body: approximately 4 L per day. The implications of this huge GFR are extremely important. When we recall that the average total volume of plasma in humans is approximately 3 L, it follows that the entire plasma volume is filtered by the kidneys some 60 times a day. The opportunity to filter such huge volumes of plasma enables the kidneys to excrete large quantities of waste products and to regulate the constituents of the internal environment very precisely. One of the general consequences of healthy aging as well as many kidney diseases is a reduction in the GFR.

TUBULAR REABSORPTION AND TUBULAR SECRETION

Raff H, Strang KT: Vander’s Human Physiology, 11th ed. McGraw-Hill, 2008.)

the term reabsorption implies a two-step process of removal from the lumen followed by movement into the blood. Excretion means exit of the substance from the body (i.e., the substance is present in the final urine produced by the kidneys). Synthesis means that a substance is constructed from molecular precursors, and catabolism means the substance is broken down into smaller component molecules. The renal handling of any substance consists of some combination of these processes.

GLOMERULAR FILTRATION Urine formation begins with glomerular filtration, the bulk flow of fluid from the glomerular capillaries into Bowman’s capsule. The glomerular filtrate (i.e., the fluid within Bowman’s capsule) is very much like blood plasma, but contains very little total protein because the large plasma proteins such as albumin and the globulins are virtually excluded from moving through the filtration barrier. Smaller proteins, such as many of the peptide hormones, are present in the filtrate, but their mass in total is miniscule compared with the mass of large plasma proteins in the blood. The filtrate contains most inorganic ions and low-molecular-weight organic solutes in virtually the same concentrations as in the plasma. Substances that are present in the filtrate at the same concentration as found in the plasma are said to be freely filtered. (Note that freely filtered does not mean all filtered. It just means that the amount filtered is in exact proportion to the fraction of plasma volume that is filtered.) Many low-molecular-weight components of blood are freely filtered. Among the most common substances included in the freely filtered category are the ions sodium, potassium, chloride, and bicarbonate; the uncharged

The volume and composition of the final urine are quite different from those of the glomerular filtrate. Clearly, almost all the filtered volume must be reabsorbed; otherwise, with a filtration rate of 180 L per day, we would urinate ourselves into dehydration very quickly. As the filtrate flows from Bowman’s capsule through the various portions of the tubule, its composition is altered, mostly by removing material (tubular reabsorption) but also by adding material (tubular secretion). As described earlier, the tubule is, at all points, intimately associated with the vasculature, a relationship that permits rapid transfer of materials between the capillary plasma and the lumen of the tubule via the interstitial space. Most of the tubular transport consists of reabsorption rather than tubular secretion. An idea of the magnitude and importance of tubular reabsorption can be gained from Table 39–2, which summarizes data for a few plasma components that undergo reabsorption. The values in Table 39–2 are typical for a healthy person on an average diet. There are at least three important generalizations to be drawn from this table: 1. Because of the huge GFR, the quantities filtered per day are enormous, generally larger than the amounts of the substances in the body. For example, the body contains about 40 L of water, but the volume of water filtered each day may be as large as 180 L. 2. Reabsorption of waste products, such as urea, is partial, so that large fractions of their filtered amounts are excreted in the urine. 3. Reabsorption of most “useful” plasma components (e.g., water, electrolytes, and glucose) is either complete (e.g., glucose) or nearly so (e.g., water and most electrolytes), so that little, if any, of the filtered amounts are excreted in the urine. For each plasma substance, a particular combination of filtration, reabsorption, and secretion applies. The relative pro-

CHAPTER 39 Renal Functions, Basic Processes, and Anatomy

405

TABLE 39–2 Average values for several substances handled by filtration and reabsorption. Substance

Amount Filtered Per Day

Amount Excreted

Reabsorbed (%)

Water (L)

180

1.8

99.0

Sodium (g)

630

3.2

99.5

Glucose (g)

180

0

100

Urea (g)

56

28

50

Reproduced with permission from Eaton DC, Pooler JP: Vander’s Renal Physiology, 7th ed. New York, NY: Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2009.

portions of these processes then determine the amount excreted. A critical point is that the rates of these processes are subject to physiological control. By triggering changes in the rates of filtration, reabsorption, or secretion when the body content of a substance goes above or below normal, these mechanisms regulate excretion to keep the body in balance. For example, consider what happens when a person drinks a large quantity of water: Within 1–2 hours, all the excess water has been excreted in the urine, partly as the result of an increase in GFR but mainly as the result of decreased tubular reabsorption of water. The body is kept in balance for water by increasing excretion. By keeping the body in balance, the kidneys serve to maintain body water concentration within very narrow limits.

METABOLISM BY THE TUBULES Although renal physiologists traditionally list glomerular filtration, tubular reabsorption, and tubular secretion as the three basic renal processes, we cannot overlook metabolism by the tubular cells. The tubular cells extract organic nutrients from the glomerular filtrate or peritubular capillaries and metabolize them as dictated by the cells’ own nutrient requirements. In so doing, the renal cells are behaving no differently from any other cells in the body. In addition, there are other metabolic transformations performed by the kidney that are directed toward altering the composition of the urine and plasma. The most important of these are gluconeogenesis, and the synthesis of ammonium from glutamine and the production of bicarbonate, both described in Chapter 47.

REGULATION OF RENAL FUNCTION By far the most complex feature of renal physiology is regulation of renal processes, details of which will be presented in later chapters. Neural signals, hormonal signals, and intrarenal chemical messengers combine to regulate the processes described above in a manner to help the kidneys meet the needs of the body. Neural signals originate in the sympathetic celiac plexus (see Chapter 19). These sympathetic neural signals exert major control over renal blood flow, glomerular filtration, and the release of vasoactive substances that affect both the kidneys and the peripheral vasculature. Hormonal signals originate in the adrenal gland, pituitary gland, and

heart. The adrenal cortex secretes the steroid hormones aldosterone and cortisol, and the adrenal medulla secretes the catecholamines epinephrine and norepinephrine. All of these hormones, but mainly aldosterone, are regulators of sodium and potassium excretion by the kidneys. The posterior pituitary gland secretes the hormone arginine vasopressin (AVP, also called antidiuretic hormone [ADH]). ADH is a major regulator of water excretion, and, via its influence on the renal vasculature and possibly collecting duct principal cells, probably sodium excretion as well. The heart secretes hormones— natriuretic peptides—that increase sodium excretion by the kidneys. The least understood aspect of regulation lies in the realm of intrarenal chemical messengers (i.e., messengers that originate in one part of the kidney and act in another part). It is clear that an array of substances (e.g., nitric oxide, purinergic agonists, superoxide, eicosanoids) influence basic renal processes, but, for the most part, the specific roles of these substances are not well understood.

OVERVIEW OF REGIONAL FUNCTION We conclude this chapter with a broad overview of the tasks performed by the individual nephron segments. Later, we examine renal function substance by substance and see how tasks performed in the various regions combine to produce an overall result that is useful for the body. The glomerulus is the site of filtration—about 180 L per day of volume and proportional amounts of solutes that are freely filtered, which is the case for most solutes (large plasma proteins are an exception). The glomerulus is where the greatest mass of excreted substances enters the nephron. The proximal tubule (convoluted and straight portions) reabsorbs about two thirds of the filtered water, sodium, and chloride. The proximal convoluted tubule reabsorbs all of the useful organic molecules that the body conserves (e.g., glucose, amino acids). It reabsorbs significant fractions, but by no means all, of many important ions, such as potassium, phosphate, calcium, and bicarbonate. It is the site of secretion of a number of organic substances that are either metabolic waste products (e.g., uric acid, creatinine) or drugs (e.g., penicillin) that clinicians must administer appropriately to make up for renal excretion. The loop of Henle contains different segments that perform different functions, but the key functions occur in the thick ascending limb. As a whole, the loop of Henle reabsorbs about

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20% of the filtered sodium and chloride and 10% of the filtered water. A crucial consequence of these different proportions is that, by reabsorbing relatively more salt than water, the luminal fluid becomes diluted relative to normal plasma and the surrounding interstitium. During periods when the kidneys excrete dilute final urine, the role of the loop of Henle in diluting the luminal fluid is crucial. The end of the loop of Henle contains cells of the macula densa, which sense the sodium and chloride content of the lumen and generate signals that influence other aspects of renal function, specifically the renin–angiotensin system (discussed in Chapter 45). The distal tubule and connecting tubule together reabsorb some additional salt and water, perhaps 5% of each. The cortical collecting tubule is where several (6–10) connecting tubules join to form a single tubule. Cells of the cortical collecting tubule are strongly responsive to and are regulated by the hormones aldosterone and ADH. Aldosterone enhances sodium reabsorption and potassium secretion by this segment, and ADH enhances water reabsorption. The degree to which these processes are stimulated or not stimulated plays a major role in regulating the amount of solutes and water present in the final urine. With large amounts of ADH present, most of the water remaining in the lumen is reabsorbed, leading to concentrated, low-volume urine. With little ADH present, most of the water passes on to the final urine, producing dilute, high-volume urine. The medullary collecting tubule continues the functions of the cortical collecting tubule in salt and water reabsorption. In addition, it plays a major role in regulating urea reabsorption and in acid–base balance (secretion of protons or bicarbonate).

CLINICAL CORRELATION A 57-year-old woman with type 2 diabetes mellitus has managed her condition quite well via dietary control and has been in good health otherwise. Lately, however, she has been feeling increasingly fatigued and so schedules a checkup with her primary care physician (PCP). No remarkable physical signs are noted, except that her BP is increased at 137/92 mm Hg. Analysis of her blood shows a slightly increased fasting blood glucose of 117 mg/dL and a low normal hematocrit of 36%. Her PCP reminds her to be extra careful about diet in terms of salt and sugar, and suggests supplemental iron to maintain her hemoglobin. She schedules another checkup in 6 months. The fatigue worsens over the next 6 months, and she suffers a bone fracture after a seemingly minor fall. At the 6-month checkup her fasting blood glucose is 121 mg/dL, and hematocrit is decreased to 29%. BP is 135/95 mm Hg. Her PCP orders additional blood tests and a bone density scan out of concern for possible loss of bone mineral

(osteoporosis). New blood test results reveal elevated levels of several waste substances, indicative of a decreased GFR. The evidence strongly points to chronic renal failure, and she is referred to a nephrologist for evaluation and treatment. Chronic renal failure that has reached the point of significant renal dysfunction is called end-stage renal disease (ESRD). It is the consequence of major loss of functional tissue mass (nephrons and interstitial tissue). One of the common causes of ESRD is diabetes mellitus. Chronic hyperglycemia causes the formation of glycosylated proteins that deposit in the glomerular filtration apparatus. This interferes with filtration function and leads to pathology of glomerular cells. Hypertension can be both a cause and an effect of ESRD. The two normal kidneys have a considerable reserve capacity. Patients can do perfectly well with just one kidney, and ESRD may progress to a considerable degree before symptoms appear. When enough nephrons are lost, function declines, although some functions are preserved better than others; thus, symptoms do not develop uniformly. Another problem in ESRD is decreased production of erythropoietin, resulting in decreased red blood cell production and a low hematocrit. The anemia and possible accumulations of toxic substances due to the low GFR may account for the fatigue. A more complex problem in ESRD involves phosphorus, calcium, and bone. As renal function is lost, the ability to excrete phosphate declines and plasma phosphate rises, in turn leading to excessive loss of calcium. The body does not replace the loss, in part because of decreased renal production of 1,25-dihydroxyvitamin D. Treatment for ESRD includes the possibility of dialysis to make up for lost excretory function, renal transplant, and various dietary controls, including adding phosphate binders to the diet to prevent accumulation of phosphate in the blood.

CHAPTER SUMMARY ■ ■

■

■ ■

■ ■

The role of the kidneys in the body includes many functions that go well beyond simple excretion of waste. A major function of the kidneys is to regulate the excretion of substances at a rate that, on average, exactly balances their input into the body, and thereby maintains appropriate body content of many substances. Another major function of the kidneys is to regulate blood volume and vascular resistance, thereby assisting with the maintenance of BP. The structure of the kidneys reflects the arrangement of tubules and closely associated blood vessels. Each functional renal unit is composed of a filtering component (glomerulus) and a transporting tubular component (the nephron and collecting duct). The tubules are made up of multiple segments with distinct functions. Basic renal mechanisms consist of filtering a large volume, reabsorbing most of it, and adding substances by secretion, and, in some cases, synthesis.

CHAPTER 39 Renal Functions, Basic Processes, and Anatomy

STUDY QUESTIONS 1. Renal corpuscles are located A) along the corticomedullary border. B) throughout the cortex. C) throughout the cortex and outer medulla. D) throughout the whole kidney. 2. Relative to the number of glomeruli, how many loops of Henle and collecting ducts are present? A) same number of loops of Henle; same number of collecting ducts B) fewer loops of Henle; fewer collecting ducts C) same number of loops of Henle; fewer collecting ducts D) same number of loops of Henle; more collecting ducts 3. In which of the following lists are all the named substances synthesized in the kidneys and released into the blood? A) insulin, renin, and glucose B) red blood cells, active vitamin D, and albumin C) renin, 1,25-dihydroxyvitamin D, and erythropoietin D) glucose, urea, and erythropoietin 4. The macula densa is a group of cells located in the wall of A) Bowman’s capsule. B) the afferent arteriole. C) the end of the thick ascending limb. D) the glomerular capillaries.

407

5. The volume of the ultrafiltrate of plasma entering the tubules by glomerular filtration in 1 day is typically A) about three times the renal volume. B) about the same as the volume filtered by all the capillaries in the rest of the body. C) about equal to the circulating plasma volume. D) greater than the total body fluid volume. 6. A substance known to be freely filtered has a certain concentration in the afferent arteriole. What can we predict about its concentration in the efferent arteriole? A) almost zero B) close to the value in the afferent arteriole C) about 20% lower than the value in the afferent arteriole D) we cannot predict without knowing what happens in the tubules

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40 C

Renal Blood Flow and Glomerular Filtration Douglas C. Eaton and John P. Pooler

H A

P

T

E

R

O B J E C T I V E S ■ ■ ■ ■ ■ ■ ■

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Define renal blood flow, renal plasma flow, glomerular filtration rate, and filtration fraction, and give normal values. State the formula relating flow, pressure, and resistance in an organ. Identify the successive vessels through which blood flows after leaving the renal artery. Describe the relative resistances of the afferent arterioles and efferent arterioles. Describe the effects of changes in afferent and efferent arteriolar resistances on renal blood flow. Describe the three layers of the glomerular filtration barrier, and define podocyte, foot process, and slit diaphragm. Describe how molecular size and electrical charge determine filterability of plasma solutes; state how protein binding of a low-molecular-weight substance influences its filterability. State the formula for the determinants of glomerular filtration rate, and state, in qualitative terms, why the net filtration pressure is positive. State the reason glomerular filtration rate is so large relative to filtration across other capillaries in the body. Describe how arterial pressure, afferent arteriolar resistance, and efferent arteriolar resistance influence glomerular capillary pressure. Describe how changes in renal plasma flow influence average glomerular capillary oncotic pressure. Define autoregulation of renal blood flow and glomerular filtration rate.

RENAL BLOOD FLOW Renal blood flow (RBF) is huge relative to the mass of the kidneys—about 1 L/min, or 20% of the resting cardiac output. Considering that the volume of each kidney is less than 150 cm3, this means that each kidney is perfused with over three times its total volume every minute. All of this blood is delivered to the cortex. A small fraction of the cortical blood flow is then directed to the medulla. Blood enters each kidney at the hilum via a renal artery. After several divisions into smaller arteries, blood reaches arcuate arteries that course across the tops of the pyramids between the medulla and cortex. From

Ch40_409-416.indd 409

these, cortical radial arteries project upward toward the kidney surface and give off a series of afferent arterioles, each of which leads to a glomerulus within Bowman’s capsule (see Figure 39–5). These arteries and glomeruli are found only in the cortex, never in the medulla. In most organs, capillaries recombine to form the beginnings of the venous system, but the glomerular capillaries instead recombine to form another set of arterioles, the efferent arterioles. The efferent arterioles soon subdivide into a second set of capillaries. These are the peritubular capillaries, which are profusely distributed throughout the cortex. The peritubular capillaries then rejoin to form the veins by which blood ultimately leaves the kidney. 409

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SECTION VII Renal Physiology

FLOW, RESISTANCE, AND BLOOD PRESSURE IN THE KIDNEYS Blood flow in the kidneys obeys the basic hemodynamic principles described in Chapter 22. The basic equation for blood flow through any organ is as follows: ΔP Q = ___ R

(1)

where Q is organ blood flow, ΔP the mean pressure in the artery supplying the organ minus mean pressure in the vein draining that organ, and R the total vascular resistance in that organ. The high RBF is accounted for by low total renal vascular resistance. The resistance is low because there are so many pathways in parallel, that is, so many glomeruli and their associated vessels. The resistances of the afferent and efferent arterioles are about equal in most circumstances and account for most of the total renal vascular resistance. Resistances in arteries preceding afferent arterioles (i.e., cortical radial arteries) and in the capillaries play some role also, but we concentrate on the arterioles because arteriolar resistances are variable and are the sites of regulation. A change in the afferent arteriole or efferent arteriole resistance produces the same effect on RBF because these vessels are in series. When the two resistances both change in the same direction (the most common state of affairs), their effects on RBF are additive. When they change in different directions—one resistance increasing and the other decreasing—the changes offset each other.

CORTEX

Interlobular artery

Interbundle plexus

AVR

DVR

Inner stripe

Vascular bundle

Outer stripe

Arcuate artery

Efferent arteriole

OUTER MEDULLA

Blood flow to the medulla is far less than cortical blood flow, perhaps 0.1 L/min, and derives from the efferent arterioles of glomeruli situated just above the corticomedullary border (juxtamedullary glomeruli). These efferent arterioles do not branch into peritubular capillaries, but rather descend downward into the outer medulla, where they divide many times to form bundles of parallel vessels called vasa recta (Latin recta for “straight” and vasa for “vessels”). These bundles of vasa recta penetrate deep into the medulla (see Figure 40–1). Vasa recta on the outside of the vascular bundles “peel off ” and give rise to interbundle plexi of capillaries that surround Henle’s loops and the collecting ducts in the outer medulla. Only the center-most vasa recta supply capillaries in the inner medulla; thus, little blood flows into the papilla. The capillaries from the inner medulla re-form into ascending vasa recta that run in close association with the descending vasa recta within the vascular bundles. The structural and functional properties of the vasa recta are rather complex, and will be elucidated further in Chapter 44. The significance of the quantitative differences between cortical and medullary blood flow is the following: the high blood flow in the cortical peritubular capillaries maintains the interstitial environment of the cortical renal tubules very close in composition to that of blood plasma throughout the body. In contrast, the low blood flow in the medulla permits an interstitial environment that is quite different from blood plasma. As described in Chapter 44, the interstitial environment in the medulla plays a crucial role in regulating water excretion.

INNER MEDULLA

410

H2O NaCl Urea

FIGURE 40–1 The renal microcirculation. Arcuate arteries run just above the corticomedullary border, parallel to the surface, and give rise to cortical radial (interlobular) arteries radiating toward the surface. Afferent arterioles originate from the cortical radial arteries at an angle that varies with cortical location. Blood is supplied to the peritubular capillaries of the cortex from the efferent flow out of superficial glomeruli. It is supplied to the medulla from the efferent flow out of juxtamedullary glomeruli. Efferent arterioles of juxtamedullary glomeruli give rise to bundles of descending vasa recta in the outer stripe of the outer medulla. In the inner stripe of the outer medulla, descending vasa recta and ascending vasa recta returning from the inner medulla run side by side in the vascular bundles, allowing exchange of solutes and water as described in Chapter 44. Descending vasa recta from the bundle periphery supply the interbundle capillary plexus of the inner stripe, whereas those in the center supply blood to the capillaries of the inner medulla. Contractile pericytes in the walls of the descending vasa recta regulate flow. DVR, descending vasa recta; AVR, ascending vasa recta. (Modified with permission from Pallone TL, Zhang Z, Rhinehart K: Physiology of the renal medullary microcirculation. Am J Physiol Renal Physiol 2003;284(2):F253–F266.)

Vascular pressures (i.e., hydrostatic or hydraulic pressures) are much higher in the glomerular capillaries than in the

CHAPTER 40 Renal Blood Flow and Glomerular Filtration

411

Sites of largest vascular resistance

Pressure (mm Hg)

100

75

50

25

Rena l vein

Intra rena l vein

lary capil bular Perit u

ent a r terio le Effer

Glom eru capil lar lary

ent a r terio le Affer

Rena l ar te ry

0

FIGURE 40–2 Blood pressure decreases as blood flows through the renal vascular network. The largest drops occur in the sites of largest resistance—the afferent and efferent arterioles. The location of the glomerular capillaries, between the sites of high resistance, results in their having a much higher pressure than the peritubular capillaries. (Reproduced with permission from Kibble J, Halsey CR: The Big Picture, Medical Physiology. New York: McGraw-Hill, 2009.)

peritubular capillaries. As blood flows through any vascular resistance, the pressure progressively decreases. Pressure at the beginning of a given afferent arteriole is close to mean systemic arterial pressure (about 100 mm Hg) and decreases to about 60 mm Hg at the point where it feeds a glomerulus. Because there are so many glomerular capillaries in parallel, pressure decreases very little during flow through those capillaries; thus, glomerular capillary pressure remains close to 60 mm Hg. Then pressure decreases again during flow through an efferent arteriole, to about 20 mm Hg at the point where it feeds a peritubular capillary (see Figure 40–2). The high glomerular pressure of about 60 mm Hg is necessary to drive glomerular filtration, whereas the low peritubular capillary pressure of 20 mm Hg is equally necessary to permit the reabsorption of fluid.

GLOMERULAR FILTRATION FORMATION OF GLOMERULAR FILTRATE The glomerular filtrate contains most inorganic ions and lowmolecular-weight organic solutes in virtually the same concentrations as in the plasma. It also contains small plasma peptides and a very limited amount of albumin (see Chapter 43). Filtered fluid must pass through a three-layered glomerular filtration barrier. The first layer, the endothelial cells of the capillaries, is perforated by many large fenestrae (“windows”), like a slice of Swiss cheese, which occupy about 10% of the endothelial surface area. They are freely permeable to everything in the blood except cells and platelets. The middle layer, the capillary basement membrane, is a gel-like acellular meshwork of glycoproteins and proteoglycans, with a structure like a kitchen sponge. The third layer consists of epithelial cells (podocytes) that surround the

capillaries and rest on the basement membrane. The podocytes have an unusual octopuslike structure. Small “fingers,” called pedicels (or foot processes), extend from each arm of the podocyte and are embedded in the basement membrane (see Figure 39–4c). Pedicels from a given podocyte interdigitate with the pedicels from adjacent podocytes. Spaces between adjacent pedicels constitute the path through which the filtrate, once it has passed through the endothelial cells and basement membrane, travels to enter Bowman’s space. The foot processes are coated by a thick layer of extracellular material, which partially occludes the slits. Extremely thin processes called slit diaphragms bridge the slits between the pedicels. Slit diaphragms are widened versions of the tight junctions and adhering junctions that link all contiguous epithelial cells together and are like miniature ladders. The pedicels form the sides of the ladder, and the slit diaphragms are the rungs. Both the slit diaphragms and basement membrane are composed of an array of proteins, and while the basement membrane may contribute to selectivity of the filtration barrier, integrity of the slit diaphragms is essential to prevent excessive leak of plasma protein (mainly albumin). Some protein-wasting diseases are associated with abnormal slit diaphragm structure. Selectivity of the barrier to filtered solute is based on both molecular size and electrical charge. Let us look first at size. The filtration barrier of the renal corpuscle provides no hindrance to the movement of molecules with molecular weights less than 7,000 d (i.e., solutes this small are all freely filtered). This includes all small ions, glucose, urea, amino acids, and many hormones. The filtration barrier almost totally excludes plasma albumin (molecular weight of approximately 66,000 d). (We are, for simplicity, using molecular weight as our reference for size; in reality, it is molecular radius and shape that is critical.) The hindrance to plasma albumin is not 100%, however, so the glomerular filtrate does contain extremely small quantities

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of albumin, on the order of 10 mg/L or less. This is only about 0.02% of the concentration of albumin in plasma and is the reason for the use of the phrase “nearly protein-free” earlier. Some small substances are partly or mostly bound to large plasma proteins and are thus not free to be filtered, even though the unbound fractions can easily move through the filtration barrier. This includes hydrophobic hormones of the steroid and thyroid classes and about 40% of the calcium in the blood. For molecules with a molecular weight ranging from 7,000 to 70,000 d, the amount filtered becomes progressively smaller as the molecule becomes larger (Figure 40–3). Thus, many normally occurring small- and medium-sized plasma peptides and proteins are actually filtered to a significant degree. Moreover, when certain small proteins not normally present in the plasma appear because of disease (e.g., hemoglobin

Filtrate/plasma concentration ratio

A. 1.0

Inulin (~ 5,000)

released from damaged erythrocytes or myoglobin released from damaged muscles), considerable filtration of these may occur as well. Electrical charge is the second variable determining filterability of macromolecules. For any given size, negatively charged macromolecules are filtered to a lesser extent, and positively charged macromolecules to a greater extent, than neutral molecules. This is because the surfaces of all the components of the filtration barrier (the cell coats of the endothelium, the basement membrane, and the cell coats of the podocytes) contain fixed polyanions, which repel negatively charged macromolecules during filtration. Because almost all plasma proteins bear net negative charges, this electrical repulsion plays a very important restrictive role, enhancing that of purely size hindrance. In other words, if either albumin or the filtration barrier were not charged, even albumin would be filtered to a considerable degree (see Figure 40–3). Certain diseases that cause glomerular capillaries to become “leaky” to protein do so by eliminating negative charges in the membranes. It must be emphasized that the negative charges in the filtration membranes act as a hindrance only to macromolecules, not to mineral anions or low-molecular-weight organic anions. Thus, chloride and bicarbonate ions, despite their negative charge, are freely filtered.

0.5

DIRECT DETERMINANTS OF GFR Hemoglobin (68,000) Albumin (~ 69,000) 0 0

35 Molecular weight (thousands)

70

B. Positively charged = more filtered

Filtration

Neutral

Molecular size Negatively charged = less filtered

FIGURE 40–3 A) As molecular weight (and therefore size) increases, filterability declines, so that proteins with a molecular weight above 70,000 d are hardly filtered at all. B) For any given molecular size, negatively charged molecules are restricted far more than neutral molecules, while positively charged molecules are restricted less. (Reproduced with permission from Kibble J, Halsey CR: The Big Picture, Medical Physiology. New York: McGraw-Hill, 2009.)

Variation in glomerular filtration rate (GFR) is a crucial determinant of renal function because, everything else being equal, a higher GFR means greater excretion of salt and water. Regulation of the GFR is straightforward in terms of physical principles but very complex functionally because there are many regulated variables. The rate of filtration in all capillaries, including the glomeruli, is determined by the hydraulic permeability of the capillaries, their surface area, and the net filtration pressure (NFP) acting across them, given as follows: Rate of filtration = Hydraulic permeability × Surface area × NFP

(2)

Because it is difficult to estimate the area of a capillary bed, a parameter called the filtration coefficient (Kf) is used to denote the product of the hydraulic permeability and the area. The NFP is the algebraic sum of the hydrostatic pressures and the osmotic pressures resulting from protein—the oncotic, or colloid osmotic pressures—on the two sides of the capillary wall. There are four pressures to consider: two hydrostatic pressures and two oncotic pressures. These are the Starling forces that were described earlier in Chapter 26. Applying this same principle to the glomerular capillaries, we have: NPF = (PGC – PBC) – (πGC – πBC)

(3)

where PGC is glomerular capillary hydraulic pressure, πBC the oncotic pressure of fluid in Bowman’s capsule, PBC the hydraulic pressure in Bowman’s capsule, and πGC the oncotic

CHAPTER 40 Renal Blood Flow and Glomerular Filtration

60 Bowman’s space

PGC

PGC

NFP

50

PBS Pressure (mm Hg)

Glomerular capillary

413

πGC

Forces

mmHg

40

30 πGC 20

10

PBC

Favoring filtration*: Glomerular capillary blood pressure (PGC)

60 0

Opposing filtration: Fluid pressure in Bowman’s space (PBS)

15

Osmotic force due to protein in plasma (π GC)

29

Net glomerular filtration pressure = PGC – PBS – πGC

16

FIGURE 40–4 Forces involved in glomerular filtration as described in the text. (Reproduced with permission from Widmaier EP, Raff H,

50% Capillary length

100%

FIGURE 40–5 Forces affecting glomerular filtration along the length of the glomerular capillaries. Note that the oncotic pressure within the capillaries (πGC) rises due to loss of water and that the net filtration pressure (shaded region) decreases as a result. (Modified with permission from Eaton DC, Pooler JP: Vander’s Renal Physiology, 7th ed. New York, NY: Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2009.)

Strang KT: Vander’s Human Physiology, 11th ed. McGraw-Hill, 2008.)

pressure in glomerular capillary plasma, shown schematically in Figure 40–4, along with typical average values. Because there is normally little total protein in Bowman’s capsule, πBC may be taken as zero and not considered in our analysis. Accordingly, the overall equation for GFR becomes: GFR = Kf (PGC – PBC – πGC)

(4)

Figure 40–5 shows that the hydraulic pressure changes only slightly along the glomeruli. This is because there are so many glomeruli in parallel, and collectively they provide only a small resistance to flow, but the oncotic pressure in the glomerular capillaries does change substantially along the length of the glomeruli. Water moves out of the vascular space and leaves protein behind, thereby increasing protein concentration and, hence, the oncotic pressure of the unfiltered plasma remaining in the glomerular capillaries. Mainly because of this large increase in oncotic pressure, the NFP decreases from the beginning of the glomerular capillaries to the end. The NFP when averaged over the whole length of the glomerulus is about 16 mm Hg. This average NFP is higher than that found in most nonrenal capillary beds. Taken together with a very high value for Kf, it accounts for the enormous filtration of 180 L of fluid per day (compared with 3 L per day or so in all other capillary beds combined). The GFR is not fixed but shows marked fluctuations in differing physiological states and in disease. To grasp this situation, it is essential to see how a change in any one factor affects GFR under the assumption that all other factors are held constant.

Table 40–1 presents a summary of these factors. It provides, in essence, a checklist to review when trying to understand how diseases or vasoactive chemical messengers and drugs change GFR. It should be noted that the major cause of decreased GFR in renal disease is not a change in these parameters within individual nephrons, but rather simply a decrease in the number of functioning nephrons, which reduces Kf.

Kf Changes in Kf are caused most often by glomerular disease, but also by normal physiological control. The details are still not completely clear, but chemical messengers released within the kidneys cause contraction of glomerular mesangial cells. Such contraction may restrict flow through some of the capillary loops, effectively reducing the area available for filtration, Kf, and, hence GFR.

PGC Hydrostatic pressure in the glomerular capillaries (PGC) is influenced by many factors. We can help depict the situation by using the analogy of a leaking garden hose. If pressure in the pipes feeding the hose changes, the pressure in the hose and, hence, the rate of leak will be altered. Resistances in the hose also affect the leak. If we kink the hose upstream from the leak, pressure at the region of leak decreases and less water leaks out. However, if we kink the hose beyond the leak, this increases pressure at the region of leak and increases the leak rate.

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TABLE 40–1 Summary of direct GFR determinants and factors that influence them. Direct Determinants of GFR: GFR = Kf (PGC − PBC − πGC)

Major Factors that Tend to Increase the Magnitude of the Direct Determinant

Kf

1. ↑ Glomerular surface area (because of relaxation of glomerular mesangial cells) Result: ↑ GFR

PGC

1. ↑ Renal arterial pressure 2. ↓ Afferent arteriolar resistance (afferent dilation) 3. ↑ Efferent arteriolar resistance (efferent constriction) Result: ↑ GFR

PBC

1. ↑ Intratubular pressure because of obstruction of tubule or extrarenal urinary system Result: ↓ GFR

πGC

1. ↑ Systemic plasma oncotic pressure (sets πGC at beginning of glomerular capillaries) 2. ↓ Renal plasma flow (causes increased rise of πGC along glomerular capillaries) Result: ↓ GFR

GFR, glomerular filtration rate; Kf, filtration coefficient; PGC, glomerular capillary hydraulic pressure; PBC, Bowman’s capsule hydraulic pressure; πGC, glomerular capillary oncotic pressure. A reversal of all arrows in the table will cause a decrease in the magnitudes of Kf, PGC, PBC, and πGC. Reproduced with permission from Eaton DC, Pooler JP: Vander’s Renal Physiology, 7th ed. New York, NY: Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2009.)

These same principles apply to PGC and GFR. First, a change in renal arterial pressure causes a change in PGC in the same direction. If resistances remain constant, PGC rises and falls as renal artery pressure rises and falls. This is a crucial point because a major influence on renal function is arterial blood pressure. Second, changes in the resistance of the afferent and efferent arterioles have opposite effects on PGC. An increase in afferent arteriolar resistance, which is upstream from the glomerulus, is like kinking the hose above the leak (it decreases PGC), whereas an increase in efferent arteriolar resistance is downstream from the glomerulus and is like kinking the hose beyond the leak (it increases PGC). Of course, dilation of the afferent arteriole raises PGC, and hence GFR, while dilation of the efferent arteriole lower PGC and GFR. It should also be clear that when the afferent and efferent arteriolar resistances both change in the same direction (i.e., they both increase or decrease), they exert opposing effects on PGC. The real significance for this is that the kidney can regulate PGC and, hence, GFR independently of RBF. The effects of changes in arteriolar resistances are summarized in Figure 40–6.

PBC Changes in this variable are usually of very minor importance. However, obstruction anywhere along the tubule or in the external portions of the urinary system (e.g., the ureter) increases the tubular pressure everywhere proximal to the occlusion, all the way back to Bowman’s capsule. The result is to decrease GFR.

πGC Oncotic pressure in the plasma at the very beginning of the glomerular capillaries is, of course, simply the oncotic pressure of systemic arterial plasma. Accordingly, a decrease in arterial plasma protein concentration, as occurs, for example, in liver disease, decreases arterial oncotic pressure and tends to increase GFR, whereas increased arterial oncotic pressure tends to reduce GFR. However, recall that πGC is the same as arterial oncotic pressure only at the very beginning of the glomerular capillaries; πGC then progressively increases along the glomerular capillaries as protein-free fluid filters out of the capillary, concentrating the protein left behind. This means that NFP and, hence, filtration progressively decrease along the capillary length. Accordingly, anything that causes a steeper increase in πGC tends to lower average NFP and hence GFR. Such a steep increase in oncotic pressure occurs when RBF is very low. Since blood is composed of cells and plasma, low RBF means that renal plasma flow (RPF) is also low. When RPF is low, any given rate of filtration removes a larger fraction of the plasma, leaving a smaller volume of plasma behind in the glomeruli to contain all the plasma protein. This causes the πGC to reach a final value at the end of the glomerular capillaries that is higher than normal. This increases the average πGC along the capillaries and lowers average NFP and, hence, GFR. Conversely, a high RPF, all other factors remaining constant, causes πGC to increase less steeply and reach a final value at the end of the capillaries that is less than normal, which will increase the GFR. These concepts can be expressed as a filtration fraction: the ratio GFR/RPF, which is normally about 20%. The increase in πGC along the glomerular capillaries is directly proportional to the filtration fraction (i.e., the greater the percentage of volume filtered from the plasma, the greater the increase in πGC). Therefore, if you know that filtration fraction has changed, you can be certain that there has also been a proportional change in πGC and that this has played a role in altering GFR.

FILTERED LOAD A term we use in other chapters is filtered load. It is the amount of substance that is filtered per unit time. For freely filtered substances, the filtered load is just the product of GFR and plasma concentration. Consider sodium. Its normal plasma concentration is 140 mEq/L, or 0.14 mEq/mL. A normal GFR in healthy young adult males is 125 mL/min, so the filtered load of sodium is 0.14 mEq/mL × 125 mL/min = 17.5 mEq/min. We can do the same calculation for any other substance, being careful in each case to be aware of the unit of measure in which concentration is expressed. The filtered load is what is presented to the rest of

CHAPTER 40 Renal Blood Flow and Glomerular Filtration

Decreased GFR

415

Increased GFR

Constrict AA

Constrict EA

Blood flow

Blood flow PGC

PGC

GFR

GFR (b)

(a)

Dilate EA

Blood flow

Dilate AA

Blood flow

PGC

PGC

GFR (c)

GFR (d)

FIGURE 40–6 Effect of changes in resistance on GFR. a–d) Constricting the afferent arteriole (AA) or dilating the efferent arteriole (EA) leads to a decreased GFR, while dilating the AA or constricting the EA leads to increased GFR. (Reproduced with permission from Widmaier EP, Raff H, Strang KT: Vander’s Human Physiology, 11th ed. McGraw-Hill, 2008.)

the nephron to handle. The filtered load varies with plasma concentration and GFR. An increase in GFR, at constant plasma concentration, increases the filtered load, as does an increase in plasma concentration at constant GFR.

RBF varies only modestly when mean arterial pressure changes. This is partly a result of the myogenic response, which is the contraction or relaxation of arteriolar smooth muscle in response to changes in vascular pressures. Autoregulation is

1.5

150

It is extremely important for the kidneys to keep the GFR at a level appropriate for the body because the excretion of salt and water is strongly influenced by the GFR. GFR is strongly influenced by renal arterial pressure. The effect is so strong that urinary excretion would tend to vary widely with ordinary daily excursions of arterial pressure. Also, vascular pressure in the thin-walled glomerular capillaries is higher than in capillaries elsewhere in the body, and hypertensive damage ensues if this pressure is too high. To protect the glomerular capillaries from hypertensive damage and to preserve a healthy GFR at different arterial pressure values, changes in GFR and RBF are minimized by several mechanisms that we collectively call autoregulation. An increase in renal artery pressure is counteracted by an increase in vascular resistance that almost offsets the increase in pressure. The word “almost” is crucial here. Higher driving pressures do indeed lead to higher blood flow and GFR, but not proportionally. Consider Figure 40–7. Within the usual range of mean arterial pressure (renal perfusion pressure),

Renal blood flow (L/min)

“Autoregulatory range”

0

0 0

80

Glomerular filtration rate (mL/min)

AUTOREGULATION

180

Renal perfusion pressure (mm Hg)

FIGURE 40–7 Autoregulation of renal blood flow (RBF) and glomerular filtration rate (GFR). Over the span of renal perfusion pressure (pressure in renal artery minus pressure in renal vein) from 80 to about 170 mm Hg, RBF and GFR rise only modestly as renal perfusion pressure increases. Outside of this range, however, the changes are much greater. (Reproduced with permission from Kibble J, Halsey CR: The Big Picture, Medical Physiology. New York: McGraw-Hill, 2009.)

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also partly the result of rather complicated intrarenal signals that affect vascular resistance and mesangial cell contraction (see Chapter 45). The myogenic response is very fast-acting and protects the glomeruli from short-term fluctuations in blood pressure. In addition to keeping changes in RBF fairly small, autoregulatory processes also keep changes in GFR fairly small. Again, GFR does increase slightly with an increase in arterial pressure.

CHAPTER SUMMARY ■

■ ■ ■

CLINICAL CORRELATION

■

A 10-year-old boy developed a severe sore throat and a mild fever. The family pediatrician took a throat swab and concluded the boy had strep throat and so prescribed a 10-day course of antibiotics. The boy recovered and resumed his normal activities. One week later the boy told his mother that his urine was “brownish.” She checked the bowl after his next urination, and it was indeed a rusty brown color. As the toilet flushed, she noticed that the water frothed up. Very concerned now, she brought her son back to the pediatrician, who performed a urine dipstick test. This revealed increased protein in the urine (accounting for the frothiness). In addition, his blood pressure was somewhat elevated, and the pediatrician noted some puffiness in the face. Further tests confirmed that this was a case of poststreptococcal glomerulonephritis (inflammation of the glomeruli). In glomerulonephritis, mesangial and endothelial cells proliferate within Bowman’s capsule, with deposition of antigen–antibody complexes between the various cells in the glomeruli. It manifests in several forms; in this case, it was the result of an immune response to the streptococci. These events disrupt the barrier function of the podocytes, allowing the passage of larger than normal amounts of albumin into the filtrate, which is then excreted in the urine. The rust-brownish color of the urine is due to the presence of intact red blood cells (hematuria) and hemoglobin released from hemolyzed red blood cells. A paradoxical feature of some forms of glomerulonephritis is decreased excretion of sodium, despite the apparent increased leakiness of the filtration barrier. The accumulation of sodium and accompanying water can lead to edema (explaining the puffiness in the boy’s face) and elevated blood pressure. When occurring in older adults, glomerulonephritis may be accompanied by a greatly reduced RBF and GFR, but this is less likely in children. Some evidence suggests that increased reabsorption of sodium in the distal nephron is responsible for the sodium retention in cases where GFR is not reduced, demonstrating that the pathology is not limited to Bowman’s capsule. In the case of poststreptococcal glomerulonephritis, no specific treatment is usually necessary, and over time normal renal function returns.

■

■

The kidneys have a very large blood flow relative to their mass because it is regulated for functional reasons rather than metabolic demand. The cortex has a much higher blood flow and a different arrangement of blood vessels than the medulla. Glomerular filtration proceeds through a three-layered barrier that restricts filtration of large macromolecules. Both molecular charge and size affect the filterability of plasma solutes. The GFR is determined by the same Starling forces that govern filtration in blood vessels elsewhere. Control of the resistances of the afferent and efferent arterioles permits independent control of glomerular filtration rate and RBF. Autoregulation of RBF limits the variation in RBF in the face of large changes in arterial pressure.

STUDY QUESTIONS 1. Blood enters the renal medulla immediately after passing through which vessels? A) arcuate arteries B) peritubular capillaries C) afferent arterioles D) efferent arterioles 2. Which cell type is the main determinant of the filterability of plasma solutes? A) mesangial cells B) podocytes C) endothelial cells D) vascular smooth muscle 3. Which of the following is not subject to physiological control on a moment-to-moment basis? A) hydrostatic pressure in glomerular capillaries B) selectivity of the filtration barrier C) filtration coefficient D) resistance of efferent arterioles 4. If autoregulation is effective, we expect to see which one of the following held almost constant? A) pressure in the renal artery. B) total renal vascular resistance. C) the filtered load of water and small ions. D) the contractile state of smooth muscle in the afferent arteriole. 5. In the face of a 20% decrease in arterial pressure, GFR decreases by only 2%. What could account for this finding? A) The resistances of the afferent and efferent arterioles both decrease equally. B) Glomerular mesangial cells contract. C) Efferent arteriolar resistance increases. D) Afferent arteriolar resistance increases.

41 C

Clearance Douglas C. Eaton and John P. Pooler

H A

P

T

E

R

O B J E C T I V E S ■ ■ ■

■ ■

■ ■ ■ ■

Define the terms clearance and metabolic clearance rate, and differentiate between general clearance and specific renal clearance. List the information required to calculate clearance. State the criteria that must be met for a substance so that its clearance can be used as a measure of glomerular filtration rate; state which substances are used to measure glomerular filtration rate and effective renal plasma flow. Given data, calculate the clearance of any excreted substance. Predict whether a substance undergoes net reabsorption or net secretion by comparing its clearance with that of inulin or by comparing its rate of filtration with its rate of excretion. Given data, calculate net rate of reabsorption or secretion for any substance. Given data, calculate fractional excretion of any substance. Describe how to estimate glomerular filtration rate from creatinine clearance and describe the limitations of this estimate. Describe how to use plasma concentrations of urea and creatinine as indicators of changes in glomerular filtration rate.

Ingested substances and metabolic waste products are constantly being removed from the body (cleared) by a number of means, including disposal in the urine and feces, biochemical transformation in the liver, and, for volatile substances, exhalation. The rate of removal can be expressed in several ways, for example, the plasma half-life. Another way to express removal rate is clearance, which is the volume of plasma per unit time from which all of a specific substance is removed. Clearance in a biomedical context has both a general meaning and a specific renal meaning. The general meaning is simply that a substance is removed from the blood by any of the mechanisms mentioned above (see Figure 1–4). Its quantitative measure is called the metabolic clearance rate. Renal clearance, on the other hand, means that the substance is removed from the blood and excreted in the urine. Evaluation of renal clearance is commonly used clinically as an overall assessment of renal health. Repeated assessments over a period of time can indicate whether renal function is stable or deteriorating.

Ch41_417-422.indd 417

CLEARANCE UNITS The units of renal clearance are often confusing to the firsttime reader, so let us be sure of the meaning. First, the units are volume per time (not amount of a substance per time). The easiest way to think of this is to ask what volume of plasma supplies the amount excreted in a given time. For example, if each liter of plasma contains 1 mg of substance X, and 0.5 mg of X is excreted in 1 hour, then half a liter of plasma supplies the amount excreted, that is, the clearance is 0.5 L/h. The reader should appreciate that removing all of a substance from a small volume of plasma is equivalent to removing some of it from a larger volume, which is actually the way the kidneys do it. For example, if all of substance X is removed from 0.5 L, this is equivalent to removing half of it from 1 L, or one quarter of it from 2 L, etc. The clearance is still 0.5 L/min in all these cases. The general meaning and specific renal meaning of clearance can be illustrated by comparing how the body handles

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two substances with similar-sounding names but very different properties: inulin and insulin. Insulin is the familiar pancreatic hormone involved in regulating blood glucose. It is a protein with a molecular weight of 5.8 kd and is small enough to be freely filtered by the glomerulus. Once in Bowman’s space, it moves along with every other filtered substance into the proximal convoluted tubule, where it is largely taken up by endocytosis and degraded into its constituent amino acids. Very little insulin escapes this uptake, and very little of the filtered insulin makes it all the way to the urine. Thus, the kidney takes part in clearing insulin from the blood, but because so little appears in the urine, the specific renal clearance is very low (<1 mL/min). However, the body has additional mechanisms for clearing insulin, and its metabolic clearance rate is quite high (half-life less than 10 minutes). Let us contrast this with inulin. Inulin is a polysaccharide starch of about 5-kd molecular weight that is not usually found in the body. Like insulin, it is freely filtered by the glomerulus, but it is not reabsorbed or secreted by the nephron. All the inulin that is filtered flows through the nephron and appears in the urine. Thus, inulin’s renal clearance is relatively large. Inulin in the blood is not taken up by other tissues, and the kidneys are the only excretion route. As we will see, this makes inulin a very special substance with respect to assessing renal function.

QUANTIFICATION OF CLEARANCE Consider again a substance X that is excreted in the urine. How do we actually calculate its clearance in the proper units? The amount of X removed from a given volume of plasma equals the amount excreted in the urine. The amount cleared from the plasma in a given time is the product of the volume of plasma cleared per unit time (Cx) and the plasma concentration (Px), that is, amount cleared/time = Cx × Px. That same

amount now appearing in the urine during this time is the product of the urine flow rate (V) and the urine concentration of X (Ux), that is, amount in urine/time = V × Ux. This equality is shown in equations (1) and (2) in Figure 41–1. Finally, by rearrangement, we solve for clearance (Cx) as shown in equation (3). Thus, we have equated the amount removed from the plasma with that appearing in the urine, and by rearrangement we end up with clearance in its proper units—volume per time. While we are addressing the quantification of clearance, note that the product of urine flow rate and urine concentration of X (numerator on the right-hand side of equation (3)) is excretion rate. Therefore, we can also state that the clearance of substance X is the excretion rate divided by the plasma concentration. The process of clearance and derivation of the clearance formula is depicted in Figure 41–1. Let us now examine the clearance of several substances important for the quantification of renal function, starting with inulin. Inulin, as described previously, is a polysaccharide that is freely filtered and neither reabsorbed nor secreted. Thus, once filtered, it must flow through the nephron into the urine (Figure 41–2). The volume of plasma cleared of inulin is the volume filtered, that is, inulin clearance equals the glomerular filtration rate (GFR). Inulin clearance is indeed the hallmark experimental method of measuring the GFR. Can something have a clearance greater than the GFR? Indeed, yes. One such substance is para-aminohippurate (PAH). This is a small (molecular weight of 194 d) watersoluble organic anion not normally found in the body, but that is used experimentally. It is freely filtered and also avidly secreted by the proximal tubule epithelium (via the transcellular route). The secretion rate is saturable. That is, there is a maximum rate of PAH secretion into the tubule. Such a tubular maximum, (Tm) is common in transport systems (see Chapter 42). However, at low plasma concentrations, almost all of the PAH entering the kidney is removed from the plasma

Amount in plasma = Cx × Px

Plasma before clearance

Urine before clearance

Urine during clearance Plasma during clearance Amount in urine = V × Px

FIGURE 41–1 Derivation of the basic clearance formula. Over time, substance X (dots) is removed from the plasma (large boxes) and put into the urine (small boxes) and excreted. The amount of X removed from the plasma during that time (Cx × Px) must equal the amount excreted (V × Ux) in that same time, as shown in equations (1) and (2). By rearrangement (equation (3)), we solve for the clearance of X.

Urine after clearance Plasma after clearance Amount in plasma = Amount in urine (1) Cx × Px = V × Ux

(2)

Cx

(3)

= V × Ux Px

CHAPTER 41 Clearance

Concentration of inulin in plasma = 4 mg/L Glomerular capillary

Bowman’s space

Rate of fluid filtration (GFR) = 7.5 L/h Concentration of inulin in filtrate = 4 mg/L Total inulin filtered = 30 mg/h No reabsorption of inulin No secretion of inulin Total inulin excreted = 30 mg/h

FIGURE 41–2 Renal handling of inulin. All filtered inulin is excreted. Since the volume of plasma cleared of inulin is the volume filtered, the inulin clearance equals the GFR. (Modified with permission from Widmaier EP, Raff H, Strang KT: Vander’s Human Physiology, 11th ed. McGraw-Hill, 2008.)

and excreted in the urine. About 20% of the excreted PAH appears by filtration and the rest by secretion. Its clearance, therefore, is nearly as great as the renal plasma flow. In fact, the PAH clearance can be used experimentally as a measure of renal plasma flow, usually called the effective renal plasma flow to indicate that its value is slightly less than the true renal plasma flow. What can the clearance of any freely filtered substance tell us? If we know the GFR (as assessed from inulin clearance) and the clearance of the substance, then any difference between clearance and GFR represents net secretion or reabsorption (or, in a few rare cases, renal synthesis). If the clearance of a substance exactly equals the GFR, then there has been no net reabsorption or secretion. If the clearance is greater than the GFR, there must have been net secretion. Finally, if the clearance is less than the GFR, there must have been net reabsorption. The word net in this description is important. As we will see in later chapters, a number of substances are reabsorbed in certain regions of the nephron and secreted in other regions. The net result of these processes is the sum of everything that happens along the nephron. Of course, if a substance is not freely filtered, low clearance may simply indicate that little of the substance entered the tubule.

A PRACTICAL METHOD OF MEASURING GFR: CREATININE CLEARANCE The gold standard for measuring GFR is the inulin clearance, and this method is used in research studies. The method is cumbersome, however, because either inulin must be infused at a rate sufficient to keep its plasma concentration constant

419

during the period of urine formation and collection or there must be multiple samplings and a complex regression analysis. For routine assessment of GFR in patients, there is a much easier method: creatinine clearance. Creatinine is an end product of creatine metabolism and is exported into our blood continuously by skeletal muscle. The rate is proportional to skeletal muscle mass, and to the extent that muscle mass is constant in a given individual, the creatinine production is constant. Creatinine is freely filtered and not reabsorbed. A small amount, however, is secreted by the proximal tubule. Therefore, the creatinine appearing in the urine represents a filtered component (mostly) and a much smaller secreted component. Because of the secretion, creatinine clearance is slightly higher than the GFR, normally by about 10–20%. For routine assessment of GFR, this degree of error is acceptable. How does one measure creatinine clearance? Usually, a patient’s urine is collected for 24 hours, and a blood sample is taken sometime during the collection period. Blood and urine are assayed for creatinine concentration, and we apply the clearance formula (Figure 41–1, equation (3)) to yield creatinine clearance. For a patient with a very low GFR, the secreted component is a relatively larger fraction of the total amount excreted; therefore, the creatinine clearance more severely overestimates GFR in patients with a very low GFR than in those with higher GFR values. Nevertheless, because of low cost and convenience, creatinine clearance continues to be the most common method for routine assessment of patient GFR and the integrity of renal filtration.

PLASMA CREATININE AND UREA CONCENTRATIONS AS INDICATORS OF CHANGES IN GFR Although creatinine clearance is a valuable clinical determinant of GFR, in routine practice, it is far more common to measure plasma creatinine alone and to use this as an indicator of GFR. If we ignore the small amount secreted, there should be an excellent inverse correlation between plasma creatinine concentration and GFR (Figure 41–3). A healthy person’s plasma creatinine concentration is about 1 mg/dL. It remains stable because each day the amount of creatinine excreted is equal to the amount of creatinine produced. Suppose one day, the GFR suddenly decreases by 50% because of an obstruction in the renal artery. On that day, the person filters only 50% as much creatinine as normal. Therefore, creatinine excretion is also reduced by 50%. (We are ignoring the small contribution of secreted creatinine.) Assuming no change in creatinine production, the person transiently goes into positive creatinine balance, and the plasma creatinine increases. However, despite the persistent 50% GFR reduction, the plasma creatinine does not continue to rise indefinitely; rather, it stabilizes at 2 mg/dL (i.e., after it has doubled). At this point, the person once again is able to excrete

420

SECTION VII Renal Physiology surement is a reasonable indicator of GFR. It is not completely accurate, however, for several reasons: (1) as before, some creatinine is secreted; (2) an original creatinine measurement when GFR was normal may not be available; (3) creatinine production may not remain completely unchanged. However, an increasing plasma creatinine is a red flag that there may be a renal problem. Because urea is also handled by filtration, the same type of analysis suggests that the measurement of plasma urea concentration could also serve as an indicator of GFR. However, it is a much less accurate indicator than plasma creatinine because the range of normal plasma urea concentration varies widely, depending on protein intake and changes in tissue catabolism, and because urea excretion is under partial hormonal regulation.

PCr, mg/100 mL

8

5 4 3 2 1 45

90

135

180 225 GFR, L/day

360

FIGURE 41–3 Steady-state relation between plasma creatinine and GFR for a person with a normal creatinine production. When GFR is low, plasma creatinine rises to high levels, making plasma creatinine a convenient indicator of GFR. (Modified with permission from Eaton DC, Pooler JP: Vander’s Renal Physiology, 7th ed. New York, NY: Lange Medical Books/McGraw- Hill, Medical Pub. Division, 2009.)

creatinine at the normal rate and so goes back in balance with a stable plasma level. The 50% GFR reduction has been just offset by the doubling of plasma creatinine concentration, restoring the filtered load of creatinine to normal. To understand this point, assume an original daily filtration volume of 180 L (1,800 dL). The original normal state is given by: Filtered creatinine = 1 mg/dL × 1,800 dL per day = 1,800 mg per day

(4)

The new steady state is given by: Filtered creatinine = 2 mg/dL × 900 dL per day = 1,800 mg per day

(5)

In the new steady state, creatinine excretion is normal, even though the plasma concentration has doubled (the person is in balance). In other words, creatinine excretion is below normal only transiently until plasma creatinine has increased as much proportionally as the GFR has decreased. What if the GFR then decreased to 300 dL per day? Again, creatinine retention would occur until a new steady state had been established (i.e., until the person was again filtering 1,800 mg per day). What would the new plasma creatinine be? 1,800 mg per day = Pcr × 300 dL per day

(6)

Pcr = 6 mg/dL

(7)

The increase in plasma creatinine results directly from the decrease in GFR. Therefore, a single plasma creatinine mea-

CLINICAL CORRELATION A 72-year-old, rather thin and frail female is experiencing bouts of atrial fibrillation. Her serum electrolytes are all within normal limits, her creatinine is 1.1 mg/dL (high normal), and there is no indication of a major renal disorder. Her body weight is 47 kg. Her primary care physician (PCP) prescribes digoxin for its antiarrhythmic effectiveness, but is concerned about overdosing and producing digitalis toxicity. The choice of an appropriate dosing regimen (amount and schedule) is a difficult one, particularly for drugs such as digoxin with significant side effects. The goal is to find a “therapeutic window” in which the body levels of the drug are high enough to be effective, but low enough not to invoke side effects. For drugs whose major excretion route is the kidneys, which include digoxin, it is often necessary to make adjustments based on the patient’s GFR. This is particularly appropriate in patients whose renal function is impaired due to disease or natural decline with age. In common medical settings it is not feasible to measure GFR via inulin clearance, or even to measure creatinine clearance using 24-hour urine collection in nonhospitalized patients. The question is: how does one obtain an estimate of GFR? A common method is to estimate creatinine clearance using a formula, known as the Cockcroft–Gault formula (shown below), that includes plasma creatinine, age, body weight, and gender. The use of this formula, or any of the several others that have been derived over the years, is subject to error. However, it is still useful as a guide for drug dosing purposes, where a precise clearance value is not really needed: creatinine clearance [mL/min] = (140–age) × body weight [Kg] × 0.85 [if female] _________________________________ 72 × serum creatinine [mg/dL]

(8)

This works out to be 34.3 mL/min in our patient. (For comparison, the estimated creatinine clearance using the

CHAPTER 41 Clearance

Cockcroft–Gault formula for a 21-year-old, 70-kg male with a serum creatinine of 1.0 mg/dL is 116 ml/min.) Her GFR, estimated by creatinine clearance, is low relative to that of young adults, but is sufficient to permit adequate excretory function. However, because the clearance of digoxin will be somewhat slow, her prescription is likely to be for lower doses, or for greater intervals between doses, than it would be in a much younger patient.

CHAPTER SUMMARY ■

■ ■

■ ■ ■ ■

Clearance has both a general meaning, describing loss of material from the body, and a specific renal meaning involving the kidney’s ability to remove substances from the blood. Clearance is always expressed in units of volume per time. Renal clearance of any substance is quantified by a general clearance formula relating urine flow to urine and plasma concentrations. Inulin clearance can be used to measure GFR because inulin is freely filtered and neither secreted nor reabsorbed. PAH clearance can be used as an estimate of renal plasma flow. Creatinine clearance is used as practical estimate of GFR. Plasma creatinine concentration is used clinically as an indicator of the GFR.

STUDY QUESTIONS 1. We can calculate the renal clearance of any substance if we know which pair of values? A) urine flow rate and urine concentration B) plasma concentration and urine concentration C) GFR and urinary excretion rate D) plasma concentration and urinary excretion rate

421

2. A drug X has a short plasma half-life and must be administered frequently to maintain therapeutic levels. The urinary concentration of X is much higher than the plasma concentration. A substantial amount of X also appears in the feces. What can we say about the renal clearance of X compared with the metabolic clearance rate of X? A) The metabolic clearance rate is higher than the renal clearance. B) The renal clearance is higher than the metabolic clearance rate. C) The two clearances are the same. D) There is insufficient information to answer the question. 3. Inulin clearance is measured twice: the first time at a low inulin infusion rate, and the second time at a higher infusion rate that results in a higher plasma inulin concentration during the test. Assuming the kidneys behave the same in both cases, which measurement will yield a higher inulin clearance? A) the first B) the second C) both measurements are the same D) there is insufficient information to answer the question 4. Which of the following indicates correct relative renal clearances? A) Glucose clearance is greater than urea clearance. B) PAH clearance is greater than inulin clearance. C) Urea clearance is greater than PAH clearance. D) Creatinine clearance is greater than PAH clearance. 5. An acute poisoning episode destroys 80% of a patient’s nephrons. If the plasma urea concentration prior to the episode was 5 mmol/L, and assuming dietary protein remains the same, what is the expected value of plasma urea now? A) 5 mmol/L B) 6.25 mmol/L C) 25 mmol/L D) continuously rising

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42 C

Tubular Transport Mechanisms Douglas C. Eaton and John P. Pooler

H A

P

T

E

R

O B J E C T I V E S ■

■ ■ ■ ■ ■ ■ ■ ■

Identify the major morphological components of an epithelial tissue, including lumen, interstitium, apical and basolateral membranes, and tight junctions. State how transport mechanisms combine to achieve active transcellular reabsorption in epithelial tissues. Define iso-osmotic transport. Define paracellular transport and differentiate between transcellular and paracellular transport. Describe qualitatively the forces that determine movement of reabsorbed fluid from the interstitium into peritubular capillaries. Explain why volume reabsorption in the proximal tubule depends on activity of the Na,K-ATPase. Compare the Starling forces governing glomerular filtration with those governing peritubular capillary absorption. Compare and contrast the concepts of Tm and gradient-limited transport. Contrast “tight” and “leaky” epithelia.

PROXIMAL TUBULE REABSORPTION Virtually all of the 180 L of water and several pounds of salt and other solutes filtered each day into Bowman’s space are reabsorbed, along with large amounts of many other substances. Quantitatively most of this reabsorption occurs in the proximal tubule, a process that is very nearly iso-osmotic, meaning that water and solutes are reabsorbed in equal proportions. Recall that filtration in the glomerulus is also iso-osmotic. Almost all solutes (except large plasma proteins) are filtered from plasma into Bowman’s space in the same proportion as water; thus, their concentrations in the glomerular filtrate are the same as in the plasma. By the end of the proximal tubule, about two thirds of the water and two thirds of the solutes have been reabsorbed. In the later portions of the nephron, reabsorption is generally not iso-osmotic, which is crucial for our ability to independently regulate solute and water balance.

Ch42_423-428.indd 423

Most of the solute reabsorbed in the proximal tubule consists of sodium and the anions (mostly chloride and bicarbonate) that must accompany sodium to maintain electroneutrality. These solutes are removed from the tubular lumen and move into the interstitium by a combination of processes that we describe below. The large amount of solute transferred from lumen to interstitium sets up an osmotic gradient that favors the parallel movement of water. The proximal tubule epithelium is very permeable to water, which follows the solute across in equal proportions. Thus, both the fluid removed from the lumen and that remaining behind are essentially iso-osmotic with the original filtrate. We say “essentially” because there must be some difference in osmolality to induce water movement, but for an epithelial barrier such as the proximal tubule that is very permeable to water, a difference of less than 1 mOsm/kg is sufficient to drive reabsorption of water. An osmolality difference of 1 mOsm/kg is equal in driving force to 19 mm Hg of hydrostatic pressure. Once in the interstitium, the solutes and water move from

423

11/26/10 10:08:31 AM

424

SECTION VII Renal Physiology

LUMEN

INTERSTITIUM

apical membrane

Interstital space

Channel or transporter

Peritubular capillary

Trancellular reabsorption

FIGURE 42–1 Transcellular and paracellular reabsorption. Transcellular reabsorption is a two-step process with separate influx and efflux steps utilizing transporters or channels. Paracellular reabsorption is always a passive process through the tight junctions. (Modified

Basolateral membrane Paracellular reabsorption

with permission from Eaton DC, Pooler JP: Vander’s Renal Physiology,

tight junction

7th ed. New York, NY: Lange Medical Books/McGraw-Hill, Medical Pub.

Basement membrane

Division, 2009.)

interstitium into the peritubular capillaries and are returned to the systemic circulation. Reabsorption across the tubular epithelium can be either through the cells (the transcellular route) or around the cells (the paracellular route), that is, through the matrix of the tight junctions that link each epithelial cell to its neighbor. The transcellular route is a two-step process: into the cells across the apical membrane facing the tubular lumen and out of the cells across the basolateral membrane facing the interstitium. These structures and pathways are depicted in Figure 42–1.

Substances cross the membranes of epithelial cells by an array of mechanisms. These mechanisms are no different from those used elsewhere in the body to transport substances across cell membranes as described in Chapter 3. We can view these mechanisms as a physiological toolbox. Renal cells use whichever set of tools is most suitable for the task. These mechanisms include simple diffusion through the bilayer, movement through channels, and movement through transporters of various types. This variety is depicted in Figure 42–2. Except for simple diffusion, all of these processes are regulated by signaling pathways. It is through regulation of transporters and

Substance A

Diffusion

1

Substance C Substance D

3

Uniporter

e

2

ran

mb

Me

Substance B

Symporter

Antiporter Substance E

Substance G

FIGURE 42–2 Mechanisms of transmembrane solute transport. With the exception of simple diffusion through the lipid bilayer, all transport involves channels and transporters that are regulated by signaling pathways. (Modified with permission from Eaton DC, Pooler JP: Vander’s Renal Physiology, 7th ed. New York, NY: Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2009.)

4

5

Substance H

Substance F

Ion channel

6

ADP + Pi ATP

Primary active transport

CHAPTER 42 Tubular Transport Mechanisms

Lumen

Interstitium

1. Insert or retrieve from storage sites 2. Transcribe and synthesize, or degrade 3. Attach ligand

L

FIGURE 42–3 Common mechanisms for regulating channel and transporter activity. 1) Transport proteins are shuttled back and forth between the surface membrane, where they function normally, and sites of sequestration at the base of microvilli or in intracellular vesicles. 2) Transport protein is synthesized and inserted in the membrane or removed and degraded. 3) Transport proteins are activated or inhibited by attaching ligands, either covalently (e.g., phosphorylation) or reversibly (e.g., ATP).

channels that the kidneys control the excretion of various substances. Figure 42–3 depicts some of the ways flux is regulated. This includes trafficking of channels and transporters between the surface membrane and inactive sites within the cell, genetic expression of new protein, degradation of existing protein, and the attachment of ligands that either directly alter protein function or target the protein for trafficking. Transporter and channel proteins are not permanent fixtures in the membrane; rather, they are constantly being shuttled between the mem-

brane and sites of inactivity or degradation, with lifetimes in the membrane generally being only a few hours. While some substances cross the epithelial barrier by the paracellular route, it is transcellular transport that controls the overall process, that is, transcellular processes set up the conditions favoring paracellular transport. All of this requires polarization of the epithelial cells, meaning that the transport proteins present in the apical membrane are different from those in the basolateral membrane. In the proximal tubule, the key process achieved by this polarized distribution of transport proteins is the movement of sodium through the cells from lumen to interstitium. The transport of virtually every other substance depends on the movement of sodium. Figure 42–4 shows the morphology of a generalized proximal tubule epithelium in which salt and water transport can be viewed as a multistep process. Step 1 is the active extrusion of sodium from epithelial cell to interstitium across the basolateral membrane. Step 2 is the passive entrance of sodium from the tubular lumen across the apical membrane into the cell to replace the sodium removed in step 1. Step 3 is the parallel movement of anions that must accompany the sodium to preserve electroneutrality. Step 4 is the osmotic flow of water from tubular lumen to interstitium. Finally, step 5 is the bulk flow of water and solute from interstitium into the peritubular capillary. Let us examine these steps more closely. The active extrusion of sodium in step 1 is via the Na,KATPase, which is the major energy consumer in the cell. The action of the Na,K-ATPase has several consequences, the key one being that it keeps the concentration of sodium within the cell low enough to favor the passive entrance of sodium from lumen to cell in all the processes of step 2. The entrance of sodium into the cell in step 2 is via multiple pathways. Quantitatively most of sodium enters via the

1. Sodium is actively extruded into the interstitium 2. Sodium enters passively from the tubular lumen 3. Anions follow the sodium 4. Water follows the solute 5. Water and solutes move by bulk flow into the peritubular capillary Lumen

Interstitium

ATP 2

Na+

3

Anions

1

Na+ K

+

Peritubular capillary

5 4

Water Water, anions

FIGURE 42–4

425

Epithelial salt and water reabsorption. See text for explanation of each individual step.

426

SECTION VII Renal Physiology

sodium–proton antiporter (NHE3 isoform). As we will see later, regulation of this transporter is a key player in regulating sodium excretion. Step 3, the movement of anions, is the most complex, as it involves two ions (chloride and bicarbonate) and a variety of transcellular and paracellular processes. We will examine the details in Chapters 44 and 47, but for now we emphasize that the movement of sodium, which is a cation, must be matched quantitatively by the equal movement of anions. Step 4 is the osmotic movement of water. The tubular cells possess a complement of aquaporins (water channels) in both the apical and basolateral membranes, and the tight junctions are also permeable to water. Therefore, as steps 1–3 lower the local luminal osmotic concentration by even a few milliosmoles per liter, water flows osmotically from lumen to interstitium. The movement of water into the interstitium in step 4 promotes step 5. This is the bulk flow of fluid from interstitium to peritubular capillary driven by Starling forces (hydrostatic and oncotic pressure gradients). The capillary hydraulic pressure opposes the uptake of interstitial fluids, but its value of 15–20 mm Hg is much lower than the 60 mm Hg in the glomerular capillaries, where there is net filtration. Meanwhile, the plasma oncotic pressure has increased to more than 30 mm Hg because loss of water by filtration in the glomerular capillaries concentrates the large plasma proteins. There is also a small but significant interstitial pressure (Table 42–1). The sum of these Starling forces is a net absorptive pressure, and it drives fluid movement into the peritubular capillaries. The reader can appreciate the fact that if cortical Starling forces are abnormal (e.g., low plasma oncotic pressure as when liver disease prevents normal production of serum albumin), absorption of fluid from the cortical interstitium can be slowed, causing a backup of fluid that inhibits fluid movement from

TABLE 42–1 Estimated forces involved in movement of fluid from interstitium into peritubular capillaries.a Forces

mm Hg

1 Favoring uptake (a) Interstitial hydraulic pressure, PInt

3

(b) Oncotic pressure in peritubular capillaries, πPC

33

2 Opposing uptake (a) Hydraulic pressure in peritubular capillaries, PPC

20

(b) Interstitial oncotic pressure, πInt

6

3 Net pressure for uptake (1 – 2)

10

a

The values for peritubular capillary hydraulic and oncotic pressures are for the early portions of the capillary. The oncotic pressure, of course, decreases as protein-free fluid enters it (i.e., as absorption occurs) but would not go below 25 mm Hg (the value of arterial plasma) even if all fluid originally filtered at the glomerulus were absorbed. Reproduced with permission from Eaton DC, Pooler JP: Vander’s Renal Physiology, 7th ed. New York, NY: Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2009.

tubular lumen to interstitium. Ultimately, this can lead to increased excretion of water and electrolytes from the body. The events just described have consequences for any filtered solute that is not specifically removed from the lumen in step 2 or 3. As water follows sodium and its anions across the epithelium, the luminal volume decreases, thereby concentrating the remaining solutes. If two thirds of the water is removed, any solute not previously removed will increase in concentration by a factor of 3. As its luminal concentration rises, this generates a concentration gradient across the tight junctions between the lumen and the interstitium. (The interstitial concentration of transported substances is essentially clamped to the plasma value because of the high peritubular blood flow and high permeability of the fenestrated capillaries.) If the tight junctions are permeable to the substance in question (“leaky”), the substance diffuses from the lumen to the interstitium, and then into the peritubular capillaries along with sodium and water. This is precisely what happens to many solutes (e.g., urea, potassium, chloride, calcium, and magnesium) in the proximal tubule. The exact fractions that are reabsorbed depend on the permeability of the tight junctions, but are generally in the range of one half to two thirds. (One substance that does not move by the paracellular route is glucose, which is impermeable in the tight junctions. We will describe the fate of filtered glucose in Chapter 43.) In summary, active sodium transport by the Na,K-ATPase is the crucial process, necessary not only for the reabsorption of sodium, but also for creating the conditions that drive the reabsorption of water and every other solute.

LIMITS ON RATE OF TRANSPORT: Tm AND GRADIENT-LIMITED SYSTEMS Although the transport capacity of the renal cortex is huge, it is not infinite. There are upper limits to the rate at which sodium or any other solute can be reabsorbed or secreted. In many situations, these limits are reached, with the consequence that, in the case of reabsorption, larger than normal amounts of the filtered load are not reabsorbed. In general, transport mechanisms can be classified by the properties of these upper limits as either (1) gradient-limited systems or (2) tubular maximum–limited (Tm) systems. These properties are significant both for normal function and, as explained in subsequent chapters, in pathological situations. The classification is based on the leakiness of the tight junctions. Consider first gradient-limited systems. When the tight junctions are very leaky to a given substance, for example, sodium, it is impossible for the removal of the substance from the lumen to reduce its luminal concentration very much below that in the cortical interstitium, because as the luminal concentration decreases, the gradient between these two media is increased, causing the substance to leak back as fast as it is removed. Thus, for sodium and all other substances whose reabsorption

CHAPTER 42 Tubular Transport Mechanisms is characterized by a gradient-limited system, the luminal concentration remains close to the interstitial concentration. However, the existence of a limit does not stop reabsorption in normal circumstances because water is being reabsorbed simultaneously, so that the luminal concentration does not decrease very much, permitting large amounts of the substance to be removed. In contrast, if unusual osmotic conditions retard water reabsorption, then removal of the substance occurs without a corresponding amount of water. Consequently, its concentration does decrease and the limiting gradient is indeed reached, resulting in unusually high amounts of the substance remaining in the large volume of unreabsorbed water. Now consider Tm-limited systems in which the tight junctions are impermeable to the solutes in question. There is no back leak and no limit on the size of the difference in concentration between lumen and interstitium. The limit on transport rate instead is placed on the capacity of the transporters to remove the substance (the inherent kinetic properties of the transport proteins and their density in the membrane). As the filtered load rises, increasing amounts of the filtered substance are reabsorbed, up to the point of saturating the transporters. Any further increase in filtered load above the saturation point does not increase the rate at which the substance is transported out of the lumen; thus, more and more is left behind. In most cases, the amount that escapes reabsorption is excreted. For many substances governed by a Tm system, their filtered loads are usually well below their Tm, and the tubule has no trouble reabsorbing virtually all that is filtered. This is the case for glucose and many other organic substances, which, under normal circumstances, are completely reabsorbed by the end of the proximal tubule. But solutes handled by gradient-limited systems are never reabsorbed completely, because a finite interstitial concentration ensures there will be a finite tubular concentration, and therefore a substantial amount passed on to the next nephron segment. This holds true for sodium. The consequences of these differences will be discussed in Chapters 43 and 45.

comprehensive analysis. The results reveal several abnormalities. His urine contains more than trace amounts of glucose and amino acids, high amounts of phosphate and potassium, and a low pH (5.5). His blood analysis indicates low bicarbonate (17 mEq/L), low potassium (3.1 mEq/L), and low phosphate (1.7 mg/dL). The diagnosis is heavy metal–induced damage to the proximal tubule cells, producing a constellation of renal defects called Fanconi syndrome. The key pathology in Fanconi syndrome is mitochondrial damage that reduces Na,K-ATPase activity in the proximal tubule. This decreases reabsorption of sodium and of many substances that are directly or indirectly tied to the reabsorption of sodium. Chief among these are bicarbonate, phosphate, potassium, and, of course, water. Glucose and amino acids in the urine provide diagnostic clues, but the losses are not serious. The patient’s low bicarbonate is consistent with renal tubular acidosis, which is a primary component of Fanconi syndrome. His respiratory system attempts to compensate for plasma acidity by increasing the rate of ventilation. (His breathing discomfort could also be related to the result of his smoking as well as heavy metal toxicity.) His low plasma potassium is the result of excessive potassium secretion in the distal nephron stimulated by the large amount of non-reabsorbed tubular sodium, and accounts for his feeling of muscle weakness. His high excretion of phosphate and acidosis lead to complicated effects in bone, including loss of bone mineral that may lead to spontaneous fractures. Treatment in this case consists of supplemental electrolytes, vitamin D to promote bone health, and any measures that will result in a reduction or elimination of the cadmium exposure.

CHAPTER SUMMARY ■ ■

CLINICAL CORRELATION A 42-year-old man has worked at a metal recycling plant for the past 5 years, where he has been exposed to toxic heavy metals, including cadmium. He has a history of smoking, but for the most part has been in good health. Over the past year, however, he has noticed gradually increasing cough and lung irritation, and some feeling of difficulty breathing. He also reports vague muscle weakness and pain in his legs. In addition, he has experienced increased thirst and urinary frequency, and has developed a craving for salty foods such as pickles and potato chips. His physical exam is unremarkable except for a somewhat high respiratory rate (tachypnea) of 21 breaths/min. A urine dipstick test reveals a mild proteinuria (increased protein in the urine), and samples of his blood and urine are sent to the clinical laboratory for a

427

■ ■

■

■

■

Reabsorption in the proximal tubule is iso-osmotic. Flux from lumen to interstitium can be transcellular, using separate transport steps in the apical and basolateral membranes; or paracellular, around the cells through tight junctions. The kidneys regulate excretion by regulating channels and transporters in epithelial cell membranes. The reabsorption of water and almost all solutes is linked, directly or indirectly, to the activity of Na,K-ATPases in the basolateral membranes. High water permeability in the proximal tubule epithelium ensures that water reabsorption is tightly coupled to solute reabsorption. Volume reabsorption is a multistep process involving transport across epithelial membranes from lumen to interstitium, and bulk flow from interstitium to peritubular capillaries driven by Starling forces. All reabsorptive processes have a limit on how fast they can occur, either because the transporters saturate (Tm systems) or because the substance leaks back into the lumen (gradientlimited systems).

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STUDY QUESTIONS 1. A healthy patient has a normal plasma osmolality (close to 300 mOsm/kg). If 100 mmol of solutes is reabsorbed iso-osmotically from the proximal tubule, approximately how much water is reabsorbed with the solute? (Remember: 1 mmol of solute ≅ 1 mOsm and 1 g H2O ≅ 1 mL.) A) 100 mL B) 300 mL C) 333 mL D) 1,000 mL 2. Quantitatively, most sodium gains entrance to proximal tubule cells by A) paracellular diffusion. B) transcellular diffusion. C) the Na,K-ATPase. D) antiport with hydrogen ions. 3. The tight junctions linking proximal tubule cells permit passive diffusion of A) glucose. B) sodium. C) all filtered solutes. D) no filtered solutes.

4. In the proximal tubule, water can move through A) apical membranes of proximal tubule cells. B) basolateral membranes of proximal tubule cells. C) tight junctions. D) all of the above. 5. A drug X is secreted into the proximal tubule by a Tm-limited system. This implies that A) X cannot easily diffuse by the paracellular route. B) all the X that enters the renal vasculature will be secreted. C) the rate of X secretion is independent of the plasma concentration. D) X is not filtered at the glomerulus.

43 C

Renal Handling of Organic Substances Douglas C. Eaton and John P. Pooler

H A

P

T

E

R

O B J E C T I V E S ■ ■ ■ ■ ■ ■ ■ ■ ■

State the physiological utility of either excreting or reabsorbing organic solutes. State the general characteristics of the proximal tubular systems for active reabsorption or secretion of organic nutrients. Describe the renal handling of glucose, and state the conditions under which glucosuria is likely to occur. Describe the renal handling of proteins and small peptides. Describe the secretion of para-aminohippurate. Outline the handling of urate. Describe the secretion of organic cations. Describe how tubular pH affects the excretion and reabsorption of weak acids and bases. Describe the renal handling of urea, including the medullary recycling of urea from the collecting duct to the loop of Henle.

OVERVIEW As pointed out in Chapter 39, a major function of the kidneys is the excretion of organic waste products, and foreign chemicals and their metabolites. Furthermore, the kidneys filter large amounts of organic substances that they do not excrete; therefore, reabsorptive processes must exist to prevent inappropriate loss of useful organic nutrients. Because the blood contains many small, filterable molecular species, the kidney has to handle all of them. An analysis of the renal handling of every one of these organic substances would be prohibitive, so we will discuss a few key solutes and establish generalities about the others. In essence, the kidneys perform a kind of triage. They (1) reabsorb organic metabolites that should not be lost, (2) eliminate waste products and unwanted foreign organic substances by not reabsorbing them or actually secreting them, and (3) partially reabsorb others. One organic substance, urea, is unique in this regard. It is a waste product that must be excreted to prevent accumulation. However, it also plays a key role in renal regulation of water balance. The renal handling of urea is briefly discussed later in

Ch43_429-436.indd 429

this chapter and again in the following chapter in the discussion of renal handling of water.

PROXIMAL REABSORPTION OF ORGANIC NUTRIENTS: GLUCOSE AND AMINO ACIDS Most of the major cellular nutrients in the plasma that the kidneys must not lose in the urine are freely filterable and must be almost completely reabsorbed. These include glucose, amino acids, acetate, Krebs cycle intermediates, some water-soluble vitamins, lactate, acetoacetate, β-hydroxybutyrate, and many others. The proximal tubule is the major site for reabsorption of the large quantities of these organic nutrients filtered each day by the renal corpuscles. We can make the following generalities: 1. They are actively transported (i.e., are reabsorbed up [against] their respective electrochemical gradients) by transport proteins that are specific for one or only a few 429

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solute species. There is not a separate transporter for every solute in the body. Two or more closely related substances may use the same transporter. For example, amino acid transporters are distinct from those for glucose, but there are not 20 separate amino acid transporters. Rather there is one for arginine, lysine, and ornithine; another for glutamate and aspartate; and so on. In most cases, reabsorption is very close to complete. 2. The “uphill” step is across the apical membrane, usually via a symporter with sodium. 3. Most are characterized as Tm systems (have an upper limit to the rate at which they can transport). These limits are usually well above the amounts normally filtered. Accordingly, the kidneys have no trouble returning all that is filtered back to the plasma. However, because none is excreted, the kidneys do not help regulate their levels in the body; the kidneys are merely reclaiming them from the tubular fluid. It is also true, however, that under abnormal conditions, the plasma concentration of these substances may increase so much that the filtered load exceeds the reabsorptive Tm. In this case, large quantities are excreted in the urine. Examples are glucose, acetoacetate, and β-hydroxybutyrate in patients with severe uncontrolled diabetes mellitus. 4. The transporters can be inhibited by a variety of drugs, and several monogenetic diseases are associated with loss of function in one or more of these proximal reabsorptive systems. In some cases, the deficit may be highly specific (e.g., involving only one amino acid), whereas in others, multiple systems may be involved (e.g., glucose and many amino acids). These defects also occur when the deficit is due to an ingested toxin (e.g., heavy metal toxicity) rather than a genetic abnormality.

GLUCOSE Under most circumstances, it would be deleterious to lose glucose in the urine, particularly in conditions of prolonged fasting. Thus, the kidneys normally reabsorb all of the glucose that is filtered. A typical plasma glucose level is about 90 mg/dL (5 mmol/L). It increases transiently to well over 100 mg/dL during meals and decreases somewhat during fasting. Usually all the filtered glucose is reabsorbed in the proximal tubule. This involves taking up glucose from the tubular lumen along with sodium via a sodium-dependent glucose symporter (SGLUT) across the apical membrane of proximal convoluted tubule epithelial cells, followed by its exit across the basolateral membrane into the interstitium via a glucose transporter (GLUT), a uniporter. Unlike the case for sodium and many other solutes, the tight junctions are not significantly permeable to glucose. Therefore, as glucose is removed from the lumen and the luminal concentration decreases, there is no backleak, resulting in virtually complete reabsorption. Because glucose reabsorption is a Tm system, abnormally high filtered loads overwhelm the reabsorptive capacity (exceed

900

Glucose filtered load, reabsorption or excretion (mg/min)

430

800

Filtered load

700 600 500

Excretion

Transport maximum

400 300

Normal

Reabsorption

200 100 0

Threshold 100

200

300

400

500

600

700

800

Plasma glucose concentration (mg/100 ml)

FIGURE 43–1 Glucose handling by the kidney. The filtered load, amount reabsorbed, and amount excreted are plotted as a function of plasma glucose concentration. At a given GFR, the filtered load is always exactly proportional to the plasma concentration. At normal levels of plasma glucose the filtered load is well below the Tm, and therefore all the filtered glucose is reabsorbed and none is excreted. However, as plasma glucose rises into the hyperglycemic range, the Tm is reached, and any glucose filtered in excess of the Tm is excreted. (Reproduced with permission from Widmaier EP, Raff H, Strang KT: Vander’s Human Physiology, 11th ed. McGraw-Hill, 2008.)

the Tm; Figure 43–1). This occurs when plasma glucose increases above roughly 300 mg/dL, a situation often found in untreated diabetes mellitus. In very severe cases, blood glucose can exceed 1,000 mg/dL, or over 55 mmol/L, leading to significant loss of glucose. Assume that the glucose Tm is 375 mg/min (a typical value). With a glomerular filtration rate (GFR) of 125 mL/min (1.25 dL/min) and a normal plasma glucose of 90 mg/dL, the filtered load is 1.25 dL/min × 90 mg/dL = 112.5 mg/min, much less than the Tm of 375 mg/min. Thus, the kidneys easily reabsorb the entire filtered load. When plasma glucose reaches 300 mg/dL, the filtered load is now 1.25 dL/ min × 300 mg/dL = 375 mg/min. At this point, the proximal convoluted tubule has reached the upper limit of what it can reabsorb, and a little glucose begins to spill into the urine. Further increases in plasma glucose above 300 mg/dL lead to progressively greater renal losses. This leads to an unwanted diuresis (high urine volume) that we will discuss later, but one can appreciate that any glucose not reabsorbed is an osmole in the tubule that has consequences for water reabsorption.

PROTEINS AND PEPTIDES Although we sometimes say the glomerular filtrate is protein free, it is not truly free of all protein; it just has a total protein content much lower than plasma. First, peptides and smaller proteins (e.g., angiotensin, insulin), although present at low

CHAPTER 43 Renal Handling of Organic Substances concentrations in the blood, are filtered in considerable quantities. Second, while the movement of large plasma proteins across the glomerular filtration barrier is extremely limited, a small amount does make it through into Bowman’s space. For albumin, the plasma protein of highest concentration in the blood, the concentration in the filtrate is normally about 1 mg/dL, or roughly 0.02% of the plasma albumin concentration (5 g/dL). Because of the huge volume of fluid filtered per day, the total filtered amount of protein is not negligible. Normally all of these proteins and peptides are reabsorbed completely, although not in the conventional way. They are enzymatically degraded into their constituent amino acids, which are then returned to the blood. For the larger proteins, the initial step in recovery is endocytosis at the apical membrane. This energy-requiring process is triggered by the binding of filtered protein molecules to specific receptors on the apical membrane. The rate of endocytosis is increased in proportion to the concentration of protein in the glomerular filtrate until a maximal rate of vesicle formation, and thus the Tm for protein uptake, is reached. The pinched-off intracellular vesicles resulting from endocytosis merge with lysosomes, whose enzymes degrade the protein to low-molecular-weight fragments, mainly individual amino acids. These end products then exit the cells across the basolateral membrane into the interstitial fluid, from which they gain entry to the peritubular capillaries. To understand the potential problem associated with a failure to take up filtered protein, remember that for a healthy young adult: Total filtered protein = GFR × concentration of protein in filtrate (1) = 180 L per day × 10 mg/L = 1.8g per day If this protein was not removed from the lumen, the entire 1.8 g would be lost in the urine. In fact, most of the filtered protein is endocytosed and degraded so that the excretion of protein in the urine is normally only 100 mg per day. The endocytic mechanism by which protein is taken up is easily saturated, so a large increase in filtered protein resulting from increased glomerular permeability causes the excretion of large quantities of protein. Discussions of the renal handling of protein logically tend to focus on albumin because it is by far the most abundant plasma protein. There are, of course, many other plasma proteins. Although present in lower levels than albumin, they are smaller and thus more easily filtered. For example, growth hormone (molecular weight, 22,000 d) is approximately 60% filterable, and insulin is 100% filterable. The total mass of these filtered hormones is insignificant; however, because even tiny levels in the plasma have important signaling functions in the body, renal filtration becomes an important influence on concentrations in the blood. Relatively large fractions of these smaller plasma proteins are filtered and then degraded in tubular cells. The kidneys are major sites of catabolism of many plasma proteins, including polypeptide hormones. Decreased rates of

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degradation occurring in renal disease may result in elevated plasma hormone concentrations. Very small peptides, such as angiotensin II, are catabolized into amino acids or dipeptides and tripeptides within the proximal tubular lumen by peptidases located on the apical surface of the plasma membrane. These products are then reabsorbed by the same transporters that normally reabsorb filtered amino acids. Finally, in certain types of renal damage, proteins released from damaged tubular cells rather than filtered at the renal corpuscles may appear in the urine and provide important diagnostic information.

PROXIMAL SECRETION OF ORGANIC ANIONS So far we have described reabsorption of useful organic substances the body does not normally excrete. There are of course many organic anions that it does excrete, both endogenously produced and foreign (see Table 43–1 for a partial listing). Many of these organic anions are filterable at the renal corpuscles, with proximal secretion adding to the amount filtered. Others, however, are extensively bound to plasma proteins and undergo glomerular filtration only to a limited extent; accordingly, proximal tubular secretion constitutes the only significant mechanism for their excretion. The active secretory pathway for organic anions in the proximal tubule in some sense is the reverse of reabsorption of organic solutes: there are active transporters for the anions at the basolateral membrane of tubular epithelial cells that are the rate-limiting step in overall transport. Transport out of the cell across the apical membrane into the lumen uses a variety of uniporters or more specific sodium-dependent antiporters. Because the basolateral membrane of proximal convoluted tubule epithelial cells contains all of these different transport-

TABLE 43–1 Some organic anions actively secreted by the proximal tubule. Endogenous Substances

Drugs

Bile salts

Acetazolamide

Fatty acids

Chlorothiazide

Hippurates

Ethacrynate

Hydroxybenzoates

Furosemide

Oxalate

Penicillin

Prostaglandins

Probenecid

Urate

Saccharin Salicylates Sulfonamides

Reproduced with permission from Eaton DC, Pooler JP: Vander’s Renal Physiology, 7th ed. New York, NY: Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2009.

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ers, the proximal tubule has the capacity to secrete all the organic anions listed in Table 43–1 and many more. Like glucose, organic anions are not significantly permeable through tight junctions or lipid membranes, so that their transport is also characterized by a Tm. If the blood concentration of an organic anion is too high, it will not be efficiently removed from the blood by the kidneys. The relatively nondiscriminating nature of this collection of transporters accounts for their ability to eliminate so many drugs and other foreign environmental chemicals from the body. In this regard, the liver’s metabolic transformations are very important. In the liver, many foreign (and endogenous) substances are conjugated with either glucuronate or sulfate. The addition of these groups renders the parent molecule far more water soluble. These two types of conjugates are actively transported by the organic anion secretory pathway. The most intensively studied organic anion secreted by this pathway is para-aminohippurate (PAH), the substance used for the measurement of effective renal plasma flow (see Chapter 41). PAH secretion involves a pair of antiporters, one at each membrane. At the basolateral membrane, PAH is taken up in exchange for the anion (base) form of a dicarboxylic acid. PAH is extruded into the lumen across the apical membrane via another antiporter. As the plasma concentration of an anion secreted by this system increases, so does the rate of secretion (until the Tm for that substance is reached). This provides a mechanism for regulating the endogenous organic anions handled by the system and for speeding the excretion of foreign organic anions. PAH is typical, in yet another way, of many of the organic anions secreted proximally. It undergoes no significant transport anywhere else along the nephron. In contrast, some of the other organic anions secreted by the proximal tubule can also undergo other forms of transport in both the proximal tubule and more distal segments. The most important of these is passive tubular reabsorption or secretion, which is described later.

Although urate reabsorption is greater than secretion, the secretory process is controlled to maintain relative constancy of plasma urate. In other words, if plasma urate begins to increase because of increased urate production, the active proximal secretion of urate is stimulated, thereby increasing urate excretion. Given these mechanisms of renal urate handling, the reader should be able to deduce the three ways by which altered renal function can lead to decreased urate excretion and hence increased plasma urate, as in gout: (1) decreased filtration of urate secondary to decreased GFR, (2) excessive reabsorption of urate, and (3) diminished secretion of urate.

PROXIMAL SECRETION OF ORGANIC CATIONS The proximal tubules possess several closely related transport systems for organic cations that are analogous to those for organic anions. Because of the large number of different transporters, a substantial amount of foreign and endogenous organic cations is transported (Table 43–2). The cations compete with one another for transport, and the transporters manifest Tm limitation. Organic cations enter across the basolateral membrane via one of the several uniporters, members of the OCT (organic cation transporter) family, and exit into the lumen via an antiporter, which exchanges a proton for the organic cation. The proximal secretion of organic cations, as for organic anions, is particularly critical for the excretion of those cations extensively bound to plasma proteins and not filterable at the renal corpuscle. However, again similar to organic anions, many of the organic cations secreted by the proximal tubules

TABLE 43–2 Some organic cations actively secreted

URATE Urate (the base form of uric acid) provides a fascinating example of the renal handling of organic anions that is particularly important for clinical medicine and is illustrative of renal pathology. An increase in the plasma concentration of urate can cause gout; therefore, its removal from the blood is important. However, it is as though the kidney cannot make up its mind what to do with urate. Urate is not protein bound and so is freely filterable. Almost all the filtered urate is reabsorbed early in the proximal tubule; however, further on in the proximal tubule, urate undergoes active tubular secretion. Then, in the straight portion, some of the urate is once again reabsorbed. The total rate of tubular reabsorption is normally much greater than the rate of tubular secretion, so the mass of urate excreted per unit time is only a small fraction of the mass filtered. Most of this transport involves antiporters that exchange urate for another organic anion.

by the proximal tubule. Endogenous Substances

Drugs

Acetylcholine

Atropine

Choline

Isoproterenol

Creatinine

Cimetidine

Dopamine

Meperidine

Epinephrine

Morphine

Guanidine

Procaine

Histamine

Quinine

Serotonin

Tetraethyl ammonium

Norepinephrine Thiamine Reproduced with permission from Eaton DC, Pooler JP: Vander’s Renal Physiology, 7th ed. New York, NY: Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2009.

CHAPTER 43 Renal Handling of Organic Substances are not protein bound and, therefore, also undergo glomerular filtration and tubular secretion; creatinine is a good example. Finally, and again analogous to organic anions, some organic cations not only are actively secreted by the proximal tubules, but may also undergo other forms of tubular handling, mainly passive reabsorption or secretion.

pH DEPENDENCE OF PASSIVE REABSORPTION OR SECRETION Many substances handled by the kidney are weak acids or bases. At a given pH, some are in the neutral form and some are in the ionized form. The state of ionization affects both the aqueous solubility and membrane permeability of the substance. In most cases, the neutral forms of organic acids and bases are more permeable in lipid membranes than the ionized forms. The neutral forms, being permeable, can equilibrate with the interstitial levels, while the ionized forms, once in the lumen, are effectively trapped there. Many weak acids are predominantly neutral at low pH (acid form) and are dissociated into an anion and a proton at higher pH. The lower the pH, the greater the amount in the neutral acid form. Imagine the case in which the tubular fluid becomes acidified relative to the plasma, which it does on a typical Western diet. For a weak acid in the tubular fluid, relatively more will be converted to the neutral form and, therefore, become more permeable. This favors diffusion out of the lumen (reabsorption). Therefore, highly acidic urine (low pH) tends to

TUBULAR LUMEN

RENAL TUBULAR CELLS

433

increase passive reabsorption of weak acids (and promote less excretion). For many weak bases, the pH dependence is just the opposite. At low pH they are protonated cations (trapped in the lumen). As the urine becomes acidified, more is converted to the impermeable charged form and is trapped in the lumen. Less is reabsorbed passively, and more is excreted. Having said this, what difference does it make? Because so many medically useful drugs are weak organic acids and bases, all these factors have important clinical implications. For example, if one wishes to enhance the excretion of a drug that is a weak acid, one attempts to alkalinize the urine (because this traps the ionic form in the lumen). In contrast, acidification of the urine is desirable if one wishes to prevent excretion of the drug. Of course, exactly the opposite applies to weak organic bases. At any luminal fluid pH, increasing the urine flow increases the excretion of both weak acids and bases (Figure 43–2). Finally, excretion can be reduced by administering another drug that interferes with any active proximal secretory pathway for the drug.

UREA Urea is a very special substance for the kidney. It is an end product of protein metabolism, waste to be excreted, and also a useful tool for the regulation of water excretion. Excess dietary protein not needed for tissue synthesis is either oxidized or converted to fat and stored for later oxidation. During fasting the body breaks down the fat and protein

PERITUBULAR PLASMA

(Filtered) HA A H

H

HA

HA

A

(Filtered) BH B H

BH  B

H

(Impermeable)

B

BH

FIGURE 43–2 pH dependence of passive reabsorption or secretion. Acidification of the urine favors reabsorption, andtherefore retention, of weak acids because the neutral, protonated forms can passively diffuse out of the tubule (top dashed line). At the same time, acidification favors secretion (and therefore loss) of weak bases because the protonated forms are charged and trapped in the lumen, and the neutral, nonprotonated forms can passively diffuse into the tubule (bottom dashed line). The processes that acidify the urine are described in Chapter 47. (Reproduced with permission from Eaton DC, Pooler JP: Vander’s Renal Physiology, 7th ed. New York, NY: Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2009.)

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for fuel, in essence consuming itself. When oxidized for fuel, protein is first split into its constituent amino acids. These are then separated into a nitrogen moiety (ammonium) and a carbohydrate moiety. The carbohydrate goes on to further metabolic processing, but the ammonium cannot be further oxidized and is a waste product. The problem is that ammonium is rather toxic to most tissues (except the medullary interstitium), and the liver immediately converts most ammonium to urea and a smaller, but crucial amount to glutamine. (We will take up the fate of this glutamine in Chapter 47.) Whether a person is well fed or fasting, urea production proceeds continuously. In fact, it constitutes about half of the normal solute content of urine; thus, it is a crucial player in osmotic considerations. The normal level of urea in the blood is quite variable (3–9 mmol/L), reflecting variations in both protein intake and renal handling of urea. (For ease in converting to osmolality, we express urea concentration in units of mmol/L rather than the clinical unit of blood urea nitrogen [BUN].) Over days to weeks, renal urea excretion must match hepatic production; otherwise, plasma levels would increase into the pathological range, producing a condition called uremia. On a shorter-term basis (hours to days), urea excretion rate may not exactly match production rate because urea excretion is also regulated for purposes other than keeping a stable plasma level. As discussed in the next chapter, urea is a key solute involved in regulating excretion of water. The gist of the renal handling of urea is the following: it is freely filtered. About half is reabsorbed in the proximal tubule. Then an amount equal to that reabsorbed is secreted back into the loop of Henle. Finally, about half is reabsorbed a second time in the medullary collecting duct. The net result is that about half the filtered load is excreted (Figure 43–3). As a molecule, urea is small (molecular weight, 60 d), water soluble, and freely filtered. Because of its highly polar nature, it does not permeate lipid bilayers, but a set of uniporters (UT family) transports urea in various places in the kidney and in other sites within the body (particularly red blood cells). Because urea is freely filtered, the filtrate contains urea at a concentration identical to that in plasma. Let us assume a normal plasma level (5 mmol/L). Roughly half the filtered load is reabsorbed in the proximal tubule. This occurs primarily by the paracellular route. As water is reabsorbed, the urea concentration increases, driving diffusion through the leaky tight junctions. By the time the tubular fluid enters the loop of Henle, about half the filtered urea has been reabsorbed, and the urea concentration has increased somewhat above its level in the filtrate because proportionally more water than urea was reabsorbed. At this point, the process becomes fairly complicated. First, conditions in the medulla depend highly on the individual’s state of hydration. Second, there is a difference between superficial nephrons, with short loops of Henle that only penetrate the outer medulla, and juxtamedullary nephrons, with long loops of Henle that reach

110% 5.5

100% 1

50% 1.2

50% 25

FIGURE 43–3 Urea handling by the kidney. The arrows indicate that urea is reabsorbed in the proximal tubule, secreted in the thin portions of the loop of Henle, and reabsorbed again in the medullary collecting ducts. The top halves of boxes indicate the percentage of the filtered load remaining in the tubule at a given location, and the bottom halves indicate tubular concentration relative to plasma. Note that while the amount remaining in the collecting duct (and thus excreted) is half the amount filtered, the concentration is much higher than that in plasma because most of the water has been reabsorbed. These numbers are highly variable, depending on several factors, particularly the hydration status. (Reproduced with permission from Eaton DC, Pooler JP: Vander’s Renal Physiology, 7th ed. New York, NY: Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2009.)

all the way down to the papilla. For simplicity we consider all nephrons together. The interstitium of the medulla has a considerably higher urea concentration than does plasma. The concentration increases from the outer to the inner medulla (part of the socalled medullary osmotic gradient that we describe in the next chapter). Since the medullary interstitial urea concentration is greater than that in the tubular fluid entering the loop of Henle, there is a concentration gradient favoring secretion into the lumen. The tight junctions in the loop of Henle are no longer permeable (as they were in the cortex), but the epithelial

CHAPTER 43 Renal Handling of Organic Substances membranes of the thin regions of the Henle loops express urea uniporters, members of the UT family. This permits secretion of urea into the tubule. In fact, the urea secreted from the medullary interstitium into the thin regions of the loop of Henle replaces the urea previously reabsorbed in the proximal tubule. Thus, when tubular fluid enters the thick ascending limb, the amount of urea in the lumen is at least as large as the filtered load (the loop of Henle has essentially reversed what was accomplished in the proximal tubule). However, because about 80% of the filtered water has now been reabsorbed, the luminal urea concentration is now several times greater than that in the plasma. Beginning with the thick ascending limb and continuing all the way to the medullary collecting ducts (through the distal tubule and cortical collecting ducts), the apical membrane urea permeability (and the tight junction permeability) is essentially zero. Therefore, an amount of urea roughly equal to the filtered load remains within the tubular lumen and flows from the cortical into the medullary collecting ducts. During the transit through the cortical collecting ducts, variable amounts of water are reabsorbed, further concentrating the urea. Just how much depends on factors discussed in the next chapter, but the luminal urea concentration can easily reach 50 times that of plasma. We indicated earlier that the urea concentration in the medullary interstitium is greater than that in plasma, but the luminal concentration in the medullary collecting ducts is even higher, so in the inner medulla the gradient now favors reabsorption, and urea is reabsorbed a second time. It is this reabsorbed urea that leads to the high medullary interstitial concentration that drives urea secretion into the thin regions of the loop of Henle. In fact, some of the urea recycles, that is, it is reabsorbed from medullary collecting ducts and secreted into thin limbs of the loop of Henle, from where it travels within the tubule to the collecting ducts again to repeat the process. The overall result of these events is that half the original amount of filtered urea passes into the final urine, an amount that, over the long term, must match hepatic production of urea if the body is to remain in balance for urea. The concentration of urea in the final urine can be more than 50× that in plasma, depending on how much water is reabsorbed. These processes are summarized in Figure 43–3.

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through a strainer. Sure enough, she indeed passed a stone and brought it to her primary care physician for laboratory analysis. She had never had a stone before. She is moderately obese and mildly hypertensive. Previous laboratory analysis showed that she has increased plasma triglycerides. She may be becoming diabetic, and to avoid carbohydrate she eats a large amount of seafood and chicken, but not many vegetables. The stone proved to be a uric acid stone, which accounts for only about 7% of all kidney stones. What might predispose her to develop uric acid stones? Uric acid has a pK of 5.75. In plasma and in all but very acidic urine, the vast majority of uric acid exists as the urate anion, which is the form recognized by renal transporters. The neutral acid has a lower solubility than the anionic urate. Therefore, increased urinary content of urate, and particularly low urinary pH, which converts much of the urate to uric acid, leads to much more urinary uric acid and increased likelihood of forming stones. Her diet of fish and chicken has a high content of purines, the precursors of uric acid. Therefore, because of the high metabolic production and low urinary pH, her urine contains high amounts of the rather insoluble uric acid. To complicate the matter, her profile fits that of a person with metabolic syndrome, a cluster of conditions that includes truncal obesity, hypertension, hyperlipidemia, and insulin resistance that will be discussed in Chapter 69. For reasons that are still being unraveled, patients with metabolic syndrome often have decreased urinary ammonium. Because ammonium is a major buffer on which hydrogen ions are excreted (see Chapter 47), low ammonium production in the face of normal acid loads leads to decreased urinary pH. The urinary pH was indeed very low. The stone formation is based primarily on her low urinary pH, which, at all pH values less than 5.75, converts most of the urate to the less soluble uric acid. The patient was counseled to include more vegetables in her diet and consume more water. These measures should increase her urinary pH and lower the urate concentration, and therefore decrease the concentration of uric acid.

CHAPTER SUMMARY

CLINICAL CORRELATION A 41-year-old mother of five children presented at a hospital ER with severe right flank pain. The pain was present all the time, and was accentuated in waves. A urine specimen was pink, with a pH of 5.1. The ER personnel suspected that she had a kidney stone located in the right ureter. Accordingly they gave her large amounts of fluid and nonsteroidal anti-inflammatories (NSAIDS) to help ease the pain. After several hours the pain eased, and she was sent home with instructions to pass all her urine

■

■ ■

■

Important organic metabolites are almost completely reabsorbed (saved), whereas waste products are for the most part excreted. Most organic solutes are transported transcellularly by a large number of different saturable multiporters (Tm systems). Normal filtered loads of glucose are completely reabsorbed, but in conditions of pathological hyperglycemia the transport saturates, leading to the appearance of glucose in the urine. Urea is reabsorbed proximally and recycled between the collecting ducts and loop of Henle in the medulla, resulting in a net excretion of about half the filtered load.

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SECTION VII Renal Physiology

STUDY QUESTIONS 1. When plasma glucose reaches such high levels that substantial amounts of glucose appear in the urine (glucosuria) A) glucose is leaking back into the tubule through tight junctions. B) there is not enough luminal sodium to move in symport with glucose. C) all the glucose transporters are working at their maximum rate. D) the glucose transporters are being inhibited by the high levels of glucose. 2. Useful small organic metabolites that should not be excreted are A) generally not filtered. B) reabsorbed paracellularly. C) taken up by endocytosis and degraded. D) reabsorbed transcellularly. 3. Organic anion secretion A) involves a step of active influx across the basolateral membrane. B) is passive and paracellular. C) is via simple diffusion through the tubular membranes. D) utilizes the same membrane transporters as organic cation secretion.

4. A high urinary pH favors A) low excretion of drugs that are weak acids. B) active reabsorption of drugs that are weak bases. C) low excretion of drugs that are weak bases. D) high passive permeability of drugs that are weak acids. 5. The tubular concentration of urea A) exceeds the plasma concentration at the hairpin turn of the loop of Henle. B) decreases to below the plasma concentration by the end of the loop of Henle. C) decreases to below the plasma concentration by the end of the proximal tubule. D) reaches its highest value in the cortical collecting duct. 6. Urea is secreted into the tubules A) in proximal tubules. B) in Henle’s loop. C) in medullary collecting ducts. D) at any of the above sites depending on hydration status.

44 C

Basic Renal Processes for Sodium, Chloride, and Water Douglas C. Eaton and John P. Pooler

H A

P

T

E

R

O B J E C T I V E S ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■

List approximate percentages of sodium reabsorbed in major tubular segments. List approximate percentages of water reabsorbed in major tubular segments. Describe proximal tubule sodium reabsorption, including the functions of the apical membrane sodium entry mechanisms and the basolateral Na,K-ATPase. Explain why chloride reabsorption is coupled with sodium reabsorption, and list the major pathways of proximal tubule chloride reabsorption. State the maximum and minimum values of urine osmolality. Define osmotic diuresis and water diuresis. Explain why there is always an obligatory water loss. Describe the handling of sodium by the descending and ascending limbs, distal tubule, and collecting duct system. Describe the role of sodium–potassium–2 chloride symporters in the thick ascending limb. Describe the handling of water by descending and ascending limbs, distal tubule, and collecting duct system. Describe the process of “separating salt from water,” and discuss why this is required to excrete either concentrated or dilute urine. Describe how antidiuretic hormone affects water reabsorption. Describe the characteristics of the medullary osmotic gradient. Explain the role of the thick ascending limb, urea recycling, and medullary blood flow in generating the medullary osmotic gradient. State why the medullary osmotic gradient is partially “washed out” during a water diuresis.

OVERVIEW BODY FLUID COMPARTMENTS Body water (about 60% of body weight) is distributed into various aqueous spaces in proportion to their osmotic content. The collective volume of all the cells in the body is called the intracellular fluid (ICF). It contains roughly two thirds of the body osmotic content, and therefore two thirds of the water.

Ch44_437-448.indd 437

The remaining one third of the osmotic content and water is called the extracellular fluid (ECF). It is mostly accounted for by interstitial fluid and blood plasma. Because of the ease with which water crosses cell membranes (see Chapter 3), the ECF and ICF are in osmotic equilibrium. Changes in body water affect the volume of one or both compartments, depending on how much solute, and what kind, accompanies the water. In contrast, additions or losses of sodium from the body are almost exclusively to or from the ECF only because the actions

437

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SECTION VII Renal Physiology

Interstitial Normal

Plasma

438

Interstitial

Add water

ICF Plasma

ECF

Add isotonic saline

ECF

Interstitial Add salt

of cellular Na,K-ATPases keep intracellular sodium nearly constant. The effects of adding sodium and water are depicted in Figure 44–1. The addition of water alone expands both the ICF and ECF (indicated by the dashed lines). Adding isotonic sodium chloride expands only the ECF because the added osmoles remain in the ECF. Adding sodium chloride without water does not change the total volume, but causes a shift of water from the ICF to the ECF in order to restore equality of osmolality between the two compartments. The transport of water by the renal tubules is straightforward—“water follows the osmoles”—so much of the description of water transport really amounts to describing solute transport, recognizing that in some regions of the kidney, low water permeability limits the amount of water that follows the osmoles. Transport of chloride is more complicated, but because of the constraints of electroneutrality, it is tied to the transport of sodium. Sodium transport is clearly the crux of the matter because the transport of chloride, water, and many other substances is linked to the transport of sodium. The excretory rates of sodium, chloride, and water vary over an extremely wide range depending on diet. For example, some persons may ingest 20–25 g of sodium chloride per day, whereas a person on a low-salt diet may ingest only 0.05 g. The healthy kidney can readily alter its excretion of salt over this range. Similarly, urinary water excretion can be varied physiologically from approximately 0.4 to 25 L per day, depending on whether one is lost in the desert or maximizing one’s water intake.

SODIUM REABSORPTION Table 44–1 is a balance sheet for sodium chloride. The major route of salt excretion from the body under normal circumstances is via the kidneys. The large amount excreted should not obscure the fact that nearly all the filtered loads of sodium

ECF

ICF Plasma

FIGURE 44–1 Distribution of total body water into the intracellular (ICF) and extracellular (ECF) compartments. As explained in the text, addition of water, salt, or both alters the volumes of the compartments. Expanded volumes are indicated by the dashed lines.

Interstitial

ICF Plasma

ECF

ICF

TABLE 44–1 Normal routes of sodium intake and loss. Route

Amount (g per Day)

Intake Food

10.5

Output Sweat

0.25

Feces

0.25

Urine

10.00

Total output

10.50

Reproduced with permission from Eaton DC, Pooler JP: Vander’s Renal Physiology, 7th ed. New York, NY: Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2009.

and chloride are reabsorbed. Table 44–2 summarizes the approximate quantitative contribution of each tubular segment to sodium reabsorption. In an individual with an average salt intake, the proximal tubule reabsorbs 65% of the filtered sodium, the thin and thick ascending limbs of Henle’s loop 25%, and the distal convoluted tubule and collecting duct system most of the remaining 10%, so that the final urine contains less than 1% of the total filtered sodium. As will be discussed in Chapter 45, reabsorption at several of these tubular sites is under physiological control by neural, hormonal, and paracrine signals, so that the exact amount of sodium excreted is regulated. Because so much sodium is filtered, even a small percentage change in reabsorption results in a relatively large change in excretion. In all nephron segments, the essential event is the primary active transport of sodium from cell to interstitial fluid by the Na,K-ATPase pumps in the basolateral membrane. These pumps keep the intracellular sodium concentration lower than

CHAPTER 44 Basic Renal Processes for Sodium, Chloride, and Water

TABLE 44–2 Comparison of sodium and water reabsorption along the tubule. Tubular Segment

439

TABLE 44–3 Normal routes of water gain and loss in adults.

Filtered Load Reabsorbed (%)

Route

Sodium

Water

Intake

Proximal tubule

65

65

Beverage

1,200

Descending thin limb of Henle’s loop

—

10

Food

1,000

Metabolically produced

350

Ascending thin limb and thick ascending limb of Henle’s loop

25

—

Distal convoluted tubule

5

—

Insensible loss (skin and lungs)

900

Collecting duct system

4–5

5 (during water loading) >24 (during dehydration)

Sweat

50

In feces

100

Urine

1,500

Total

Amount (mL per Day)

2,550

Output

Reproduced with permission from Eaton DC, Pooler JP: Vander’s Renal Physiology, 7th ed. New York, NY: Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2009.

Total

2,550

Reproduced with permission from Eaton DC, Pooler JP: Vander’s Renal Physiology, 7th ed. New York, NY: Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2009.

that in the surrounding media. Because the inside of the cell is negatively charged with respect to the lumen, luminal sodium ions enter the cell passively, down their electrochemical gradient. The entry paths are far more numerous than the exit paths. We will examine these entry paths more closely as we go through the tubule segment by segment.

CHLORIDE REABSORPTION Because chloride reabsorption is dependent on sodium reabsorption, the tubular locations that reabsorb chloride and the percentages of filtered chloride reabsorbed by these segments are similar to those for sodium (see Table 44–1). When examining chloride reabsorption, it is helpful to keep in mind the absolute constraint of electroneutrality: any finite volume of fluid reabsorbed must contain equal amounts of anion and cation equivalents. Let us do a “guesstimate” calculation. One liter of normal filtrate contains 140 mEq of sodium, and thus must contain about 140 mEq of anions, mainly chloride (110 mEq) and bicarbonate (24 mEq). (We say “about” because there are other cations [e.g., potassium and calcium] and anions [e.g., sulfate and phosphate] that must factor into the calculation to achieve an exact balance, but their contributions are much smaller than sodium, chloride, and bicarbonate.) If 65% of the filtered sodium is reabsorbed in the proximal tubule, then 0.65 × 140 = 91 mEq of sodium in each liter of filtrate is reabsorbed. Therefore, 91 mEq of some combination of chloride and bicarbonate must also be reabsorbed to accompany this sodium. As will be described in Chapter 47, about 90% of the filtered bicarbonate is reabsorbed in the proximal tubule (0.9 × 24 ≈ 22). This leaves 91 – 22 = 69 mEq of chloride that must be reabsorbed in the proximal tubule. This is more than 60% of the 110 mEq of filtered chloride and almost as much as the fractional reabsorption of sodium and water. Later segments reabsorb almost all of the remaining 40%.

WATER REABSORPTION A balance sheet for total body water is given in Table 44–3. These are average values, which are subject to considerable variation. The two sources of body water are metabolically produced water, resulting largely from the oxidation of carbohydrates, and ingested water, obtained mostly from liquids, but also from so-called solid food (e.g., a rare steak is approximately 70% water). There are several sites from which water is always lost to the external environment: skin, lungs, gastrointestinal tract, and kidneys. Menstrual flow and, in lactating women, breast milk constitute two other potential sources of water loss in women. The loss of water by evaporation from the cells of the skin and the lining of respiratory passageways is a continuous process, often referred to as insensible loss because people are unaware of its occurrence. Additional water evaporates from the skin during production of sweat. Fecal water loss is normally quite small but can be severe in diarrhea. Gastrointestinal loss can also be large during severe bouts of vomiting. Under conditions of normal hydration, the kidneys are, of course, the main route of water loss. With a large water load, the renal response is to produce a large volume of very dilute urine (osmolality much lower than that in blood plasma). In contrast, during a state of dehydration, the urine volume is low and very concentrated (i.e., the urine osmolality is much greater than that in blood plasma). That the urine osmolality is so variable brings us to a crucial aspect of renal function. Terrestrial animals must be able to independently control excretion of salt and water, because their ingestion and loss is not always linked (see Tables 44–1 and 44–3). To excrete water in excess of salt and vice versa (i.e., produce a range of urine osmolalities), the kidneys must be able to separate the reabsorption of solute from the reabsorption of water,

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that is, to “separate salt from water.” How do they do this? Regardless of hydration state, the proximal tubule reabsorbs water and solute in equal proportions (isosmotic reabsorption), but the loop of Henle reabsorbs proportionally more solute than water. This is a key step in the separation process—reabsorption of solute, leaving water in the tubule. By the time tubular fluid leaves the loop of Henle and enters the distal tubule, the loss of solute has typically decreased the osmolality to about 110 mOsm/kg H2O. If an individual is overhydrated and, therefore, requires maximum water excretion, most of this dilute fluid simply passes through the collecting duct system to appear in the urine, with only limited further water reabsorption. In contrast, when an individual is dehydrated, the vast majority of this dilute water is reabsorbed in the collecting ducts, leaving a low volume of concentrated final urine. The ability of the kidneys to produce low-volume hyperosmotic urine is a major determinant of one’s ability to survive without water, which for most people is at least several days, and longer if conditions are right. The human kidney can produce a maximal urinary concentration of 1,400 mOsm/kg in extreme dehydration. This is almost five times the osmolality of plasma. The sum of the urea, sulfate, phosphate, other waste products, and a small number of nonwaste ions excreted each day normally averages approximately 600 mOsm per day. These solutes continue to be excreted even in severe dehydration; therefore, the minimal volume of water in which this mass of solute can be dissolved is roughly 600 mOsm/1,400 mOsm/L = 0.43 L per day. This volume of urine is known as the obligatory water loss. It is not a strictly fixed volume but changes with different physiological states. For example, increased tissue catabolism, as during fasting or trauma, releases excess solute and so increases obligatory water loss. The obligatory water loss contributes to dehydration when a person is deprived of water intake. The obligatory solute loss also explains why a thirsty sailor cannot drink seawater for hydration. To excrete all the salt in the seawater plus the obligatory solute would require more urinary water than was contained in the seawater consumed.

INDIVIDUAL TUBULAR SEGMENTS The important principles regarding individual tubular segments are how the reabsorption of sodium, chloride, and water is related to one another and how the amount of reabsorption varies quantitatively from one segment to another.

PROXIMAL TUBULE As shown in Figure 44–2, several apical membrane entry pathways are involved in the active transcellular reabsorption of sodium in the proximal tubule. In the early portion, a large fraction of the filtered sodium enters the cell across the apical membrane via antiport with protons. As will be described in Chapter 47, these protons, which are released when carbon dioxide combines with

LUMEN

HCO3 CO2 + H2O

INTERSTITIUM

Na+ H+

H+

ATP

K+

Hbase base–

Na+

base–

Cl– H2O Glucose, Na+ phosphate, amino acids, organics etc H2O, Cl–

HCO3 Na+ H2O Cl–

H2O, Cl–

FIGURE 44–2 Major pathways for reabsorption of sodium, chloride, and water in the proximal tubule. The entire proximal tubule is the major site for reabsorption of salt and water. Sodium entry is coupled to the secretion or uptake of a variety of substances, the major one being hydrogen ions, which are secreted in exchange for sodium via the NHE3 antiporter. These hydrogen ions, once in the lumen, combine with filtered bicarbonate and secreted organic base (see text and Chapter 47 for further explanation). Additional sodium enters in symport with glucose, amino acids, and phosphate. Sodium is transported to the interstitium mostly via the basolateral Na,K-ATPase, but also in symport with bicarbonate. (The coupling between sodium and bicarbonate is described fully in Chapter 47.) Chloride that enters in antiport with organic base leaves mostly via channels. In addition, a substantial amount of chloride is reabsorbed paracellularly. Water moves both paracellularly and intracellularly via aquaporins. (Modified with permission from Eaton DC, Pooler JP: Vander’s Renal Physiology, 7th ed. New York, NY: Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2009.)

water, cause the secondary active reabsorption of filtered bicarbonate. Therefore, in the early proximal tubule, bicarbonate is a major anion reabsorbed with sodium and the luminal bicarbonate concentration decreases markedly (Figure 44–3). Organic nutrients and phosphate are also absorbed with sodium, and their luminal concentrations also decrease rapidly. A major percentage of chloride reabsorption in the proximal tubule occurs via paracellular diffusion. The concentration of chloride in Bowman’s capsule is, of course, essentially the same as it is in plasma (about 110 mEq/L). Along the early proximal tubule, the reabsorption of water causes the chloride concentration in the tubular lumen to increase somewhat above that in the peritubular capillaries (see Figure 44–3). Then, as the fluid flows through the middle and late proximal tubules, this concentration gradient, maintained by continued water reabsorption, provides the driving force for paracellular chloride reabsorption by diffusion. There is also an important component of active chloride transport from lumen to cell in the later proximal tubule. As illustrated in Figure 44–2, it uses parallel Na–H and Cl–base antiporters. Chloride is actively transported into the cell in exchange for the downhill antiport (secretion) of small organic

CHAPTER 44 Basic Renal Processes for Sodium, Chloride, and Water

1.2

Cl−

1.0

Na+ osmolarity

TF/P

0.8 Pi

0.6

0.4

0.2

Amino acids, glucose, lactate

− HCO3

2 4 6 Distance from Bowman's space (mm)

base anions. These include formate and oxalate, which are continuously generated in the cell by dissociation of their respective uncharged acids into a proton and the base. Simultaneously, the protons released within the cell by the dissociation of those acids are actively transported into the lumen by the Na–H antiporters. In the lumen, the protons and organic bases recombine to form the neutral acids, which then diffuse across the apical membrane back into the cell, where the entire process is repeated. Notice that both the protons and the organic bases endlessly recycle, moving into the cells while paired as a neutral molecule and then move out via separate transporters after the proton dissociates. The overall achievement of the parallel Na–H and Cl–base antiporters is the same as though the Cl and Na were simply cotransported into the cell together. Importantly, the recycling of protons and bases means that most of the protons are not acidifying the lumen but are simply combining with base and moving back into the cells. It should also be recognized that everything ultimately depends on the basolateral membrane Na,KATPases to establish the gradient for sodium that powers the apical Na–H antiporter. Regarding water reabsorption, the proximal tubule, as mentioned, has a very high permeability to water, allowing very small differences in osmolality (less than 1 mOsm/L) to drive the reabsorption of very large quantities of water, normally about 65% of the filtered water. This osmolality difference is created by the reabsorption of sodium and the various solutes linked directly or indirectly with sodium (Table 44–4). If the tight coupling between proximal sodium and water reabsorption is disrupted, we have a phenomenon known as osmotic diuresis. The term diuresis simply means increased urine flow, and osmotic diuresis denotes the situation in which the increased urine flow is due to an abnormally high amount of any substance in the glomerular filtrate that is reabsorbed

441

FIGURE 44–3 Changes in tubular fluid composition along the proximal convoluted tubule, expressed as the ratio of concentration in the tubule relative to the plasma value. Values above 1.0 indicate that relatively less of the substance than water has been reabsorbed, and therefore its concentration increases. Values below 1.0 indicate that relatively more of the substance than water has been reabsorbed. Inorganic phosphate, bicarbonate, glucose, and lactate are preferentially reabsorbed with sodium early in the proximal tubule, and their concentrations rapidly fall. In contrast, the concentration of chloride increases somewhat because chloride reabsorption lags behind sodium and, hence, water reabsorption in the early proximal tubule. The concentration of sodium and the total concentration of all solutes (osmolarity) remains nearly the same as in plasma. (Modified with permission from Rector FC. Sodium, bicarbonate, and chloride absorption by the proximal tubule. Am J Physiol. 1983;244(5):F461–F471.)

incompletely or not at all by the proximal tubule (e.g., infused mannitol, a monosaccharide that is not transported). As water is reabsorbed in the proximal tubule, the concentration of any unusual unreabsorbed solute rises, and its osmotic presence retards the further reabsorption of water (here and downstream as well). The failure of water to follow the sodium being removed from the lumen means that the sodium concentration in the proximal tubular lumen decreases slightly below that in the interstitial fluid. This concentration difference, even though small, drives a passive diffusion of sodium across the epithelium (mostly the tight junctions) back into the lumen, that is, sodium transport reaches the gradient limit we described in Chapter 42. The result is that more than the usual amount of

TABLE 44–4 Summary of mechanisms by which reabsorption of sodium drives reabsorption of other substances in the proximal tubule. Reabsorption of sodium 1. Creates transtubular osmolality difference, which favors reabsorption of water by osmosis; in turn, water reabsorption concentrates many luminal solutes (e.g., chloride and urea), thereby favoring their reabsorption by diffusion 2. Achieves reabsorption of many organic nutrients, phosphate, and sulfate by cotransport across the luminal membrane 3. Achieves secretion of hydrogen ion by countertransport across the luminal membrane; these hydrogen ions are required for reabsorption of bicarbonate (as described in Chapter 47) 4. Achieves reabsorption of chloride by indirect cotransport across the luminal membrane (the parallel Na/H and Cl/base countertransporters) Reproduced with permission from Eaton DC, Pooler JP: Vander’s Renal Physiology, 7th ed. New York, NY: Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2009.

442

SECTION VII Renal Physiology

FIGURE 44–4

Major transport pathways for sodium and chloride in thick ascending limb. The major transporter in the thick ascending limb is the Na–K–2Cl symporter (NKCC), which is the target for inhibition by loop diuretics such as furosemide and bumetanide. In addition to NKCC, the cells contain potassium channels that recycle potassium from the cell interior to the lumen and to the interstitium (see Chapter 46). Besides transcellular routes, some sodium also moves paracellularly in response to the lumen positive potential. The apical membranes and tight junctions have a very low water permeability, and water is not reabsorbed in this segment. Because the cells reabsorb salt, but not water, the thick ascending limb is the point in the nephron at which salt is separated from water. This ultimately allows water excretion and salt excretion to be controlled independently. (Modified with permission from Eaton DC, Pooler JP: Vander’s

LUMEN

INTERSTITIUM

+ Na+ Na

Na+

2CI– K+

ATP

Na+ K+

K+ K+

Cl– K+ H2O

Cl–

Renal Physiology, 7th ed. New York, NY: Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2009.)

sodium is not reabsorbed as well as the unusual solute, and both are passed on to the loop of Henle. Thus, osmotic diuretics inhibit the reabsorption of both water and sodium (as well as other ions). Osmotic diuresis can occur in persons with uncontrolled diabetes mellitus; the filtered load of glucose exceeds the tubular maximum (Tm) for this substance, and the unreabsorbed glucose then acts as an osmotic diuretic.

HENLE’S LOOP Henle’s loop reabsorbs both salt and water, but, taken as a whole, more salt (about 25% of the filtered loads) than water (10% of the filtered water). See Table 44–2. This is a key difference from the proximal tubule, which reabsorbs water and sodium in essentially equal proportions. Also as shown in Table 44–2, the reabsorption of salt and reabsorption of water occur in different parts of the loop. The descending limb reabsorbs water but not sodium or chloride. In contrast, the ascending limbs (both thin and thick) reabsorb sodium and chloride but little water. As a whole, the loop reabsorbs some water and more salt, leaving a dilute fluid in the lumen. The differences between the two limbs reveal that the cells lining the descending and ascending regions have different permeability properties. The basolateral membranes of all renal cells are quite permeable to water due to the presence of aquaporins. As a result, the cytosolic osmolality is always close to that of the surrounding interstitium. But the apical membranes do not always contain aquaporins. The descending limbs contain aquaporins, so water is reabsorbed there, driven by the increasing osmolality of the medullary interstitium. The ascending limbs do not express aquaporins in the apical membranes, and the tight junctions are not permeable to water. Therefore, even though an osmotic gradient exists between the lumen (dilute) and interstitium (concentrated), water does not move down the gradient, and water flowing into the ascending limb remains there and is passed on to the distal tubule.

What are the mechanisms of sodium and chloride reabsorption by the ascending limbs? These are mainly passive in the thin ascending limb and active in the thick ascending limb. Water reabsorption in the descending limb concentrates luminal sodium somewhat. Then when tubular fluid, now containing an increased sodium concentration, reaches the epithelium of the thin ascending limb, this gradient drives reabsorption, probably by the paracellular route. As tubular fluid then enters the thick ascending limb, the transport properties of the epithelium change again, and active processes become dominant. As shown in Figure 44–4, the major apical entry step for the sodium and chloride in this segment is via the Na–K–2Cl symporter (NKCC2 isoform). (The Na–K–2Cl symporter requires that equal amounts of potassium and sodium be transported, a topic we will address in Chapter 46.) The Na–K–2Cl symporter is the target for a major class of diuretics collectively known as the loop diuretics, which include the drugs furosemide (Lasix) and bumetanide. The apical membrane of this segment also has a Na–H antiporter isoform, which, like the isoform in the proximal tubule, provides another mechanism for sodium movement into the cell. In addition to the active transcellular reabsorption of sodium, a large percentage (approaching 50%) of total sodium reabsorption in this segment occurs by paracellular diffusion. There is a high paracellular conductance for sodium in the thick ascending limb, and the luminal potential in this segment is positive, which is a significant driving force for cations. (We will see in later chapters that this paracellular pathway also allows substantial reabsorption of potassium and calcium.) However, none of this would work without the continuous operation of the Na,K-ATPase in the basolateral membrane. To summarize the most important features of the loop of Henle, the descending limb reabsorbs water but not sodium chloride, whereas the ascending limb reabsorbs sodium chloride but not water. The crucial events occur in the thick ascending limb. By reabsorbing salt but not water, this assures that the net for the loop as a whole is reabsorption of more salt than

CHAPTER 44 Basic Renal Processes for Sodium, Chloride, and Water

LUMEN

INTERSTITIUM

ATP

Na+ K+

LUMEN

INTERSTITIUM

ATP Na+

K+ Cl–

Na+ K+

Na+ Na+ Cl–

443

K+ H2O

H2O

ADH stimulates H2O

Cl–

FIGURE 44–5 Major transport pathways for sodium and chloride in the distal convoluted tubule. The apical membrane contains the Na–Cl symporter (NCC), which is the target for inhibition by thiazide diuretics. There is also some sodium reabsorption via apical sodium channels. The apical membranes and tight junctions have a very low water permeability. (Modified with permission from

Cl–

Eaton DC, Pooler JP: Vander’s Renal Physiology, 7th ed. New York, NY: Lange Medical

FIGURE 44–6 Major transport pathways for sodium, chloride, and water in principal cells of the cortical collecting duct. Sodium reabsorption is via apical sodium channels. Activity of these channels is controlled by the hormone aldosterone (see Chapter 45). Chloride reabsorption is passive via the paracellular pathway. Water reabsorption is via aquaporins, the activity of which is controlled by the antidiuretic hormone (ADH). (Modified with

Books/McGraw-Hill, Medical Pub. Division, 2009.)

permission from Eaton DC, Pooler JP: Vander’s Renal Physiology, 7th ed. New York, NY: Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2009.)

water. The ascending limb is called a diluting segment (it dilutes the tubular fluid), and fluid leaving the loop to enter the distal convoluted tubule is hypo-osmotic (more dilute) compared with plasma.

DISTAL CONVOLUTED TUBULE The distal tubule continues to reabsorb sodium and chloride, the major luminal entry step being via the Na–Cl symporter (Figure 44–5). This transporter differs significantly from the Na–K–2Cl symporter in the thick ascending limb and is sensitive to different drugs. In particular, the Na–Cl symporter is blocked by the thiazide diuretics. Sodium channels also permit sodium entry in the distal convoluted tubule. Like the ascending limb of the loop of Henle, the distal tubule is not permeable to water, so that it further dilutes the already somewhat dilute fluid entering it from the thick ascending limb.

COLLECTING DUCT SYSTEM In the collecting ducts, there is a division of labor among several different cell types. Reabsorption of sodium and water is associated with principal cells (so called because they make up approximately 70% of the cells; Figure 44–6). Reabsorption of chloride occurs partially via paracellular pathways, but active reabsorption is also associated with another class of collecting duct cells, the intercalated cells (see Figure 47–3). The principal cells reabsorb sodium, the luminal entry step being via epithelial sodium channels. Regulation of this entry

step is enormously important in controlling sodium excretion, and we will expand on this topic in Chapter 45. Some sodium chloride reabsorption continues in the medullary collecting ducts, probably via some form of epithelial sodium channels. Although with modern diets containing excess sodium there is usually a substantial amount of sodium in the final urine, it is possible to reabsorb virtually all of the remaining sodium if dietary access to sodium is limited. Principal cells in the collecting ducts are also the crucial players in reabsorbing water. As indicated earlier, there is always a substantial amount of dilute fluid entering the collecting duct system, which reabsorbs variable amounts of the water. The water permeability of the principal cells in the collecting duct system—both the cortical and medullary portions—is subject to physiological control by circulating antidiuretic hormone (ADH; see Figure 44–6). The inner medullary collecting duct has at least a finite water permeability even in the absence of ADH, but the outer medullary and cortical regions have a vanishingly low water permeability without ADH. Depending on levels of ADH, therefore, water permeability for most of the collecting duct system can vary from very low to very high. When water permeability is very low (absence of ADH), the hypo-osmotic fluid entering the collecting duct system from the distal convoluted tubule remains hypoosmotic as it flows along the ducts. When this fluid reaches the medullary portion of the collecting ducts, there is now a huge osmotic gradient favoring reabsorption, which occurs to some extent. That is, although there is little cortical water reabsorption without ADH, there is still a finite medullary absorption because of the enormous osmotic gradient. However, because

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so much water is not reabsorbed in the cortex, most of the water entering the medullary collecting duct flows on to the ureter. The result is the excretion of a large volume of very hypo-osmotic (dilute) urine, or water diuresis. What happens when the collecting duct system’s water permeability is very high (plentiful ADH)? As the hypo-osmotic fluid entering the collecting duct system from the distal convoluted tubule flows through the cortical collecting ducts, most of the water is rapidly reabsorbed. This is because of the large difference in osmolality between the hypo-osmotic luminal fluid and the isosmotic (285 mOsm/kg) interstitial fluid of the cortex. In essence, the cortical collecting duct is reabsorbing the large volume of water that did not accompany solute reabsorption in the ascending limbs of Henle’s loop and distal convoluted tubule. In other words, the cortical collecting duct reverses the dilution carried out by the diluting segments. Once the osmolality of the luminal fluid approaches that of the cortical interstitial fluid, the cortical collecting duct then behaves analogously to the proximal tubule, reabsorbing approximately equal proportions of solute (mainly sodium chloride) and water. The result is that the tubular fluid, which leaves the cortical collecting duct to enter the medullary collecting duct, is isosmotic with cortical plasma, but its volume is greatly reduced compared with the amount entering from the distal tubule. In the medullary collecting duct, solute reabsorption continues, but in the presence of ADH water reabsorption is proportionally even greater. This is because the ADH has signaled much of the medullary collecting duct epithelium to have high water permeability, and the medullary interstitium is hyperosmotic relative to normal plasma (for reasons discussed later). Therefore, the tubular fluid becomes more and more hyperosmotic, and reduced in volume. How does ADH convert epithelial water permeability from very low to very high? An alternative name for ADH is arginine vasopressin (because the hormone can constrict arterioles and thus increase arterial blood pressure), but the major renal effect of ADH is antidiuresis, that is, “against a high urine volume” (see Chapter 61). ADH acts in the collecting ducts on the principal cells, the same cells that reabsorb sodium, to recruit vesicles containing aquaporins into the luminal membrane. In the absence of ADH, the aquaporins are withdrawn from the apical membrane by endocytosis. (As stated earlier, the water permeability of the basolateral membranes of renal epithelial cells is always high because of the constitutive presence of other aquaporin isoforms; thus, the permeability of the luminal membrane is rate limiting.)

URINARY CONCENTRATION: THE MEDULLARY OSMOTIC GRADIENT The production of hypo-osmotic urine is, we hope by now, an understandable process: the tubules (particularly the thick ascending limb of Henle’s loop) reabsorb relatively more solute than water, and the dilute fluid that remains in the lumen is excreted. The production of hyperosmotic urine is also

TABLE 44–5 Composition of medullary interstitial fluid and urine during the formation of a concentrated urine or a dilute urine. Interstitial Fluid at Tip of Medulla (mOsm/L)

Urine (mOsm/L)

Concentrated urine Urea = 650 +

Urea = 700 a

Na + Cl − = 750

Nonurea solutes = 700 (Na+, Cl−, K+, urate, creatinine, etc.)

Dilute urine Urea = 300

Urea = 30–60

Na+ + Cl− = 350a

Nonurea solutes = 10–40 (Na+, Cl−, K+, urate, creatinine, etc.)b

a

Some other ions (e.g., K+) contribute to a small degree to this osmolarity.

b

Depending on the sodium balance state, sodium in the urine can vary between undetectable and the majority of the osmolytes. Reproduced with permission from Eaton DC, Pooler JP: Vander’s Renal Physiology, 7th ed. New York, NY: Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2009.

straightforward in that reabsorption of water from the lumen into a hyperosmotic interstitium concentrates that luminal fluid, leaving concentrated urine to be excreted. The question is: how do the kidneys generate a hyperosmotic medullary interstitium? Not only is the medullary interstitium hyperosmotic, but there is also a gradient of osmolality, increasing from a nearly isosmotic value at the corticomedullary border to a maximum of greater than 1,200 mOsm/kg at the papilla. This peak value is not constant and changes depending on conditions. It is highest during periods of water deprivation and dehydration, when urinary excretion is lowest, and is “washed out” to only about half of that during excess hydration and when urinary excretion is high (see Table 44–5). The main components of the system that develops the medullary osmotic gradient are (1) the addition of sodium to the medullary interstitium by the thick ascending limb; (2) a vasculature that minimizes removal of that sodium, due both to the unusual arrangement of descending components in close apposition to ascending components and to a low rate of blood flow, and (3) the recycling of urea between the medullary collecting ducts and the deep portions of the loops of Henle (see Figure 43–3). Some aspects of the process are still uncertain. However, the essential points are clear, and it is these essential points on which we now focus. Let us begin with a condition in which there is no gradient and follow its establishment. Assume that both the plasma entering the medulla and the medullary interstitium have a normal sodium concentration (140 mEq/L) and that the medullary interstitium is isosmotic with normal plasma. The reabsorption of sodium and chloride by the thick ascending limb in the outer medulla is the first step. As sodium is deposited in the interstitium, the interstitial sodium concentration begins to increase above 140 mEq/L. This drives the diffusion of sodium into neighboring blood vessels. For those portions of the thick

CHAPTER 44 Basic Renal Processes for Sodium, Chloride, and Water ascending limb in the cortex, the reabsorbed sodium simply mixes with material reabsorbed by the nearby proximal convoluted tubules. Because the cortex contains abundant peritubular capillaries and a high blood flow, the reabsorbed material immediately moves into the vasculature and returns to the general circulation. However, in the medulla, the vascular anatomy and blood flow are quite different, and reabsorbed sodium that is deposited in the outer medullary interstitium is not immediately removed, that is, it accumulates. The degree of accumulation is a function of the arrangement of the vasa recta, their permeability properties, and the volume of blood flowing within them.

VASA RECTA As described in Chapter 40, blood enters and leaves the outer medulla through parallel bundles of descending and ascending vasa recta. These vessels are permeable to sodium, and they initially take up most of the sodium that is being transported by the thick ascending limbs into the interstitium of the outer medulla. The ascending vessels return that sodium to the general circulation, but the descending vessels carry it down into the inner medulla, where it diffuses out across the endothelia of the vasa recta and the interbundle capillaries that they feed, thereby increasing the sodium concentration (and osmolality) throughout the medulla. It is here that the anatomy of the vasculature becomes particularly important. If inner medullary blood with its somewhat elevated sodium concentration simply flowed into a venous drainage system, very little additional increase in interstitial sodium concentration would occur. However, the interbundle capillaries drain into ascending vasa recta that lie right next to descending vasa recta. The walls of the ascending vasa recta are fenestrated, allowing rapid and thorough equilibration of water and small solutes between plasma and interstitium. As the total sodium content of the medulla increases, blood in the ascending vessels acquires an increasingly higher sodium concentration. Meanwhile, blood entering the medulla has a normal sodium concentration of about 140 mEq/L. Thus, there is a gradient of concentration between ascending and nearby descending vessels. Accordingly, some of the medullary sodium begins to recirculate, diffusing out of ascending vessels (containing an elevated sodium concentration) and reentering nearby descending vessels (containing a normal sodium concentration). The process of crossing between ascending and descending vessels is called countercurrent exchange. Over time, the content of sodium in the ascending vessels and medullary interstitium increases until a steady state is reached in which the amount of new sodium pumped into the outer medulla from thick ascending limbs matches the amount of extra sodium leaving in ascending vasa recta and returning to the general circulation. At its peak, the concentration of sodium in the inner medulla may reach 300 mEq/L, which is more than double its value in the general circulation. Since sodium is accompanied by an anion, mostly chloride, the contribution of salt to the medullary osmolality is about 600 mOsm/kg.

445

What happens to water in the medulla during this time? Although solute can accumulate without a major effect on renal volume, the amount of water in the medullary interstitium must remain relatively constant; otherwise, the medulla would undergo significant swelling or shrinking. The endothelial cells of descending vasa recta, although not as leaky as the fenestrated endothelium of ascending vasa recta, contain aquaporins, allowing water to be drawn from the plasma into the increasingly hyperosmotic medullary interstitium in a manner similar to water being drawn out of tubular elements. This loss of water from descending vasa recta decreases the plasma volume of blood penetrating deeper into the medulla and raises its osmolality, thereby reducing the tendency to dilute the inner medullary interstitium. Water leaving descending vessels moves by bulk flow into nearby ascending vasa recta and is removed from the medulla; thus, there is no accumulation of water. Just as there is countercurrent exchange of solute between descending and ascending vessels, there is countercurrent exchange of water. In descending vessels water leaves and solute enters, while in ascending vessels water enters and solute leaves (see Figures 44–7 and 40–1). Water and salt reabsorption in the thin regions of Henle’s loops also influences the osmotic gradient. While their quantitative contribution is not known, it is surely less than that of the thick ascending limbs and vasa recta. The magnitude of blood flow in the vasa recta is a crucial variable. If blood flow is relatively high, water from the isosmotic plasma entering the medulla in descending vasa recta dilutes the hyperosmotic interstitium (“washes it out”), which occurs to some extent during a water diuresis. But medullary blood flow is lowest in conditions where medullary osmolality is highest. Therefore, the diluting effect of water diffusing out of descending vasa recta during periods of minimal blood flow is not great.

UREA There is one additional major player involved in the development of the medullary osmotic gradient—urea. As indicated above, the peak osmolality in the renal papilla reaches over 1,200 mOsm/kg. About half of this is accounted for by sodium and chloride, and most of the rest (500–600 mOsm/kg) is accounted for by urea. To develop such a high concentration of urea (remember that the normal plasma concentration is only about 5 mmol/L), there must be a process of recycling. This involves the tubules as well as the vasa recta. We described this recycling process in Chapter 43 and review the key points here. Urea is freely filtered, and about half is reabsorbed in the proximal tubule. Urea is secreted in the loop of Henle (thin regions), driven by the high urea concentration in the medullary interstitium, thus restoring the amount of tubular urea back to the filtered load. From the end of the thin limbs to the inner medullary collecting ducts, little urea transport occurs. Because the vast majority of water is reabsorbed prior to the inner medullary collecting ducts (by the cortical and outer medullary collecting ducts), the luminal urea

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FIGURE 44–7 Renal water handling in states of maximum antidiuresis and maximum diuresis. Numbers to the right indicate interstitial osmolality; numbers in the tubules indicate luminal osmolality. The dashed line indicates the corticomedullary border. Arrows indicate sites of water movement. In both antidiuresis and diuresis, most (65%) of the filtered water is reabsorbed in the proximal tubule and another 10% in the descending loop of Henle. The greater relative reabsorption of solute versus water by the loop as a whole and distal tubule results in luminal fluid that is quite dilute (110 mOsm) as it enters the collecting ducts. During antidiuresis (A), most of the remaining water is reabsorbed in the cortical collecting ducts, stimulated by the actions of ADH, with some additional reabsorption in the medullary collecting ducts. The equilibration of tubular fluid with the high medullary osmolality results in final fluid that is very hyperosmotic (1,200 mOsm). During diuresis (B), no water reabsorption occurs in the cortical collecting duct, but some occurs in the inner medullary collecting duct. Despite the medullary water reabsorption, continued medullary solute reabsorption reduces solute content relatively more than water content, and the final urine is very dilute (70 mOsm). In the parallel vasa recta, there is considerable exchange of both solute and water, so that plasma osmolality and solute concentrations equilibrate with the surrounding interstitium. The ascending vasa recta ultimately remove all the solute and water reabsorbed in the medulla. Because there is always some net volume reabsorption in the medulla, the vasa recta plasma flow out of the medulla always exceeds the plasma flow in. (Modified with permission from Eaton DC,

A 110

CORTEX

300

300

MEDULLA 500

Vasa recta

900

1200

1200

110

300

Maximum antidiuresis B 110

CORTEX MEDULLA

350

Vasa recta

400 70

600

Pooler JP: Vander’s Renal Physiology, 7th ed. New York, NY: Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2009.)

concentration increases up to 50 times its plasma value (i.e., 500 mmol/L or more). In the inner medullary collecting ducts, this drives urea reabsorption via specialized ADH-sensitive urea uniporters, increasing the medullary interstitial concentration close to the same high value as in the tubular lumen. The concentrated urea remaining in the collecting ducts, typically about half the filtered load, is excreted. The combination of a high urea concentration, along with the high sodium and chloride, brings the medullary osmolality to a value exceeding 1,200 mOsm/kg H2O. The importance of urea in contributing to the medullary osmotic gradient is emphasized in the case of low protein intake, which results in a greatly reduced metabolic production of urea. In this condition, the ability of the kidneys to produce highly concentrated urine is reduced. To summarize the generation of the renal osmotic gradient: salt (without water) is deposited in the interstitium of the outer medulla by the thick ascending limbs. That salt enters descending vasa recta and is distributed to the inner medulla. It accumulates in the medullary interstitium because a combination of low blood flow and countercurrent exchange between ascending and

Maximum diuresis

descending vasa recta minimizes removal. Adding to the osmolality of the medulla is urea, which recycles from the inner medullary collecting ducts to the thin limbs of the loop of Henle. Urea also participates in countercurrent exchange between ascending and descending vasa recta for the same reasons that salt does. The magnitude of the osmotic gradient is variable, being greatest during states of dehydration and lowest during a water diuresis (see Figure 44–8). Key controlling factors are levels of ADH and the magnitude of medullary blood flow. Let us conclude by addressing a common student question: under conditions of high ADH, why does not the water being reabsorbed from the medullary collecting ducts dilute the medullary interstitium and destroy the osmotic gradient? The answer is 2-fold. First, with high ADH most of the total water reabsorbed from the tubule occurs in the cortex, and there simply is not very much water left to be reabsorbed in the medulla. Second, the thick ascending limb keeps adding solute to the medulla. Proportionally more sodium is added from the thick ascending limb than water is added from the inner medullary collecting ducts.

CHAPTER 44 Basic Renal Processes for Sodium, Chloride, and Water

447

A Volume of remaining filtrate

100%

75%

50%

No ADH

25% Maximum ADH Proximal tubule

Loop of Henle

Cortical collecting duct

Medullary collecting duct

B

Osmolality (mOsmol/kg)

1200

Maximum ADH

900

600

300 No ADH Proximal tubule

Loop of Henle

Cortical collecting duct

Medullary collecting duct

FIGURE 44–8 Volume of remaining filtrate (A) and tubular osmolality (B) at different sites along the tubule in conditions of maximum ADH and no ADH. Under all conditions the majority of the filtered volume is reabsorbed in the proximal tubule. Additional reabsorption occurs in the thin limbs of the loop of Henle, the exact amount depending on ADH because the interstitial osmolality varies with ADH. In the absence of ADH no further reabsorption occurs until the inner medulla, whereas with maximal ADH most of the remaining volume is reabsorbed in the cortical collecting ducts. The osmolality of the final urine is strongly dependent on ADH, as is the maximum osmolality in the loop of Henle because the peak medullary interstitial osmolality also varies with ADH.

CLINICAL CORRELATION A 19-year-old male college freshman is convinced by his roommates to seek evaluation after noting his amazing amounts of water drinking and urination. He said that he has always consumed lots of water, and thought there was nothing wrong other than the inconvenience of urinating a lot. He only urinates once per night, and does not feel special urgency, although he does urinate many times during the day and seeks cold water to drink, sometimes in preference to food. At the university clinic, a physical exam reveals nothing unusual. He reports no family history of diabetes mellitus. While in high school, he had a severe bout of vomiting and diarrhea, diagnosed as viral gastroenteritis, in

which he lost over 10 lb of body weight and showed signs of severe dehydration, but recovered without ill effects. Blood tests show normal levels of glucose, urea (BUN), creatinine, calcium, and osmolality. A urine sample, in which he was able to void a volume greater than 1 L, reveals no glucose but it does have an unusually low osmolality of 62 mOsm/ kg. At this point, he was sent to the university hospital for a pyelogram, consisting of administering contrast media intravenously and taking serial digital radiographs of the kidneys and urinary tracts. The contrast medium appears in the renal cortex almost immediately and is freely filtered. In another 10 minutes, it makes its way to the renal papilla. Examination of the student’s radiographs revealed normal kidneys, but rather enlarged ureters and bladder. He was

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kept in the hospital and put on water deprivation overnight, during which time he urinated a considerable volume and lost 5 lb of body weight. His water deprivation was maintained during the morning, and he continued to produce urine. His blood pressure was normal while sitting, but it decreased considerably when he was standing (orthostatic hypotension). A urine sample taken at this time yielded an osmolality of 279 mOsm/kg, and his plasma osmolality was 301 mOsm/kg. His physicians strongly suspected this to be a case of diabetes insipidus. The fact that water loss continued well into a state of dehydration ruled out nonosmotic causes (e.g., psychogenic polydipsia) as a cause of the excessive urination. Accordingly, he was given an intravenous injection of aqueous arginine vasopressin (ADH). Serial urine measurements showed that the urine osmolality increased to a peak value of over 500 mOsm/kg, demonstrating that the kidneys were able to respond well to the ADH. This is a case of diabetes insipidus due to a failure of adequate ADH secretion by the posterior pituitary gland. In this case, the cause of the patient’s decrease in posterior pituitary function could not be ascertained from his medical history. For more on diabetes insipidus, see Chapter 61.

CHAPTER SUMMARY ■ ■

■ ■

■

■

The reabsorption of most of the filtered water, anions, and osmotic content is linked to the active reabsorption of sodium. In all conditions, the vast majority of the filtered volume is reabsorbed iso-osmotically in the proximal tubule in a manner that is entirely dependent on active sodium reabsorption. The capacity to generate urine with a variable osmolality depends on “separating salt from water” in the diluting segments. Reabsorption of water remaining in the lumen beyond the loop of Henle depends on hydration status, allowing the kidneys to excrete either a high-volume dilute urine, a low-volume concentrated urine, or anything in between. Levels of ADH determine whether the hypo-osmotic fluid leaving the diluting segments is excreted largely as is or whether most of this fluid is subsequently reabsorbed. The existence of the medullary osmotic gradient depends on (1) transport of salt without water into the medullary interstitium by the thick ascending limb, (2) recycling of urea, and (3) low-volume countercurrent blood flow in the vasa recta.

STUDY QUESTIONS 1. Chloride reabsorption parallels sodium reabsorption mainly because A) chloride is almost always transported via a symporter with sodium. B) chloride is the most abundant negatively charged species available to balance the reabsorption of the positive charge on sodium. C) chloride has a very high passive permeability. D) chloride and sodium are both part of the sodium chloride molecule and cannot be separated. 2. The obligatory water loss in the kidney A) is another name for insensible loss of water. B) occurs because there is always at least some excretion of waste solutes. C) occurs because there is an upper limit to how fast aquaporins can reabsorb water. D) is the amount of water that accompanies salt excretion. 3. Which region of the tubule secretes water? A) the descending thin limb B) the cortical collecting duct C) the medullary collecting duct (when ADH is absent) D) no region secretes water 4. If the thick ascending limb stopped reabsorbing sodium, then the final urine would be A) isosmotic with plasma in all conditions. B) dilute, depending on ADH. C) concentrated, depending on ADH. D) dilute or concentrated, depending on ADH. 5. If a healthy young person drinks a large amount of water, which of the following is unlikely to happen? A) an increase in medullary blood flow B) an increase in water permeability in the medullary collecting ducts C) a decrease in interstitial osmolality at the tip of the renal papilla D) a decrease in the urea concentration in the final urine. 6. A healthy young person drinks a large amount of water. Over the next several hours, most of the water entering the glomerular filtrate is A) excreted. B) reabsorbed in the cortical collecting duct. C) reabsorbed in the proximal tubule. D) reabsorbed in the loop of Henle.

45 C

Regulation of Sodium and Water Excretion Douglas C. Eaton and John P. Pooler

H A

P

T

E

R

O B J E C T I V E S ■ ■ ■ ■ ■ ■ ■ ■ ■

■

■

Describe the relationship between renin and angiotensin II. Describe the detectors that regulate renin secretion. Define pressure natriuresis and diuresis. Define tubuloglomerular feedback, and describe the mechanism for tubuloglomerular feedback and autoregulation of glomerular filtration rate. List the major factors that regulate sodium excretion. State the tissue origin of aldosterone, its renal sites of action, and its effect on sodium reabsorption. State the origin of atrial natriuretic peptides, the stimulus for their secretion, and their effect on sodium reabsorption and glomerular filtration rate. Describe the origin of antidiuretic hormone and the two major reflex controls of its secretion. Distinguish between the reflex changes that occur when an individual has suffered iso-osmotic fluid loss because of diarrhea as opposed to a pure water loss (i.e., solute water loss as opposed to pure water loss). Diagram in flow-sheet form the pathways by which sodium and water excretions are altered in response to sweating, diarrhea, hemorrhage, high-salt diet, and low-salt diet. Describe the control of thirst.

GOALS The excretion of sodium and water is regulated by an array of signals, some originating within the kidneys themselves (intrarenal signals) and some from other regions of the body. The regulatory processes are complex, and it is imperative to grasp the goals of regulation so that individual mechanisms fit into a logical framework. A key concept is that the kidneys work in partnership with the cardiovascular system. Together they ensure that (1) there is enough blood volume to fill the vascular tree, (2) enough pressure to drive blood flow through peripheral tissues, and (3) the blood, and therefore the cells throughout the body, has the proper osmolality. One way or another, all the regulatory mechanisms that control sodium and water excretion exist for the purpose of meeting these goals. There is also an indirect, but related goal. Variations in renal blood flow

Ch45_449-462.indd 449

(RBF) and glomerular filtration rate (GFR) are major means of regulating sodium excretion. However, the kidneys cannot allow blood flow and filtration to reach such extreme levels that they compromise the metabolic health of the kidneys or interfere with the excretion of substances other than sodium. Thus, another goal is to limit the sodium-related changes in RBF and GFR that might otherwise reach deleterious levels.

SODIUM EXCRETION: THE CARDIOVASCULAR CONNECTION The kidneys play a direct role in maintaining cardiac output, first by ensuring that there is sufficient blood volume to allow the heart to fill between beats, and second by contributing to 449

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Direct renal influences

ECF volume

Blood cell production

Total peripheral resistance

the plasma and tissue interstitial space. Thus, maintenance of blood volume is largely a matter of maintaining ECF volume. It is obvious why water is crucial for ECF volume, but why is sodium so important? The answer stems from two facts. First ECF osmolality is tightly regulated, and second the osmotic content of the ECF depends critically on its sodium content. We can approximate ECF osmolality as follows: ECF solute content ECF osmolality = ______________ ECF volume

(1)

By rearrangement the above expression becomes: ECF solute content ECF volume = ______________

Blood volume

ECF osmolality

FIGURE 45–1

Influence of the kidneys on the cardiovascular system. The kidneys affect blood volume via their production of erythropoietin, which stimulates red blood cell production, and via their control of salt and water excretion. They also influence total peripheral resistance via the actions on angiotensin II (see text for details).

Furthermore, since almost all of the ECF solute is accounted for by sodium and an equivalent number of anions (mostly chloride and bicarbonate), the amount of ECF solute is approximately twice the sodium content. We can write the previous expression as follows: 2×ECF sodium content ECF volume = ________________ ECF osmolality

the control of total peripheral resistance (see Figure 45–1). Let us examine the renal involvement in these cardiovascular issues, with blood volume first. Blood is composed primarily of red blood cells (about 45%) and blood plasma (about 55%). The kidneys are crucial for both parts—they secrete the hormone erythropoietin, which stimulates production of red blood cells, and they regulate the extracellular fluid (ECF) volume, of which blood plasma is a significant part. Although not exact, there is an approximate proportionality between blood volume and total ECF volume. Blood volume tends to increase and decrease as ECF volume increases and decreases due to shifts of fluid between

Arterial baroreceptors

Cardiopulmonary baroreceptors

Brainstem vasomotor center Brainstem vasomotor center Hypothalamus

Intrarenal baroreceptors

(2)

(3)

Therefore, in the face of tightly controlled ECF osmolality, ECF volume varies directly with sodium content. This raises the following question: how do the kidneys know how much sodium is present in the ECF? There is no mechanism for the body to assay sodium content per se. Instead the detection of sodium content is indirect, based mainly on vascular pressures. That is, variations in vascular pressures are interpreted by the body as variations in sodium content. Vascular pressures are assessed by baroreceptors—cells that deform in response to changes in local intravascular pressure. Three sets of baroreceptors are important for controlling sodium excretion (see Figure 45–2). Two have already been described in Chapter 29. These are (1) the arterial Total peripheral resistance Cardiac performance Sympathetic drive to kidney Venous compliance Venous compliance Sympathetic drive to kidney Total peripheral resistance Cardiac performance ADH

Renin-angiotensin system GFR, salt and water reabsorption

FIGURE 45–2 Baroreceptors and the major processes they influence. Arterial baroreceptors sense pressures in the aorta and carotid arteries and send afferent information to the brainstem vasomotor center, which then regulates cardiovascular and renal processes via autonomic efferents. Cardiopulmonary baroreceptors sense pressure in the cardiac atria and pulmonary arteries, thereby being responsive to the filling of the vascular tree. They send afferent information in parallel with the arterial baroreceptors. While there is overlap between the influences of the two sets of baroreceptors, the cardiopulmonary baroreceptors have a particularly important influence on the hypothalamus, which regulates secretion of ADH. The intrarenal baroreceptors have a major role in the renin–angiotensin system (see text for details). (Modified with permission from Eaton DC, Pooler JP: Vander’s Renal Physiology, 7th ed. New York, NY: Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2009.)

CHAPTER 45 Regulation of Sodium and Water Excretion baroreceptors, nerve cells that mediate the classic baroreceptor reflex, and (2) the cardiopulmonary baroreceptors that are also nerve cells and work in parallel with the arterial baroreceptors. The third set of baroreceptors consists of intrarenal baroreceptors, which are not nerve cells. We will describe their operation shortly, but first we briefly summarize the neural baroreceptors as a review. The medullary cardiovascular centers stimulate vascular tone (vasoconstriction) throughout the body via the sympathetic nervous system. In the arterioles of the peripheral vasculature this sympathetic tone maintains total peripheral resistance, and in the peripheral venous system it maintains central venous pressure via its influence on the compliance of large veins. Arterial baroreceptors exert a tonic inhibition of the medullary cardiovascular centers, resulting in a brake on sympathetic drive. An increase in arterial pressure causes greater firing of the baroreceptors, more inhibition, and therefore even less sympathetic drive to the periphery, while a decrease in arterial pressure reduces firing in the baroreceptors and less inhibition, allowing more sympathetic drive. The resulting changes in vascular tone alter total peripheral resistance and help stabilize arterial pressure. The cardiopulmonary baroreceptors act in the same way, but respond not to arterial pressure, but rather to pressures in the cardiac atria and pulmonary vessels. The medullary cardiovascular centers also send both sympathetic stimulatory and parasympathetic inhibitory signals to the heart in response to variations in baroreceptor input. The kidneys, being part of the peripheral vasculature, respond to changes in sympathetic drive and contribute to changes in total peripheral resistance. However, as we will describe later, changes in sodium excretion in response to sympathetic drive are even more important than the renal contribution to total peripheral resistance.

RENAL CONTROL OF VASCULAR RESISTANCE If deviations in blood pressure are sustained, the kidneys are capable of strongly reinforcing the effects of the vasomotor centers on vascular resistance. How does this work? The major detectors involved in the kidney’s ability to regulate vascular resistance are the previously described neural baroreceptors, and the intrarenal baroreceptors. The intrarenal baroreceptors sense renal afferent arteriolar pressure. Anatomically, these structures are not nerve cells and do not send signals to the brainstem vasomotor center, but rather are specializations of the cells of the afferent arteriole: granular cells (also called juxtaglomerular cells) that form part of the juxtaglomerular apparatus described in Chapter 40. They act entirely within the kidney. Although granular cells acting as intrarenal baroreceptors do not send signals centrally, neural signals originating in the vasomotor centers (generated in response to neural baroreceptors) reach the granular cells via the renal sympa-

451

thetic nerve. Thus, the activity of the granular cells is affected both by direct sensing of pressure in the renal arterioles and by pressures sensed by neural baroreceptors elsewhere in the body In response to changes in pressures sensed by baroreceptors, a number of renal events are set in motion that have powerful effects on total peripheral resistance, and, as we will see later, on sodium excretion. The critical events are signaling pathways known as renin–angiotensin systems (RAS).

RENIN–ANGIOTENSIN SYSTEMS An important hormone in the control of sodium excretion and blood pressure is angiotensin II. It is a potent vasoconstrictor, and also a mediator of multiple actions in the kidneys that affect sodium excretion. Thus, it affects blood pressure directly as a vasoconstrictor and indirectly via regulation of renal sodium excretion and therefore blood volume. There are many local RAS systems in individual tissues, including the kidneys, brain, and the heart. There is also a global or systemic RAS. All RAS systems, whether global or local, consist of a large protein substrate called angiotensinogen, several enzymes, and several products. The key product is angiotensin II. When angiotensin II binds to cell surface receptors, it initiates actions that affect blood pressure and excretion of sodium. The first key enzyme in all RAS systems is renin (pronounced REE-nin). It acts upon angiotensinogen to produce a small (10-amino acid) product called angiotensin I. Angiotensin I is acted upon by another enzyme, angiotensinconverting enzyme (ACE), to produce the highly active eightamino acid peptide angiotensin II. In the global RAS system, the source of angiotensinogen circulating in the blood is the liver. The source of circulating renin is the granule cells in the kidney. Renin is secreted both into the interstitium of the kidney and into the lumen of the afferent arterioles, where it acts on circulating angiotensinogen to produce circulating angiotensin I. ACE, which is expressed on the luminal surface of endothelial cells in many parts of the vasculature, then converts angiotensin I to angiotensin II (see Figure 45–3). The major source of angiotensin II that affects the kidneys is produced by a local RAS system within the kidneys themselves. Thus, the kidneys are regulated by both the global RAS system and a local RAS system. The circulating level of angiotensinogen in the global RAS system is normally high and is not rate limiting. Furthermore, ACE activity usually converts most of the angiotensin I into angiotensin II. Therefore, the major controller of angiotensin II production is the amount of angiotensin I produced by the action of renin. Consequently, understanding angiotensin II production requires an understanding of the regulation of renin secretion. Two primary regulators of renin secretion have been described: the first are the neural baroreceptors, which influence the activity of renal sympathetic nerves that stimulate granular cell production of renin and vasoconstriction at the same time. This occurs via a β1-adrenergic receptor–protein

452

SECTION VII Renal Physiology

Stimuli to renin Liver

Kidney Angiotensinogen (453 aa) Renin (enzyme)

Angiotensin I (10 aa)

Angiotensin-converting enzyme (endothelium)

Angiotensin I

Angiotensin-converting enzyme (endothelium)

Angiotensin II

Angiotensin II (8 aa)

Cardiovascular system

Adrenal cortex Aldosterone Kidney

FIGURE 45–3

Major components of the global RAS. Angiotensin II acts on the vascular system as a vasoconstrictor and stimulates adrenal production of aldosterone. It also acts within the kidneys to promote sodium reabsorption (although the major source of renal angiotensin II is the intrarenal RAS system). (Reproduced with permission from Widmaier EP, Raff H, Strang KT:

Salt and H2O retention

Vasoconstriction

Blood pressure

Vander’s Human Physiology, 11th ed. McGraw-Hill, 2008.)

kinase A-dependent process. The second regulators of renin secretion are the intrarenal baroreceptors, that is, the very same granular cells that respond to adrenergic stimulation also deform in response to changes in afferent arteriolar pressure; when the pressure decreases, renin production increases. Thus, granular cells act as both detectors (of renal arteriolar pressure) and signal generators (releasing renin) in response to changes in pressure and sympathetic activity. The signals from the vasomotor system to the renin-producing granular cells ensure that there is tight coordination between the rapid activity of the systemic baroreceptor reflex and the slower-acting RAS. However, the intrarenal pressure detector can function in the absence of renal innervation (e.g., after a renal transplantation). There is also a third detector mechanism that regulates renin release. It is another component of the juxtaglomerular appa-

ratus (Figure 45–4) that monitors the amount of tubular sodium chloride directly bathing the macula densa cells. This amount of sodium chloride depends on both the rate of filtration (GFR) and the rate of sodium reabsorption in all the nephron elements preceding the macula densa. When sodium chloride delivery to the apical surface of macula densa cells increases, renin production decreases, that is, high tubular sodium loads inhibit renin production. The utility of this load detector control of renin secretion is that in situations in which the body contains excess sodium and is excreting sodium rapidly, it is advantageous not to produce very high quantities of angiotensin II. In review, three separate mechanisms regulate renin secretion (neural signals, afferent arteriolar pressure, and NaCl at the macula densa). The multiple controls reflect the importance

CHAPTER 45 Regulation of Sodium and Water Excretion

453

Mesangial cells Glo

1. Renal sympathetic nerve activity stimulates renin secretion from granular cells.

m

nt ere Aff riole e art

ulu

nin

Re

s

R

nt re e fe iol Ef rter a

2. Changes in systemic blood pressure deform membrances of granular cells to stimulate release of renin.

er

en

in

Granular cells Chemical transmitters

Macula d en sa

3. Osmotic stretch in response to changes in NaCI delivery deform membranes to stimulate release of chemical messengers that reduce renin secretion.

of the RAS system and angiotensin II, in particular, in cardiovascular control. A significant action of circulating angiotensin II produced by the global RAS system is general arteriolar vasoconstriction. This vasoconstriction acts in parallel with sympathetically mediated neural signals to increase total peripheral resistance, thereby increasing blood pressure. The importance of this system makes the RAS a natural target for pharmacological intervention to reduce high blood pressure. A number of blood pressure–lowering pharmacological agents are aimed at components of the RAS systems, including ACE inhibitors and angiotensin II receptor blockers (ARBs).

CONTROL OF SODIUM EXCRETION GLOMERULAR FILTRATION RATE Many factors influence sodium excretion. One simple principle to remember amid the complexities is that the amount of sodium excreted is the difference between the filtered load and the amount reabsorbed. Therefore, a major control over sodium excretion is regulation of the filtered load via regulation of GFR. As detailed in Chapter 40, GFR is a function of afferent arteriolar pressure (reflecting systemic arterial pressure) and the resistances of the afferent and efferent arterioles. Changes in resistance are produced by changes in renal sympathetic nerve activity and levels of angiotensin II. In the face of a decrease in blood pressure there is a decrease in GFR directly, and an

FIGURE 45–4 Control of renin secretion. Three primary mechanisms regulate renin secretion. First, renal sympathetic nerve activity activates β1-adrenergic receptors on granular cells of the afferent arteriole to stimulate renin secretion. Second, the granular cells also act as intrarenal baroreceptors, responding to changes in pressure within the afferent arteriole, which, except in cases of renal artery stenosis, is a reflection of changes in arterial blood pressure. Deformation of the granular cells alters renin secretion: when pressure falls, renin production increases. Third, macula densa cells in the thick ascending limb sense the delivery of tubular sodium chloride, leading to the release of chemical transmitters that alter renin secretion from the granular cells: when sodium chloride delivery increases, renin production decreases. (Modified with permission from Eaton DC, Pooler JP: Vander’s Renal Physiology, 7th ed. New York, NY: Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2009.)

additional decrease due to increased renal sympathetic nerve activity that is part of the neural baroreceptor reflex. These actions all decrease sodium excretion. If the low pressure persists, large amounts of renin are released and the subsequent actions of angiotensin II reinforce these actions. All of this makes logical sense: in the face of low arterial pressure, the kidneys conserve sodium. On the other hand, if the sodium content of the body increases significantly and plasma volume is increased, or if there is an inappropriate increase in arterial pressure, sympathetic vasoconstrictive activity is reduced, RBF and GFR increase, and sodium excretion increases. The filtered load of sodium is always enormous, and it is imperative that the kidneys reabsorb the vast majority of it under all conditions. Because even a small fractional change in reabsorption results in a large change in the absolute amount excreted, precise control over reabsorption is an essential aspect of maintaining sodium balance. While GFR is an important variable, most controls focus on reabsorption. As with many other aspects of renal function, certain details of this control system are still not understood. Thus, we emphasize again that the most important goal of regulating sodium balance, even if we do not know all of the mechanistic details, is to regulate ECF volume.

ECF VOLUME Dietary sodium loads always expand the ECF volume. Under most circumstances, sodium loads are accompanied by water loads, as when one eats pizza and beverage, thus accounting

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SECTION VII Renal Physiology

ANGIOTENSIN II

for the increase in volume. But even if the load is the unusual case of salt without water, the ECF still expands because the added osmoles in the ECF increase its osmolality and draw water from the intracellular space (see Figure 44–1). The kidneys respond to sodium loads by decreasing sodium reabsorption, thus allowing more sodium to be excreted. Much of the decrease in reabsorption occurs as a result of decreased levels of angiotensin II, via a mechanism described in the next section. At least some of the signaling is via cardiopulmonary baroreceptors that inhibit the medullary vasomotor centers and lead to less sympathetic drive, which in turn leads to less production of angiotensin II. In response, the kidneys permit a large amount of sodium to be excreted. A pure water load, which also expands the ECF volume, does not lead to increased sodium excretion. This is partly because pure water loads are excreted much more rapidly than salt loads and partly because pure water loads simultaneously reduce plasma osmolality. A major decrease in ECF volume, such as occurs with prolonged vomiting and diarrhea or a major hemorrhage, always involves loss of sodium. The low volume sensed by cardiopulmonary baroreceptors leads to strong sympathetic stimulation of the kidneys, lower RBF, lower GFR, activation of the RAS, and stimulation of tubular sodium reabsorption. These actions reduce sodium excretion to low levels, thereby helping preserve ECF volume. Figure 45–5 summarizes the multiple responses to low ECF volume, of which reduction in sodium excretion is a significant part.

–

JUXTAGLOMERULAR APPARATUS

As important as angiotensin II is to vascular resistance, it plays an even more important role in regulating sodium reabsorption in the kidneys. It has direct tubular actions and it stimulates the secretion of the hormone aldosterone from the adrenal cortex, another major player in the connection between sodium excretion and the cardiovascular system (see Figure 45–3 and Chapter 65). Finally, angiotensin II acts in a negative feedback manner to inhibit renin production by acting directly on granular cells. Angiotensin II affects blood pressure by altering peripheral vascular resistance, but within the kidneys, angiotensin II exerts significant sodium-retaining actions that begin by binding to G protein–coupled receptors and activating intracellular signaling cascades: (1) it constricts renal arterioles (as it does arterioles elsewhere), thereby reducing RBF and GFR; (2) it constricts glomerular mesangial cells, also reducing GFR; and (3) it stimulates sodium reabsorption in the proximal tubule. All of these actions reduce sodium excretion. The number of functioning Na–H exchangers in the apical membrane of proximal tubule cells is strongly influenced by angiotensin II. These proteins can shuttle back and forth between locations where they are functioning and where they are inactive. When angiotensin II is present, the Na–H exchangers move to locations in the apical membrane where they transport ions, thereby increasing the reabsorption of sodium.

LOW EFFECTIVE CIRCULATING VOLUME

Controlled variable

LOW PRESSURE BARORECEPTORS

HIGH PRESSURE BARORECEPTORS

ADH

SYMPATHETIC NERVOUS SYSTEM

Sensors

+ Renin

RENIN-ANGIOTENSINALDOSTERONE AXIS +

+

+

Mediators

+

+

Effectors + STARLING FORCES

+

RENAL SODIUM & WATER RETENTION

VASOCONSTRICTION

CARDIAC EXCITATION

+ +

+ MEAN ARTERIAL BLOOD PRESSURE

FIGURE 45–5 Responses to low vascular volume. Because adequate vascular volume is essential for the long-term maintenance of arterial pressure, loss of volume, as occurs in prolonged diarrhea, vomiting, or hemorrhage, invokes multiple corrective responses. Following a rapidly acting stimulation of the heart and peripheral resistance, the kidneys are stimulated to reduce excretion of sodium and water, thereby preserving existing volume. (Reproduced with permission from Kibble J, Halsey CR: The Big Picture, Medical Physiology. New York: McGraw-Hill, 2009.)

CHAPTER 45 Regulation of Sodium and Water Excretion Conversely, when the levels of angiotensin II decrease, the Na–H exchangers are withdrawn to sites where they are inactive, along with a concomitant reduction in activity of the basolateral Na,K-ATPase, resulting in much less sodium reabsorption. Thus, variation in levels of angiotensin II is a very powerful bidirectional response system. When the levels of angiotensin II are high, the kidneys filter less sodium and reabsorb more, thereby greatly reducing the amount excreted. In contrast, when there is little angiotensin II, large amounts of sodium remain in the tubule and are excreted.

PRESSURE NATRIURESIS AND DIURESIS Just as ECF volume exerts control over sodium excretion, so does arterial pressure. Increased pressure in the renal artery causes the kidneys to increase their excretion of sodium. This phenomenon has been given the name pressure natriuresis (and because natriuresis tends to increase water excretion, it can be properly called pressure natriuresis and diuresis). It is an entirely intrarenal phenomenon, that is, it is not activated by external signals (although, as described later, it can be severely attenuated, or even prevented by external signals). Pressure natriuresis and diuresis serves as a backup system that comes into play if fast-acting neural reflex systems of regulating blood pressure fail to completely correct large increases. The mechanism of pressure natriuresis is a fascinating interaction between renal hemodynamics and intricate signaling cascades. It begins when higher renal artery pressure drives higher blood flow in the medulla. The medulla has relatively poor autoregulation (compared with the highly effective autoregulation in the cortex); accordingly medullary blood flow tends to vary in closer relation to renal artery pressure. The higher medullary blood flow when pressure is high leads to increased interstitial pressure that is transmitted throughout the kidney. In turn, the higher interstitial pressure activates intrarenal signals (arachidonic acid metabolites), which command the proximal tubule cells to reduce their transport capacity. They do this by withdrawing Na–H antiporters (similar to what happens when angiotensin II falls) and reducing Na,KATPase activity. Together these events reduce sodium reabsorption and increase excretion. Higher interstitial pressure may also increase backleak from the interstitium into later portions of the tubule, further reducing reabsorption. If the increased pressure is maintained, the RAS system is suppressed and the production of angiotensin II is lowered, which augments and sustains the withdrawal of Na–H antiporters. Although pressure natriuresis is an intrarenal process, it can be overridden by external signals. When the ECF volume is normal or high and pressure in the renal artery increases, pressure natriuresis and diuresis are very effective in increasing excretion of sodium and water and reducing blood volume. On the other hand, if ECF volume is low and renal artery pressure increases, there is much less salt and water loss. In effect, it is more important to prevent further loss of volume than it is

455

to correct the elevated arterial pressure. Another example of override occurs during exercise. Arterial pressure increases, but sodium excretion decreases. An implicit assumption about all the processes that control sodium excretion is that there are parallel movements of water, and therefore volume. This is indeed true, and maintaining ECF volume is, as we have said, the most important reason for regulating sodium excretion. While most of the time it is appropriate that water accompany the movement of sodium, it is not always true (because there are occasions when the inputs of salt and water are not in parallel). Therefore, the kidneys possess ways of independently controlling water and sodium excretion. Such independent controls are exerted in regions of the nephron beyond both the proximal tubule and loop of Henle, namely, in the collecting tubules and ducts. As described in the next section, the chief player with respect to independent control of sodium excretion is the hormone aldosterone.

LONG-TERM CONTROL: ALDOSTERONE REGULATION OF SODIUM BALANCE Aldosterone is a major stimulator of sodium reabsorption in the distal nephron; that is, regions of the tubule beyond the proximal tubule and loop of Henle. Aldosterone-stimulated sodium retention is an effector system that is vital in correcting prolonged reductions in body sodium, blood pressure, and volume. The most important physiological factor controlling secretion of aldosterone is the circulating level of angiotensin II, which stimulates the adrenal cortex to produce aldosterone. This targets the distal nephron to increase sodium reabsorption and thus increase total body sodium and blood volume to produce a long-term correction to total body sodium content and mean blood pressure. Aldosterone stimulates sodium reabsorption mainly in the cortical connecting tubule and cortical collecting duct, specifically by the principal cells. An action on this late portion of the nephron is what one would expect for fine-tuning the output of sodium, because more than 90% of the filtered sodium has already been reabsorbed by the time the filtrate reaches the collecting duct system. The percentage of sodium reabsorption dependent on the influence of aldosterone is approximately 2% of the filtered load. Thus, all other factors remaining constant, in the complete absence of aldosterone, a person would excrete 2% of the filtered sodium, whereas in the presence of high plasma concentrations of aldosterone, virtually no sodium would be excreted. Two percent of the filtered sodium may seem trivial but is actually a significant amount because a large quantity of sodium is filtered: Total filtered Na per day = GFR × PNa = (4) 180L per day × 145 mmol/L = 26,100 mmol per day

456

SECTION VII Renal Physiology

Thus, aldosterone controls the reabsorption of 0.02 × 26,100 mmol per day = 522 mmol per day. In terms of sodium chloride, the form in which most sodium is ingested, this amounts to the control of approximately 30 g NaCl per day, an amount considerably more than the average person consumes. Therefore, by control of the plasma concentration of aldosterone between minimal and maximal, the excretion of sodium can be finely adjusted to the intake so that total body sodium remains constant. We should emphasize that aldosterone exerts control over sodium, but not water. While changes in water excretion may accompany aldosterone-mediated changes in sodium excretion, this is not always the case. Aldosterone also stimulates sodium transport by other epithelia in the body, namely, sweat and salivary ducts and the intestine. The net effect is the same as that exerted on the kidney: movement of sodium from lumen to blood. Thus, aldosterone is an all-purpose stimulator of sodium retention. In the kidney, aldosterone acts like many other steroid hormones to increase the genetic expression of key proteins (see Chapter 65). The effect of these proteins is to increase the activity or number of apical membrane sodium channels and basolateral membrane Na,K-ATPase pumps to promote increased reabsorption of sodium (Figure 45–6). Angiotensin II produced by the global RAS system is the main stimulator of aldosterone secretion, although there are others, including elevated plasma potassium concentration, as described in Chapter 46 in the context of the renal handling of potassium. The atrial natriuretic factors (discussed later) inhibit aldosterone secretion. Since levels of angiotensin II are

LUMEN

INTERSTITIUM

Inactive products

11ß-HSD

receptor

Glucocorticoids Aldosterone

transcription protein synthesis ATP Na+

Na+ K+

FIGURE 45–6 Mechanism of aldosterone action. Aldosterone enters principal cells and interacts with cytosolic aldosterone receptors. The aldosterone-bound receptors interact with nuclear DNA to promote gene expression. The aldosterone-induced gene products activate sodium channels in the apical membrane and sodium pumps in the basolateral membrane, causing increased sodium reabsorption. Glucocorticoids such as cortisol are also capable of binding to the aldosterone receptor. However, they are inactivated by 11β-hydroxysteroid dehydrogenase (11β-HSD). (Modified with permission from Eaton DC, Pooler JP: Vander’s Renal Physiology, 7th ed. New York, NY: Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2009.)

controlled by renin, this emphasizes once again the importance of the global RAS system. Both renin and aldosterone have relatively short plasma half-lives (~15 minutes), while the half life of angiotensin II is very short (<1 minute). Therefore, prolonged stimulation by aldosterone requires the continuous stimulation of renin secretion. Figure 45–7 shows how decreased plasma volume, via the RAS–aldosterone system, leads to decreased volume excretion.

AUTOREGULATION REVISITED The control of sodium excretion is mediated in part by changes in RBF and GFR. However, if changes in these processes are too large, there are negative consequences. In essence, the body cannot allow controls of sodium excretion to “take over” the kidneys to either the detriment of the metabolic health of the kidneys or the excretion of other substances. Substantial reductions in RBF severely compromise already oxygen-poor regions of the kidney such as the medulla. Substantial increases in glomerular capillary pressures are likely to damage the glomeruli. In addition, the ability of the kidneys to regulate the excretion of water and many substances other than sodium depends on keeping tubular flow (i.e., GFR) within a certain limited range. These goals are met by several processes that collectively result in autoregulation of both RBF and GFR (see Figure 40–7). While these processes do not exist, strictly speaking, for the purpose of regulating sodium excretion, they nevertheless do affect it. Autoregulation involves the myogenic response described in Chapter 40 and a rather complicated intrarenal signaling system called tubuloglomerular feedback. This feedback (from the tubule to the glomerulus) is associated with the macula densa sodium chloride load detector (see Figure 45–4). Earlier in this chapter, we described the actions of the macula densa in the context of control over renin secretion, where we said that in conditions when GFR is very high and therefore filtering a large amount of sodium, it inhibits renin release. And, as detailed below, the macula densa also reduces GFR and RBF. The macula densa cells at the end of the thick ascending limb have Na–K–2Cl symporters that avidly take up Na, Cl, and K when GFR, and hence, NaCl delivery is high. Sodium also enters the macula densa cells via a Na–H antiporter. Since the action of this antiporter causes the cells to lose a hydrogen ion for every sodium ion entering, this increases intracellular pH. A combination of cellular volume change, increased intracellular chloride, and higher intracellular pH initiates intracellular signaling processes that lead to the release of ATP from the basolateral surface of the cells in close proximity to the glomerular mesangial cells (see Figure 39–6). This ATP stimulates purinergic P2 receptors on the mesangial cells and afferent arteriolar smooth muscle cells. P2 receptor stimulation increases calcium in these cells and promotes contraction. Contraction of mesangial cells decreases the effective filtration area, which decreases GFR. Contraction of the afferent

CHAPTER 45 Regulation of Sodium and Water Excretion

457

Plasma volume

Activity of renal sympathetic nerves

Arterial pressure

Direct effect of less stretch

GFR, which causes flow to macula densa

NaCl delivery to macula densa

Renal juxtaglomerular cells Renin secretion

Plasma renin

Plasma angiotensin II

Adrenal cortex Aldosterone secretion

Plasma aldosterone

FIGURE 45–7 Pathways by which low plasma volume leads to increased aldosterone secretion and subsequent reduction in salt and water excretion. (Reproduced with permission from Widmaier EP, Raff H, Strang KT: Vander’s Human Physiology, 11th ed. McGraw-Hill, 2008.)

arteriolar smooth muscle cells increases afferent resistance and decreases RBF and GFR. In addition, it is the increased calcium in the afferent arteriolar cells that reduces renin secretion. The ATP may also be metabolized to adenosine, which can stimulate adenosine receptors that produce the same result as the P2 receptors (in contrast to the vasodilatory actions of adenosine in most other tissues). In addition to purinergic agonists that mediate tubuloglomerular feedback, there are other intrarenal signaling systems, specifically including nitric oxide and arachidonic acid metabolites, that participate in modulating the strength of the vasoconstrictive actions. Because the actions of the sodium chloride load detector and tubuloglomerular feedback are complicated, we summarize them here. High salt content in the thick ascending limb of a given nephron generates signals that reduce glomerular blood flow and reduce filtration in that nephron, thus blunting (but not eliminating) the increase in sodium excretion initiated by other processes in conditions (e.g., volume expansion) in which the appropriate overall response is increased sodium excretion. The same signals that reduce filtration also reduce the secretion of renin.

Cortical collecting ducts Sodium and H2O reabsorption

Sodium and H2O excretion

OTHER MECHANISMS FOR CONTROLLING SODIUM BALANCE: NATRIURETIC PEPTIDES Although there are several other renal mechanisms for controlling sodium balance independent of water balance, under normal physiological circumstances, none are as important as aldosterone. Only under certain pathophysiological conditions do these other mechanisms contribute significantly to the regulation of sodium balance. Important among these are a family of hormones called natriuretic peptides, so named because they promote excretion of sodium in the urine. The key ones are atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP; named as such because it was first discovered in the brain). The main source of both natriuretic peptides is the heart. The natriuretic peptides have both vascular and tubular actions. They relax the afferent arteriole, thereby promoting increased filtration, and act at several sites in the tubule. They inhibit release of renin, inhibit the actions of angiotensin II that normally promote reabsorption of sodium,

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SECTION VII Renal Physiology

and act in the medullary collecting duct to inhibit sodium absorption. The major stimulus for increased secretion of the natriuretic peptides is distention of the atria, which occurs during plasma volume expansion. This is probably the stimulus for the increased natriuretic peptides that occurs in persons on a high-salt diet. Although most experts assume that these peptides play some physiological role in the regulation of sodium excretion in this and other situations in which plasma volume is expanded, it is not currently possible to quantify their contribution precisely, although it is surely less than aldosterone. These peptides are greatly increased in patients with heart failure and can serve as diagnostic indicators.

SUMMARY OF THE CONTROL OF SODIUM EXCRETION An array of signals, some originating in baroreceptors outside the kidneys and some originating within the kidneys, alters vascular resistances and transport proteins in order to control sodium excretion, with the main goals of maintaining ECF volume acutely and arterial pressure in the long term (see Figure 45–8). In response to sodium loads and losses, consequent changes in pressure are detected by neural and intrarenal baroreceptors that directly or indirectly signal the kidneys to modify sodium excretion, thereby excreting loads or preserving existing sodium. GFR, which determines the filtered load of sodium, is a function of arterial pressure and the amount of smooth muscle contraction in renal arterioles. Sodium reabsorption is controlled by a combination of signals that affect transport proteins in the renal tubules. The main controlling signals come from renal sympathetic nerves and the RAS–aldosterone hormonal system. The latter is activated both by sympathetic nerves and by low pressure at the

Dietary sodium

Arterial pressure

RAS system

GFR

Angiotensin II

+ + ECF volume

+ ±

Intrarenal messengers

+

Sodium excretion

–

+ –

Aldosterone

+ Natriuretic peptides

FIGURE 45–8 Important variables that affect sodium excretion. Increases in dietary sodium, particularly via the ensuing rise in ECF volume, lead to increased sodium excretion. Increased arterial pressure, increased GFR, and the actions of natriuretic peptides also increase sodium excretion. Activation of the renin– angiotensin system (RAS) decreases sodium excretion via the actions of both angiotensin II and aldosterone. Intrarenal messengers, depending on the specific messenger, can either increase or decrease sodium excretion.

intrarenal baroreceptors. Elevated arterial blood pressure also exerts direct effects on the kidneys (pressure natriuresis) via a separate intrarenal signaling system. When considering mechanisms of sodium excretion, it is useful to consider two conceptually different categories of mechanisms: (1) GFR and proximal tubule mechanisms that lead to coupled changes in sodium and water excretion and (2) distal nephron effects in which sodium can be reabsorbed independently of water. The proximal mechanisms are primarily involved in excreting excess ECF volume, whereas the distal mechanisms alter sodium excretion when ingestion of sodium is not balanced by ingestion of water. Both types of mechanisms can alter blood pressure because of the intimate relationship among total body sodium and water, blood volume, and blood pressure.

CONTROL OF WATER EXCRETION As with sodium excretion, water excretion is regulated in partnership with the cardiovascular system. A central goal in regulating both salt and water excretion is to preserve vascular volume. It is also crucial to maintain plasma osmolality at a level that is healthy for tissue cells. It is not surprising then that signals related to osmolality and volume are the main regulators of water excretion. The relation between urinary water excretion, urinary solute excretion, and urine osmolality is shown in the following expression (where, as before, we approximate osmolality simply as total moles divided by volume): Urine solute excretion Urine water excretion = ________________ Urine osmolality

(5)

At a given urine osmolality, water excretion varies directly with urinary solute excretion. More solute excreted (due, e.g., to a higher GFR or reduced sodium reabsorption) means more water excreted (because “water follows the osmoles”). This is the basis for most diuretics, which promote sodium excretion, and therefore water excretion. But the kidneys can also vary the amount of water accompanying the excreted solute. They do this by regulating how much water is reabsorbed in the collecting ducts. As we already know, the kidneys first generate hypo-osmotic tubular fluid in the loop of Henle. Then as the fluid subsequently flows through the collecting duct system, variable amounts of water are reabsorbed by allowing the tubular fluid to equilibrate to varying degrees with the surrounding interstitium. The final osmolality, and hence final volume, depends on the peak medullary osmolality and how closely the tubular osmolality approaches that value. We also know that equilibration with the interstitium is a function of water permeability in the collecting ducts via aquaporins under the control of the hormone ADH. Therefore, the regulation of water excretion that is independent of solute excretion focuses on controls over ADH secretion. Antidiuretic hormone (ADH; arginine vasopressin [AVP] in humans) is a small peptide (nine amino acids) produced by

CHAPTER 45 Regulation of Sodium and Water Excretion neurons in the hypothalamus. The cell bodies are located in the supraoptic and paraventricular nuclei of the hypothalamus, and their axons extend downward to the posterior pituitary gland, from which ADH is released into the blood (for more detail, see Chapter 61). There is normally a moderate rate of ADH secretion, allowing considerable water reabsorption in the renal collecting ducts and resulting in urine that is more concentrated than plasma. ADH secretion can increase or decrease from this level, giving the control system a bidirectional responsiveness. And because the collecting ducts are very sensitive to ADH, this allows the body to control water excretion rate over a very wide range. There are many sources of synaptic input to the ADH-secreting neurons. The most important signals originate in osmoreceptors and cardiovascular baroreceptors.

459

Excess H2O ingested

Body fluid osmolarity ( H2O concentration)

Firing by hypothalamic osmoreceptors

Posterior pituitary Vasopressin secretion

OSMORECEPTOR CONTROL OF ADH SECRETION

Plasma vasopressin

Plasma osmolality is one of the most tightly regulated variables in the body. It is set mainly by the ratio of ECF sodium (plus its associated anions) to water. Other solutes (e.g., glucose and potassium) make some contribution, but those other solutes are regulated for reasons other than their osmolality. Thus, except under unusual circumstances, variations in plasma osmolality reflect variations in sodium concentration. If the body keeps the inputs and outputs of sodium and water matched in lock step, osmolality remains constant. But inputs are often not matched. The major effect of gaining or losing water or salt without corresponding changes in the other is a change in the osmolality of the body fluids. When osmolality deviates from normal, strong reflexes come into play to change ADH secretion, and thus change the excretion of water. Key receptors that initiate reflexes controlling ADH secretion are osmoreceptors: neurons responsive to changes in osmolality. Most osmoreceptors are located in tissues surrounding the third cerebral ventricle. These tissues contain fenestrated capillaries, which allow rapid adjustment of interstitial composition when plasma composition changes. The hypothalamic cells that secrete ADH receive synaptic input from the osmoreceptors. Via these connections, an increase in osmolality increases their rate of ADH secretion. In turn, this causes water permeability of the collecting ducts to increase, water reabsorption is maximal, and a very small volume of highly concentrated (hyperosmotic) urine is excreted. By this means, relatively less filtered water than solute is excreted, which lowers body fluid osmolality toward normal. Conversely, decreased osmolality inhibits ADH secretion. For example, when a person drinks pure water, the excess water lowers the body fluid osmolality, which inhibits ADH secretion via the hypothalamic osmoreceptors. As a result, water permeability of the collecting ducts becomes very low, little water is reabsorbed from these segments, and a large volume of extremely dilute (hypo-osmotic) urine is excreted. In this manner, the excess water is rapidly eliminated and plasma osmolality is increased (see Figure 45–9).

Collecting ducts Tubular permeability to H2O

H2O reabsorption

H2O excretion

FIGURE 45–9 Mechanism for increased water excretion in response to a pure water load. Decreased plasma osmolality leads, via osmoreceptors, to decreased secretion of ADH (vasopressin), in turn causing decreased collecting duct water reabsorption and more water excretion. (Reproduced with permission from Widmaier EP, Raff H, Strang KT: Vander’s Human Physiology, 11th ed. McGraw-Hill, 2008.)

The osmoreceptor–ADH system is very sensitive, responding to an osmolality change of only 1 or 2 mOsm/kg. However, common perturbations are often a good deal greater than this. For example, if a 70-kg person consumes 1 L of pure water, ECF osmolality is reduced by about 7 mOsm/kg. And exercise for several hours on a warm day can increase ECF osmolality by 10 mOsm/kg or more. Such routine perturbations result in strong ADH responses that remain active until osmolality returns to its previous value. ADH has a plasma half-life of only a few minutes, so prolonged stimulation of water permeability in the kidneys requires continuous stimulation of the ADH-secreting neurons.

BARORECEPTOR CONTROL OF ADH SECRETION There is a second major influence on ADH secretion. This originates in systemic baroreceptors (the same ones that influence sympathetic drive to the kidneys). A decreased extracellular volume or major decrease in arterial pressure reflexively

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Plasma volume

Venous, atrial, and arterial pressures Reflexes mediated by cardiovascular baroreceptors Posterior pituitary Vasopressin secretion

Plasma vasopressin

Collecting ducts Tubular permeability to H2O

H2O reabsorption

H2O excretion

FIGURE 45–10 Decreased water excretion in response to decreased plasma volume. Low pressure sensed by neural baroreceptors reduces inhibition of the hypothalamic cells whose axons release ADH (vasopressin) from the posterior pituitary gland. The subsequent increase in ADH increases water reabsorption in the collecting ducts and helps preserve existing volume. (Reproduced with permission from Widmaier EP, Raff H, Strang KT: Vander’s Human Physiology, 11th ed. McGraw-Hill, 2008.)

activates increased ADH secretion. The response is mediated by neural pathways originating in cardiopulmonary baroreceptors, and if arterial pressure decreases, from arterial baroreceptors (see Figure 45–10). Decreased cardiovascular pressures cause less firing by the baroreceptors, which relieves inhibition of stimulatory pathways and results in more ADH secretion. In effect, the low cardiovascular pressures are interpreted as low volume, and the response of increased ADH appropriately serves to minimize loss of water (i.e., volume). Conversely, baroreceptors are stimulated by increased cardiovascular pressures, interpreted as excess volume, and this causes inhibition of ADH secretion. The decrease in ADH results in decreased reabsorption of water in the collecting ducts, and more excretion. The adaptive value of these baroreceptor reflexes is to help stabilize ECF volume and, hence, blood pressure. There is a second adaptive value to this reflex: large decreases in plasma volume, as might occur after a major hemorrhage, elicit such high concentrations of ADH—much higher than those needed to produce maximal antidiuresis— that the hormone is able to exert direct vasoconstrictor effects on arteriolar smooth muscle. The result is increased total

peripheral resistance, which helps restore arterial blood pressure independently of the slower restoration of body fluid volumes. Renal arterioles and mesangial cells also participate in this constrictor response, so a high plasma concentration of ADH, quite apart from its effect on tubular water permeability, may promote retention of both sodium and water by lowering GFR. We have described two different major afferent pathways controlling the ADH-secreting hypothalamic cells: one from baroreceptors and one from osmoreceptors. These hypothalamic cells are, therefore, true integrators, whose activity is determined by the total synaptic input to them. Thus, a simultaneous increase in plasma volume and decrease in body fluid osmolality causes strong inhibition of ADH secretion. Conversely, a simultaneous decrease in plasma volume and increase in osmolality produces very marked stimulation of ADH secretion. However, what happens when baroreceptor and osmoreceptor inputs oppose each other (e.g., if plasma volume and osmolality are both decreased)? In general, because of the high sensitivity of the osmoreceptors, the osmoreceptor influence predominates over that of the baroreceptors when changes in osmolality and plasma volume are small to moderate. However, a dangerous reduction in plasma volume will take precedence over decreased body fluid osmolality in influencing ADH secretion; under such conditions, water is retained in excess of solute even though the body fluids become hypo-osmotic (for the same reason, plasma sodium concentration decreases). In essence, when blood volume reaches a life-threatening low level, it is more important for the body to preserve vascular volume and thus ensure an adequate cardiac output than it is to preserve normal osmolality. The ADH-secreting cells also receive synaptic input from many other brain areas. Thus, ADH secretion and, hence, urine flow can be altered by pain, fear, and a variety of other factors, including drugs such as alcohol, which inhibits ADH release. However, this complexity should not obscure the generalization that ADH secretion is determined over the long term primarily by the states of body fluid osmolality and plasma volume. Figure 45–11 summarizes the major factors known to control renal sodium and water excretion in response to severe sweating. Sweat is a hypo-osmotic solution containing mainly water, sodium, and chloride. Therefore, sweating causes both a decrease in ECF volume and an increase in body fluid osmolality. The renal retention of water and sodium helps preserve existing water and salt that are depleted by sweating.

THIRST AND SALT APPETITE Large deficits of salt and water can be only partly compensated by renal conservation of these substances, and ingestion is the ultimate compensatory mechanism. The centers that mediate thirst are located in the hypothalamus (very close to those areas that produce ADH). The subjective feeling of thirst, which drives one to obtain and ingest water, is stimulated both

CHAPTER 45 Regulation of Sodium and Water Excretion

461

Begin Severe sweating

Loss of hypoosmotic salt solution

Plasma volume

Reflexes

GFR

Plasma aldosterone

Sodium excretion

Plasma osmolarity ( H2O concentration)

Plasma vasopressin

Reflexes

H2O excretion

FIGURE 45–11 Coordinated response to severe sweating. A combination of decreased ECF volume and increased plasma osmolality activates reflexes that preserve both salt and water. (Reproduced with permission from Widmaier EP, Raff H, Strang KT: Vander’s Human Physiology, 11th ed. McGraw-Hill, 2008.)

by reduced plasma volume and by increased body fluid osmolality. The adaptive significance of both is self-evident. Note that these are precisely the same changes that stimulate ADH production, and the receptors—osmoreceptors and the nerve cells that respond to the cardiovascular baroreceptors—that initiate the ADH-controlling reflexes are near those that initiate thirst. The thirst response, however, is significantly less sensitive than the ADH response. There are also other pathways controlling thirst. For example, dryness of the mouth and throat causes profound thirst, which is relieved by merely moistening them. Also, when animals such as the camel (and humans, to a lesser extent) become markedly dehydrated, they will rapidly drink just enough water to replace their previous losses and then stop. What is amazing is that when they stop, the water has not yet had time to be absorbed from the gastrointestinal tract into the blood. Some kind of metering of the water intake by the gastrointestinal tract has occurred, but its nature remains a mystery. Neural afferents from the pharynx and upper gastrointestinal tract are likely to be involved. Angiotensin II is yet another factor that stimulates thirst: by its direct effect on the brain. This hormone constitutes one of the pathways by which thirst is stimulated when ECF volume is decreased. Salt appetite, which is the analog of thirst, is also an extremely important component of sodium homeostasis in most mammals. It is clear that salt appetite in these species is innate and consists of two components: (1) hedonistic appetite and (2) regulatory appetite. In other words, (1) animals like salt and eat it whenever they can regardless of whether they are

salt deficient and (2) their drive to obtain salt is markedly increased in the presence of deficiency. The significance of these animal studies for humans, however, is unclear. Salt craving does seem to occur in humans who are severely salt depleted, but the contribution of such regulatory salt appetite to everyday sodium homeostasis in healthy persons is probably slight. On the other hand, humans do seem to have a strong hedonistic appetite for salt, as manifested by almost universally large intakes of sodium whenever it is cheap and readily available. Thus, the average American intake of salt is 10–15 g per day even though humans can survive quite normally on less than 0.5 g per day. As pointed out previously, a large salt intake may be a contributor to the pathogenesis of hypertension in susceptible individuals.

CLINICAL CORRELATION A 57-year-old man has a long history of smoking and hypertension, but in prior years, has refused the use of any medications for treatment. Six months ago, he suffered a fall from a tractor and injured the right side of his back. He recovered well, but 2 weeks ago, his blood pressure was 147/102, and his physician finally convinced him to start on an ACE inhibitor. At this follow-up visit, his blood pressure was only mildly increased, but he was feeling very tired and agitated, without any specific symptoms. Laboratory analysis of his blood revealed azotemia (high levels of creatinine and urea), and he was referred to a nephrologist.

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Further tests, after taking him off all medications, showed activation of the RAS. When he was put back on the ACE inhibitor, his renin levels increased markedly, but not his aldosterone. At this point, a renal angiogram indicated moderate left renal artery blockage and major right renal artery blockage. His diagnosis is renovascular hypertension, caused by activation of the RAS system. He has generalized atherosclerosis, but the major problem is stenosis (narrowing) of his right renal artery, perhaps exacerbated by trauma during his accident 6 months prior. Decreased renal perfusion pressure activates renin secretion from his right kidney, in turn leading to increased angiotensin II and aldosterone. This is causing a significant increase in blood pressure. The high blood pressure and levels of angiotensin II suppress secretion of renin from his left kidney, but this makes no difference in the face of the high secretion from the right kidney. The increased pressure in the left renal artery maintains total GFR sufficiently high to provide adequate excretion of nitrogenous waste. However, after an ACE inhibitor is given, his levels of angiotensin II and aldosterone decrease. Consequently, his systemic and left renal artery pressure decreases, resulting in a decrease in GFR and excretion of nitrogenous waste, leading to the azotemia. Furthermore, when he is given an ACE inhibitor and there are decreased levels of angiotensin II, the suppressive effect that the usually high angiotensin II is having on his left kidney is removed, and renin secretion from the left kidney rises markedly. Renal artery stenosis is sometimes treated by renal artery angioplasty and placement of a stent to maintain the patency of the renal artery.

CHAPTER SUMMARY ■

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Sodium and water excretion are regulated primarily to meet the needs of the cardiovascular system via preservation of vascular volume, blood pressure, and plasma osmolality. Baroreceptors at various sites inform the kidneys of vascular pressures and volume status. Angiotensin II, produced by local and systemic RAS, is a crucial regulator of sodium excretion and blood pressure via its actions in the kidneys, peripheral vasculature, and adrenal glands. Sodium excretion is regulated by both the rate of filtration (GFR) and rate of reabsorption. ECF volume status is a major determinant of sodium excretion.

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■

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A major action of angiotensin II is to stimulate sodium reabsorption via Na–H antiporter activity in the proximal tubule. Elevated renal artery pressure leads to increased sodium excretion (pressure natriuresis) without external signals. Long-term regulation of sodium excretion and, therefore, blood pressure centers on the actions of aldosterone in the distal nephron. Water excretion tends to parallel solute excretion, but is also regulated independently by controlling water reabsorption in the collecting ducts. ADH secretion is regulated by plasma osmolality via hypothalamic osmoreceptors, and blood pressure, via the baroreceptor– vasomotor center system.

STUDY QUESTIONS 1. Which of the following cell types are not nerve cells? A) pituitary cells that secrete ADH B) baroreceptors located in pulmonary vessels C) baroreceptors located in the arch of the aorta D) intrarenal baroreceptors 2. In the normal RAS system leading to the production of aldosterone, the rate-limiting step is A) the production of angiotensin I. B) the production of angiotensinogen. C) the activity of ACE. D) the responsiveness of the adrenal gland to angiotensin II. 3. A person eats a large bag of very salty potato chips with no beverage. Which response is most likely to ensue? A) movement of aquaporins into the membrane of cortical collecting duct principal cells B) enhanced activity of Na–H antiporters in the proximal tubule C) enhanced activity of Na,K-ATPase pumps in collecting duct principal cells D) decreased levels of natriuretic peptides in the blood 4. In response to a major hemorrhage A) GFR increases. B) ADH secretion is reduced. C) granular (juxtaglomerular) cells are stimulated by neural input. D) neural baroreceptor firing rate increases. 5. Tubuloglomerular feedback contributes to the regulation of A) GFR. B) sympathetic neural activity. C) ADH secretion. D) ACE activity.

46 C

Regulation of Potassium Balance Douglas C. Eaton and John P. Pooler

H A

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State the normal balance and distribution of potassium between cells and extracellular fluid. Describe how potassium moves between cells and the extracellular fluid, and how, on a short-term basis, the movement protects the extracellular fluid from large changes in potassium concentration. Describe how plasma levels of potassium do not always reflect the status of total body potassium. State how insulin and epinephrine influence the cellular uptake of potassium, and identify the situations in which these hormonal influences are most important. State the relative amounts of potassium reabsorbed by the proximal tubule and thick ascending limb of Henle’s loop regardless of the state of potassium intake. Describe how nephron segments beyond the thick ascending limb can manifest net secretion or reabsorption; describe the role of principal cells and intercalated cells in these processes. List inputs that control the rate of potassium secretion by the distal nephron. Describe the actions of renal outer medulla (ROMK) and BK potassium channels in conditions of low, normal, and high potassium excretions. Describe how changes in plasma potassium influence aldosterone secretion. State the effects of most diuretic drugs and osmotic diuretics on potassium excretion. Describe the association between perturbations in acid–base status and the plasma potassium level.

REGULATION OF POTASSIUM BETWEEN THE INTRACELLULAR AND EXTRACELLULAR COMPARTMENTS Potassium, like all other important ions, is distributed between the intracellular fluid and extracellular fluid (ECF) of the body. The vast majority of potassium is intracellular, and only about 2% of total body potassium is in the ECF. This small fraction, however, is absolutely crucial for body function, and the con-

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centration of potassium in the ECF is a closely regulated quantity. Major increases and decreases (called hyperkalemia and hypokalemia) from the normal plasma values of 3.5–5 mEq/L are cause for medical intervention. The importance of maintaining this concentration relatively constant stems primarily from the role of potassium in the excitability of nerve and muscle, especially the heart (review Chapters 4 and 23). Given that the vast majority of body potassium is within cells, the extracellular potassium concentration is crucially dependent on (1) the total amount of potassium in the body and (2) the distribution of this potassium between the extracellular and intracellular fluid compartments. Total body

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potassium is determined by the balance between potassium intake and excretion. Healthy individuals remain in potassium balance, as they do in sodium balance, by excreting an amount of urinary potassium equal to the amount of potassium ingested minus the small amounts eliminated in the feces and sweat. Normally, potassium losses via sweat and the gastrointestinal tract are small, but very large quantities can be lost from the digestive tract during vomiting or diarrhea. The control of renal potassium handling is the major mechanism by which total body potassium is maintained in balance. The fact that most body potassium is intracellular follows strictly from the size and properties of the intracellular and extracellular compartments. About two thirds of the body fluids are intracellular (the collective cytosolic volume of all the cells in the body), and typical cytosolic potassium concentrations are about 140–150 mEq/L. One third of the body fluids are extracellular, with a potassium concentration of about 4 mEq/L. In a clinical setting, only the extracellular concentration can be measured (the intracellular potassium is, in a sense, hidden behind the wall of the cell membrane). Furthermore, the extracellular value does not necessarily reflect total body potassium. A patient may, for example, be hyperkalemic and yet at the same time be depleted of total body potassium. The high level of potassium within cells is maintained by the collective operation of the Na,K-ATPase plasma membrane pumps, which actively transport potassium into cells. Because the amount of potassium in the extracellular compartment is very small (40–60 mEq total), even very slight shifts of potassium into or out of cells produce large changes in extracellular potassium concentration. Similarly, a meal rich in potassium (e.g., steak, potato, and spinach) could easily double the extracellular concentration of potassium if most of that potassium were not transferred from the blood to the intracellular compartment. It is crucial, therefore, that dietary loads be taken up into the intracellular compartment rapidly to prevent major changes in plasma potassium concentration. The tissue contributing most to the sequestration of potassium is skeletal muscle, simply because it contains the largest collective intracellular volume. Muscle effectively buffers extracellular potassium by taking up or releasing it and keeping the plasma potassium concentration close to normal. On a moment-tomoment basis, this is what protects the ECF from large swings in potassium concentration. Major factors involved in these homeostatic processes include insulin and epinephrine, both of which cause increased potassium uptake by muscle (and certain other cells) through stimulation of plasma membrane Na,K-ATPases. Another influence is the GI tract, which contains an elaborate neural network (the “gut brain”) that sends signals to the central nervous system. It also contains a complement of enteroendocrine cells that releases an array of peptide hormones. Together these neural and hormonal signals affect many target organs, including the kidneys (see later discussion) in response to dietary input. The increase in plasma insulin concentration after a meal is a crucial factor in moving ingested and absorbed potassium

into cells rather than allowing it to accumulate in the ECF. This new potassium then slowly comes out of cells between meals to be excreted. Moreover, a large increase in plasma potassium concentration facilitates insulin secretion at any time, and the additional insulin induces greater potassium uptake by the cells, a negative feedback system for opposing acute elevations in plasma potassium concentration. In the natural order of things, insulin also stimulates glucose uptake and metabolism by cells: a necessary source of energy to drive the insulin-activated Na,K-ATPase responsible for moving potassium into cells. The effect of epinephrine on cellular potassium uptake is probably of greatest physiological importance during exercise when potassium moves out of muscle cells that are rapidly firing action potentials. In fact, very intense intermittent exercise such as wind sprints can transiently double plasma potassium. However, at the same time, exercise increases adrenal medullary secretion of epinephrine, which stimulates potassium uptake by muscle and other cells. Similarly, trauma causes loss of potassium from damaged cells, and epinephrine released due to stress stimulates other cells to take up plasma potassium. Still another influence on the distribution of potassium between the intracellular fluid and ECF is the ECF hydrogen ion concentration: an increase in ECF hydrogen ion concentration (acidemia; see Chapter 47) is often associated with net potassium movement out of cells, whereas a decrease in ECF hydrogen ion concentration (alkalemia) causes net potassium movement into them. It is as though potassium and hydrogen ions were exchanging across plasma membranes (i.e., hydrogen ions moving into the cell during acidemia and out during alkalemia and potassium doing just the opposite), but the precise mechanism underlying these “exchanges” has not yet been clarified. However, like the effect of insulin, it probably involves an inhibition (acidemia) or activation (alkalemia) of the Na,KATPase.

RENAL POTASSIUM HANDLING OVERVIEW Although other tissues play an important role in the momentto-moment control of plasma potassium concentration, in the final analysis, the kidney determines total body potassium content. Therefore, understanding potassium handling by the kidneys is the key to understanding potassium balance. Potassium is freely filtered into Bowman’s space. Under all conditions, almost all the filtered load (~90%) is reabsorbed by the proximal tubule and thick ascending limb of the loop of Henle. Then, if the body is trying to conserve potassium, most of the rest is reabsorbed in the distal nephron and medullary collecting ducts, leaving almost none in the urine. In contrast, if the body is ridding itself of potassium, a large amount is secreted in the distal nephron, resulting in a large excretion. When secretion occurs at high rates, the amount excreted may

CHAPTER 46 Regulation of Potassium Balance

TABLE 46–1 Summary of tubular potassium transport.

Transport

Normal- or Highpotassium Diet

Low-potassium Diet or Potassium Depletion

Proximal tubule

Reabsorption (60–80%)

Reabsorption (55%)

Thick ascending limb

Reabsorption (5–25%)

Reabsorption (30%)

Distal convoluted tubule

Secretion

Reabsorption

Principal cells, connecting tubule, and cortical collecting duct

Substantial secretion (>15%)

Little secretion

H,K-ATPase-containing intercalated cells, cortical collecting duct

Reabsorption (10%)

Reabsorption (10%)

H,K-ATPase-containing cells, medullary collecting duct

Reabsorption (5%)

Reabsorption (5%)

Percentages are in reference to the filtered load of potassium. H, hydrogen; K, potassium; ATPase, adenosine triphosphatase. Reproduced with permission from Eaton DC, Pooler JP: Vander’s Renal Physiology, 7th ed. New York, NY: Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2009.

exceed the filtered load. The chief means of regulation lies in control of secretion in parts of the nephron beyond the loop of Henle. Let us look at potassium handling by various nephron segments and then address the issue of control. Since potassium is freely filtered, a normal plasma level of 4 mEq/L and GFR of 150 L per day or more results in a daily filtered load of about 600 mEq per day. The subsequent events in various tubule segments are summarized in Table 46–1. In the proximal tubule, about 65% of the filtered load is reabsorbed, mostly via the paracellular route. Much of the flux is driven by the concentration gradient set up when water is reabsorbed (thus concentrating all solutes remaining in the tubular lumen). Some may also move by entrainment with the rapidly reabsorbed water (solvent drag). Either way, this accounts for major potassium absorption in an essentially unregulated manner. In the loop of Henle, there is additional reabsorption. The major events take place in the thick ascending limb, where the Na–K–2Cl multiporter in the apical membrane reabsorbs potassium (see Figure 44–3). Some of this potassium is returned to the lumen across the apical membrane via potassium channels, and the rest exits the cells across the basolateral membrane by a combination of passive flux through channels and through symporters with chloride, resulting in net transcellular reabsorption. Some potassium is also reabsorbed by the paracellular route in this segment, driven by a lumen-positive voltage. Usually about 25% of the filtered load is reabsorbed in the thick ascending limb, so that only about 10% is passed on to the distal nephron. In the distal nephron, there is continuous reabsorption if dietary loads are very small, but a major superimposed secretion that greatly exceeds the amount reabsorbed when dietary

465

loads are high. It is in these distal segments where most regulation of potassium excretion is exerted. The distal nephron is composed of a number of segments, including the distal convoluted tubule, connecting tubule, initial collecting tubule, and cortical collecting duct; that is, all of the tubule segments between the end of the thick ascending limb and the medullary collecting duct. It is not possible to finely differentiate between these segments in terms of function, although the connecting tubule stands out as being particularly important in potassium handling because of its rich complement of transport elements. It appears that most of the potassium secretion occurs prior to segments where most of the water is absorbed (cortical collecting duct). Finally, the medullary collecting ducts reabsorb small amounts of potassium under all conditions. When the sum of upstream processes has already reabsorbed almost all the potassium, the medullary collecting ducts bring the final urine excretion down to a few percent of the filtered load, for an excretion of about 10–15 mEq per day. On the other hand, if upstream segments are secreting avidly, the modest reabsorption in the medullary collecting ducts does little to prevent an excretion that can reach 1,000 mEq per day. Figure 46–1A and B depicts the overall renal handling of potassium in different tubule regions in conditions of high and low potassium excretion. A complication in the renal handling of potassium in all regions, specifically including the proximal tubule and thick ascending limb, is that its active transport is always coupled to the active transport of another solute. Active influx of potassium across the basolateral membrane via the ubiquitous Na,K-ATPase is coupled to efflux of sodium, while influx of potassium across apical membranes via H–K antiporters is accompanied by efflux of protons. Thus, in describing the renal handling of potassium in various segments, we always have to keep in mind the fate of these other solutes. In the proximal tubule, the Na,K-ATPase in the basolateral membrane is very active in moving sodium from the cell to the interstitium, necessitating that potassium be simultaneously taken up from the interstitium. Since we know that potassium is being put into the interstitium surrounding the proximal tubule, this pumped potassium must therefore recycle right back to the interstitium by passive flux through channels in the basolateral membrane. In the thick ascending limb, the interaction with sodium is even more complicated. As mentioned above, potassium is actively transported into the cells across both membranes and exits the cells passively across both membranes. It is pumped into the epithelial cells from the tubular lumen with sodium via Na–K–2Cl antiporters and from the interstitium via the Na,K-ATPase. Since there is far less potassium than sodium in the lumen, potassium must recycle back to the lumen by passive channel flux to keep a supply of potassium available to run the multiporter with sodium. Otherwise, sodium reabsorption would be limited only to the amount of potassium present in the tubular fluid. Quantitatively, the sum of all these transcellular and paracellular processes is net reabsorption of about 25% of the filtered load.

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1

1 3

2

3

2 6

5

5

4

A

4

B

FIGURE 46–1 Potassium transport at different locations of the tubule in conditions of low or high excretion. In low excretion (A) the majority of filtered potassium is reabsorbed in the proximal tubule, mainly by the paracellular route (1). In the thick ascending limb (2) most of the rest is reabsorbed, mostly by the transcellular route. In the cortical (3) and medullary collecting duct (4) there is some additional reabsorption via intercalated cells. Some of the potassium reabsorbed into the medullary interstitium recycles back into the thin limbs of the loop of Henle (5). In high excretion (B) the events in most regions of the tubule are the same as when there is little potassium excretion, but in the distal nephron, particularly in the connecting tubule, there is major secretion (6) that in some cases is greater than the sum of the reabsorptive processes. (Modified with permission from Eaton DC, Pooler JP: Vander’s Renal Physiology, 7th ed. New York, NY: Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2009.)

SECRETION IN THE DISTAL NEPHRON AND ITS REGULATION There are two cell types in the epithelium of the distal nephron: principal cells (about 70% of the cells) and intercalated cells. The intercalated cells are further subdivided into type A (more numerous) and type B (sparse) intercalated cells. The principal cells secrete potassium at highly variable rates, while the type A intercalated cells reabsorb potassium. The principles governing both secretion and reabsorption are straightforward. Secretion of potassium by principal cells involves the uptake of potassium from the interstitium via the Na,KATPase and secretion into the tubular lumen through channels (Figure 46–2). Type A intercalated cells reabsorb potassium via the H,K-ATPase in the apical membrane, which actively takes up potassium from the lumen. They then allow potassium to enter the interstitium across the basolateral membrane via potassium channels. Regulation of potassium excretion involves multiple controls over the secretory processes in the distal nephron, something like a passenger van where everyone in it has an accelerator and a brake pedal. As is the case with regulation of sodium excretion, we cannot predict just how these controls operate in every situation. Fortunately, with potassium as well as sodium, the healthy kidneys do a remarkable job of increasing potassium excretion in response to high dietary loads and reducing excretion in the face of restricted diets. Much of the regulation involves controlling the activity of potassium channels. The kidneys and other body organs express numerous potassium channel species; for simplicity we do not usually differentiate between types. However, in principal cells of the

distal nephron, two types of channels stand out as being those that secrete potassium in a regulated manner: ROMK (standing for renal outer medulla, because that is where they were first identified) and BK (since each channel has a “big” capacity to secrete potassium, also called maxi-K). While ROMK and BK channels both conduct potassium, they play different roles and are regulated by quite different mechanisms. At very low dietary loads of potassium, there is virtually no secretion

LUMEN

INTERSTITIUM

amiloride aldosterone Na+

Na+

ATP Na+ K+

K+

K+

K+

Na+ K+

K+

FIGURE 46–2 Generalized pathway for potassium secretion by principal cells. Potassium secretion is tied to sodium reabsorption via the Na,K-ATPase. The drug amiloride inhibits sodium entry, and therefore inhibits potassium secretion. Aldosterone stimulates both sodium and reabsorption and potassium secretion at multiple points. (Modified with permission from Eaton DC, Pooler JP: Vander’s Renal Physiology, 7th ed. New York, NY: Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2009.)

CHAPTER 46 Regulation of Potassium Balance

Low K excretion

BK ROMK (sequestered) (closed)

Normal K excretion

High K excretion

ROMK (open)

ROMK (open)

BK (open)

K

K

BK (closed)

K

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FIGURE 46–3 Activity of ROMK and BK potassium channels in principal cells under different conditions. When the body is conserving potassium and little is being excreted, ROMK channels are mostly sequestered in intracellular vesicles and BK channels are closed; thus, there is virtually no secretion. Under modest potassium loads (normal conditions), ROMK channels secrete potassium, while BK channels remain closed. When potassium excretion is very high, as on a high-potassium diet, ROMK channel activity is maximized and BK channels are open, allowing substantial secretion. (Reproduced with permission from Eaton DC, Pooler JP: Vander’s Renal Physiology, 7th ed. New York, NY: Lange Medical Books/ McGraw-Hill, Medical Pub. Division, 2009.)

by either kind of channel. ROMK channels are sequestered in intracellular vesicles and BK channels are closed. At normal potassium loads, ROMK channels are moved to the apical membrane and secrete potassium. BK channels are still closed, held in reserve and ready to respond to appropriate signals when needed. At high excretion rates, both types of channel are present in the luminal membrane and avidly secreting potassium (Figure 46–3). Figure 46–4 shows factors known to influence the secretion, and thus the ultimate excretion of potassium. The following provides a brief description of how specific factors affect potassium excretion: 1. Plasma potassium. The role of plasma potassium is the most understandable influence. First, the filtered load is directly proportional to plasma concentration. Second, the environment of the principal cells, that is, the cortical interstitium, has a potassium concentration that is nearly the same as in plasma. The Na,K-ATPase that takes up potassium is highly sensitive to the potassium concentration in this space, and varies its pump rate up and down when potassium levels in the plasma vary up and down.

High potassium diet

Thus, plasma potassium concentration does exert an influence on potassium excretion, but is not the dominant factor under normal conditions. 2. Aldosterone. We discussed the role of aldosterone in regulating sodium excretion in Chapter 45. Here we describe its role in potassium excretion. One stimulator of aldosterone secretion is an increase in plasma potassium concentration. This is a direct action of potassium on the adrenal cortex and does not involve the renin–angiotensin system. Aldosterone, as well as increasing expression of the Na,K-ATPase, also stimulates expression of ROMK channels in the distal nephron. Both actions have the effect of increasing potassium secretion. Greater pumping by the Na,K-ATPase supplies more potassium from the interstitium to the cytosol of the principal cells, and more ROMK channels provide more pathways for secretion. 3. Delivery of sodium to the distal nephron. Any change in sodium handling prior to the distal nephron determines how much is sent on from the thick ascending limb, that is, delivered to the distal nephron. Changes in upstream handling of sodium include changes in filtered load and reab-

High flow rate in distal nephron

High Na delivery to distal nephron Aldosterone

Nonchloride anions in distal nephron

High plasma potassium

Potassium secretion in distal nephron

FIGURE 46–4

Factors that increase secretion of potassium by principal cells as described in the text. (Modified with permission from Eaton

DC, Pooler JP: Vander’s Renal Physiology, 7th ed. New York, NY: Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2009.)

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sorption in prior segments. Sodium delivery influences potassium secretion because more sodium delivered means more sodium taken up by principal cells, and therefore more sodium pumped out by the Na,K-ATPase, in turn causing more potassium to be pumped in. The increased intracellular potassium can just recycle back to the interstitium, but the usual result is more potassium secretion. 4. Distal nephron flow rate. The role of flow rate in regulating potassium secretion is a story by itself. Increased flow is detected by mechanosensitive elements of the principal cells. This includes bending of the central cilium that protrudes from the apical surface into the tubule lumen. Bending of the central cilium initiates intracellular release of calcium and activation of BK channels. Under most conditions, increased delivery of sodium is the chief cause of increased flow, because the sodium is accompanied by water. Thus, increased delivery of sodium implies increased flow. Increased flow has another effect. By sweeping away potassium that reaches the tubule by secretion, luminal potassium concentration is kept low enough to preserve a favorable concentration gradient for secretion. 5. Concentration of nonchloride anions. In order for principal cells to secrete potassium there must be a route (open channels and/or functioning transporters) and driving forces (electrochemical gradients). In addition to the majority secretion via potassium channels, a smaller component involves secretion via potassium-chloride symport. Under conditions in which the luminal chloride concentration is low due to replacement of luminal chloride with anions that are not usually in high concentration, the effect is to increase the electrochemical gradient for chloride secretion. In turn this increases the normally modest secretion of potassium via potassium-chloride symport. 6. Dietary potassium. The influence of dietary potassium on renal function is both the most obvious regulator of potassium excretion and the least understood. A major task of the kidneys is to maintain potassium balance by increasing and decreasing potassium excretion in parallel with dietary load. The healthy kidneys do this very well. The problem is in understanding the signaling—how do the kidneys know how much potassium a person has consumed? While very large potassium loads can increase plasma potassium somewhat, the changes in excretion associated with diet do not seem to be accounted for on the basis of changes in either plasma potassium or the other identified factors. However, the previously mentioned gastrointestinal signals influence not only the cellular uptake of potassium absorbed from the GI tract, but also renal handling of potassium, and seem to be one of the links between dietary load and excretion. One of the manifestations of changing dietary loads is to regulate the distribution of ROMK channels between the apical membrane and intracellular storage, that is, high-potassium diets lead to insertion of apical channels and therefore higher potassium secretion. In contrast, during periods of prolonged low potassium ingestion, there are few ROMK channels in

the apical membrane. Another adaptation to prolonged periods of low potassium ingestion is an increase in H,KATPase activity in intercalated cells, resulting in even more efficient reabsorption of filtered potassium.

PERTURBATIONS IN RENAL HANDLING OF POTASSIUM A potential problem in the renal handling of potassium that is not a problem in healthy kidneys is the simultaneous balance of sodium and potassium. Given that so much of the transport of these ions is by coupled mechanisms, it is remarkable that the kidneys can deal with every combination of dietary load: both high, both low, one high, etc. This is all the more remarkable when we consider that aldosterone is a regulator of both. If a person is consuming very little sodium or potassium, we expect, in order to preserve body stores of sodium, for aldosterone levels to be high enough to stimulate avid reabsorption of sodium. But this should also lead to avid secretion of potassium, which is an unwanted action since the body is also trying to conserve potassium. The answer is simply that potassium cannot be secreted unless there are open apical channels. If the actions of intracellular signaling cascades have caused most of the ROMK channels to be sequestered in intracellular vesicles, then potassium that is taken up from the interstitium via the Na,K-ATPase recycles back via basolateral channels to the interstitium and is not secreted.

Effects of Diuretics Diuretics are agents that increase urine flow and reduce ECF volume, usually by increasing the renal excretion of sodium. Most diuretics have the unwanted side effect of simultaneously increasing the renal excretion of potassium. Potassium excretion is almost always increased in individuals undergoing osmotic diuresis (high filtration of solute that is not reabsorbed) or treatment with diuretics that block sodium reabsorption in the proximal tubule, loop of Henle, or distal convoluted tubule (i.e., sites that are upstream from the principal cells). All of these events increase flow rate past the potassium-secreting principal cells, which is a major stimulator of potassium secretion. The potassium loss may cause severe potassium depletion (see Figure 46–5). Let us integrate this information about diuretics with our understanding of the action of aldosterone. High aldosterone levels in individuals with heart failure or other diseases of secondary hyperaldosteronism generally do not cause potassium hypersecretion because these patients simultaneously have low fluid delivery to the distal nephron. However, consider what happens when such persons are treated with diuretics to eliminate their retained sodium and water. The diuretics increase fluid delivery to the distal nephron, and now patients have both increased aldosterone and increased flow. This combination causes marked increases in potassium secretion and excretion. To prevent the potassium loss, drugs that block the renal actions of aldosterone may be given; such drugs are

CHAPTER 46 Regulation of Potassium Balance

469

Diuretics affecting proximal tubule, loop of Henle, or distal convoluted tubule

Inhibition of NaCI reabsorption Inhibition of potassium reabsorption Inhibition of water reabsorption

Rate of fluid delivery to cortical collecting duct

Potassium secretion

Potassium excretion

Potassium depletion

FIGURE 46–5 Pathway by which diuretic drugs affecting the proximal tubule, loop of Henle, or distal convoluted tubule cause potassium depletion. The decrease in potassium reabsorption is a less important factor in causing the increased potassium excretion than the increased secretion by the principal cells of the cortical collecting ducts. (Modified with permission from Eaton DC, Pooler JP: Vander’s Renal Physiology, 7th ed. New York, NY: Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2009.)

weak diuretics because they block only the aldosteronestimulated fraction of sodium reabsorption with its small amount of associated water reabsorption. However, unlike most common diuretics, they are “potassium sparing” because they simultaneously block aldosterone’s stimulation of potassium secretion. Another class of “potassium-sparing” diuretics blocks sodium channels in the principal cells of the cortical collecting duct, preventing sodium entry from lumen to cell. Therefore, the basolateral membrane Na,K-ATPase pumps slow their uptake of potassium in exchange for sodium, and potassium secretion across the apical membrane also slows. To recapitulate the effects of diuretics: increased delivery of sodium resulting from the filtration of osmotic diuretics or from blocking sodium absorption upstream from the distal nephron increases potassium secretion; however, blocking sodium reabsorption in the distal nephron does not.

Effects of Acid–Base Changes Primary acid–base disturbances are a major cause of secondary potassium imbalances (and, as discussed in Chapter 47, imbalances in body potassium can perturb acid–base status). The existence of an elevated plasma pH (alkalemia) is often (i.e., frequently, but not always) associated with hypokalemia.

Similarly, low plasma pH (acidemia) is usually associated with hyperkalemia. Whether these relations between acid– base and potassium actually occur in a particular patient depends on many factors, including the cause of the acid– base disturbance. There are two known reasons for the effects of acid–base status on potassium. First, changes in the extracellular concentration of hydrogen ions lead to a de facto exchange of these ions with cellular cations, the most important of which is potassium. During an alkalemia, for example, the low extracellular hydrogen ion concentration induces the efflux of hydrogen ions that are normally bound to intracellular buffers. The loss of the positively charged hydrogen ions is balanced by the uptake of other cations, in this case potassium. Thus, an alkalemia (with hydrogen ions leaving tissue cells to replenish the loss from the ECF) induces cells to take up potassium, causing a hypokalemia. Conversely, a low pH with a concomitant cellular uptake of hydrogen ions (“cellular buffering”) often leads cells to dump potassium, causing a hyperkalemia. In addition to these exchanges of potassium for hydrogen ions, there is an effect of intracellular pH on cellular Na,K-ATPase and potassium channel activity. Low intracellular pH inhibits pumps everywhere, allowing potassium to escape from cells (particularly muscle cells) and increase plasma potassium. Ordinarily, the

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increase in plasma potassium would stimulate potassium uptake by the Na,K-ATPase in principal cells, but low intracellular pH also inhibits the pumps there as well as luminal membrane potassium channels. Therefore, the principal cells respond inappropriately and do not effectively secrete the excess plasma potassium (paradoxical potassium retention). A high intracellular pH reverses these effects and relieves this inhibition (effectively stimulating the pump and the potassium channels). Alkalemia promotes potassium loss and contributes to the production of a hypokalemia. Thus, a patient suffering from alkalemia (induced, for example, by excessive base input) will manifest increased urinary excretion of potassium solely as a result of the alkalemia and will, therefore, become potassium deficient. Finally, it should be emphasized that although alkalemia is often associated with hypokalemia, and acidemia is often associated with hyperkalemia, there are exceptions when this is not the case

promotes the excretion of sodium by blocking sodium channels in the distal nephron without simultaneously increasing potassium excretion. Follow-up work finds hypersecretion of aldosterone by the left adrenal gland due to a benign tumor (adenoma), and the left adrenal gland is removed surgically.

CHAPTER SUMMARY ■

■

■

■

CLINICAL CORRELATION A 60-year-old African American woman has a history of hypertension going back several decades, but blood pressure medications have kept it under control and she has generally been in good health. Recently, however, she has been feeling fatigued and has occasional problems with constipation. Furthermore, her blood pressure medications no longer seem to be effective. Most recently, she has experienced shortness of breath (dyspnea) on several occasions. On a visit to her physician, her blood pressure is 142/101. Laboratory work shows a normal plasma sodium of 144 mEq/L and a low potassium of 2.9 mEq/L (clearly hypokalemic). A disorder of aldosterone secretion is suspected, and assays for plasma aldosterone and renin are ordered. In the meantime, the patient is put on an angiotensin receptor blocker and the diuretic amiloride, which is a potassium-sparing diuretic. Laboratory results reveal an increased plasma aldosterone and low renin. The reasons for the long-standing hypertension are unknown, and the new symptoms were still too vague to permit a definite diagnosis. However, given the clearly identified hypokalemia, those symptoms are consistent with muscular problems that are created by low plasma potassium. This information, combined with the refractory hypertension, points to an overabundance of aldosterone. The aldosterone drives excessive distal nephron secretion of potassium, accounting for the hypokalemia, and the excessive reabsorption of sodium leads to an upward creep in arterial pressure. The combination of high aldosterone and low renin identifies this as a case of primary hyperaldosteronism (high levels of aldosterone in spite of low plasma renin; see Chapter 65). The initial precautionary treatment with the angiotensin receptor blocker did not correct the high aldosterone, indicating that the high secretion is being driven by something other than angiotensin II. The amiloride is helpful because it

■

Only a small fraction of body potassium is extracellular, and the extracellular concentration may not be a good indicator of total body potassium status. On a short-term basis, uptake and release of potassium by tissue cells prevent large swings in extracellular potassium concentration. Overall renal handling is accomplished by reabsorbing nearly all filtered potassium and then secreting an amount of potassium that maintains balance between ingestion and excretion. It is mainly the principal cells of the connecting tubule and cortical collecting duct that alter rates of potassium secretion. Potassium secretion (and thus excretion) is increased by high sodium delivery to the distal nephron, particularly when this is caused by diuretics acting upstream.

STUDY QUESTIONS 1. Potassium excretion is controlled mainly by controlling the rate of A) potassium reabsorption in the proximal tubule. B) potassium reabsorption in the distal nephron. C) potassium secretion in the proximal tubule. D) potassium secretion in the distal nephron. 2. In the thick ascending limb A) the net amounts of potassium and sodium that are reabsorbed are the same. B) the major pathway for moving potassium from lumen to cell is via the Na,K-ATPase. C) most of the potassium that is absorbed into the cells leaks back into the lumen via potassium channels. D) the major pathway for moving potassium from cell to interstitium is via the Na–K–2Cl multiporter. 3. For which substance is it possible to excrete more than is filtered? A) sodium B) potassium C) chloride D) it is not possible to excrete any of the above-mentioned ions in amounts greater than the filtered loads 4. After a potassium-rich meal, the key action of insulin that prevents a large increase in plasma potassium is to A) decrease absorption of potassium from the GI tract. B) increase uptake of potassium by tissue cells. C) increase the filtered load of potassium. D) increase tubular secretion of potassium. 5. A key role of “BK” potassium channels in the kidney is to A) reabsorb potassium when the body is depleted of potassium. B) recycle potassium in the thick ascending limb. C) secrete potassium when distal nephron flow rate is very low. D) help the body excrete potassium in response to very large loads.

47 C

Regulation of Acid–Base Balance Douglas C. Eaton and John P. Pooler

H A

P

T

E

R

O B J E C T I V E S ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■

State the Henderson–Hasselbalch equation for the carbon dioxide– bicarbonate buffer system. State the major sources for the input of fixed acids and bases into the body, including metabolic processes and activities of the gastrointestinal tract. Describe how the input of fixed acids and bases affects body levels of bicarbonate. Explain why body levels of carbon dioxide are usually not altered by the input of fixed acids and bases. Explain why some low pH fluids alkalinize the blood after they are metabolized. Describe the reabsorption of filtered bicarbonate by the proximal tubule. Describe how bicarbonate is excreted in response to an alkaline load. Describe how excretion of acid and generation of new bicarbonate are linked. Describe how the titration of filtered buffers is a means of excreting acid. Describe how the conversion of glutamine to ammonium and subsequent excretion of ammonium accomplishes the goal of excreting acid. Describe how the kidneys handle ammonium that has been secreted in the proximal tubule. State how total acid excretion is related to titratable acidity and ammonium excretion. Define the four categories of primary acid–base disturbance and the meaning of compensation. Describe the renal response to respiratory acid–base disorders. Identify nonrenal problems that may cause the kidneys to generate a metabolic alkalosis.

OVERVIEW Regulating acid–base balance is a key task of the body, and perturbations of acid–base balance are among of the most important problems confronting clinicians in a hospital setting. Regulating blood levels of acids and bases is a partnership between the kidneys and the respiratory system (see Chapter 37).

Ch47_471-484.indd 471

It is essential for the body to regulate the concentration of free protons (hydrogen ions) in the ECF. While most substances regulated by renal processes exist at plasma levels in the millimolar range or greater, the normal hydrogen ion concentration is a seemingly miniscule 40 nmol/L (1 nmol is one millionth of a millimole). Even though very small, this level is crucial for body function. As functional groups on membrane proteins protonate and deprotonate, the resulting change in

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charge affects the shape, and therefore the behavior, of those proteins. The plasma levels of hydrogen ions are constantly being altered by a number of processes, including (1) metabolism of ingested food, (2) secretions of the gastrointestinal (GI) tract, (3) de novo generation of acids and bases from metabolism of stored fat and glycogen, and (4) changes in the production of carbon dioxide. The essence of the physiological response to these changes comes down to two processes: (1) matching the excretion of acid/base equivalents to their input, that is, maintaining balance, and (2) regulating the ratio of weak acids to their conjugate bases in buffer systems. Buffer systems limit changes in pH to a small range. The two processes of excreting acids and bases, and regulating physiological buffer concentrations are intimately related, but they are not identical. It is possible for them to be in balance even though buffer ratios are inappropriate.

ACID–BASE FUNDAMENTALS An acid, when dissolved in solution, dissociates into a hydrogen ion and the conjugate base of the acid, thereby increasing the concentration of free hydrogen ions (decreasing the pH). A base, when dissolved in solution, associates with existing free hydrogen ions and decreases their concentration (increases the pH). These processes are shown in equation (1). The addition of acids drives the reaction to the right; the addition of bases drives it to the left. Strong acids such as hydrochloric acid release all their hydrogen ions, whereas weak acids such as acetic acid keep most of the hydrogen ions bound and release only a small fraction. However, weak acids strongly affect plasma levels of free hydrogen ions. A weak acid present at a millimolar concentration, even if it released just a few percent of its hydrogen ions, would completely overwhelm the existing nanomolar level of free hydrogen ions if buffering systems did not intervene: → Conjugate base + H+ Acid ←

(1)

A buffer system consists of a mixture of a weak acid and its conjugate base. It limits the change in pH on addition of other acids or bases. When another acid is added, most of the hydrogen ions released by that acid combine with the base of the buffer system, greatly restricting the increase in free hydrogen ions. Similarly, when another base is added, most of the free hydrogen ions removed by the base are replaced by hydrogen ions that dissociate from the acid of the buffer system. In any buffer system, the ratio of the acid to its conjugate base fixes the free aqueous concentration of hydrogen ion (which is only a trivial fraction of the concentration of the acid and base), as shown in equation (2), or in the more familiar pH form (the Henderson– Hasselbalch equation), as shown in equation (3): [Acid]

[H+] = K _____ [Base]

(2)

Base pH = pK + log ____

(3)

[Acid]

We should emphasize that buffers do not eliminate added acid or base equivalents, but only limit the effect of the equivalents on blood pH. In the face of persistent imbalance between input and output, the acid or base component of the buffer is gradually reduced in concentration as it is converted to the other component. Eventually acid or base equivalents added to the body, even though transiently associated with blood buffers, must be excreted by the kidneys to maintain balance. Buffers exist in the extracellular fluid, the intracellular fluid (the cytosol of the various cells in the body), and the matrix of bone. Although these buffers are in different compartments, they communicate with each other. Phosphate and albumin are important buffers in the ECF. Hemoglobin in red blood cells is an important intracellular buffer, since changes in plasma pH lead to uptake or release of protons from red blood cells. For several reasons, the most important buffer system in the body turns out to be the CO2–bicarbonate buffer system. Fortunately, we can understand acid–base balance by looking at this single buffer system alone and ignore the others, because all buffer systems must have ratios of weak acid to conjugate base that result in the same pH. One property that sets the CO2–bicarbonate buffer system apart from other buffer systems is that the concentrations of CO2 and bicarbonate are regulated independently of each other. Because the concentrations of both components are regulated, the ratio of their concentrations is regulated. Therefore, this regulates pH. In the CO2–bicarbonate buffer system, CO2 is not a weak acid per se, but it acts like a weak acid because it readily combines with water to form carbonic acid. (CO2 is often called a volatile acid because it can evaporate. All other acids, for example, sulfuric and lactic, are called fixed acids.) Carbonic acid dissociates like any other weak acid into a proton and its conjugate base, which is bicarbonate [equation (4a)]. Considered this way, and given the ubiquitous presence of water in our body, it is clear that carbon dioxide is effectively an acid. The concentration of carbonic acid in our blood is trivial (about 3 μmol/L), and at first glance it appears that this system has little effective buffering capacity. However, the supply of CO2 is effectively infinite because it is being produced continuously (over 10 mol per day). Any carbonic acid consumed in a reaction is immediately replaced by new generation from existing CO2: → H CO ← → HCO – + H+ CO2 + H2O ← 2 3 3

(4a)

(carbonic anhydrase)

→ HCO – + H+ CO2 + H2O ← 3

(4b)

The reaction on the left side of equation (4a) to form carbonic acid is rather slow, but most tissues express one or several isoforms of the enzyme, carbonic anhydrase, intracellularly, extracellularly, or both. This enzyme greatly speeds the reaction between CO2 and water to form bicarbonate and a hydrogen ion. In so doing it actually skips the step of forming carbonic acid, as shown in equation (4b). However, as with all enzyme-catalyzed reactions, the enzyme increases the velocity

CHAPTER 47 Regulation of Acid–Base Balance of the reaction but not the equilibrium concentrations of reactants and products. Unlike the other buffer systems in the body, where addition or loss of hydrogen ions changes the concentration of the weak acid, in the CO2–bicarbonate system, the concentration of the weak acid (CO2) is held essentially constant. This is because the partial pressure of arterial CO2 (Paco2) is regulated by our respiratory system to be about 40 mm Hg (see Chapters 37 and 38). This partial pressure corresponds to a CO2 concentration in blood of 1.2 mmol/L. Any change in Pco2 resulting from the addition or loss of hydrogen ions or change in metabolism is sensed by the arterial chemoreceptors and chemoreceptors in the brainstem (see Chapter 38), which alter the rate of ventilation to restore the concentration. There are times when the Pco2 does indeed differ from 40 mm Hg, but this reflects changes in the activity of the respiratory system, not a change in Pco2 in response to addition or loss of hydrogen ions. Although adding or removing hydrogen ions from a source other than CO2 does not change Pco2, such changes do alter the concentration of bicarbonate. Adding hydrogen ions drives the reaction in equations (4a) and (4b) to the left and reduces bicarbonate on a nearly mole-for-mole basis. We say nearly because the other blood buffers also take up some of the load. Removing hydrogen ions drives the reaction to the right and increases bicarbonate in the same way. There are many ways of adding or removing hydrogen ions, but, regardless of the process, the result is to change the concentration of bicarbonate. Be aware that, from the acid–base perspective, any metabolic process or reaction that produces hydrogen ions is identical to the one that removes bicarbonate, because in both cases the end result is loss of bicarbonate. The same logic applies to processes that remove hydrogen ions. A reaction in which a hydrogen ion is a reactant is equivalent to one in which bicarbonate is a product, that is, in both cases the end result is an increase in bicarbonate. From the foregoing, we conclude that the task of maintaining hydrogen ion balance really becomes one of maintaining bicarbonate balance (again assuming that the respiratory system keeps Pco2 constant). When hydrogen ions are added (or bicarbonate is removed), the body has to generate new bicarbonate to replace that which was lost. Analogously, the removal of hydrogen ions (or addition of base) increases bicarbonate, and the extra bicarbonate has to be excreted. Excretion and generation of new bicarbonate is the responsibility of the kidneys. Before moving on, let us clarify a common misconception. Students sometimes get the impression that somehow fixed acid equivalents can be converted to CO2 and excreted by exhalation, or that CO2 can be converted to acids that are excreted in the urine. Neither is true: fixed acid equivalents can only be excreted by the kidneys, and CO2 can only be removed from the body via the lungs. Fixed acids consume bicarbonate and generate CO2, but just exhaling the CO2 does not restore the bicarbonate that disappeared when the acid was added. Without actual renal excretion of those acid equiv-

473

alents, continuous acid input would soon reduce plasma bicarbonate to zero. Similarly, no more than a few millimoles of CO2 are dissolved in the urine, and there is far less carbonic acid. If somehow the kidneys could convert the acid equivalents of CO2 to fixed acid and excrete those acid equivalents, it would require excreting over 10,000 mmol of fixed acids per day—clearly an impossibility.

SOURCES OF ACIDS AND BASES METABOLISM OF DIETARY PROTEIN Although the oxidative metabolism of most foodstuff is acid– base neutral, protein contains some amino acids that contribute acid or base. When sulfur-containing amino acids and those with cationic side chains are metabolized to CO2, water, and urea, the end result is addition of fixed acid. Phosphorylated proteins also contribute to an acid load. Similarly, the oxidative metabolism of amino acids with anionic side chains adds base (consumes hydrogen ions). Depending on whether a person’s diet is high in either meat or fruit and vegetables, the net input can be acid or base. For typical American diets, the input is usually acidic.

METABOLISM OF DIETARY WEAK ACIDS Fruits and vegetables, particularly citrus fruit, contain many weak acids and the salts of those acids (i.e., the conjugate base plus a cation, usually potassium). We all know that citrus juice is acidic, with some fruit juices having a pH below 4.0. Interestingly, metabolism of these acidic substances alkalinizes the blood, sometimes called the fruit juice paradox. The complete oxidation of the protonated form of an organic acid (e.g., citric acid) to CO2 and water is acid–base neutral, no different in principle than the oxidation of glucose. However, the complete oxidation of the base form adds bicarbonate to the body, that is, organic anions are precursors of bicarbonate. One can think of the metabolic process as taking a hydrogen ion from the body fluids to protonate the base, converting it to the acid, and then oxidizing the acid. The loss of the hydrogen ion, as emphasized above, adds bicarbonate. Acidic fruits and vegetables contain a mixture of organic acids in the protonated form and base form. Although the pH is low, there is far more base than free hydrogen ions. Before oxidation, the mixture is acidic, but on complete oxidation to CO2 and water, the result is addition of base.

GI SECRETIONS The GI tract, from the salivary glands to the colon, is lined with an epithelium and glands that can secrete hydrogen ions, bicarbonate, or a combination. In addition, the major exocrine secretions of the pancreas and liver that flow into the duodenum contain large amounts of bicarbonate. To accomplish these

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tasks, the GI tract (and the kidneys as we discuss later) uses the CO2–bicarbonate system in an ingenious way. When we generate bicarbonate and protons from CO2 and water in a given medium, say in the blood or in a cell, the result is always acidification, because the concentration of protons rises. However, cells of the GI tract separate the protons from the bicarbonate. They transport protons out of the cell into one medium (e.g., the lumen of the GI tract), and bicarbonate into another (the interstitium bathing the basolateral surface). Therefore, the lumen becomes acidified, and the surroundings (and therefore the blood leaving the tissue) become alkalinized (see Figure 47–1). In other regions of the GI tract, the cells reverse the direction of these processes, that is, they transport bicarbonate into the lumen (alkalinizing it) and protons into the surroundings. Thus, different regions of the GI acidify and alkalinize the blood. Normally, the sum of GI tract secretions is nearly acid–base neutral (i.e., the secretion of acid in one site, e.g., the stomach, is balanced by the secretion of bicarbonate elsewhere, e.g., the pancreas). Typically, there is a small net secretion of bicarbonate into the lumen of the GI tract, resulting in addition of protons to the blood. However, in conditions of vomiting or diarrhea, one kind of secretion may vastly exceed the other, resulting in a major loss of acid or base to the outside world complete with a major retention of base or acid in the blood.

ANAEROBIC METABOLISM OF CARBOHYDRATE AND FAT The normal oxidative metabolism of carbohydrate and fat is acid–base neutral. Both carbohydrate (glucose) and triglycerides are oxidized to CO2 and water. Although there are intermediates in the metabolism (e.g., pyruvate) that are acids or bases, the sum of all the reactions is neutral. However, some

conditions lead to production of fixed acids. The anaerobic metabolism of carbohydrate produces a fixed acid (lactic acid). In conditions of poor tissue perfusion, this can be a major acidifying factor, and the metabolism of triglyceride to β-hydroxybutyrate and acetoacetate also adds fixed acid (ketone bodies). These processes normally do not add much of an acid load but can add a huge acid load in unusual metabolic conditions (e.g., severe uncontrolled diabetes mellitus).

INTRAVENOUS SOLUTIONS: LACTATED RINGER’S Another way in which acid–base loads can enter the body is via intravenous solutions. Hospitalized patients receive a variety of intravenous solutions, a common one being lactated Ringer’s solution, a mixture of salts that contains lactate at a concentration of 28 mEq/L. The pH is about 6.5. However, this is an alkalinizing solution for the same reason described as the fruit juice paradox earlier. Lactate is the conjugate base of lactic acid, and when oxidized to CO2 and water, it takes a hydrogen ion from the body fluids, thereby producing bicarbonate. Lactated Ringer’s should not be confused with lactic acidosis associated with strenuous exercise or certain forms of shock. In these situations, the body produces equal numbers of hydrogen ions and lactate, and the result is to acidify the body fluids.

RENAL HANDLING OF ACIDS AND BASES A simplified overview of the renal processing of acids and bases is as follows: the kidneys reabsorb most of the filtered bicarbonate in the proximal tubule, thus conserving plasma

LUMEN

H2O

CO2

INTERSTITIUM

Carbonic anhydrase H+

H+

HCO3–

HCO3–

H-secreting cell

H2O

FIGURE 47–1 Generic model of hydrogen ion secretion (upper cell) and bicarbonate secretion (lower cell). The source of secreted ions is CO2 and water. Every hydrogen ion moved out of a cell across one membrane must be accompanied by the transport of a bicarbonate ion out of the cell across the other membrane. (Modified with permission from Eaton DC, Pooler JP: Vander’s Renal Physiology, 7th ed. New York, NY: Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2009.)

CO2

Carbonic anhydrase HCO3–

HCO3–

H+

HCO3–secreting cell

H+

CHAPTER 47 Regulation of Acid–Base Balance

TABLE 47–1 Normal contributions of tubular segments to renal hydrogen ion balance. Proximal tubule Reabsorbs most filtered bicarbonate (normally about 80%)a Produces and secretes ammonium Thick ascending limb of Henle’s loop Reabsorbs second largest fraction of filtered bicarbonate (normally about 10–15%)a Distal convoluted tubule and collecting duct system Reabsorbs virtually all remaining filtered bicarbonate as well as any secreted bicarbonate (type A intercalated cells)a Produces titratable acid (type A intercalated cells)a Secretes bicarbonate (type B intercalated cells) a

Processes achieved by hydrogen ion secretion.

Reproduced with permission from Eaton DC, Pooler JP: Vander’s Renal Physiology, 7th ed. New York, NY: Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2009.

bicarbonate. The proximal tubule also secretes limited amounts of organic bases or weak organic acids and acid equivalents. Then, in the distal nephron (mostly the collecting tubules), the kidneys secrete either protons or bicarbonate to balance the net input into the body (summarized in Table 47–1). The first task is to reabsorb most of the filtered bicarbonate. Bicarbonate is freely filtered at the renal corpuscles. Reabsorption is an active process, but it is not accomplished in the conventional manner of importing bicarbonate across the apical membrane and exporting it across the basolateral membrane. Rather, the mechanism involves the tubular secretion of hydrogen ions. An enormous amount of hydrogen ion secretion occurs in the proximal tubule, with additional secretion in the thick ascending limb of Henle’s loop and collecting duct system. The basic pattern is illustrated in the upper part of Figure 47–1 without indicating any specific transporters. Within the cells, hydrogen ions and bicarbonate are generated from CO2 and water, catalyzed by carbonic anhydrase. The hydrogen ions are actively secreted into the tubular lumen,

LUMEN

475

where they combine with filtered bicarbonate to form water and carbon dioxide; thus, the filtered bicarbonate “disappears.” At the same time, the cellular bicarbonate is transported across the basolateral membrane into the interstitial fluid and then into the peritubular capillary blood. The overall result is that the bicarbonate filtered from the blood at the renal corpuscle is converted to CO2 and water, replaced by bicarbonate that is generated inside the cell. Thus, no net change in plasma bicarbonate concentration occurs. It is also important to note that the hydrogen ion that was secreted into the lumen is not excreted in the urine. It has been incorporated into water. Any secreted hydrogen ion that combines with bicarbonate in the lumen does not contribute to the urinary excretion of hydrogen ions, but only to the conservation of bicarbonate. Specific transporters are required for these transmembrane movements of hydrogen ions and bicarbonate. First, particularly prominent in the apical membrane of the proximal tubule is the Na–H antiporter (NHE3) as described in Chapter 44 and shown in Figure 47–2. This transporter is the major means not only of hydrogen ion secretion, but also of sodium uptake from the proximal tubule lumen. The same NHE3 antiporter also mediates hydrogen ion secretion in the thick ascending limb. Second, a primary active H-ATPase exists in all the hydrogen ion–secreting distal tubular segments. The type A intercalated cells of the collecting duct system possess this primary active H-ATPase as well as a primary active H,K-ATPase, which simultaneously moves hydrogen ions into the lumen and potassium into the cell, both actively (Figure 47–3). The basolateral membrane exit step for bicarbonate generated when H ions are secreted is via Cl–HCO3 antiporters or Na–HCO3 symporters (Figures 47–2 and 47–3), depending on the tubular segment. In both cases, the movement of bicarbonate is down its electrochemical gradient (i.e., the exit step is passive). Symport with sodium is the dominant means of extruding bicarbonate in the proximal tubule and is particularly interesting because the efflux of sodium is up its electrochemical gradient. This is a rare case of sodium active transport

INTERSTITIUM

Filtered HCO3–

H2O

CO2

Carbonic anhydrase H+ Carbonic anhydrase

+

Na

H+

–

3HCO3

Na+ ATP

–

3HCO3 +

Na

K+ H2O

CO2

FIGURE 47–2 Predominant proximal tubule mechanism for reabsorption of bicarbonate. Hydrogen ions and bicarbonate are produced intracellularly. The hydrogen ions are secreted via a Na–H antiporter (member of the NHE family), while the bicarbonate is transported into the interstitium via an Na–3HCO3 symporter (member of the NBC family). Because more sodium enters via the Na–H antiporter than leaves via the Na–3HCO3 symporter, additional sodium is removed via the Na,K–ATPase. (Modified with permission from Eaton DC, Pooler JP: Vander’s Renal Physiology, 7th ed. New York, NY: Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2009.)

476

SECTION VII Renal Physiology

LUMEN

INTERSTITIUM H2O

CO2

Carbonic anhydrase ATP +

H

H+

–

+

HCO3

H ATP H+ K+

–

HCO3 Cl–

Cl–

A

LUMEN

FIGURE 47–3 Type A and type B intercalated cells. A) Predominant collecting tubule mechanisms in type A intercalated cells for the secretion of hydrogen ions that result in formation of titratable acidity. The apical membrane contains H-ATPases and H,K-ATPases, which transport hydrogen ions alone or in exchange for potassium. B) The type B intercalated cell secretes bicarbonate and simultaneously transports hydrogen ions into the interstitium. The difference between this cell type and the type A cell and those in the proximal tubule is that the location of the transporters for hydrogen ions and bicarbonate are switched between apical and basolateral membranes. (Modified with permission from Eaton DC, Pooler JP:

INTERSTITIUM

H2O

CO2

Carbonic anhydrase –

HCO3

–

HCO3 Cl–

ATP H

+

H+

ATP K+ Cl–

B

Vander’s Renal Physiology, 7th ed. New York, NY: Lange Medical Books/ McGraw-Hill, Medical Pub. Division, 2009.)

that does not use ATP as the energy source, but uses the gradient of another ion. (However, this process can only occur if the Na,K–ATPase sets up the Na gradient that powers the removal of hydrogen ions via Na–H exchange in the apical membrane.) Through its secretion of hydrogen ions, the proximal tubule reabsorbs 80–90% of the filtered bicarbonate. The thick ascending limb of Henle’s loop reabsorbs another 10%, and almost all the remaining bicarbonate is reabsorbed by the distal convoluted tubule and collecting duct system (although this depends on diet and other conditions; see later discussion). Throughout the tubule, intracellular carbonic anhydrase is involved in the reactions generating hydrogen ion and bicarbonate. In the proximal tubule, carbonic anhydrase is also located in the lumen-facing surface of apical cell membranes, and this carbonic anhydrase catalyzes the intraluminal generation of CO2 and water from the large quantities of secreted hydrogen ions combining with filtered bicarbonate.

RENAL EXCRETION OF ACID AND BASE Acid or base loads generated from the processes described earlier result in changes in plasma bicarbonate. In essence, an acid or base load, regardless of original source, is turned into an excess or deficit of bicarbonate. In response to base loads, the process is relatively straightforward: we reabsorb most of the filtered bicarbonate, but excrete just enough bicarbonate in the urine to match the input. The kidneys do this in two ways: (1) allow some filtered bicarbonate to pass through to the urine and (2) secrete bicarbonate via type B intercalated cells. The type B intercalated cells, which are found only in the cortical collecting duct, do indeed secrete bicarbonate. In essence, the type B intercalated cell is a “flipped-around” type A intercalated cell (Figure 47–3B). Within the cytosol, hydrogen ions and bicarbonate are generated via carbonic anhydrase. However, the H-ATPase pump is located in the basolateral membrane, and the Cl–HCO3 antiporter is in the

CHAPTER 47 Regulation of Acid–Base Balance apical membrane. Accordingly, bicarbonate moves into the tubular lumen and hydrogen ion is actively transported out of the cell across the basolateral membrane and enters the blood, where it combines with a bicarbonate ion and reduces plasma bicarbonate. Thus, the overall process achieves the disappearance of excess plasma bicarbonate and the excretion of bicarbonate in the urine. How do the kidneys excrete an acid load, which always generates a bicarbonate deficit? First, they reabsorb all the filtered bicarbonate. Then they secrete additional hydrogen ions that attach to buffers in the tubular fluid other than bicarbonate. The now protonated buffer is excreted. Meanwhile, the bicarbonate generated in the cell is transported into the blood, replacing the bicarbonate lost when the acid load entered the body. It is important to realize that both parts of this process must occur, that is, new bicarbonate and excretion of hydrogen ions on buffers. If there were no new bicarbonate, plasma levels would not be restored, and if hydrogen ions were not excreted, they would react with and remove the bicarbonate just generated.

HYDROGEN ION EXCRETION ON URINARY BUFFERS We see that the identical transport process of hydrogen ion secretion achieves both reabsorption of bicarbonate (without new bicarbonate) and acid excretion, with addition of new bicarbonate to the blood. At first glance, this seems like a contradiction: how can the same process produce two different end results? The answer lies in the fate of the hydrogen ion once it is in the lumen. For secreted hydrogen ions that combine with bicarbonate, we are simply replacing bicarbonate that would have left the body. In contrast, when secreted hydrogen ions combine with a nonbicarbonate buffer in the lumen, the hydrogen ion is excreted, and the bicarbonate produced in the cell and transported across the basolateral membrane is new bicarbonate, not a replacement for filtered bicarbonate.

477

There are two sources of tubular nonbicarbonate buffers: filtration and synthesis. Normally, the most important filtered buffer is phosphate, while ammonia is the most important synthesized buffer. Ammoniagenesis is crucial to renal acid excretion because its rate can be greatly increased in the face of large acid loads, whereas the availability of filtered buffers, while somewhat variable, is not regulated for purposes of acid excretion. Figure 47–4 illustrates the sequence of events that achieves hydrogen ion excretion on filtered phosphate and the addition of new bicarbonate to the blood. It must be emphasized also that neither filtration per se nor excretion of free hydrogen ions makes a significant contribution to hydrogen ion excretion. First, the filtered load of free hydrogen ions, when the plasma pH is 7.4 (40 nmol/L/H+), is less than 0.1 mmol per day. Second, there is a minimum urinary pH— approximately 4.4—that can be achieved. This corresponds to a free hydrogen ion concentration of 0.04 mmol/L. With a typical daily urine output of 1.5 L, the excretion of free hydrogen ions is only 0.06 mmol per day, a tiny fraction of the normal 50–100 mmol of hydrogen ion ingested or produced every day. To excrete these additional amounts of protons, they must associate with tubular buffers.

PHOSPHATE AND ORGANIC ACIDS AS URINARY BUFFERS Free plasma phosphate exists in a mixture of monovalent (acid) and divalent forms (base). In the following equation, monovalent dihydrogen phosphate (on the left) is a weak acid, and divalent monohydrogen phosphate (on the right) is its conjugate base: → HPO 2– + H+ H2PO4– ← 4

(5)

We can write the above equation in the form of the Henderson–Hasselbalch equation:

INTERSTITIUM

LUMEN Filtered HPO42–

H2O

CO2

Carbonic anhydrase H+ H2PO4–

excreted H2PO4–

Na

+

H+

3HCO3– Na+

3HCO3–

FIGURE 47–4 Excretion of hydrogen ions on filtered phosphate. Divalent phosphate (base form) that has been filtered and not reabsorbed reaches the collecting tubule, where it combines with secreted hydrogen ions to form monovalent phosphate (acid form), which is then excreted in the urine. The bicarbonate entering the blood is new bicarbonate, not merely a replacement for filtered bicarbonate. (Modified with permission from Eaton DC, Pooler JP: Vander’s Renal Physiology, 7th ed. New York, NY: Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2009.)

478

SECTION VII Renal Physiology [HPO 2–]

4 pH = 6.8 + log _______ [H PO –] 2

(6)

4

At the normal plasma pH of 7.4, we find that about 80% of the plasma (and filtered) phosphate is in the base (divalent) form and 20% is in the acid (monovalent) form. As the tubular fluid is acidified in the collecting ducts, most of the base form takes up secreted hydrogen ions. Depending on final urine pH, most of the base (HPO42−) has been protonated to acid (H2PO4−). The secreted hydrogen ions that combined with the base form are excreted, and the bicarbonate that was generated intracellularly enters the blood. How much phosphate is available for this process? The amount is somewhat variable, depending on a number of factors (see Chapter 48), but a typical plasma concentration is about 1 mmol/L, of which about 90% is free (the rest being loosely bound to plasma proteins). At a GFR of 180 L per day, the total filtered load of phosphate is about 160 mmol per day. The fraction reabsorbed is also variable: from 75% to 90%. Thus, unreabsorbed divalent phosphate available to take up secreted hydrogen ions amounts to roughly 40 mmol per day. In other words, the kidneys can excrete acid loads using the phosphate buffer system at a rate of about 40 mmol per day. However, the availability of phosphate cannot be easily increased to increase acid excretion.

HYDROGEN ION EXCRETION ON AMMONIUM Ordinarily, hydrogen ion excretion associated with phosphate and other filtered buffers is not sufficient to balance the normal hydrogen ion production of 50–100 mmol per day nor can it take care of any unusually high (usually pathological) production of acid loads. To excrete the rest of the hydrogen ions and achieve balance, there is a second means of excreting hydrogen ions that involves ammoniagenesis and excretion of hydrogen ions as ammonium. Quantitatively, far more hydrogen ions can be excreted by means of ammonium than via filtered buffers. There are many nuances to hydrogen ion excretion via ammonium, but the basic concepts are straightforward. As described in Chapter 43, the catabolism of protein and oxidation of the constituent amino acids by the liver generates CO2, water, urea, and some glutamine. Although the metabolism of the side chains of amino acids can lead to addition of acid or base, the processing of the core of an amino acid—the carboxyl group and amino group—is acid–base neutral. After many intermediate steps, processing of the carboxyl group of the amino acid produces bicarbonate, and processing of the amino group produces ammonium. Processing does not stop there, however, because ammonium in more than minuscule levels is quite toxic. Ammonium is further processed by the liver to either urea or glutamine. In both cases, each ammonium consumed also consumes a bicarbonate. Thus, the bicarbonate produced from the carboxyl group is just an intermediate, consumed as fast as it is made, and the process as a whole is acid–base neutral. We can write this process as follows:

2NH4+ + 2HCO3– 2 amino acids (+oxygen) Urea or glutamine (+ CO2 and water)

(7)

When the urea (or glutamine) is excreted, the body has completed the catabolism of protein in a manner that promotes total body nitrogen balance, and is acid–base neutral. The renal handling of urea is somewhat complicated from the osmotic point of view, as described in earlier chapters, but is acid–base neutral. Glutamine, however, is different. Although the production of glutamine by the liver is acid–base neutral, it is important to recognize that glutamine can be thought to contain the two components from which it was synthesized: a base component (bicarbonate) and an acid component (ammonium). Ammonium is the protonated form of ammonia. It is an acid because it contains a dissociable proton as shown in equation (8). The pK of ammonium is near 9.2, making it an extremely weak acid (i.e., only at high pH will it release its proton), but it is an acid nevertheless. At physiological pH, over 98% of the total exists as ammonium, and less than 2% exists as ammonia. For renal acid–base purposes, this is a good thing because virtually all excreted ammonia is in the protonated form and takes a hydrogen ion with it: → H+ + NH NH4+ ← 3

(8)

Glutamine released from the liver is taken up by proximal tubule cells, both from the lumen (filtered glutamine) and from the renal interstitium. The cells of the proximal tubule then convert the glutamine back to bicarbonate and NH4+, in essence reversing what the liver has done. The NH4+ is secreted into the lumen of the proximal tubule, and the bicarbonate exits into the interstitium and then into the blood (Figure 47–5A). This is new bicarbonate, just like the new bicarbonate generated by titrating nonbicarbonate buffers. Further processing of the NH4+ is complicated, but eventually the ammonium is excreted (Figure 47–5C). The ammonium ion has interesting chemical properties in that it can masquerade as other ions, in some cases as a hydrogen ion and in other cases as a potassium ion. This is because some transporters and some channels are not completely selective for the species they usually move compared with ammonium. As the concentration of ammonium rises, there is an increasing tendency for ammonium to substitute for these other ions and “sneak” its way across membranes. Also, whenever ammonium is present in body fluids, a small fraction (2% at physiological pH) always exists as ammonia because the dissociation, although limited in extent, is nearly instantaneous. Ammonium, being a small hydrated ion, is essentially impermeant in lipid bilayers and must be handled by channels or transporters if it is to move across membranes, but the neutral ammonia has a finite permeability. In terms of cellular handling, cells sometimes transport ammonium as such and at other times transport ammonia and a proton in parallel, the end result being the same in both cases. It would “make sense” if the ammonium secreted into the proximal tubule simply stayed in the lumen and was excreted, but the kidneys have a more complicated way of doing

CHAPTER 47 Regulation of Acid–Base Balance

LUMEN

LUMEN

INTERSTITIUM

479

INTERSTITIUM

NH4+ Filtered glutamine

2CI–

glutamine NH4+

NH4+ Na+

–

HCO3 Na+

Na+

–

Na+

HCO3

+

NH4

K+

NH4+ Na+

NH4+ A

(to thick ascending limb)

NH4+

NH3 H+

NH4+

B

LUMEN

INTERSTITIUM

ATP +

ATP

K

H+ +

NH4

H+ NH3 NH3

C

Na+ NH4+

NH3 H+

NH3 NH3

(excretion)

FIGURE 47–5 Ammoniagenesis and excretion. A) Ammonium production from glutamine. Glutamine is originally synthesized in the liver from NH4+ and bicarbonate. When glutamine reaches the proximal tubule cells, it is converted via several intermediate steps (not shown) back to NH4+ and bicarbonate. B) Ammonium reabsorption in the thick ascending limb. Ammonium reaches the thick ascending limb from two sources. Most comes as a result of secretion in the proximal tubule. Some also enters the thin limbs from the medullary interstitium in the form of neutral ammonia and is subsequently reprotonated in the lumen (ammonium recycling). Ammonium is reabsorbed in the thick ascending limb by several mechanisms, the predominant one being entrance via the NKCC multiporter (where ammonium substitutes for potassium). C) Ammonium secretion in the inner medulla. Several mechanisms are involved. A prominent one involves uptake and secretion of neutral ammonia via specific transporters in parallel with hydrogen ion secretion, resulting in reformation of ammonium in the lumen. In the innermost medulla, the high interstitial ammonium concentration allows ammonium to substitute for potassium on the Na,K–ATPase. (Modified with permission from Eaton DC, Pooler JP: Vander’s Renal Physiology, 7th ed. New York, NY: Lange Medical Books/ McGraw-Hill, Medical Pub. Division, 2009.)

things. An array of channels and transporters participates in moving ammonium or ammonia into or out of the tubule in various segments. So long as all the ammonium produced from glutamine and secreted in the proximal tubule ends up being excreted, the process accomplishes the goal of excreting acid, even if ammonium is transported as such in some places and moved as H+ and NH3 separately in other places. But if ammonium is returned to the circulation, it is metabolized by the liver back to urea, consuming bicarbonate in the process, thereby nullifying the renal generation of bicarbonate.

Most of the ammonium synthesized from glutamine in the proximal tubule is secreted via the NHE3 antiporter in exchange for sodium (with ammonium substituting for a hydrogen ion); but some may also diffuse into the lumen as ammonia and then combine with a secreted hydrogen ion. The next major transport event occurs in the thick ascending limb (Figure 47–5B). In this segment about 80% of the tubular ammonium is reabsorbed, mostly by the Na–K–2Cl multiporter (with ammonium now substituting for potassium). In the medullary portions of the thick ascending limb, this reabsorption results in accumulation of ammonium (and therefore some ammonia)

480

SECTION VII Renal Physiology

in the interstitium, with the concentration progressively increasing toward the papilla, analogous to the osmotic gradient. The high interstitial concentration surrounding the loops of Henle leads to some secretion of ammonia into the thin descending limbs, where the ammonia becomes protonated in the lumen. Therefore, there is a certain amount of recycling, with the consequence that a considerable amount of ammonium is trapped in the medullary interstitium (similar to the situation with urea). Finally, in the medullary collecting ducts, there is secretion, mainly by parallel transport of hydrogen ions and ammonia. Thus, the ammonium that was reabsorbed in the thick ascending limb and accumulated in the medullary interstitium is now put back into the tubule and excreted.

TABLE 47–2 Renal contribution of new bicarbonate to the blood in different states. Alkalosis

Normal State

Acidosis

Titratable acid (mmol per day)

0

20

40

Plus NH4+ excreted (mmol per day)

0

40

160

Minus HCO3− excreted (mmol per day)

80

1

0

Total (mmol per day)

–80 (lost from body)

59 (added to body)

200 (added to body)

Urine pH

8.0

6.0

4.6

QUANTIFICATION OF RENAL ACID–BASE EXCRETION

Reproduced with permission from Eaton DC, Pooler JP: Vander’s Renal Physiology, 7th ed. New York, NY: Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2009.

We can now quantify the excretion of acid/base equivalents by looking at three quantities in the urine: (1) the amount of titratable acidity, (2) the amount of ammonium, and (3) the amount of bicarbonate, if any. Titratable acidity can be measured by titrating the urine with strong base (NaOH) to a pH of 7.4. (The amount of NaOH required to increase the pH back to 7.4 must equal the amount of hydrogen ion that was secreted and combined with phosphate and organic buffers.) Urinary ammonium equals the urinary volume times the urinary ammonium concentration. (Ammonium does not contribute to titratable acidity because with a pK of 9.2, few hydrogen ions are removed by titration to pH 7.4.) Similarly, urinary bicarbonate equals the urinary volume times the urinary bicarbonate concentration. Thus, we can write the net acid excretion as:

known neural or hormonal signals conveying acid–base information to the kidneys. In effect, the kidneys act as “pH meters” and Pco2 detectors and adjust their transport of hydrogen ion and ammonium excretion accordingly. Hydrogen ion transport is also stimulated independently by aldosterone. An increase in Pco2, as occurs during respiratory acidosis due to hypoventilation, produces a decrease in plasma pH and, thereby, signals an increased tubular hydrogen ion secretion. A decrease in Pco2, as occurs during respiratory alkalosis due to hyperventilation, causes a decrease in secretion. Because the tubular membranes are quite permeable to CO2, an altered arterial Pco2 causes an equivalent change in Pco2 within the tubular cells. In turn, this causes altered intracellular hydrogen ion concentration by driving the reactions shown in equations (4a) and (4b) to the right or left. This change in intracellular pH, along with signals generated in response to altered Pco2 at the basolateral surface, adjusts the rate of hydrogen ion secretion. We can see that these renal responses are appropriate. If the Pco2 is high (causing a decrease in plasma pH), the increased hydrogen ion secretion increases plasma bicarbonate, thereby increasing plasma pH closer to normal (despite the continued high Pco2). Similarly, if the pH is low because of low bicarbonate, the new bicarbonate restores the bicarbonate (and, therefore, the pH) toward normal.

Net acid excretion = (9) Titratable acid excreted + NH4+ excreted – HCO3– excreted Note that there is no term for free hydrogen ion in the urine because, even at a minimum urine pH of 4.4, the number of free hydrogen ions is trivial. Typical urine data for the amounts of bicarbonate contributed to the blood by the kidneys in three potential acid–base states are given in Table 47–2. Note that in response to acidosis, as emphasized previously, increased production and excretion of NH4+ is quantitatively much more important than increased formation of titratable acid.

REGULATION OF THE RENAL HANDLING OF ACIDS AND BASES Renal acid–base processing is regulated in response to different body conditions. The key regulatory signals are the concentrations of free hydrogen ions and CO2 in the fluids to which the various transport elements are exposed, that is, the pH and Pco2 of the interstitium and cytosol within renal cells. There are no

CONTROL OF RENAL GLUTAMINE METABOLISM AND AMMONIUM EXCRETION In addition to regulating hydrogen ion secretion per se, there are several homeostatic controls over the production and tubular handling of NH4+. First, the generation of glutamine by the liver is increased by low plasma pH. In this case, the liver shifts some of the disposal of ammonium ion from urea to glutamine. Second, the renal metabolism of glutamine is

CHAPTER 47 Regulation of Acid–Base Balance

TABLE 47–3 Summary of processes that acidify or alkalinize the blood. Nonrenal mechanisms of acidifying the blood Consumption and metabolism of protein (meat) containing acidic or sulfur-containing amino acids Consumption of acidic drugs Metabolism of substrate without complete oxidation (fat to ketones and carbohydrate to lactic acid). GI tract secretion of bicarbonate (puts acid in blood) Nonrenal mechanisms of alkalinizing the blood Consumption and metabolism of fruit and vegetables containing basic amino acids or the salts of weak acids Consumption of antacids Infusion of lactated Ringer’s solution GI tract secretion of acid (puts bicarbonate in the blood) Renal mechanisms of acidifying the blood Allow some filtered bicarbonate to pass into the urine Secrete bicarbonate (type B intercalated cells) Renal means of alkalinizing the blood Secrete protons that form urine titratable acidity (type A intercalated cells) Excrete NH4+ synthesized from glutamine GI, gastrointestinal. Reproduced with permission from Eaton DC, Pooler JP: Vander’s Renal Physiology, 7th ed. New York, NY: Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2009.

also subject to control by extracellular pH. A decrease in extracellular pH stimulates renal glutamine oxidation by the proximal tubule, whereas an increase does just the opposite. Thus, an acidosis that lowers plasma pH, by stimulating renal glutamine oxidation, causes the kidneys to contribute more new bicarbonate to the blood, thereby counteracting the acidosis. This pH responsiveness increases over the first few days of an acidosis and allows the glutamine–NH4+ mechanism for new bicarbonate generation to become the predominant renal process for opposing the acidosis. Conversely, an alkalosis inhibits glutamine metabolism, resulting in little or no renal contribution of new bicarbonate via this route. Table 47–3 provides a summary of the processes of adding acids and bases to the body fluids. The unifying and, therefore, simplifying principle is that all processes of acid or base addition boil down to addition or loss of bicarbonate. All processes that acidify the blood end up removing bicarbonate, and all processes that alkalinize the blood end up adding bicarbonate.

ACID–BASE DISORDERS AND THEIR COMPENSATION In this section we briefly address the topic of acid–base disorders in the context of the kidney. This topic is covered more thoroughly in the context of the respiratory system in Chapter 37. Acid–base disorders develop when either arterial Pco2, bicarbonate, or both deviate from their normal range. Clinicians

481

assign acid–base disorders to the following four categories: (1) high Pco2 is a respiratory acidosis, (2) low Pco2 is a respiratory alkalosis, (3) low bicarbonate is a metabolic acidosis, and (4) high bicarbonate is a metabolic alkalosis: [Bicarbonate]

pH = 6.1 + log __________ 0.03 P

(10)

co2

It should be clear from the Henderson–Hasselbalch equation [equation (10)] for the CO2–bicarbonate buffer system that changing either the Pco2 or the bicarbonate concentration increased or decreases the pH. If only one of these is changed, it is called a primary uncompensated disorder. In most cases the situation is more complicated because there is at least some, and usually considerable, compensation. Compensation exists when either Pco2 or bicarbonate levels remain altered for a period of time and the body changes the other variable in the same direction. For example, if the Pco2 is abnormally low, renal compensation consists of reducing plasma bicarbonate. Similarly, if bicarbonate is abnormally low, respiratory compensation consists of reducing arterial Pco2. The compensatory changes bring the ratio of bicarbonate to Pco2 closer to a normal value, and therefore minimize the change in pH. However, compensation for an acid–base disorder is not correction, because even if the compensation has returned the pH to the normal range, both Pco2 and bicarbonate values are still abnormal. Consider a case where the Pco2 is too high (respiratory acidosis) due to hypoventilation (review Chapter 37). The body compensates by increasing bicarbonate. If bicarbonate is increased high enough, this restores pH to the normal range; however, it does not correct the original respiratory problem that resulted in an increased Pco2 . The same logic applies to any other acid–base disorder. The astute reader may recognize a potential problem in the interpretation of acid–base disorders. When any acid–base disorder is well compensated, that is, the degree of compensation is such that the pH is in the normal range, both the Pco2 and bicarbonate are increased or decreased in the same direction. Suppose both the Pco2 and bicarbonate are high. Is this a respiratory acidosis with renal compensation, or is it a metabolic alkalosis with respiratory compensation? Fortunately in a clinical setting it would be rare not to have additional information. For example, the high Pco2 of chronic bronchitis patient is, in all likelihood, a respiratory acidosis resulting from impaired ventilation, not a compensation for a metabolic alkalosis. Nevertheless, in real life there are often mixed acid–base disorders that indeed present a challenge in the clinic.

RENAL RESPONSE TO RESPIRATORY ACIDOSIS AND ALKALOSIS In a respiratory acidosis, the low alveolar ventilation causes an increase in Pco2, in turn causing a decrease in pH. The pH would be restored to normal if the bicarbonate were increased to the same degree as Paco2. The normal kidneys respond to the

482

SECTION VII Renal Physiology

increased Pco2 by contributing new bicarbonate to the blood in the manner previously described. The renal compensation in response to respiratory alkalosis is just the opposite. Respiratory alkalosis is the result of hyperventilation, as occurs at high altitude (see Chapter 71), in which the person transiently eliminates carbon dioxide faster than it is produced, thereby decreasing Pco2 and increasing pH. The decreased Pco2 and increase in extracellular pH signal reduced tubular hydrogen ion secretion and increased bicarbonate secretion. Bicarbonate is lost from the body, and the loss results in decreased plasma bicarbonate and a return of plasma pH toward normal. There is no titratable acid in the urine (the urine is alkaline in these conditions), and there is little or no NH4+ in the urine because the alkalosis inhibits NH4+ production and excretion.

RENAL RESPONSE TO METABOLIC ACIDOSIS There are many possible causes of metabolic acidosis, including the kidneys themselves. These include (1) increased input of acid by ingestion, infusion, or production; (2) decreased renal production of bicarbonate, as in renal failure; or (3) direct loss of bicarbonate from the body, as in diarrhea. The result is the same regardless of whether there is loss of bicarbonate or addition of hydrogen ions: that is, a lower concentration of bicarbonate and a lower plasma pH. The renal response (if the kidneys are not the cause) is to produce more bicarbonate, thereby returning pH toward normal. (Note that this is a response, not compensation, because the primary problem is not a respiratory change in Pco2.) To do this, the kidneys must reabsorb all the filtered bicarbonate and contribute more new bicarbonate through increased formation and excretion of NH4+ and titratable acid. This is precisely what healthy kidneys do in the case of any acid load, but if the acid load is too great or the problem is in the kidneys themselves, the bicarbonate concentration will remain low.

FACTORS CAUSING THE KIDNEYS TO GENERATE OR MAINTAIN A METABOLIC ALKALOSIS The normal kidneys are able to excrete large amounts of bicarbonate. However, in some situations, the kidneys fail to do this, and thereby either generate a metabolic alkalosis or maintain a metabolic alkalosis that originates from another cause. Recall that secretion of hydrogen ions, after all filtered bicarbonate has been reabsorbed, generates new bicarbonate. Also recall that secretion of hydrogen ions is coupled to the reabsorption of sodium in the proximal tubule and thick ascending limb, and that some is coupled to the reabsorption of potassium in the distal nephron. Some conditions that signal strong reabsorption of sodium or potassium ions have the undesired effect of causing the secretion of too many hydrogen ions. The most important situations in which this occurs

are (1) volume contraction, (2) chloride depletion, and (3) the combination of aldosterone excess and potassium depletion. In any metabolic alkalosis, by definition the plasma bicarbonate concentration is elevated. This problem is not a defect in the ability of the kidneys to excrete bicarbonate; if a person is fed a large load of bicarbonate, the kidneys can excrete the load without a major increase in bicarbonate levels. The problem seems to be in regulation of bicarbonate excretion. The key event in all these situations is oversecretion of hydrogen ion (and sometimes of NH4+ as well), either producing a metabolic alkalosis or failing to respond as usual to an existing metabolic alkalosis.

INFLUENCE OF EXTRACELLULAR VOLUME CONTRACTION The presence of total body volume contraction because of salt loss stimulates sodium reabsorption, and also hydrogen ion secretion because the transport of these ions is linked via the Na/H antiporters in the proximal tubule. In addition, the renin– angiotensin system (RAS) is usually activated, resulting in stimulation of aldosterone secretion. Besides stimulating sodium reabsorption, aldosterone stimulates hydrogen ion secretion by type A intercalated cells. The net result is that all the filtered bicarbonate is reabsorbed so that the already elevated plasma bicarbonate associated with the preexisting metabolic alkalosis is locked in, and the plasma pH remains high. The urine, instead of being alkaline, as it should be when the kidneys are normally responding to a metabolic alkalosis, is somewhat acid. The generation or maintenance of a metabolic alkalosis in volume contraction may also occur when the volume is normal or high but the body “thinks” volume is low, specifically in congestive heart failure and advanced liver cirrhosis.

INFLUENCE OF CHLORIDE DEPLETION We referred to extracellular volume contraction without distinguishing between sodium and chloride losses as the cause because loss of either of these ions will lead to extracellular volume contraction. However, we emphasize that specific chloride depletion, in a manner independent of and in addition to extracellular volume contraction, helps maintain metabolic alkalosis by stimulating hydrogen ion secretion. The most common reasons for chloride depletion are chronic vomiting and heavy use of diuretics. The result is that bicarbonate excretion remains essentially zero, and the metabolic alkalosis is not corrected.

INFLUENCE OF ALDOSTERONE EXCESS AND SIMULTANEOUS POTASSIUM DEPLETION As noted, aldosterone stimulates hydrogen ion secretion. Potassium depletion, by itself, also weakly stimulates tubular hydrogen ion secretion and NH4+ production. However,

CHAPTER 47 Regulation of Acid–Base Balance

483

Extensive use of diuretics

Extracellularvolume contraction

Potassium depletion

Renin secretion

(Helps maintain the alkalosis)

Plasma renin

Plasma angiotensin II

Aldosterone secretion

Plasma aldosterone

Tubular secretion of hydrogen ion

Reabsorption of all filtered bicarbonate and contribution of new bicarbonate to blood

FIGURE 47–6 Pathway by which overuse of diuretics leads to a metabolic alkalosis. NH4+ production and excretion are increased by the presence of a high aldosterone and potassium depletion. The extracellular volume contraction, via both aldosterone and as yet unidentified nonaldosterone mechanisms, helps to maintain the alkalosis once it has been generated. If the diuretics have also caused chloride depletion, this too will contribute to the maintenance of the metabolic alkalosis (not shown). (Modified with permission from Eaton DC, Pooler JP: Vander’s Renal

Generation of metabolic alkalosis

Physiology, 7th ed. New York, NY: Lange Medical Books/ McGraw-Hill, Medical Pub. Division, 2009.)

the combination of potassium depletion of even moderate degree and high levels of aldosterone stimulates tubular hydrogen ion secretion markedly (NH4+ production also increases significantly). As a result, the renal tubules not only reabsorb all filtered bicarbonate, but also contribute inappropriately large amounts of new bicarbonate to the body, thereby causing metabolic alkalosis. Note that there may have been nothing wrong with the acid–base balance to start with: the alkalosis is actually generated by the kidneys themselves. Of course, if alkalosis were already present, this high aldosterone–potassium depletion combination would not only prevent the kidneys from responding appropriately, but would also make the alkalosis worse. This phenomenon is important because the combination of a markedly elevated aldosterone and potassium depletion occurs in a variety of clinical situations, the most common of which is the extensive use of diuretic drugs (e.g., from extensive, inappropriate

diuretic use for weight loss) that can generate a metabolic alkalosis (Figure 47–6).

CLINICAL CORRELATION A 7-year-old boy is brought by his mother to his pediatrician. The boy has been vomiting on and off for over a day and has not been able to eat or drink anything. He seems jittery and complains of tingling around his mouth. His blood pressure is 107/77, and his heart rate is 89. After the pediatrician notes signs of dehydration, he directs them to a local hospital ER. At the hospital, blood gas analysis shows an arterial pH of 7.52 and Pco2 of 45 mm Hg, for a calculated bicarbonate of 36 mEq/L, which is high. Analysis of his urine, which is scant, yields a chloride of 17 mEq/L,

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which is low. He is given intravenous normal saline (0.9% NaCl) and an antiemetic to reduce the vomiting. The boy has lost a lot of hydrogen ions, chloride, and water, resulting in hypovolemia and a metabolic alkalosis. The relatively rapid development of the alkalosis leads to a transient hypocalcemia (see Chapter 48), in turn leading to hyperexcitability of peripheral neurons, tending to produce muscle spasms and perioral tingling. His slightly high Pco2 represents a partial compensation for the alkalemia. His body responds to the volume depletion by decreasing the excretion of salt and water via decreased GFR and activation of the RAS, which stimulates sodium reabsorption. Given the elevated plasma bicarbonate, the kidneys should begin excreting bicarbonate, but it is difficult for them to do so in the face of the volume depletion. First, aldosterone is stimulating the type A intercalated cells to secrete hydrogen ions, just the opposite of what is needed. Second, it is difficult for the type B intercalated cells to increase their secretion of bicarbonate, a process that is accomplished by exchanging cellular bicarbonate for luminal chloride via an antiporter. Less luminal chloride is available to exchange with bicarbonate due to upstream reabsorption. Since there is no renal pathology per se, and the vomiting is transient, his case can be treated by replacing fluid loss and restoring chloride.

CHAPTER SUMMARY ■ ■ ■ ■ ■ ■ ■

■

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Plasma pH is regulated by controlling the concentrations of CO2 (Pco2) and bicarbonate. Fixed acid or base loads are turned into excesses or deficits of bicarbonate in the body. Fixed acids and bases can enter the body via GI processes, metabolism, intravenous infusions, and renal processes. Under all conditions, the kidneys must recover virtually all filtered bicarbonate. The kidneys excrete acid by means of filtered or synthesized urinary buffers. Phosphate is the most important filtered urinary buffer. The kidneys excrete acid by converting glutamine to bicarbonate and ammonium, excreting the ammonium, and returning the bicarbonate to the blood. Primary acid–base disorders that change either Pco2 or bicarbonate can be compensated by changing the other variable in the same direction, thereby preserving the ratio of bicarbonate to Pco2. Some situations, including volume contraction and aldosterone excess, can cause the kidneys to excrete too much acid, generating a metabolic alkalosis.

STUDY QUESTIONS 1. A patient excretes 2 L of alkaline (pH 7.6) urine having a bicarbonate concentration of 28 mmol/L. What do we know about titratable acid excretion? A) It is 56 mmol. B) There is negative titratable acidity. C) Titratable acid plus ammonium sums to 56 mmol. D) We cannot determine without data for ammonium and phosphate. 2. Which of the following is an acid load per se or becomes an acid load after metabolism? A) eating a large steak B) eating unsweetened grapefruit juice C) eating sweetened grapefruit juice D) intravenous infusion of sodium lactate 3. How does the proximal tubule handle filtered bicarbonate? A) Bicarbonate is taken up by the tubular cells on a symporter with sodium. B) Bicarbonate is taken up by the tubular cells via antiport with small base anions (e.g., formate). C) Bicarbonate is taken up by the tubular the cells via antiport with chloride. D) Bicarbonate combines with a proton in the lumen and is converted to carbon dioxide and water. 4. In which situation(s) would you expect to see decreased or no renal excretion of acid equivalents? A) during a major metabolic acidosis such as diabetic ketoacidosis B) during a time when the pancreas is secreting a high amount of bicarbonate-rich fluid into the GI tract C) in response to consuming a large number of antacid tablets D) all of the above situations 5. What is the fate of ammonium secreted in the proximal tubule? A) It flows through to the urine. B) It is mostly reabsorbed in the collecting ducts. C) It is mostly reabsorbed in the thick ascending limb and secreted again in the collecting ducts. D) It is mostly reabsorbed in the thick ascending limb and combined with bicarbonate to form urea. 6. A person develops a decreased arterial Pco2 because of hyperventilation. If this condition persists, what kind of response would we expect by the kidneys? A) more urinary titratable acidity B) more urinary bicarbonate C) more urinary ammonium D) a decreased urinary pH

48 C

Regulation of Calcium and Phosphate Balance Douglas C. Eaton and John P. Pooler

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State the normal total plasma calcium concentration and the fraction that is free. Describe the distribution of calcium between bone and extracellular fluid and the role of bone in regulating extracellular calcium. Describe and compare the roles of the gastrointestinal tract and kidneys in calcium balance. Describe and compare bone remodeling and calcium buffering by bone. Describe the role of vitamin D in calcium balance. Describe how the synthesis of the active form of vitamin D (calcitriol) is regulated. Describe the regulation of parathyroid hormone secretion, and state the major actions of parathyroid hormone. Describe renal handling of phosphate. Describe how parathyroid hormone changes renal phosphate excretion.

OVERVIEW Calcium plays a key role in a multitude of physiological processes. Therefore, it is essential to regulate both the total amount of calcium in the body and its plasma concentration. Regulation is accomplished by the cooperative effort of several organ systems, including the gastrointestinal (GI) tract (Chapter 52), the endocrine system (Chapter 64), and the kidneys. The importance of calcium centers on its being (1) a structural component of bone, (2) an intermediate in intracellular signaling cascades, and (3) a regulator of the conformation of membrane proteins. These functions derive largely from the chemical properties of the calcium cation. Unlike sodium, potassium, and magnesium, calcium is “sticky,” meaning that it avidly binds to anionic sites on proteins and readily forms complexes with small anions such as phosphate and citrate. These associations have consequences for physiological function. When calcium binds and unbinds from membrane proteins, this alters the net charge, and hence the conformation of those proteins. In the case of voltage-gated channels, this affects membrane excitability (see Chapter 2). The propensity

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to complex with phosphate is a key aspect of the normal formation and maintenance of bone structure. Furthermore, when levels of calcium and/or small anions such as phosphate are increased, they approach the solubility limit of the complexes, leading to pathologies such as the formation of stones in the urinary tract and deposition of calcium complexes in soft tissue. For these reasons, the body possesses elaborate means to regulate plasma calcium. While calcium obeys the principles of input–output balance as do the other substances we have discussed, its regulation is fundamentally different. First, whole body calcium balance is regulated predominantly by input rather than output. Control of input from the GI tract is a crucial determinant of whole body calcium. Output by the kidneys plays an important, but secondary, role. Second, moment-to-moment regulation of plasma calcium is achieved by shifting calcium in and out of bone. Bone stores of calcium are an enormous buffer system that keeps plasma calcium nearly constant regardless of whole body balance. Thus, ordinary variations in ingestion and excretion have little effect on plasma levels because of this tight buffering. 485

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The long-term regulation of total calcium in bone is, of course, important for bone growth during childhood and bone integrity in adult life. Here the kidneys play an important but indirect role because they (1) excrete calcium in the urine and (2) are involved in forming the active form of vitamin D, which is a major controller of GI input. Normal levels of plasma calcium are about 10 mg/dL (2.5 mmol/L or 5 mEq/L). This calcium exists in three general forms. First, almost half is in the free ionized (Ca2+) form. This is the only form that is biologically active in target organs. Second, about 15% is complexed to anions with relatively low molecular weights, such as citrate and phosphate. Third, the remaining 40% is reversibly bound to plasma proteins.

EFFECTOR SITES FOR CALCIUM BALANCE GI TRACT Most dietary calcium simply passes through the GI tract to the feces. The amount absorbed depends on many factors, including the quantity of calcium in the diet. Some of the calcium that is absorbed moves by a regulated active transcellular process in the duodenum, while the majority is absorbed by unregulated paracellular diffusion in the rest of the small intestine. In the active transport system calcium enters duodenal cells passively through calcium-selective channels, binds reversibly to mobile cytosolic calcium-binding proteins (called calbindins), and is then actively transported out the basolateral side via a Ca-ATPase and to some extent by a Na–Ca antiporter. Calbindins contain multiple binding sites for calcium and are free to diffuse throughout the cytosol. They act as ferry boats for calcium, permitting large amounts of calcium to move from place to place within a cell, in this case from apical to basolateral membrane, all the while keeping the concentration of free calcium at a low level (see Figure 48–1).

KIDNEYS The kidneys handle calcium by filtration and reabsorption. The free component of plasma calcium is freely filterable. Most of the filtered calcium is reabsorbed in the proximal tubule (about 60% of the filtered load) and the remainder in the thick ascending limb of Henle’s loop, distal convoluted tubule, and collecting duct system. Overall reabsorption is normally 97–99%, leaving only a few percent of the filtered load to be excreted. Calcium reabsorption in the proximal tubule and thick ascending limb of Henle’s loop is largely passive and paracellular, and the electrochemical forces driving it are dependent directly or indirectly on sodium reabsorption as they are for so many other substances. In contrast, calcium reabsorption in the more distal segments is active and transcellular. It uses the same general mechanism as in the GI tract; that is, entrance

Lumen

Interstitium

ATP Ca

Calbindin Ca

Ca

Ca

Ca

Ca Na Ca

FIGURE 48–1 Generic method for transcellular calcium transport in the GI tract and kidney. In all body cells the free intracellular calcium concentration must be kept to minuscule levels to prevent formation of insoluble complexes and activation of deleterious signaling pathways, even though the concentrations of calcium at the two external surfaces of the cells are thousands of times higher. The epithelial cells accomplish this by using diffusible calbindins. As calcium enters the cells through channels in the luminal surface, the calcium concentration in the microenvironment near the channels is slightly raised, thus promoting the binding of calcium to calbindins. At the basolateral surface active extrusion of calcium via ATPases and sodium–calcium antiporters lowers the calcium concentration in the local microenvironment, promoting dissociation of calcium from the calbindins. Ion charge symbols (Ca2+ and Na+) omitted for clarity.

via calcium-specific channels, diffusion bound to calbindins, and active exit across the basolateral membrane by a combination of Ca-ATPase and Na–Ca antiport activity (Figure 48–2). Endocrine control of renal calcium handling is exerted in the distal tubule. The amount of calcium excreted in the urine, when averaged over time, is equal to the net addition of new calcium to the body via the GI tract; thus, the kidneys help maintain a stable balance of total body calcium. However, the change in renal excretion in response to changes in dietary input is much less than the equivalent responses to dietary sodium, water, or potassium. For example, only about 5% of an increment in dietary calcium appears in the urine, whereas virtually all of an increased ingestion of water or sodium soon appears in the urine. The reason is that most of the dietary increment never gains entry to the blood because it fails to be absorbed from the GI tract. In contrast, when dietary intake of calcium is reduced to extremely low levels, there is a slow reduction of urinary calcium, but some continues to appear in the urine for weeks. What determines renal calcium excretion? First, calcium is not secreted. Second, while the filtered load is highly variable, being the product of free plasma calcium and GFR, the GFR is regulated mainly to meet the needs of sodium balance, not calcium. In fact, an increase in urinary calcium excretion can be induced simply by administering salt. This feature is used clinically as an emergency procedure when calcium levels in the blood get

CHAPTER 48 Regulation of Calcium and Phosphate Balance

Lumen

Interstitium

Na Cl

ATP Thiazides block

Na K

PTH stimulates

Ca

Ca

Ca

Ca Ca

Na Ca

FIGURE 48–2 Mechanism of calcium reabsorption in the distal convoluted tubule, which is the major site for regulated reabsorption. Ca enters via apical Ca channels, under the control of PTH, and is actively transported across the basolateral membrane via Na–Ca antiport and via a Ca-ATPase. The apical membrane also contains the Na–Cl symporter (NCC), which is the target for inhibition by thiazide diuretics. Interestingly, inhibition of NCC with thiazide diuretics promotes calcium reabsorption (probably by enhancing the basolateral sodium gradient and increasing Na–Ca exchange). Thus, thiazides may reduce the calcium loss associated with osteoporosis. Ion charge symbols (Ca2+, Cl–, K+, and Na+) omitted for clarity. (Modified with permission from Eaton DC, Pooler JP: Vander’s Renal Physiology, 7th ed. New York, NY: Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2009.)

alarmingly high, the treatment consisting of administering large amounts of saline, with the consequence that large amounts of calcium-containing fluid pass through the kidneys to the urine. Thus, we are left with changes in the active reabsorption in the distal nephron as the means of exerting independent control of calcium excretion. We will describe this control shortly.

BONE Bone serves as the powerful short-term calcium-buffering system that prevents large swings in plasma calcium. About 0.5 g of calcium passes back and forth between bone and the blood plasma each day. Bone is also the repository of calcium that keeps blood supplied with calcium during times of negative whole body calcium balance. The calcium in bone exists in the form of crystalline hydroxyapatite (see Chapter 64). Calcium can move back and forth between blood and hydroxyapatite in the inner recesses of bone via an interconnected cellular network of osteocytes. The equilibrium between crystalline hydroxyapatite and its dissolved components is highly labile, dependent on the concentrations of calcium, phosphate, hydrogen ions, and specific noncollagenous proteins in the immediate environment. The formation and dissolution of hydroxyapatite protects the blood plasma from short-term swings in calcium concentration. This process does not require hormonal signals. However, the

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set point for plasma calcium concentration maintained by the rapid movement of calcium in and out of bone is critically regulated by hormonal control, as discussed later. The slow remodeling process in bone described in Chapter 64 is important for bone integrity and calcium stores on a much slower time scale, but this action has little effect on plasma calcium levels.

HORMONAL CONTROL OF EFFECTOR SITES The regulation of calcium is achieved mostly through the actions of two hormones: the active form of vitamin D (1,25(OH)2D; calcitriol) and parathyroid hormone (PTH). The chemistry and production of these hormones is described in Chapter 64 along with the actions of calcitonin, which plays an extremely minor role, if any. Briefly, calcitriol is synthesized through a series of steps beginning with cholesterol and culminating in the kidney, where a crucial hydroxylation step creates the active form. PTH is a small peptide that is synthesized by parathyroid glands lying behind the thyroid gland. Simply stated, the active form of vitamin D regulates what comes into the body and PTH regulates what is in the ECF.

VITAMIN D The major action of calcitriol is to increase active absorption of calcium and phosphate by the duodenum. A key mechanism is to stimulate synthesis of the proteins involved in the steps described earlier. In addition, vitamin D has some independent actions on bone that are not entirely clear. Vitamin D also stimulates the renal tubular reabsorption of calcium and phosphate, again by increasing the synthesis of the protein components in the transport pathway. The influences of vitamin D on bone and the kidney are far less important than its actions on the GI tract to stimulate absorption of calcium and phosphate.

PTH PTH secretion is acutely regulated by levels of free plasma calcium in a reciprocal manner—a decrease in plasma calcium stimulates secretion, and an increase inhibits secretion. Phosphate also affects PTH secretion: increased plasma phosphate stimulates PTH secretion by stimulating the capacity of the parathyroid gland to synthesize PTH, so that chronically high levels of phosphate lead to increased PTH. PTH exerts at least four distinct effects on calcium homeostasis (summarized in Figure 48–3 showing the response to hypocalcemia and discussed in detail in Chapter 64): 1. PTH actions on bone normally increase the movement of calcium from bone into the ECF. They do this by favoring the dissolving of hydroxyapatite into its components.

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Plasma calcium

PTH

Synthesis of 1,25 (OH)2-vit D

Rapid

FIGURE 48–3

Physiological responses to reduced plasma calcium concentration. Reduced plasma calcium stimulates secretion of PTH. In response, the bone matrix immediately releases calcium from hydroxyapatite into the ECF. PTH also stimulates renal calcium reabsorption. On a slower time scale PTH stimulates osteoclastic bone resorption and increased synthesis of calcitriol (vitamin D) in the kidney, leading to increased absorption of dietary calcium from the GI tract.

Renal Ca reabsorption

2. PTH stimulates the activation of an intermediate form of vitamin D to calcitriol. The major control point is the second hydroxylation step that occurs in the kidneys. This step is stimulated by PTH. If plasma calcium decreases acutely, the subsequent increase in PTH immediately stimulates calcium release from bone, thus restoring plasma calcium levels, and also stimulates calcium uptake (via calcitriol from the GI tract, on a slower time scale). This ensures that enough new calcium will enter the body to replace that “borrowed” from bone. 3. PTH increases renal–tubular calcium reabsorption, mainly by an action on the distal convoluted tubule and connecting tubule. At these locations, it acts rapidly through activation of kinases that phosphorylate regulatory proteins on a short-term basis. It also acts, on a slower time scale, to increase synthesis of all the components of the transport pathway. The increased uptake of calcium from the tubular lumen stimulates basolateral extrusion (by a combination of Ca-ATPase activity and Na–Ca antiporter activity) and thus decreases urinary calcium excretion. 4. PTH reduces the proximal tubular reabsorption of phosphate, thereby increasing urinary phosphate excretion and decreasing extracellular phosphate concentration. The adaptive values of the first three effects all result in a higher extracellular calcium concentration and thus compen-

Rapid

Slow

Slow

dissolution of hydroxyapatite

Osteoclastic bone resorption

Intestinal Ca absorption

Restoration of plasma calcium

sate for the lower calcium concentration that originally stimulated PTH secretion. Regarding the fourth effect, when PTH acts on bone, both calcium and phosphate are released into the blood. Similarly, calcitriol enhances the intestinal absorption of both calcium and phosphate, so that the processes that are restoring calcium to its normal level are simultaneously acting to increase the plasma phosphate above normal. But this is an unwanted action because of the tendency to form insoluble precipitates of calcium phosphate. Under the influence of PTH, plasma phosphate does not actually increase, because of PTH’s inhibition of tubular phosphate reabsorption. Indeed, this effect is so potent that plasma phosphate may actually decrease when PTH levels are high. All of the above describes the effects of an increase in PTH induced by a decrease in plasma calcium. An increase in extracellular calcium concentration reduces PTH secretion, thereby producing increased urinary and fecal calcium loss and net movement of calcium from the ECF into bone. There are nuances to the actions of PTH on bone that have important clinical implications. The response of bone to PTH depends on the pattern of its plasma concentration over time. PTH can either promote resorption of hydroxyapatite (its usual action) or, if administered intermittently, promote deposition. Primary hyperparathyroidism, resulting from a primary defect in the parathyroid glands (usually a hormonesecreting tumor), generates a continuous excess hormone level and causes enhanced bone resorption. This leads to bone

CHAPTER 48 Regulation of Calcium and Phosphate Balance thinning and the formation of completely calcium-free areas or cysts. In this condition, plasma calcium often increases and plasma phosphate decreases, the latter caused by increased urinary phosphate excretion. A seeming paradox is that urinary calcium excretion is increased despite the fact that tubular calcium reabsorption is enhanced by PTH. The reason is that the increased plasma calcium concentration induced by the effects of PTH causes the filtered load of calcium to increase even more than it increases the reabsorptive rate. Because the filtered load is so great, there is also an increased amount not reabsorbed (i.e., excreted). This result nicely illustrates the necessity of taking both filtration and reabsorption (and secretion, if relevant) into account when analyzing excretory changes of any substance. And, as mentioned earlier, the high urinary calcium content promotes the formation of stones. In contrast to what happens with the continuous presence of elevated PTH that accelerates bone resorption and release of calcium, intermittent increases (produced by injections once per day) actually increase deposition of calcium in bone. Intermittent injection of PTH is used therapeutically to increase bone density in osteoporosis patients.

OVERVIEW OF RENAL PHOSPHATE HANDLING Normally, approximately 75% of the filtered phosphate is actively reabsorbed, almost entirely in the proximal tubule in symport with sodium. Reabsorption is a tubular maximum– limited (Tm) system, and the normal filtered load is just a little higher than the Tm. Thus, while most filtered phosphate is reabsorbed, some always spills into the urine. (Recall that this phosphate is responsible for accepting hydrogen ions in the collecting duct and is the primary ion responsible for titratable acidity.) Since the reabsorptive capacity is saturated at normal filtered loads, any increase in filtered load simply adds to the amount excreted. This occurs when plasma phosphate concentration increases for any reason, such as increased dietary phosphate intake or release of phosphate from bone. Systemic acidosis promotes release of calcium and phosphate from bone. The increase in plasma phosphate and the consequent increase in filtered load of phosphate provides more titratable buffer in the collecting tubule to help remove the excess hydrogen ion that promoted the phosphate release. Much of the physiology we have described is illustrated by the case of chronic renal failure, in which a low glomerular filtration rate limits the ability of the kidneys to excrete a number of substances, specifically including phosphate. An almost universal complication of chronic renal failure is increased plasma phosphate (hyperphosphatemia). Another common finding is increased levels of PTH, due in part to the high plasma phosphate. The PTH stimulates excessive bone resorption, leading to osteoporosis. This is an example of secondary hyperparathyroidism (because the pathology is not in the gland itself, but in the signals that drive it). One goal in the

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treatment of hyperphosphatemia associated with chronic renal failure is reduction of phosphate absorption from the GI tract. This is accomplished by encouraging the ingestion of high doses of calcium. The calcium forms complexes with phosphate in the GI tract, reducing the availability of absorbable phosphate. The high levels of PTH in a healthy patient should signal the kidneys to form more calcitriol, but in chronic renal failure a further complication is a reduced ability to synthesize calcitriol in the kidney. Another clinical intervention in this case is to provide exogenous calcitriol. This hormone suppresses expression of the PTH gene in the parathyroid gland. The calcitriol increases GI absorption of phosphate, the very thing we are trying to inhibit, but its ability to lower the synthesis of PTH is the more important action because this reduces the excessive resorption of bone stimulated by PTH. Thus, administering vitamin D or its active metabolite calcitriol is a useful clinical tool.

CLINICAL CORRELATION A 53-year-old African American male is hospitalized with major vomiting, diarrhea, dehydration, and confusion, and the physicians are unable to obtain a history. His heart rate is 84, and blood pressure is 122/63. Temperature is 36.7°C. His blood work is normal, except for his calcium and phosphate. Calcium is high at 15 mg/dL, and phosphate is low at 1.6 mg/dL. He is given intravenous saline to replace fluid loss, and then additional saline and a loop diuretic to induce excretion of calcium. After a day, this procedure has brought his serum calcium down to 11.5 mg/dL (still somewhat high). His physicians suspect primary hyperparathyroidism, which is usually caused by a parathyroid adenoma producing too much PTH and causing his high calcium and low phosphate. Measurement of plasma PTH however shows a suppressed intact PTH concentration. If the parathyroid glands are normal and the hypercalcemia is due to some other cause, the production of intact PTH should be very low, because secretion should be suppressed by the elevated blood calcium. On the other hand, if he has primary hyperparathyroidism, the PTH levels should be much higher than what was measured. His physicians are unsure of a diagnosis, so they look for causes other than primary hyperparathyroidism. They realize that this patient is showing the presence of something that is acting like intact PTH and binding to the PTH receptor throughout the body, but has a different enough amino acid sequence so that it is not detected in the clinical assay for authentic intact PTH produced by the parathyroid glands. Further workup eventually reveals a carcinoma of the right kidney that is the source of this PTH receptor agonist—it is called PTH-related peptide (PTHrP) and is a common cause of humoral hypercalcemia of malignancy, which is what the patient has. The right kidney is removed surgically. On the third postsurgical day, the serum calcium and phosphate have returned to the normal range.

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CHAPTER SUMMARY ■ ■ ■ ■ ■

Moment-to-moment regulation of plasma calcium primarily involves calcium flux between bone and plasma. Calcium has a strong tendency to associate with small anions and anionic sites on proteins. The most important action of vitamin D is to ensure adequate absorption of calcium from the GI tract. PTH is essential both to maintain proper calcium flux between bone and plasma and to maintain adequate levels of vitamin D. Keeping phosphate levels in the normal range allows normal calcium retrieval from bone.

STUDY QUESTIONS 1. The most important action of calcitriol is to stimulate A) calcium deposition in bone. B) calcium resorption from bone. C) calcium absorption from the GI tract. D) calcium reabsorption from the renal tubules. 2. Why does prolonged excessive PTH lead to high urinary levels of calcium? A) PTH inhibits calcium renal calcium reabsorption in the proximal tubule, allowing more to be excreted. B) PTH stimulates resorption of calcium from bone, which raises plasma calcium and increases the filtered load. C) PTH inhibits renal calcium reabsorption in the distal nephron, allowing more to be excreted. D) PTH stimulates renal calcium secretion in the distal nephron.

3. In response to a sudden decrease in plasma calcium, what is the source for most of the calcium that restores plasma levels? A) bone B) the GI tract C) the renal tubules D) the organelles of tissue cells 4. Compared with other common plasma cations such as magnesium and potassium, calcium is unusual because it tends to A) form complexes with small anions and negative groups on proteins. B) form precipitates of elemental metal. C) substitute for other ions on transporters. D) diffuse passively through lipid bilayers. 5. In a case of acute hypercalcemia, one can rapidly lower plasma calcium and increase urinary calcium excretion by A) feeding large amounts of phosphate B) withholding phosphate from the diet C) injecting PTH D) giving large amounts of saline 6. Which condition(s) would directly or indirectly increase urinary excretion of phosphate? A) the actions of PTH on bone B) the actions of osteoclasts in bone C) the actions of PTH on the kidneys D) all of the above would increase urinary phosphate excretion

SECTION VIII GI PHYSIOLOGY

Overview of the GI System—Functional Anatomy and Regulation Kim E. Barrett

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Understand the basic functions of the gastrointestinal system and the design features that subserve these. Describe the functional layers of the gastrointestinal tract and the specializations that contribute to function. Identify the segments of the gastrointestinal tract and the specialized functions attributed to each. Understand the circulatory features of the intestine and variations that occur after meals. Understand the integrated response to a meal and the need for mechanisms that regulate the function of the gastrointestinal tract as a whole. Describe modes of communication in the gastrointestinal tract. Understand principles of endocrine regulation. Understand the design of the enteric nervous system and neurocrine regulation. Describe immune and paracrine regulatory pathways.

OVERVIEW OF THE GASTROINTESTINAL SYSTEM AND ITS FUNCTIONS DIGESTION AND ABSORPTION The gastrointestinal system exists primarily to convey nutrients and water into multicellular organisms. Most nutrients in a normal human diet are macromolecules and thus not readily permeable across cell membranes. Likewise, nutrients are not usually taken predominantly in the form of solutions, but rather as solid food. Thus, in addition to the food uptake, the

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intestine serves to physically reduce the meal into a suspension of small particles mixed with nutrients in solution. These are then chemically altered, resulting in molecules capable of traversing the intestinal lining. These processes are referred to as digestion, and involve gastrointestinal motility as well as the influences of pH changes, biological detergents, and enzymes. The final stage in the assimilation of a meal involves movement of digested nutrients out of the intestinal contents, across the intestinal lining, and into either the blood supply to the gut or the lymphatic system, for transfer to more distant sites in the body. Collectively, this directed movement of nutrients is referred to as absorption. The efficiency of absorption may vary widely for different molecules in the diet, as well as those 491

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supplied via the oral route with therapeutic intent, such as drugs. The barriers to absorption encountered by a given nutrient will depend heavily on its physicochemical characteristics, and particularly on whether it is hydrophilic (such as the products of protein and carbohydrate digestion) or hydrophobic (such as dietary lipids). Generally, the gastrointestinal tract does not rely solely on diffusion to provide for uptake, but rather has evolved active transport mechanisms that take up specific solutes with high efficiency. There is also significant excess capacity in the systems for both digestion and absorption of a meal, including an excess of enzymes and other secreted products as well as an excess in the surface area available for absorption in healthy individuals. Thus, assimilation of nutrients is highly efficient, assuming adequate amounts are presented to the lumen.

EXCRETION The gastrointestinal system also serves as an important organ for excretion of substances out of the body. This excretory function extends not only to the nonabsorbable residues of the meal, but also to specific classes of substances that cannot exit the body via other routes. Thus, in contrast to the renal system, which handles predominantly water-soluble waste products, the intestine works together with the biliary system to excrete hydrophobic molecules, such as cholesterol, steroids, and drug metabolites.

HOST DEFENSE The inner surface of the intestinal tract exists in continuity with the exterior of the body. This, of course, is essential to its function of bringing nutrients from the environment into the body: however, this also implies that the intestine, like the skin and respiratory system, is a potential portal into the body for less desirable substances. Indeed, we exploit this property to deliver drugs via the oral route. In addition, the intestine is potentially vulnerable to infectious microorganisms that can enter the gut with the ingestion of food and water. To protect, itself and the body, the intestine has evolved a sophisticated system of immune defenses. The gastrointestinal immune system is characterized by specific functional capabilities, most notably by being able to distinguish between “friend” and “foe”: mounting immune defenses against pathogens while being tolerant of dietary antigens and beneficial commensal bacteria.

ENGINEERING CONSIDERATIONS Given the functions of the gastrointestinal system discussed earlier, we will now consider the anatomic features needed to support these functions. In this discussion, the gastrointestinal system can be thought of as a machine (Figure 49–1) in which distinct portions conduct the various processes needed for assimilation of a meal without uptake of significant quantities of harmful substances or microorganisms.

Chopper

Blender Acid sterilizer Reservoir Reaction vessel Detergent supplier

Enzyme supplier Neutralizer

Catalytic and absorptive surface

Residue combuster Dessicator and pelleter

Emission control device

FIGURE 49–1 The gastrointestinal system as a machine that conducts digestive, absorptive, immune, and excretory functions. (Modified with permission from Barrett KE, Barman SM, Boitano S, Brooks H: Ganong’s Review of Medical Physiology, 23rd ed. McGraw-Hill Medical, 2009.)

DESIGN OF HOLLOW ORGANS The gastrointestinal tract is a long muscular tube stretching from mouth to anus. Within the lining of this tube, blindended glandular structures invaginate into the wall of the gut and empty their secretions into the lumen, defined as the cavity within the gut. At various points along the length of the gastrointestinal tract, more elaborate glandular organs are also attached to the intestine and are connected to the intestinal lumen via ducts, allowing secretions to drain into the intestine where they can be mixed with intestinal contents. Examples of such organs include the pancreas and salivary glands. Glands in general can be considered as structures that convert raw materials from the bloodstream into physiologically useful secretions, such as acid and enzyme solutions. In general, the glands have a common structure. Specialized secretory cells form blind-ended structures known as acini where a primary secretion is produced. Clusters of such acini, which can be likened to a bunch of grapes, then empty into tubelike ductular structures, with larger ducts collecting the secretions from a group of smaller ones until a main collecting duct is reached that connects directly to the gut lumen. The liver, which will be considered in this section as a critical participant in gastrointestinal function overall, has a highly specialized structure that will be discussed in detail in Chapter 55. For now, suffice to say that the liver is designed not only to secrete substances into the gastrointestinal lumen via the biliary system, but also to receive absorbed substances from the intestine that travel first to the liver via the portal circulation before being distributed to the body as a whole.

CHAPTER 49 Overview of the GI System—Functional Anatomy and Regulation

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Lumen Epithelium Basement membrane

Mucosa

Lamina propria Muscularis mucosa

Submucosa

Circular muscle Myenteric plexus

Muscularis propria

FIGURE 49–2 Organization of the wall of the intestine into functional layers. (Adapted

Longitudinal muscle

with permission from Madara J. and Anderson J.: Textbook of Gastroenterology, 4th ed., pp. 151–165. Copyright

Mesothelium (Serosa)

CELLULAR SPECIALIZATION The tube that comprises the gastrointestinal tract is made up of functional layers composed of specialized cell types (Figure 49–2). The first layer encountered by an ingested nutrient is the epithelium, which forms a continuous lining of the entire gastrointestinal tract as well as lining the glands and organs that drain into the tube. The epithelium must provide for the selective uptake of nutrients, electrolytes, and water while rejecting harmful solutes. The surface area of the intestinal epithelium is amplified by being arranged into crypt and villus structures (Figure 49–3). The former are analogous to the glands discussed earlier, whereas villi are fingerlike projections that protrude into the intestinal lumen, which are covered by epithelial cells. In the large intestine, only crypts are seen, interspersed with surface epithelium between the crypt openings. The majority of the gastrointestinal epithelium is columnar in nature, where a single layer of tall, cylindrical cells separates the gut lumen from the deeper layers of the wall of the gut. The structure of the columnar epithelium can be compared to a six packs of soda cans, with the cans representing the cells and the plastic holder that links them as a series of intercellular junctions that provide a barrier to passive movement of solutes around the cells. However, in the first part of the intestinal tube, known as the esophagus, the epithelial lining is a stratified squamous epithelium. In this site, the epithelium forms a multilayer reminiscent of the structure of the skin, with cells migrating toward the lumen from a basal germinal layer. The epithelium of the gut as a whole is subject to constant renewal, unlike the majority of tissues in the adult body. Gastrointestinal epithelial cells turn over every 3 days or so in humans, undergoing a cycle of division and differentiation

Lippincott Williams and Wilkins, Philadelphia, 2003.)

before succumbing to programmed cell death (or apoptosis) and being shed into the lumen or engulfed by their neighbors. Epithelial cells arise from stem cells that are anchored permanently in specific positions in the gut lining, located at the base of crypts in the intestine and in the middle of gastric glands in the fundic region of the stomach. Following several cycles of

Small intestine LUMEN

Villus

Crypt

Colon LUMEN

Surface

Crypt

FIGURE 49–3 Comparison of the morphology of the epithelial layers of the small intestine and colon. (Modified with permission from Barrett KE: Gastrointestinal Physiology. New York: Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2006.)

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division, epithelial cells also differentiate into specialized cell types with specific functions in the digestive process. In the stomach, some epithelial cells migrate downwards deeper into the gland, and become chief or parietal cells that contribute specific products to the gastric juice, or endocrine cells that regulate the function of the latter secretory cell types. The remaining gastric epithelial cells migrate upwards to become cells capable of secreting mucus and bicarbonate ions. In the intestine, some stem cells give rise to Paneth cells, which remain in the crypt base and secrete antimicrobial peptides. The majority of the daughter cells that arise from stem cell divisions migrate upwards toward the villus (or surface epithelium in the colon), and of these, most are destined to differentiate into absorptive epithelial cells with the capacity for the final steps of nutrient digestion and uptake. A few cells, however, differentiate into goblet cells, which produce mucus, or enteroendocrine cells that respond to luminal conditions, and regulate the functions of the other epithelial cell types as well as those of more distant organs. Beneath the epithelium is a basement membrane, overlying a layer of loose connective tissue known as the lamina propria. This contains nerve endings and blood vessels, as well as a rich assortment of immune and inflammatory cells. Taken together, the epithelium and lamina propria are referred to as the mucosa. The mucosa also contains a thin layer of smooth muscle known as the muscularis mucosae. Beneath this layer, there is a plexus of nerve cell bodies known as the submucous (or submucosal) plexus, designed to relay information to and away from the mucosa, including the epithelial cells. Then, beyond the mucosa are the smooth muscle layers that provide for overall gut motility. These are arranged circumferentially around the outer side of the intestinal tube. Closest to the mucosa is a layer of circular muscle that reduces the diameter of the intestinal lumen when it contracts. On the outer side of the gut, a layer of smooth muscle in which the fibers are arranged longitudinally along the axis of the tube provides for intestinal shortening. Working together, these two outer muscle layers can provide for complex motility patterns that subserve specific gut functions, as will be described in more detail later. Sandwiched between the circular and longitudinal muscle layers, the myenteric plexus of nerves regulates their function.

DIVISION OF INTESTINE INTO FUNCTIONAL SEGMENTS Movement of the meal along the length of the intestine is a regulated process, and involves selective retention in specific sites to promote optimal digestion and absorption. This is accomplished by specialized smooth muscular structures known as sphincters, whose function is also coordinated with that of the system as a whole (Figure 49–4). For example, the pylorus, which controls outflow from the stomach, retains the meal in the gastric lumen and releases it slowly to match the availability

Esophagus

Upper and lower esophageal sphincters

Stomach Pylorus Sphincter of Oddi Pancreas

Liver

Gallbladder

Colon

Small intestine

Ileocecal valve

Internal and external anal sphincters

FIGURE 49–4 Overall anatomy of the gastrointestinal system and division of the GI tract into functional segments by sphincters and valves. (Modified with permission from Barrett KE: Gastrointestinal Physiology. New York: Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2006.)

of nutrients to the capacity of the enzymes required for digestion and the absorptive surface area. Similarly, the ileocecal valve retains the majority of the gastrointestinal flora within the colon, opening only intermittently to permit the residues of the digested meal, along with water and cellular debris, to enter the large intestine. Finally, the sphincter of Oddi relaxes in conjunction with a meal to allow the outflow of both biliary and pancreatic secretions into the lumen. Most gastrointestinal sphincters are under involuntary control, and perform their normal cycles of relaxation and contraction without conscious input. Many may also function in a manner that is largely autonomous of the central nervous system (CNS), being controlled instead by the enteric nervous system. On the other hand, the external anal sphincter can be controlled voluntarily, a skill learned during toilet training in infancy, and the esophageal sphincters are regulated by the CNS.

ORGANS AND SYSTEMS INVOLVED IN THE RESPONSE TO A MEAL Several intestinal and extraintestinal tissues cooperate to respond appropriately to the ingestion of a meal. Collectively, these tissues can sense, signal, and respond to meal ingestion with altered function. Moreover, the tissues and their functions are interactive and highly efficient, and redundancy

CHAPTER 49 Overview of the GI System—Functional Anatomy and Regulation

The oral cavity is concerned with initial intake of food and with shaping and lubricating the bolus of ingested materials such that it can be swallowed. The teeth reduce large portions of food into sizes suitable for passage through the esophagus. Salivary glands, which drain into the oral cavity, supply an aqueous environment and also mucus that coats the surface of the bolus and thus aids in swallowing. The aqueous environment also permits diffusion of taste molecules to specific receptors on the tongue that relay information centrally as to whether the meal is palatable. Salivary secretions also reduce microbial contamination of the oral cavity. Finally, the structures of the oral cavity are also intimately involved in swallowing. The esophagus transfers the bolus from the mouth to the stomach. Its upper third is surrounded by striated muscle overlaid by a thick submucous elastic and collagenous network. The muscle then transitions to smooth muscle that works in concert with the swallowing reflex to propel the bolus toward the stomach. Toward the lowest portion of the esophagus, the smooth muscle gradually thickens and interacts with neurogenic and hormonal factors, as well as the diaphragm, to serve functionally as a lower esophageal sphincter. The higher pressure in this segment prevents excessive backflow, or reflux, of the gastric contents into the esophageal lumen. Failure of this process leads to gastroesophageal reflux disease (GERD), where refluxed contents of the stomach can cause damage to the esophageal epithelium. GERD is one of the most common gastrointestinal disorders.

STOMACH The stomach is a muscular bag that functions primarily as a reservoir, controlling the rate of delivery of the meal to more distal segments of the gastrointestinal tract. Anatomically, it is divided into three regions, the cardia (which overlaps with the lower esophageal sphincter), fundus, and antrum, each with distinctive structures that subserve specific functions (Figure 49–5). The cardia begins where the squamous epithelium of the esophagus gives way to the columnar epithelium of the remainder of the gastrointestinal tract; it functions mostly to secrete mucus and bicarbonate to protect the luminal surface from the corrosive gastric contents. At the microscopic level, the surface area of the stomach is amplified by pits, which represent the entrances to deep gastric glands. The specific structures of

Cardia

Fundus and body

Secretion Reservoir

urva ture

v ur

ter c

s Le

rc se

Mixing Grinding

ea

ORAL CAVITY AND ESOPHAGUS

Lower esophageal sphincter— prevention of reflux

at ure

exists among the majority of GI regulatory mechanisms. In this section, we will introduce the functions of each segment of the gastrointestinal tract and the structural features that underlie these. More detailed discussions will be provided in subsequent chapters. Specific features of the circulatory systems designed to carry absorbed nutrients away from the gut, and the neuromuscular system that provides for motility and regulation, will also be considered.

495

Gr

Antrum Pylorus— control of emptying

FIGURE 49–5

Functional regions of the stomach. (Modified

with permission from Barrett KE: Gastrointestinal Physiology. New York: Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2006.)

these glands differ in the three regions of the stomach; they are shallowest in the cardia, intermediate (though with deep pits) in the antrum, and deepest in the fundus. The fundic (or gastric) glands contain specific secretory cells that produce the characteristic components of gastric juice— acid and pepsin—that are products of parietal and chief cells, respectively. Thus, the fundus is a secretory region. On the other hand, the antrum (also referred to as the pyloric zone) engages in extensive motility patterns, mixing the gastric contents and grinding and sieving ingested particles. Eventually, the meal is gradually emptied into the small intestine via the pylorus. The stomach also undergoes receptive relaxation. The gastric musculature relaxes as it is stretched during filling, ensuring that the pressure in the stomach does not increase significantly as its volume expands. This response ensures that the meal is not forced back into the esophagus, and is integral to the reservoir function of the stomach. An individual lacking a significant portion of his or her stomach cannot tolerate large meals due to the loss of this reservoir function, making gastric restriction a treatment for obesity.

DUODENAL CLUSTER UNIT The first segment of the small intestine immediately distal to the pylorus, approximately 12 in in length, is referred to as the duodenum. Together with the pancreas and biliary system, the duodenum makes up the duodenal cluster unit. This segment of the gastrointestinal system acts as a critical regulator of digestion and absorption. Endocrine cells within the wall of the duodenum, as well as chemosensitive and mechanosensitive nerve endings, monitor the characteristics of the luminal contents and emit signals that coordinate the function of more distant regions of the gastrointestinal tract to ready them for

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the arrival of the meal, or to retard the flow of contents from the stomach. The exocrine pancreas and gallbladder also drain into the duodenum with egress of secretions controlled by opening of the sphincter of Oddi.

Splenic flexure Transverse colon Hepatic flexure

SMALL INTESTINE The remainder of the small intestine consists of the jejunum and ileum. The jejunum serves as the site of the majority of nutrient absorption in the healthy individual, and has a markedly amplified surface area due to the presence of surface folds and tall, slender villi. The surface area of the jejunum is also amplified considerably by an abundance of microvilli on the apical surface of villus epithelial cells. More distally, the ileum has fewer folds and shorter, sparser villi, and is less actively engaged in nutrient absorption other than for specific solutes such as conjugated bile acids, which are exclusively salvaged by transporters expressed in the terminal ileum. However, if jejunal absorption is impaired, the ileum represents an anatomic reserve that can be called on for absorption. As a result, the small intestine has excess capacity for both digestion and absorption, and thus malabsorption is a relatively rare event.

Descending colon Tenia coli

Ascending colon Ileum

Haustra Cecum Appendix Rectum

Sigmoid colon Internal External

anal sphincter

FIGURE 49–6 Anatomy of the large intestine comprised of the cecum, colon, rectum, and anus. (Reproduced with permission from Barrett KE, Barman SM, Boitano S, Brooks H: Ganong’s Review of Medical Physiology, 23rd ed. McGraw-Hill Medical, 2009.)

COLON The colon, or large intestine, serves as a reservoir for the storage of wastes and indigestible materials prior to their elimination by defecation. In general, colonic epithelial cells (or colonocytes) do not express absorptive transporters for conventional nutrients such as monosaccharides, peptides, amino acids, and vitamins but may be actively involved in the uptake of other luminal constituents. As its name implies, the large intestine is of a considerably larger diameter than the small intestine, with a thicker wall and folds known as haustrations. The colon is divided into several regions: the ascending, transverse, descending, and sigmoid colon, which are defined anatomically but may also subserve different functions (Figure 49–6). For example, in the ascending and transverse colon, there is an emphasis on reclamation of fluid as well as salvage of other dietary byproducts, such as absorption of short-chain fatty acids produced by the bacterial fermentation of dietary fiber. The smooth muscle of the colon, under the influence of the enteric nervous system, produces mixing motility patterns that maximize the time for reabsorption of fluid and other useful solutes. Other luminal solutes, such as bile acids and bilirubin, are also modified in the colon by bacterial metabolism. In fact, the healthy colon contains an abundant ecosystem comprised primarily of anaerobic bacteria, and these symbionts are important contributors to whole body nutritional status. The descending colon serves primarily as the storage reservoir for fecal wastes. When these are propelled through the sigmoid colon into the rectum, stretch receptors initiate a reflex relaxation of the internal anal sphincter and also send afferent impulses to the CNS indicating a need to defecate. Defecation can, however, be postponed to a convenient time

by contraction of the external anal sphincter and levator ani muscles, which are under voluntary control. Compared with other segments of the gastrointestinal tract, propulsive motility in the colon is relatively sluggish until a reflex sufficient to trigger mass peristalsis and defecation occurs, and contents may remain in the colon for days.

SPLANCHNIC CIRCULATION AND LYMPHATICS Blood supply to the intestines is vitally important in carrying away absorbed nutrients, particularly those that are water soluble, to sites of usage elsewhere in the body. Likewise, most lipids enter the lymphatic drainage of the gut initially, because they are packaged in particles (chylomicrons) too large to pass through the pores between capillary endothelial cells. Lymph fluid containing absorbed lipids is emptied into the bloodstream via the thoracic duct. The circulation of the gastrointestinal tract is unusual because of its anatomy (Figure 49–7). Unlike venous blood draining from other organs of the body, which returns directly to the heart, blood flow from the intestine flows first to the liver via the portal vein. Conversely, the liver is unusual in receiving a considerable portion of its blood supply not as arterial blood, but as blood that has first perfused the intestine. This anatomic arrangement ensures that substances absorbed from the gut flow first to the hepatocytes where they can be detoxified if necessary. Gastrointestinal blood flow is also notable for the range of its dynamic regulation. Even in the fasting state, the splanchnic circulation receives blood flow (25% of cardiac

CHAPTER 49 Overview of the GI System—Functional Anatomy and Regulation

Vena cava Hepatic vein

Hepatic sinusoids

Hepatic artery Intestinal artery (from mesentery)

Portal vein Liver

Intestinal capillaries

Intestine

497

myenteric plexus. Many of these fibers are contained in the vagus nerve, which follows blood vessels to innervate the stomach, small intestine, cecum, and ascending and transverse colon. The remainder of the colon receives parasympathetic innervation via the pelvic nerve. The most striking aspect of intestinal neurophysiology is the enteric nervous system contained wholly within the gut wall. This system consists of neurons with their cell bodies in the myenteric or submucosal plexuses. The anatomy of the enteric nervous system and its relationship to other gut structures is shown in Figure 49–8. The enteric nervous system serves as a relay station to conduct and interpret information supplied by extrinsic autonomic afferents carrying impulses that originate centrally, and also to pass information from sensory efferents that have their endings in the epithelium or smooth muscle. Thus, the enteric nervous system can ultimately cause changes in motility and/or secretory behavior in response to centrally mediated signals. The enteric nervous system can also function autonomously and mediate reflexes that do not involve the CNS at all.

FIGURE 49–7 Schematic anatomy of the splanchnic circulation. (Modified with permission from Barrett KE: Gastrointestinal Physiology. New York: Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2006.)

Myenteric plexus Circular muscle

output) that is disproportionate to the mass of the organs perfused (5%). Under these circumstances, the liver receives approximately 65% of its blood flow via the portal system. In the postprandial period, blood is diverted from the skeletal muscles and other body systems, and flow through vessels perfusing the intestine can increase more than 5-fold. Under these circumstances, the liver receives more than 85% of its blood supply via the portal system. These dramatic changes in blood distribution are produced by hormonal and neurogenic stimuli occurring secondary to the ingestion of a meal.

Deep muscular plexus Submucosal plexus Longitudinal muscle

Mucosa A Paravascular nerve

NEUROMUSCULAR SYSTEM The motility functions of the gastrointestinal tract are essential to propel ingested nutrients along the length of the alimentary canal, and also to control the length of time available for digestion and absorption. The motility patterns of the intestine are brought about by the integrated control of the contraction and relaxation of the circular and longitudinal muscle layers. Extrinsic innervation of the gut occurs via both sympathetic and (more prominently) parasympathetic pathways. Sympathetic innervation primarily involves postganglionic adrenergic nerves originating in prevertebral ganglia. These nerves synapse mainly with others in the enteric nervous system, discussed later, but a few may directly innervate secretory cells in various glands (especially the salivary glands) or the smooth muscle cells of blood vessels, leading to vasoconstriction. Parasympathetic innervation, on the other hand, is via preganglionic nerve fibers that synapse with cell bodies in the

Subserous nerve

Submucosal plexus

Muscularis mucosae

Submucosal artery

Perivascular nerves

Mesentery Myenteric plexus

Deep muscular plexus Mucosal plexus

B

FIGURE 49–8 Plexuses of the enteric nervous system and their relationship to the other functional layers of the gut wall. Panel A shows intact tissue while Panel B is a transverse section. (Adapted with permission from Furness J. and Costa M. Neuroscience 1980;5:1–20. Copyright Pergamon Press.)

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REGULATION OF GASTROINTESTINAL FUNCTION

COMMUNICATION IN THE GI TRACT

For nutrient assimilation to occur, specific tissues and regions of the gastrointestinal system must sense, signal, and respond to the ingestion of a meal (Figure 49–9). To conduct the business of the gastrointestinal system most efficiently, the various segments must also communicate. Thus, the activities of the gastrointestinal tract and the organs that drain into it are coordinated temporally via the action of a series of chemical mediators, with the system being referred to collectively as neurohumoral regulation, implying the combined action of soluble and neuronal pathways. The integrated regulation of gastrointestinal function underlies the efficiency of the system and its ability to provide for the effective uptake of nutrients even when they are in short supply.

GENERAL FEATURES OF NEUROHUMORAL REGULATION

Nutrients

Special senses

Chemo/mechanosensitive nerve endings

Vagus nerve

ENS

Stomach Intestines Pancreas Gallbladder Sphincters

Changes in secretion and motility

FIGURE 49–9 Overview of neural control of the gastrointestinal system. Nutrients activate both special senses (smell, taste) and specific sensory nerve endings that exist within the wall of the gut. These responses are conveyed via the autonomic nervous system and enteric nervous system (ENS) to alter the function of the gastrointestinal tract and organs draining into it, resulting in changes in secretion and motility. Such functional changes may additionally feed back on neural control to allow for appropriate homeostasis of the system. (Modified with permission from Barrett KE: Gastrointestinal Physiology. New York: Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2006.)

CHARACTERISTICS OF CHEMICAL SIGNALS Neurohumoral regulation is effected by several classes of chemical messengers including peptides, derivatives of amino acids, small molecule neurotransmitters, and lipid mediators. The gastrointestinal messengers that have been assigned definite physiologic roles are listed in Table 49–1.

Higher centers

Dorsal vagal complex

Communication that depended simply on diffusion of locally released signals would not be adequate for the timely transfer of information from one intestinal segment to another. Likewise, the gastrointestinal tract also needs to communicate its status to organs that drain into it, such as the pancreas and gallbladder. Thus, the system has evolved mechanisms for communication over significant distances, although local messengers also play a role in fine-tuning information delivery or, in some cases, amplifying or antagonizing it. Overall, information is carried between the various sites by chemical entities possessing specific physicochemical properties. Another general principle underlying communication is that of functional redundancy. Several different mediators may often produce the same physiologic response, and single mediators may alter the function of more than one system.

SPECIFIC MODES OF COMMUNICATION Four modes of communication are recognized within the gastrointestinal system—endocrine, neurocrine, paracrine (of which autocrine is a special case), and juxtacrine regulation, most often ascribed to cells of the immune system. A diagrammatic representation of each of these is provided in Figure 49–10.

ENDOCRINE COMMUNICATION Because of its ability to regulate multiple sites in an essentially simultaneous fashion, endocrine regulation is critical to the integrated function of the gastrointestinal system in response to a meal. The intestine is extremely well supplied with cell types containing endocrine mediators (hormones); in fact, if all of the endocrine cells within the gut were assembled as a single structure, they would make up the largest endocrine organ in the body.

CHAPTER 49 Overview of the GI System—Functional Anatomy and Regulation

499

TABLE 49–1 Major physiologic neurohumoral regulators of gastrointestinal function. Endocrine

Neurocrine

Paracrine

Immune/Juxtacrine

Gastrin

Acetylcholine

Histamine

Histamine

Cholecystokinin

Vasoactive intestinal polypeptide

Prostaglandins

Cytokines

Motilin

Substance P

Somatostatin

Reactive oxygen species

Secretin

Nitric oxide

5-Hydroxytryptamine

Adenosine

Glucose-dependent insulinotropic peptide

Cholecystokinin 5-Hydroxytryptamine Somatostatin Calcitonin gene-related peptide

Endocrine hormones are packaged within secretory granules and released in response to nervous activity, as well as chemical and mechanical signals coincident with food ingestion. The endocrine cells of the gut have been identified with letters to describe their hormonal contents; gastrin, secretin, cholecystokinin (CCK), and glucose-dependent insulinotropic peptide (also referred to as gastric inhibitory peptide,

Endocrine

Paracrine (autocrine)

Neurocrine

Immune/Juxtacrine

FIGURE 49–10 Modes of communication in the gastrointestinal system. Information is conveyed by endocrine, neurocrine, paracrine, and immune/juxtacrine routes. Autocrine regulation is a special class of paracrine regulation. (Modified with permission from Barrett KE: Gastrointestinal Physiology. New York: Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2006.)

or GIP) are stored in G, S, I, and K cells, respectively. Cells containing motilin have not been named, and indeed, there is some debate as to whether this peptide is stored in endocrine cells or nerve endings. Some endocrine cells may have processes that contact the luminal contents and are activated to release their mediators in response to specific features of luminal composition, such as acidity, osmolarity, or nutrients such as amino acids and free fatty acids. In other cases, hormone release in response to changes in luminal composition can also be activated by a reflex arc that first involves activation of a sensory enteric nerve ending, with subsequent release of specific neurotransmitters close to the surface of the endocrine cell to stimulate exocytosis. Yet other endocrine cells are designed to respond to conditions existing in the interstitium. The hormones that are released from endocrine cells diffuse into the lamina propria and thence into the portal circulation. From there, they travel to target organs and modify secretion, motility, and cell growth. All of the currently known GI hormones are peptides, but not all peptides isolated from the gastrointestinal tract are hormones. The GI hormones are synthesized in various segments of the gastrointestinal tract (Figure 49–11), but only gastrin appears to be present in the stomach of healthy individuals. The remaining hormones are present in greatest amounts in the duodenum and jejunum, with tapering expression of CCK and secretin into the ileum. However, under normal conditions, most of the release of gastrin occurs in the stomach, and of the other hormones in the duodenum and to some extent the jejunum. Ileal expression of some hormones, therefore, represents another example of the “reserve capacity” of the intestine that can be called upon to regulate gastrointestinal function if required. Further, in health, there appears to be little, if any, expression of gastrointestinal hormones in the colon.

NEUROCRINE REGULATION Neurocrine regulation is mediated by specific nerve endings of both the enteric and central nervous systems. Neurotransmitters stored in these nerve endings are released on receipt

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SECTION VIII GI Physiology

Gastrin

CCK

Secretin

GIP

Motilin

Fundus Antrum

Duodenum

Jejunum

Ileum

FIGURE 49–11 Sites of production of the five gastrointestinal hormones along the length of the gastrointestinal tract. The width of the bars reflects the relative abundance at each location. (Modified with permission from Barrett KE, Barman SM, Boitano

Colon

S, Brooks H: Ganong’s Review of Medical Physiology, 23rd ed. McGraw-Hill Medical, 2009.)

of an electrical signal, and diffuse across synaptic clefts to alter secretomotor function in the gastrointestinal system. These neurotransmitters thus provide information exchange that is exquisitely spatially specific, and because of their relative instability, there is very little spillover of information conveyed by neurotransmitters even to immediately adjacent sites. Some endocrine mediators may also convey information among the various parts of the gastrointestinal system by activating nerve endings in addition to their ability to circulate to distant sites; the most classic example of this mode of communication is mediated by CCK, for which receptors exist on sensory nerve endings in the small intestinal mucosa.

PARACRINE COMMUNICATION Some substances are designed to act only in the immediate area of their release, and yet are released from cell types other than nerves. This paracrine communication provides an important additional layer of control for gastrointestinal secretomotor function, particularly in response to changes in local conditions. Paracrine regulators, like neurotransmitters, are readily metabolized or retaken up to limit the duration of their activity. A special case of paracrine regulation is labeled autocrine, which involves the release of a substance that then acts on its cell of origin. Intestinal epithelial cells may engage in autocrine regulation since they are capable of releasing growth factors that influence their proliferation and/or migration along the crypt– villus axis.

IMMUNE COMMUNICATION A final class of communication in the gastrointestinal system is mediated by the release of substances by cells of the mucosal immune system. These cells are activated by antigenic substances or products of pathogenic microorganisms, and release a variety of chemical mediators including amines (such as histamine), prostaglandins, and cytokines. Immune regulation is important in changing the function of the secretomotor systems of the gastrointestinal tract during times of threat- for example, invasion of the mucosa by pathogens. Immune mediators may also be responsible for intestinal dysfunction in the setting of inflammation or conditions such as food allergies, where inappropriate immune responses to substances that would normally be innocuous may be deleterious for the host. Finally, immune cell types may be activated by endogenous substances such as bile acids in the lumen, or by specific peptide neurotransmitters. Immune regulation thus contributes to gastrointestinal regulation not only under pathological circumstances, but also in response to normal physiologic events.

PRINCIPLES OF ENDOCRINE REGULATION ESTABLISHED GI HORMONES As noted above, five gastrointestinal peptides have fulfilled the criteria to be named as hormones (Table 49–2). These fall into three groups based on structural and signaling similarities.

CHAPTER 49 Overview of the GI System—Functional Anatomy and Regulation

501

TABLE 49–2 Factors influencing release of gastrointestinal hormones.

a

Gastrin

CCK

Secretin

GIP

Motilin

Proteins/amino acids

↑

↑

↔

↔

↓a

Fatty acids

↔

↑

↑

↑

↓a

Glucose

↔

↔

↔

↑

↓a

Acid

↓

↔

↑

↔

↔

Neural stimulation

↑

↑

↔

↔

↑

Stretch

↑

↔

↔

↔

↔

Peptide-releasing factors

↔

↑

↔

↔

↔

Motilin release is reduced by feeding, but the precise mechanism is unclear.

GASTRIN/CCK FAMILY Gastrin and CCK occur in the gastrointestinal system in various forms, and are structurally related peptides that also bind to closely related receptors known as CCK-A and CCK-B. CCK and gastrin share a common C-terminal pentapeptide, which is amidated as a final step in processing in I and G cells, respectively. Amidation is believed to increase the stability of these hormones by blocking carboxypeptidase activity. The major biologically active forms of gastrin are 17- and 34-amino-acid peptides, which may or may not be sulfated; this posttranslational modification is of unknown function. CCK also occurs as a family of peptides of decreasing length (CCK-58, CCK-39, CCK-33, and CCK-8), but unlike gastrin, all of the released peptides are sulfated. The sulfation of CCK peptides appears critical for their high-affinity interaction with their receptor (CCK-A). CCK was named for its ability to contract (-kinin) the gallbladder (cholecysto-), but it also affects the function of numerous other tissues and cell types, and can be considered as the master regulator of the duodenal cluster unit. It has also been shown to signal the CNS to indicate satiety, or fullness. CCK also appears to cooperate with a major systemic regulator of food intake—leptin—that is released by adipocytes to signal the status of fat stores throughout the body. CCK-A and CCK-B receptors are G protein–coupled receptors that signal via increases in cytoplasmic calcium. The specificity of CCK and gastrin for these receptors is defined by their structures. Gastrin is highly specific for CCK-B, whereas CCK binds to both CCK-A and (with lower affinity) CCK-B, giving it a broader activity that may overlap to some extent with that of gastrin.

SECRETIN FAMILY The secretin family of gastrointestinal peptides includes not only the hormones secretin and GIP, but also a systemic hormone, glucagon, as well as a neuropeptide, vasoactive intestinal polypeptide (VIP). Although there is some homology among the amino acid sequences of these peptides, each is believed to bind

to distinct receptors on target cells. All of the receptors for these family members, however, share the common property of signaling predominantly via associated G proteins of the Gs class, and thus via increasing intracellular levels of cAMP. Secretin itself is a 27-amino acid peptide that is synthesized by S cells located predominantly in the duodenal mucosa, and is released in response to a low intraluminal pH. This accords nicely with the major known biological action of secretin, which is to stimulate secretion of bicarbonate by the cells lining the pancreatic and biliary ducts, as well as the duodenal epithelial cells themselves. Up to 80% of the bicarbonate secretory response that occurs in the course of digesting and absorbing a meal is likely due to the direct influence of secretin. GIP, or glucose-dependent insulinotropic peptide (formerly known as gastric inhibitory peptide, which fortuitously has the same initials), is released from intestinal K cells in response to all of the major components of a meal—carbohydrates, protein, and fat. Its primary physiologic actions are to inhibit gastric acid secretion and to amplify glucose-stimulated release of insulin from the endocrine pancreas, making it an incretin. The former action represents an example of a feedback regulatory event that contributes to the termination of gastric secretory function once the bulk of the meal has moved into the small intestine. The latter action represents a feedforward signal from the gut to the insulin-secreting cells of the endocrine pancreas such that the insulin response to absorption of glucose is amplified (see Chapter 66).

MOTILIN Human motilin is a 22-amino acid linear peptide that is released cyclically from the gut in the fasting state, and is responsible for stimulating a specific pattern of gastrointestinal motility known as the migrating motor complex that will be discussed in detail in Chapter 54. A closely related peptide, ghrelin, is predominantly produced in the stomach, and its plasma concentrations are increased by fasting and reduced by feeding. Ghrelin may be an important mediator of signaling between the intestine and hypothalamus to increase metabolic efficiency at times when nutrient supplies are limited.

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CANDIDATE GI HORMONES As mentioned earlier, the gastrointestinal tract is a rich source of stored peptides, and several peptides have received attention for their potential physiologic roles. The most compelling evidence exists for three such peptides—enteroglucagon, pancreatic polypeptide, and peptide YY (tyrosine–tyrosine). Enteroglucagon is a member of the secretin family, whereas the other two peptides are related to each other, but not to any of the other hormone families thus far discussed. While none of these peptides have yet fulfilled all of the criteria needed to classify them as a hormone, it is possible that they may do so in the future. Intestinal L cells make peptides that are closely related to pancreatic glucagon, and arise from differential processing of the same gene. One of these peptides, glucagonlike peptide-1, is a 30-amino acid peptide that inhibits gastric secretion and emptying, and also potently augments the secretion of insulin in response to glucose (making it another incretin). The enteroglucagons are released in response to luminal sugars, and thus may contribute to the axis by which circulating glucose concentrations are regulated during the period of glucose absorption after a meal, by coordinating the activities of the intestine and endocrine pancreas. As such, these presumed enteroglucagons act in concert with GIP. Cells of the pancreatic islets synthesize pancreatic polypeptide as a 36-amino acid linear peptide and release it in response to ingestion of a meal, although the signals between the gut and pancreas have not been defined. Likewise, although the peptide can be shown to inhibit pancreatic enzyme and bicarbonate secretion, the physiologic significance of this is unclear because infusion of an antibody to neutralize the actions of pancreatic polypeptide during meal digestion and absorption had no effect on the extent of pancreatic secretion. Thus, the precise role of this peptide remains elusive. Finally, peptide YY is synthesized and released by enteroendocrine cells in the distal small intestine and colon in response to the presence of fat in the ileal lumen. Its actions are largely inhibitory, reducing gastrointestinal motility as well as gastric acid secretion and secretion of chloride by the intestinal epithelium. Some have proposed that peptide YY can be considered

an ileal brake, that is, a substance that acts to slow propulsive motility and reduce luminal fluidity if nutrients remain unabsorbed by the time the meal reaches the ileum, thereby maximizing contact time and ability to absorb nutrients.

PRINCIPLES OF NEUROCRINE REGULATION “LITTLE BRAIN” MODEL OF THE ENTERIC NERVOUS SYSTEM The enteric nervous system is often referred to as the “little brain” (as opposed to the “big brain” of the CNS) because many of its responses are autonomous of central input. The gastrointestinal system is unique in being the only organ system outside the CNS with such an extensive system of intrinsic neural circuits. The various neurons of the enteric nervous system can be considered to perform functions in two primary areas (Figure 49–12). First, program circuits receive inputs regarding the physiologic status of the intestine, and translate these into appropriate changes in function. Second, integration circuits relay such information to the CNS, and in turn integrate information derived from the CNS with that supplied from intrinsic circuits to modify functional outcomes. As discussed earlier, the intrinsic nerves of the gastrointestinal system are arranged into two plexuses—myenteric and submucosal. Within these plexuses, the neurons can be subdivided according to their functions (Table 49–3). In the myenteric plexus, inhibitory and excitatory nerves control the function of the circular and longitudinal muscle layers. There are also ascending and descending interneurons that relay information through the myenteric plexus along the length of the gastrointestinal tract. In the submucosal plexus, secretomotor neurons, some of which also innervate blood vessels to promote vasodilatation, regulate the secretion of fluid and electrolytes and contractions of the muscularis mucosa. The plexuses also contain cell bodies of primary afferent nerves with projections to the mucosa designed to sense the physiologic environment.

Epithelium

Secretomotor neuron

Sensory neuron

FIGURE 49–12 Schematic diagram of the enteric nervous system (ENS) and its interactions with the central nervous system (CNS). PC, program circuit; IC, integration circuit. (Reproduced with permission from Barrett KE: Gastrointestinal

Smooth muscle

PC

IC CNS

Physiology. New York: Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2006.)

ENS

CHAPTER 49 Overview of the GI System—Functional Anatomy and Regulation

TABLE 49–3 Classification of enteric nerves. Type

Primary Neurotransmitters

Myenteric neurons Stimulatory motor neurons

Acetylcholine

Inhibitory motor neurons

Nitric oxide

Ascending and descending interneurons

Acetylcholine, 5-hydroxytryptamine

Sensory neurons

Substance P

Submucosal neurons Noncholinergic secretomotor neurons

Vasoactive intestinal polypeptide

Cholinergic secretomotor neurons

Acetylcholine

Sensory neurons

Substance P

ENTERIC NEUROTRANSMITTERS Most, if not all, enteric neurons store multiple neurotransmitters, but not all of the transmitters in a given nerve may be equally important in terms of information transfer. Some general patterns are also apparent. Thus, excitatory nerves depend largely on cholinergic neurotransmission. The actions of acetylcholine in muscarinic stimulatory pathways for either muscle contraction or secretory functions may be amplified by coreleased tachykinins such as substance P and neurokinin A. Acetylcholine also serves to deliver information from the parasympathetic branch of the autonomic nervous system, largely via the vagus nerve, to the enteric neurons, although in this case it acts via nicotinic receptors. Inhibitory nerves in the myenteric plexus, on the other hand, exert their effects predominantly via the release of nitric oxide, although several other neurotransmitters also play varying roles depending on the species and the segment of intestine being considered. These additional inhibitory neurotransmitters include VIP, ATP, and pituitary adenylate cyclase activating peptide (PACAP). VIP is also a critical neurotransmitter for noncholinergic neurons in the submucosal plexus that function to stimulate secretomotor function as well as vasodilation. Interneurons in the myenteric plexus utilize various neurotransmitters to deliver information along the vertical axis, but one common transmitter in such nerves is serotonin (5-hydroxytryptamine [5-HT]). Other interneurons containing acetylcholine and somatostatin have been implicated in the generation of a motility pattern known as the migrating motor complex (see Chapter 54). Finally, the intrinsic primary afferents that relay information to the enteric program and integration circuits utilize tachykinins for sensory transmission. These neurons ultimately control intestinal movements, blood flow, and secretion in response to distension, luminal chemistry, and mechanical deformation of the mucosal surface.

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On the other hand, painful sensations are conveyed via spinal afferents that pass through the dorsal root ganglia. Vagal communication is largely mediated through the enteric nervous system and involves cholinergic transmission. Parasympathetic vagal input and vagovagal reflexes play a critical role in regulating numerous gut functions, particularly during the early phases of response to a meal. The pelvic nerve plays an analogous role in the distal colon and rectum. On the other hand, sympathetic innervation to the intestine, mediated by norepinephrine, is relatively limited in its extent and implications under physiologic circumstances. Instead, it seems likely that sympathetic regulation is called upon to override the normal control of gut function, by slowing motility and inhibiting secretion, as a defense mechanism during times of threat to whole body homeostasis.

PARACRINE AND IMMUNE REGULATION IMPORTANT MEDIATORS Paracrine and immune regulation of gastrointestinal function both involve the release of substances from nonexcitable cell types, including enteroendocrine cells, enterochromaffin and enterochromaffinlike (ECL) cells, and immune elements in the lamina propria, which then act on neighboring cell types in the immediate environment. Important paracrine/immune mediators are summarized, along with their major sources of origin, in Table 49–4. Note that some paracrines are also stored in nerves, and thus play a dual role in signaling in the gut. For example, somatostatin, an important inhibitory peptide in the gut, is synthesized by enteroendocrine D cells as well as being stored in interneurons of the enteric nervous system. Other paracrines may also derive from multiple cell sources. Thus, histamine is released from ECL cells in the gastric glands as a classic

TABLE 49–4 Important paracrine and immune mediators in the gastrointestinal tract. Mediator

Major Sources

Selected Functions

Histamine

1. ECL cells 2. Mast cells

1. Gastric acid secretion 2. Intestinal chloride secretion

5-Hydroxytryptamine

Enterochromaffin cells

Response to luminal nutrients

Somatostatin

D cells

Various inhibitory effects throughout GI tract

Prostaglandins

Subepithelial myofibroblasts

Intestinal secretion; vascular regulation

Adenosine

Various cell types

Intestinal secretion; vascular regulation

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paracrine, but also from mucosal mast cells in response to antigenic stimulation, where it acts as an immune mediator.

MECHANISMS OF ACTIVATION Paracrine and immune regulators are primarily responsible for fine-tuning physiologic responses that are set into motion by hormonal and neural regulation, and as such are usually released in response to triggers that also act in the immediate environment. Thus, both the endocrine and immune cells that release these substances can be considered as the gut equivalent of the taste buds in the tongue that sample various components of ingested food and send information about its palatability. More distally, therefore, enteroendocrine cells are triggered in response to specific meal components, or by potentially injurious solutes in the lumen in the case of immune cells. In some cases, the cells responsible for releasing paracrine and/or immune effectors also receive neural input, and/or are sensitive to the actions of circulating gastrointestinal hormones. The gastric ECL cell in the fundic region is an excellent example of this, releasing histamine in response to both acetylcholine released from enteric nerve endings and gastrin traveling through the bloodstream from the gastric antrum.

INTEGRATION OF REGULATORY SYSTEMS There is considerable cross-talk between the regulatory systems discussed in this chapter, as well as functional redundancy. Moreover, communication mediated by one mode, for example, endocrine, may secondarily activate other modes of communication to amplify the eventual physiologic responses in target organs. An example of this is seen with the GI hormone CCK. On release from the gastrointestinal mucosa, CCK not only travels through the bloodstream to activate secretory and motor responses in other sites, but also binds to receptors on primary efferent nerve endings within the intestinal wall that can transmit vagovagal reflexes to propagate additional signaling. Conversely, a neurocrine messenger, gastrin-releasing peptide, acts on G cells to release a hormone that then can distribute the signal more broadly. Finally, the existence of multiple inputs to many of the cell types involved in the integrated response to a meal not only provides functional redundancy, underscoring the importance of gastrointestinal function for whole body homeostasis, but also permits synergism, or potentiated responses, at the level of the target cell type. Synergism, or a greater than additive physiologic response, can be predicted to occur if the two (or more) messengers in question activate their target cell by different intracellular signaling cascades. Integration of intestinal responses also involves the transmission of negative, or inhibitory, signals. Such feedback

inhibition controls the rate of delivery of nutrients such that this is matched with digestive and secretory capacity. Feedback mechanisms also terminate gut secretory responses when they are no longer needed to assimilate a meal, to conserve resources and, in some cases, minimize possible adverse consequences of overly prolonged exposure to gastrointestinal secretions.

CHAPTER SUMMARY ■ ■ ■ ■ ■ ■

■

■

■

■

The GI system fulfills the functions of digestion and absorption, excretion, and host defense. The GI system reflects a complex and cooperative network of various organs. Cellular specialization underlies the various functional responses required of the GI system. The GI system is highly efficient, interactive, and redundant. The circulatory features of the GI tract and liver set them apart from other organs. Communication between the various segments of the GI tract, as well as the organs that drain into it, is vital for the integrated response to a meal. Communication is achieved via the endocrine, neurocrine, paracrine, and immune mediators that act at sites distant from the site of stimulation and locally. The enteric nervous system serves to regulate the motility and secretory responses of the gut, and to integrate this regulation with information from the CNS. Stimulatory and inhibitory nerves and neurotransmitters are involved in the communication and regulation of the information. Paracrine and immune messengers act locally to modulate endocrine and neurocrine signaling.

STUDY QUESTIONS 1. A patient receiving chemotherapy for a prostate tumor develops severe abdominal pain and diarrhea. Following the treatment, his or her gastrointestinal symptoms subside. The resolution of his or her symptoms most likely reflects repair of which of the following cell types? A) epithelial cells B) smooth muscle cells C) lymphocytes D) enteric nerves E) Paneth cells 2. A pharmaceutical scientist trying to develop a new drug for hypertension gives a candidate compound orally to rats. He or she determines that the drug is adequately absorbed from the intestine, but levels in the systemic circulation remain below the therapeutic range. The drug is most likely metabolized by which organ? A) small intestine B) kidney C) lung D) liver E) spleen

CHAPTER 49 Overview of the GI System—Functional Anatomy and Regulation 3. A mouse is genetically engineered to lack CCK-B receptors. This animal would be expected to display increased circulating levels of which of the following hormones? A) gastrin B) motilin C) secretin D) CCK E) insulin 4. An experiment was conducted in which a balloon was inflated inside the stomach of a human volunteer and gastric pressures measured. Despite the increase in gastric volume, gastric pressures remained relatively constant. This remarkable pressure–volume relationship could be abolished by which of the following pharmacological agents? A) adrenergic agonist B) inhibitor of the enzyme responsible for nitric oxide synthesis C) cholinergic agonist D) CCK E) an antibody to gastrin

505

5. In a study of the secretion of gastrointestinal hormones, their concentrations in the portal vein are measured during luminal perfusion of the small intestine with solutions of various pH levels. Which hormone will increase in the portal vein plasma during perfusion with a buffered solution of pH 3? A) CCK B) gastrin C) GIP D) motilin E) secretin

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50 C

Gastric Secretion Kim E. Barrett

H A

P

T

E

R

O B J E C T I V E S ■ ■ ■ ■ ■ ■

Understand the physiological role of gastric acid secretion, as well as that of other gastric secretory products. Identify the regions of the stomach and cell types from which the various gastric secretions originate. Understand how gastric secretion is initiated in response to anticipation of a meal, and how secretion is amplified once the meal has been ingested. Define cephalic, gastric, and intestinal phases of the secretory response. Describe how secretion is terminated once the meal has left the stomach. Define the cellular basis for acid secretion and the morphological changes that take place in parietal cells to achieve this.

BASIC PRINCIPLES OF GASTRIC SECRETION ROLE AND SIGNIFICANCE The stomach is a muscular reservoir into which the meal enters after being swallowed. While limited digestion may begin in the oral cavity as a result of enzymes contained in saliva, the gastric juices represent the first significant source of digestive capacity. However, the digestive functions of the stomach are not necessary for assimilation of a mixed meal, and indeed, surgical removal of the majority of the stomach usually allows adequate nutrition. However, some degree of gastric secretory function is required for the absorption of an essential vitamin, B12, and gastric acid may also be important in the absorption of dietary nonheme iron. Gastric secretions also serve to sterilize the meal.

GASTRIC SECRETORY PRODUCTS The functions outlined in the previous section are subserved by a number of products secreted by the stomach (Table 50–1). The most characteristic secretory product of the stomach is hydrochloric acid. The acidity of the gastric secretions begins

Ch50_507-516.indd 507

the digestive process via simple hydrolysis and is also antimicrobial. Enzymatic digestion of the meal also occurs as a result of gastric secretions. A proteolytic enzyme, pepsin, is secreted as an inactive precursor, pepsinogen, and autocatalytically cleaved at the low pH existing in the stomach lumen. Pepsin is specialized for its role in mediating protein digestion in the stomach because it exhibits optimum activity at low pH. The gastric juice also contains intrinsic factor, synthesized by parietal cells, and lipase, that contributes to the initial digestion of triglycerides. Intrinsic factor binds to vitamin B12, also known as cobalamin, and is required for the eventual absorption of this vitamin more distally in the intestine. The stomach also secretes products important in protecting the mucosa from the harsh effects of the luminal mixture of acid and enzymes. Throughout the stomach, the surface cells are covered with a layer of mucus. Mucus consists of a mixture of mucin glycoproteins, surface phospholipids that endow hydrophobic properties on the surface of the mucus layer, and water. The stability of this layer is additionally enhanced by the activity of small peptides, known as trefoil factors, which interact with the carbohydrate side chains of mucin molecules. Bicarbonate ions are also secreted into the base of this mucus layer and protect the gastric surface from excessively low and potentially injurious pH via simple neutralization. Finally, the stomach secretes a number of products into the mucosa that play critical roles in

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TABLE 50–1 Important gastric secretory products. Product

Source

Functions

Hydrochloric acid

Parietal cell

Hydrolysis; sterilization of meal

Intrinsic factor

Parietal cell

Vitamin B12 absorption

Pepsinogen

Chief cell

Protein digestion

Mucus, bicarbonate

Surface mucous cells

Gastroprotection

Trefoil factors

Surface mucous cells

Gastroprotection

Histamine

ECL cells

Regulation of gastric secretion

Gastrin

G cells

Regulation of gastric secretion

Gastrin-releasing peptide

Nerves

Regulation of gastric secretion

Acetylcholine (ACh)

Nerves

Regulation of gastric secretion

Somatostatin

D cells

Regulation of gastric secretion

regulating the secretory and motility functions of the stomach, including gastrin, histamine, and prostaglandins. The roles of these factors will be discussed in more detail later.

Acid, intrinsic factor, pepsinogen

Mucus layer

ANATOMICAL CONSIDERATIONS FUNCTIONAL REGIONS OF THE STOMACH The stomach lies between the esophagus and the duodenum, and is delimited by the lower esophageal sphincter and the pylorus, respectively (Figure 49–5). The wall of the stomach contains thick vascular folds known as rugae, and the surface epithelium is invaginated with a series of gastric pits. Each pit opens to four to five blind-ended gastric glands. The stomach can also be divided into three major regions by both structure and function. Most proximal is the cardia that represents approximately 5% of the gastric surface area, and is a transitional zone where the stratified squamous epithelium of the esophagus gives way to the columnar epithelium that lines the remainder of the stomach and intestinal tract. The fundus or body of the stomach contains approximately 75% of the gastric glands, and in this region the oxyntic glands consist of specialized cell types from which arise the characteristic secretions of the stomach (Figure 50–1). Finally, the antrum of the stomach, immediately proximal to the pylorus, is responsible for the secretion of gastrin, the primary regulator of postprandial gastric secretion. The antrum also fulfills important motility functions that will be described in Chapter 54.

GASTRIC CELL TYPES The oxyntic, or parietal, glands found in the gastric fundus contain a variety of specific cell types (Figure 50–1). These include parietal cells, which are specialized to secrete acid and

Surface mucous cells (mucus, trefoil peptide, bicarbonate secretion) Cell migration

Mucous neck cells (stem cell compartment)

Parietal cells (acid, intrinsic factor secretion)

ECL cell (histamine secretion)

Chief cells (pepsinogen secretion)

FIGURE 50–1 Structure of a gastric gland from the fundus and body of the stomach. These acid – and pepsinogen-producing glands are referred to as “oxyntic” glands in some sources. Notice the mitotic figures in several mucous neck cells indicating rapid cell turnover. (Adapted with permission from Barrett KE: Gastrointestinal Physiology. New York: Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2006.)

CHAPTER 50 Gastric Secretion

A

B

Golgi complex

Golgi complex

509

Intracellular canaliculus Tubulovesicular membrane Intracellular canaliculus Basal folds

Mitochondria

Mitochondria Tubulovesicular membrane Basal folds

Intracellular canaliculus

Basement lamina Basement lamina Parietal cell (Nonsecreting) Parietal cell (secreting)

FIGURE 50–2 A) Ultrastructural appearance of a resting parietal cell. Note the elaborate system of intracellular membranes and a large number of mitochondria. B) Ultrastructural appearance of a parietal cell during active secretion. The apical membrane is massively amplified by fusion of tubulovesicles and the secretory canaliculi. (Modified with permission from Ito S: Functional gastric morphology. In: Physiology of the Gastrointestinal Tract, 2nd ed. Johnson LR (editor). New York: Raven Press, 1987.)

intrinsic factor, and chief cells, which store pepsinogen in apical granules that can release their contents via exocytosis. The glands also contain endocrine cells that are responsible for releasing products that regulate gastric function, particularly the enterochromaffin-like (ECL) cells that synthesize histamine. Toward the top of the gland where it joins with the gastric pit, and moving out onto the gastric surface, the gland contains surface mucous cells that secrete mucus. In the isthmus and neck region of the gland lie the mucus neck cells, which are the precursors for all of the other differentiated cell types in the gland. These anchored stem cells give rise to daughter cells, which migrate downward to become parietal, chief, or endocrine cells, or upward to become surface mucous cells. The surface mucous cells turn over every 1–3 days in adult humans. The parietal cells are remarkable for their secretory capacity and energetic requirements. These cells secrete acid against a concentration gradient of more than 2.5 million–fold, from the cytoplasmic pH of 7.2 to a luminal pH of less than 1 when secretion is maximally activated. To sustain such massive rates of secretion, the parietal cell is packed with mitochondria, which are estimated to take up about 30–40% of the cell’s volume. The resting parietal cell also contains numerous membranous compartments known as tubulovesicles, as well as a central canaliculus that deeply invaginates the apical membrane (Figure 50–2A). This morphology changes dramatically on cell stimulation (Figure 50–2B) as will be described more fully later. In the antral mucosa, the glands do not contain parietal or chief cells, but instead are composed of both mucus-secreting cells and enteroendocrine cells that regulate gastric function. Particularly, the glands contain G cells, which synthesize and release gastrin across their basolateral poles, and have func-

tionally significant communication with the gastric lumen. D cells, which secrete somatostatin, are also present.

INNERVATION Nerves carried through the parasympathetic vagus nerve, with both efferent and afferent pathways, richly innervate the stomach. Vagal afferents convey information from the dorsal vagal complex, which is integrated with that coming from higher centers, such as the hypothalamus, to set the overall level of secretory function at any given moment. Visceral inputs also contribute to gastric regulation. Notably, the output of taste receptors travels to a brain region called the nucleus tractus solitarius, where this information is again translated into signals that regulate secretion and other gastric functions. The enteric nerve plexuses throughout the gastrointestinal tract also encircle the walls of the stomach. These allow for some degree of autonomous function, in addition to transmitting effects of central input. The dorsal vagal complex represents an important site where the various influences that can alter gastric secretion are integrated. Thus, the dorsal vagal complex receives central input from the hypothalamus, as well as visceral input from the nucleus tractus solitarius.

REGULATION OF GASTRIC SECRETION Control of the secretion of the characteristic products of the cell types lining the stomach represents a paradigm for control of gastrointestinal function as a whole. Thus, the secretory

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capacity of the stomach is closely integrated with signals coincident with the ingestion of a meal, and modulated as the meal moves through the gastrointestinal tract to provide optimum digestion. There are many mechanisms, therefore, whereby the function of the stomach is controlled.

REGULATORY STRATA

Humoral Control

Short and Long Reflexes Neural input provides an important mechanism for regulation of gastric secretion (Figure 50–3). Reflexes contribute to both the stimulation and inhibition of secretion. For example, distension of the stomach wall activates reflexes that stimulate acid secretion at the level of the parietal cell. These may be short reflexes, which involve neural transmission contained entirely within the enteric nervous system. In addition, long reflexes involve the activation of primary afferents that travel through the vagus nerve, which in turn are interpreted in the dorsal vagal complex and trigger vagal outflow via efferent nerves that travel back to the stomach and activate parietal cells or other components of the secretory machinery. These long reflexes are also called vagovagal reflexes. Acetylcholine (ACh) is an important mediator of both short and long reflexes

Dorsal vagal complex

Vago-vagal reflex

Acid Pepsin

G cell GRP

Stretch receptor

in the stomach. It participates in the stimulation of parietal, chief, and ECL cells, as well as the synapses between nerves within the enteric nervous system. In addition, a second important gastric neurotransmitter is gastrin-releasing peptide (GRP). GRP is released by enteric nerves in the vicinity of gastrin-containing G cells in the gastric antrum.

Oxyntic gland

ENS reflex

Gastrin Blood stream

FIGURE 50–3

Neural regulation of gastric secretion in response to gastric distension. Stretch of the stomach wall increases acid secretion via both intrinsic reflexes and vagovagal reflexes. (Modified with permission from Barrett KE: Gastrointestinal Physiology. New York: Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2006.)

The gastric secretory response is also regulated by soluble factors that originate from endocrine and other regulatory cell types, such as ECL cells (Figure 50–4). The primary endocrine regulator of gastric secretion is gastrin, which travels through the bloodstream to stimulate parietal and ECL cells via their cholecystokinin (CCK)-B receptors. Gastric secretion is also modified by paracrine mediators. Histamine is released from ECL cells under the combined influence of gastrin and acetylcholine, and diffuses to neighboring parietal cells to activate acid secretion via histamine H2 receptors. At one time, histamine was thought to be the final common mediator of acid secretion, based in part on the clinical observation that histamine H2 receptor antagonists can profoundly inhibit acid secretion. However, it is now known that parietal cells express receptors for not only histamine, but also acetylcholine (muscarinic m3) and gastrin (CCK-B) (Figure 50–5). Because histamine H2 receptors are linked predominantly to signaling pathways that involve cAMP, while ACh and gastrin signal through calcium, when the parietal cell is acted upon simultaneously by all three stimuli, a potentiated, or synergistic, effect on acid secretion results. The physiological implication of this potentiation, or synergism, is that a greater level of acid secretion can be produced with relatively small increases in each of the three stimuli. The pharmacological significance is that simply interfering with the action of any one of them can significantly inhibit acid secretion. In fact, synergism is a common theme in the control of several different functions throughout the gastrointestinal system. Acid secretion is also subject to negative regulation by specific mediators. Specifically, somatostatin is released from D cells in the antral mucosa when luminal pH decreases below 3, and inhibits the release of gastrin from G cells. Elsewhere in the stomach, somatostatin can also exert inhibitory influences on ECL, parietal, and chief cells.

Luminal Regulators Specific luminal constituents also modulate gastric secretion indirectly. The example of pH is described earlier, but acid output, at least, is also increased by components of the meal. Short peptides and amino acids, derived from dietary protein, are capable of activating gastrin release from G cells.

REGULATION OF SECRETION IN THE INTERDIGESTIVE PHASE Between meals, the stomach secretes acid and other secretory products at a low level, perhaps to aid in maintaining the

CHAPTER 50 Gastric Secretion

511

FUNDUS

ANTRUM Peptides/amino acids

GRP

H+

G cell

ACh

H+ −

Parietal cell

D cell

P SST

Gastrin Chief cell ACh

?

?

Histamine ACh Circulation

ECL cell

FIGURE 50–4 Regulation of gastric acid and pepsin (P) secretion by soluble mediators and neural input. Gastrin is released from G cells in the antrum and travels through the circulation to influence the activity of ECL cells and parietal cells. The specific agonists of chief cells are not well understood. Gastrin release is negatively regulated by luminal acidity via the release of somatostatin from antral D cells. SST; somatostatin. (Adapted with permission from Barrett KE: Gastrointestinal Physiology. New York: Lange Medical Books/

Nerve ending

McGraw-Hill, Medical Pub. Division, 2006.)

sterility of the stomach. However, because no food is present, and thus no buffering capacity of the gastric contents, the low volume of secretions produced nevertheless has a low pH— usually around 3.0. Basal acid output in the healthy human is in the range of 0–11 mEq/h, and is believed to reflect the combined influences of histamine and ACh, released from ECL cells and nerve endings, respectively. Gastrin secretion during the interdigestive period, on the other hand, is minimal. This is because gastrin release is suppressed by a luminal pH of 3 or below.

REGULATION OF POSTPRANDIAL SECRETION In conjunction with a meal, gastric acid secretion occurs in three phases—cephalic, gastric, and intestinal—and increases to 10–63 mEq/h. The major portion of secretion occurs dur-

ing the gastric phase, when the meal is actually present in the stomach. Secretion of other gastric products usually parallels that of acid.

Cephalic Phase Even before the meal is ingested, the stomach is readied to receive it by the cephalic (i.e., related to the head) phase of secretion. In fact, during the cephalic phase, several gastrointestinal systems in addition to the stomach become activated, including the pancreas and gallbladder. Higher brain centers respond to the sight, smell, taste, and even the thought of food, and relay information to the dorsal vagal complex. In turn, vagal outflow initiates both secretory and motor behavior in the stomach and more distal segments. Gastric secretion occurring during the cephalic phase readies the stomach to receive the meal. Vagal outflow activates enteric nerves that in turn release GRP and ACh. Release of GRP in the vicin-

Secreting

Resting Canaliculus

H+, K+ ATPase

Tubulovesicle

Ca++ M3 CCK−B

M3 H2

Ca++ cAMP

ACh

CCK−B Gastrin

H2 Histamine

FIGURE 50–5 Parietal cell receptors and schematic representation of the morphological changes depicted in Figure 50-2. Amplification of the apical surface area is accompanied by an increased density of H+,K+-ATPase molecules at this site. Note that acetylcholine (ACh) and gastrin signal via calcium, whereas histamine signals via cAMP. (Adapted with permission from Barrett KE: Gastrointestinal Physiology. New York: Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2006.)

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ity of antral G cells releases gastrin that travels through the bloodstream to activate parietal and chief cells in an endocrine fashion.

gastrin and CCK. The intestinal phase of secretion may serve to ready the stomach for its next meal. Of course, there is also overlap between the gastric and intestinal phases of secretion since the meal moves only gradually into the duodenum.

Gastric Phase The gastric phase of secretion is quantitatively the most important. In addition to vagal influences continuing from the cephalic phase, secretion is now amplified further by mechanical and chemical stimuli that arise from the presence of the meal in the lumen. These include the luminal signals discussed earlier, and signals arising from stretch receptors embedded in the wall of the stomach. Thus, as the stomach distends to accommodate the volume of the meal, these receptors initiate both short and long reflexes to further enhance secretory responses either directly, via the release of acetylcholine in the vicinity of parietal cells, or indirectly, via the activation of ECL or G cells. The gastric phase also involves changes in motility and is accompanied by a marked increase in gastric blood flow, which supplies the metabolic requirements of the actively secreting cell types. Due to the combined influence of neurocrine and endocrine signals, further amplified by histamine release from ECL cells, secretory cells of the stomach are highly active during the gastric phase. Moreover, pepsinogen released by chief cells is rapidly cleaved to pepsin in an autocatalytic reaction that occurs optimally at pH 2, and this pepsin then acts on ingested protein to release short peptides and amino acids that further enhance gastrin release. Moreover, many dietary substances, including proteins, are highly effective buffers. Thus, while acid secretory rates remain high, the effective pH in the bulk of the lumen may increase to pH 5. This ensures that the rate of acid secretion during the gastric phase is not attenuated by an inhibition of gastrin release due to somatostatin.

Intestinal Phase As contents move out of the stomach into the duodenum, the buffering capacity of the lumen is reduced and the pH begins to decrease. At around pH 3, somatostatin release is triggered from D cells, and acts to suppress gastrin release. D cells themselves may be capable of responding to luminal acidity. There is also evidence for a neural pathway, involving the activation of chemoreceptors sensitive to pH, which in turn leads to release of the neuropeptide calcitonin gene-related peptide (CGRP). This peptide may then act on the D cells to induce release of somatostatin. Other signals also limit the extent of gastric secretion when the meal has moved into the small intestine. For example, the presence of fat in the small intestine is associated with a reduction in gastric secretion. This feedback response is believed to involve several endocrine and paracrine factors, including GIP. Nevertheless, a portion of gastric secretion occurs once the meal is in the intestine. The mediators of this response are largely unknown, although CCK may play a role since the CCK-B receptors on parietal cells do not discriminate markedly between

CELLULAR BASIS OF SECRETION ACID SECRETION The basolateral membrane of the parietal cell contains receptors for histamine, gastrin, and ACh (Figure 50–5). The downstream targets of the signaling pathways linked to receptor occupancy are presumed to include cytoskeletal elements, ion channels, and the receptors themselves, the latter representing a mechanism of negative feedback. Cytoskeletal rearrangements are implied by the dramatic morphological changes that occur as parietal cells transition from rest to secretion. At rest, the cytoplasm is filled with the tubulovesicles and intracellular canaliculi. When the parietal cell is stimulated, the canaliculi fuse with the apical plasma membrane (Figure 50–5). The intracellular tubulovesicles, in turn, fuse to the canaliculi, massively amplifying the surface area of the apical membrane that is in contact with the gland lumen by a factor of approximately 5–10-fold. At rest, the tubulovesicles are the site for storage of the majority of a membrane-bound transporter, H+,K+-ATPase, or proton pump, where it is therefore sequestered from the lumen. Following fusion of the tubulovesicles and canaliculi, the density of proton pumps in the apical pole of the cell is massively increased (Figure 50–5). These pumps are the sites of active pumping of protons into the gastric lumen. Protons are generated adjacent to the apical membrane as a result of the activity of the enzyme carbonic anhydrase II (Figure 50–6). This enzyme generates protons and bicarbonate ions from the reaction of water and carbon dioxide. Protons are then pumped out of the cell across the apical membrane in exchange for potassium ions, with the consumption of cellular energy. The potassium ions also originate from the cell cytosol, where they are maintained at levels above their chemical equilibrium by the activity of Na+,K+-ATPase. They can therefore readily exit across the apical membrane through potassium channels that are also localized to the tubulovesicles, and which are opened when the parietal cell is stimulated. Specialized chloride channels are also present in this site, and serve to allow the apical exit of chloride ions to match the protons pumped from the cell. Thus, the final secretory product is actually hydrochloric acid. The overall mechanism should also remind you of absorption of bicarbonate by the renal tubule, as was discussed in Chapter 47. A bicarbonate ion is generated for every proton that is secreted, and if these were allowed to accumulate in the cytosol, deleterious effects on cellular metabolism would result from the resulting increase in pH. Thus, as the protons are secreted apically, the parietal cells also discharge bicarbonate ions across the basolateral membrane to maintain cytosolic pH within narrow limits. At least a portion of this bicarbonate

CHAPTER 50 Gastric Secretion

Lumen

513

Blood Stream

Na+, K+ ATPase +

2K

Potassium channel

3Na+ H2O + CO2 C.A.II

H+

HCO3

K+ +

Na+ NHE-1

+

H , K ATPase H+

H+ + HCO3

Cl

HCO3 Cl

ClC Chloride channel

Apical

transport occurs in exchange for the chloride ions that are needed for apical secretion, via a chloride–bicarbonate exchanger. Some bicarbonate is likely also lost secondary to pumping into intracellular vesicles (distinct from the tubulovesicles) that then move to the basolateral membrane and fuse with it, discharging their contents. The bicarbonate leaving the cell is then picked up by the bloodstream. The arrangement of the microvasculature in the gastric mucosa carries a portion of this bicarbonate up to the basolateral pole of surface epithelial cells, which secrete bicarbonate to defend themselves against the potentially injurious effects of acid and pepsin. This movement of bicarbonate into the bloodstream during gastric secretion is referred to as the alkaline tide. The transport mechanisms that exist in parietal cells are depicted in Figure 50–6. In addition to those already mentioned earlier, the basolateral membrane contains a sodium– hydrogen exchanger, NHE-1, which expels protons from the cell in exchange for sodium ions, a process driven secondarily by the low intracellular sodium concentration established by the Na+,K+-ATPase. At first blush, this may seem counterintuitive, since basolateral fluxes of protons would be predicted to oppose the normal secretion of acid across the apical membrane. However, the role of NHE-1 is not to participate in acid secretion, but to fulfill “housekeeping” functions, namely to allow for the efflux of protons generated in resting cells by ongoing metabolic activities. A basolateral potassium channel that has also been identified in parietal cells likely also plays a similar homeostatic role.

OTHER PRODUCTS The stomach also secretes a number of additional products that are important in gastrointestinal physiology. Here, we

Cl /HCO3 exchanger

Basolateral

FIGURE 50–6 Ion transport proteins of parietal cells. Protons are generated in the cytosol via the action of carbonic anhydrase II (C.A.II). Bicarbonate ions are exported from the basolateral pole of the cell either by vesicular fusion or via a chloride/bicarbonate exchanger. NHE-1, sodium–hydrogen exchanger (Adapted with permission from Barrett KE: Gastrointestinal Physiology. New York: Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2006.)

will briefly review how the secretion of these products is controlled at the cellular level, although it should be noted that considerably less information exists on this topic than for gastric acid. Intrinsic factor is synthesized and released by parietal cells, presumably via a process of exocytosis, and activated by the same secretagogues that initiate acid secretion. However, while intrinsic factor is usually secreted in parallel with acid, these processes are not dependent on each other. Thus, proton pump inhibitors have no inhibitory effect on the secretion of intrinsic factor. Pepsinogen is secreted by chief cells via a classical process of compound exocytosis, and is thereafter activated to its catalytic form in the presence of a low pH. The active enzyme is inactivated if the pH increases above 5 (i.e., soon after the meal has moved into the duodenum, in healthy individuals). As for other cell types that release their products via exocytosis, calcium is a key intracellular mediator effecting the secretory response, and ACh and GRP, both agents that elevate intracellular calcium, are known to be important chief cell secretagogues. The precise roles of gastrin and histamine, on the other hand, remain controversial. One additional secretagogue that may be important, however, is secretin, especially during the intestinal phase of gastric secretion. Surface epithelial cells throughout the stomach secrete mucus and bicarbonate. The viscosity of mucus may limit diffusion of acid through the plane of the gel via a mechanism known as viscous fingering. Thus, acid secreted under hydrostatic pressure from the gastric glands may emerge as a discrete stream through the gel, restricting access of the acid to the gastric surface. Mucussecreting cells also package phospholipids that are secreted concurrently with mucins, in a manner analogous to the secretion of surfactant in the lung. These phospholipids may limit the back-diffusion of apical solutes, such as protons, toward the epithelium. Secretion of the components of the

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mucus layer is increased by a variety of secretagogues, and is presumed to be under the control of both cholinergic and gastrin-dependent signaling pathways, as well as local reflexes that may involve CGRP and tachykinins. Likewise, prostaglandins are potent mucus secretagogues, providing a partial explanation as to why nonsteroidal anti-inflammatory drugs (NSAIDs), which prevent prostaglandin synthesis, predispose the gastric mucosa to injury and ulceration.

CLINICAL CORRELATION A 55-year-old man is referred to a gastroenterologist for evaluation of a persistent burning sensation in his upper abdomen that has occurred intermittently for several months. The pain begins 2–3 hours after eating, often awakens him at night, and is lessened by a meal. His history reveals that he smokes one pack of cigarettes per day and ingests half a bottle of red wine every night with dinner. Initially, over-the-counter antacids reduced his symptoms to some extent, but recently they have provided little, if any, relief. The physician refers the patient for an upper endoscopy procedure, which shows several eroded areas of the duodenal mucosa. A test for Helicobacter pylori infection is also positive. A diagnosis of peptic ulcer disease is made, and the patient is started on a triple regimen of two antibiotics and a proton pump inhibitor. The doctor also advises him to stop smoking and reduce his intake of alcohol, and over the next 2 months, the patient’s symptoms resolve and do not recur. Peptic ulcer disease, so called because its pathogenesis is related to the injurious effects of gastric acid and pepsin, involves erosions through the epithelial lining of the stomach or duodenum that may ultimately lead to bleeding from mucosal blood vessels. For duodenal ulcer disease, at least, a failure in mucosal defense mechanisms seems more likely to be the underlying pathogenic defect. There are two major exogenous causes of both gastric and duodenal ulcers: gastric colonization with a gram-negative, spiral-shaped bacterium known as H. pylori and ingestion of NSAIDs. In the absence of NSAID use, the vast majority of all ulcer patients can be shown to be infected with H. pylori, which is specialized to colonize the gastric niche because it secretes large amounts of the enzyme, urease. This product converts urea to ammonium ions in the vicinity of the bacteria, thereby protecting them from the deleterious effects of gastric acidity. In genetically susceptible individuals, infection with H. pylori can have profound effects on both gastric and duodenal physiology. NSAID-induced ulcers, on the other hand, likely arise because the drugs suppress the synthesis of prostaglandins that normally protect the mucosa via their effects on mucus and bicarbonate secretion as well as blood flow. Acid also contributes to ulcer pathogenesis,

even if secreted in normal amounts, due to its role in sustaining the activation of pepsin, and, in the case of duodenal ulcers, the direct injurious effects of protons on the epithelial cells in this site. In fact, a clinical adage, “no acid, no ulcer,” also gives clues as to possible treatments. Patients with ulcer disease are treated typically with drugs that suppress acid secretion, thereby giving the mucosa the opportunity to heal itself. In the past, this was accomplished primarily with H2 antihistamines. However, more recently, profound acid suppression—essentially total in nature— has been accomplished with proton pump inhibitors. In addition to acid suppression, ulcer patients who can be demonstrated to be infected with H. pylori usually receive antibiotics to eradicate the microorganism, a treatment that markedly reduces the risk of any relapse.

CHAPTER SUMMARY ■ ■ ■ ■

■

Gastric secretion plays important roles in digestion, absorption of specific nutrients, and host defense. Acid secretion occurs in phases that correspond temporally to the ingestion of a meal. Regulation of acid secretion involves neurocrine, paracrine, and endocrine components. The stomach secretes other important products such as pepsinogen, intrinsic factor, mucus, and bicarbonate and trefoil peptides. Various disease states can result from, or are associated with, abnormal gastric secretory function.

STUDY QUESTIONS 1. A 40-year-old man comes to his physician complaining of epigastric pain. An upper endoscopy reveals duodenal erosions, and a test of gastric secretory function reveals markedly elevated levels of basal acid secretion that are increased only modestly by intravenous infusion of a gastrin analog. What is the most likely diagnosis? A) Zollinger–Ellison syndrome (a gastrin-secreting tumor) B) H. pylori infection C) gastroesophageal reflux disease D) gastroparesis (impaired gastric motility) E) achalasia (failure of the lower esophageal sphincter to relax) 2. In an experiment, rabbits are administered a cholinergic agonist, pentagastrin, or histamine intravenously, and gastric acid secretion measured. Which treatment, when coadministered with each of these agents, would be expected to block gastric acid secretion produced by any of the stimuli? A) histamine H2 antagonist B) antibodies to gastrin C) anticholinergic drug D) histamine H1 antagonist E) proton pump inhibitor

CHAPTER 50 Gastric Secretion 3. A patient suffering from anemia comes to his physician complaining of frequent bouts of gastroenteritis. A blood test reveals circulating antibodies directed against gastric parietal cells. His anemia is ascribable to hyposecretion of which of the following gastric secretory products? A) histamine B) gastrin C) pepsinogen D) hydrochloric acid E) intrinsic factor 4. Two medical students studying for their physiology final decide to take a break for a lunchtime hamburger. Before reaching the cafeteria, nervous impulses from the dorsal vagal complex will initiate gastric acid secretion by triggering release of which neurotransmitter from the enteric nervous system? A) norepinephrine B) vasoactive intestinal polypeptide C) substance P D) GRP E) nitric oxide 5. Compared to the cephalic phase, the gastric phase of gastric acid secretion is characterized by which of the following patterns? Acid Secretion

Gastrin Secretion

Somatostatin Secretion

A) Increased

Increased

Increased

B) Increased

Increased

Decreased

C) No change

Increased

No change

D) Decreased

Decreased

Increased

E) Decreased

Decreased

Decreased

F) No change

Decreased

No change

515

6. A patient who is being treated for long-standing osteoarthritis with a NSAID also takes a drug that inhibits acid secretion to reduce the toxicity of her NSAID treatment. She comes to her physician complaining of recurrent bouts of diarrhea during a series of business trips to Guatemala. The apparent increase in her sensitivity to infections acquired by the oral route is most likely due to reduced secretory function of which of the following? A) stomach B) pancreas C) gallbladder D) salivary glands E) lymphocytes

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51 C

Pancreatic and Salivary Secretion Kim E. Barrett

H A

P

T

E

R

O B J E C T I V E S ■ ■ ■ ■ ■ ■ ■ ■ ■ ■

Understand the role played by the pancreas in digestion and absorption of a mixed meal. Understand the structure of the exocrine pancreas and the cell types that give rise to proteinaceous and fluid components of the pancreatic juice. Identify the key constituents of the pancreatic juice and the enzymes that are secreted in inactive forms. Describe the factors that regulate the release of secretin and the role of this hormone in stimulating pancreatic ductular secretion. Understand the role of CCK and other factors in regulating pancreatic acinar cells. Identify the signaling events activated in pancreatic acinar cells by secretagogues. Compare and contrast the structure of the salivary glands with that of the exocrine pancreas. Identify the functions of saliva and the constituents responsible for these. Define the ion transport pathways that modify salivary composition. Define the regulatory pathways for saliva production.

BASIC PRINCIPLES OF PANCREATIC SECRETION ROLE AND SIGNIFICANCE The exocrine pancreas is the source of the majority of enzymes required for digestion of a mixed meal (i.e., carbohydrate, protein, and fat). Pancreatic enzymes are produced in great excess, underscoring their importance in the digestive process. However, unlike the digestive enzymes produced by the stomach and in the saliva, some level of pancreatic function is necessary for adequate digestion and absorption. In general, nutrition is impaired if production of pancreatic enzymes decreases below 10% of normal levels, or if outflow of the pancreatic juice into the intestine is physically obstructed.

Ch51_517-526.indd 517

PANCREATIC SECRETORY PRODUCTS The exocrine pancreas is largely the site of synthesis and secretion of enzymes. These fall into four main groups— proteases, amylolytic enzymes, lipases, and nucleases—as shown in Table 51–1. In addition, other proteins are produced that modulate the function of pancreatic secretory products, such as colipase and trypsin inhibitors. Finally, the pancreas secretes monitor peptide, which represents an important feedback mechanism linking pancreatic secretory capacity with the requirements of the intestine for digestion. Almost 80% (w/w) of the proteins secreted by the exocrine pancreas are proteases. Of the proteases, trypsinogen, the inactive precursor of trypsin, is the most abundant. This likely reflects a central role for trypsin in initiating the digestion of proteins, which will be discussed further in Chapter 58.

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SECTION VIII GI Physiology

TABLE 51–1 Pancreatic acinar cell secretory products. Proteases

Amylolytic Enzyme

Lipases

Nucleases

Others

Trypsinogena

Amylase

Lipase

Deoxyribonuclease

Procolipasea

Chymotrypsinogena

Nonspecific esterase

Ribonuclease

Trypsin inhibitors

Proelastasea

Prophospholipase A2a

Monitor peptide

Procarboxypeptidase Aa Procarboxypeptidase Ba a

Stored and secreted in inactive forms.

Like pepsinogen in the stomach, pancreatic proteases are packaged and stored as inactive precursors. This is also true for at least one lipolytic enzyme, prophospholipase A2. The need to store these enzymes in their inactive forms relates to the toxicity of the active products toward the pancreas. Under normal circumstances, therefore, the pancreas does not digest itself.

ANATOMIC CONSIDERATIONS IN PANCREAS Endocrine functions of the pancreas are restricted to cells located in the islets of Langerhans, which are scattered throughout the pancreatic parenchyma (see Chapter 66). The exocrine functions, on the other hand, are conducted by a series of blind-ended ducts that terminate in structures known as acini (Figure 51–1). Many such acini, arranged like clusters of grapes, disgorge their products into a branching ductular system that empties into larger and larger collecting ducts, eventually reaching the main pancreatic duct or Wirsung’s duct. A minor part of the pancreas is drained by an accessory collecting duct, known as the duct of Santorini. Pancreatic juice mixed with bile from the liver (see Chapter 56) enters the duodenum a short distance distal to the pylorus, under the control of the sphincter of Oddi. Both the acinar and ductular cells contribute distinct products to the pancreatic juice, and both are regulated during the course of responding to a meal.

exocytosis and fuse with each other and the apical membrane, thereby discharging their contents into the lumen.

DUCTULAR CELLS The cells lining the intercalated ducts of the pancreas also play an important role in modifying the composition of the pancreatic juice. They are classical columnar epithelial cells, comparable to those lining the intestine itself. When stimulated, these cells transport bicarbonate ions into the pancreatic juice, with water following paracellularly. Thus, the effect of the duct cells is to dilute the pancreatic juice and to render it alkaline.

Endocrine cells of pancreas Exocrine cells (secrete enzymes)

Duct cells (secrete bicarbonate)

Gallbladder

Pancreas

ACINAR CELLS Pancreatic acinar cells are the source of the majority of the proteinaceous components of the pancreatic juice. Their basolateral membrane faces the bloodstream and contains receptors for a variety of neurohumoral agents responsible for regulating pancreatic secretion. The apical pole of the cell, on the other hand, is packed at rest with large numbers of zymogen granules that contain the digestive enzymes and other regulatory factors. When the cell is stimulated by secretagogues, the granules undergo a process of compound

Pancreatic duct

Common bile duct from gallbladder

Duodenum

FIGURE 51–1

Structure of the pancreas. (Reproduced with

permission from Widmaier EP, Raff H, Strang KT: Vander’s Human Physiology, 11th ed. McGraw-Hill, 2008.)

CHAPTER 51 Pancreatic and Salivary Secretion

REGULATION OF PANCREATIC SECRETION PHASES OF SECRETION Pancreatic secretory activity related to meal ingestion occurs in phases. The majority of the secretory response (approximately 60–70%) occurs during the intestinal phase, but there are also significant contributions from the cephalic (20–25%) and gastric (10%) phases. During the cephalic and gastric phases, secretions are low in volume with high concentrations of digestive enzymes, reflecting stimulation primarily of acinar cells. This stimulation arises from cholinergic vagal input during the cephalic phase, and vagovagal reflexes activated by gastric distension during the gastric phase. During the intestinal phase, on the other hand, ductular secretion is strongly activated, resulting in the production of high volumes of pancreatic juice with decreased concentrations of protein, although the total quantity of enzymes secreted during this phase is actually also markedly increased. Ductular secretion during this phase is driven primarily by the endocrine action of secretin on receptors localized to the basolateral pole of duct epithelial cells. The inputs to the acinar cells during the intestinal phase consist of cholecystokinin (CCK) as well as neurotransmitters including acetylcholine (ACh) and gastrin-releasing peptide (GRP). The large magnitude of the intestinal phase is also attributable to amplification by so-called enteropancreatic reflexes transmitted via the enteric nervous system.

ROLE OF CCK CCK can be considered a master regulator of the duodenal cluster unit and especially the pancreas (Figure 51–2). It is a potent stimulus of acinar secretion, acting both directly on

CCK

Gallbladder

Pancreas

Stomach

Contraction

Acinar secretion

Reduced emptying

Sphincter of Oddi

Relaxation

• Protein, carbohydrate, lipid absorption and digestion • Matching of nutrient delivery to digestive and absorptive capacity

FIGURE 51–2 Multiple effects of cholecystokinin (CCK) in the duodenal cluster unit. CCK serves to coordinate nutrient delivery to match intestinal capacity. (Reproduced with permission from Barrett KE: Gastrointestinal Physiology. New York: Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2006.)

519

CCK-A receptors localized to the basolateral membranes of acinar cells and via stimulation of vagal afferents evoking vagovagal reflexes that stimulate acinar cell secretion through cholinergic and noncholinergic neurotransmitters. CCK can also modulate the activity of other neurohumoral regulators on the pancreas in a synergistic fashion. Notably, while CCK is a weak agonist of pancreatic ductular secretion of bicarbonate by itself, it markedly potentiates the effect of secretin on this transport mechanism. During the integrated response to a meal, therefore, it is likely that the ability of secretin to evoke pancreatic bicarbonate secretion is amplified by occurring against the background of a CCK “tone.” Nevertheless, CCK predominantly affects acinar cell secretion. Thus, during the initial response to a meal (i.e., the cephalic and gastric phases), pancreatic secretions are low in volume with a high concentration of enzymes and enzyme precursors. The output of pancreatic enzymes, but not that of bicarbonate, that occurs in response to a meal can essentially be reproduced by the intravenous administration of postprandial concentrations of CCK. This situation should be contrasted with secretory flows occurring in the intestinal phase, where secretin also plays a role, as discussed later.

Factors Causing CCK Release CCK is synthesized and stored by “I” cells, endocrine cells located predominantly in the duodenum (Figure 51–3). Control of CCK release is carefully regulated to match needs for CCK bioactivity. In part, this is accomplished by the activity of two luminally active CCK-releasing factors, which are small peptides. One is derived from the duodenum, and called CCKreleasing peptide (CCK-RP). It is released in response to fatty acids and aromatic amino acids. The other luminal peptide that controls CCK secretion is monitor peptide, which is a product of pancreatic acinar cells. Release of monitor peptide can be neurally mediated, including by the release of ACh and GRP during the cephalic phase, and mediated by subsequent vagovagal reflexes during the gastric and intestinal phases of the response to a meal. Likewise, once CCK release has been stimulated by CCK-RP, it too can cause monitor peptide release. The significance of factors that regulate CCK release lies in their ability to match pancreatic secretion of proteolytic enzymes to the need for these enzymes. When meal proteins and peptides are present in the lumen in large quantities, they compete for the action of trypsin and other proteolytic enzymes, meaning that CCK-RP and monitor peptide are degraded only slowly. Thus, CCK release is sustained, causing further secretion of pancreatic juice. On the other hand, once the meal has been fully digested and absorbed, CCK-RP and monitor peptide will be degraded by the pancreatic proteases leading to the termination of CCK release, and thus a marked reduction in the secretion of pancreatic enzymes.

ROLE OF SECRETIN The other major regulator of pancreatic secretion is secretin, released from duodenal S cells. When the meal enters the

520

SECTION VIII GI Physiology

Protein

Ach GRP as cre Pan

− Trypsin

LUMEN Amino acids −

−

Fatty acids

Monitor peptide

CCK−RP

FIGURE 51–3 Mechanisms responsible for controlling cholecystokinin (CCK) release from duodenal I cells. CCK-RP, CCK-releasing peptide; ACh, acetylcholine; GRP, gastrinreleasing peptide. Solid arrows represent stimulatory effects while dashed arrows indicate inhibition. (Reproduced with permission from Barrett KE: Gastrointestinal Physiology. New York: Lange

I cell EPITHELIUM

CCK BLOODSTREAM

Medical Books/McGraw-Hill, Medical Pub. Division, 2006.)

small intestine, the volume of pancreatic secretions increases rapidly, shifting from a low-volume, protein-rich fluid to a high-volume secretion. As the secretory rate increases, the pH and bicarbonate concentration in the pancreatic juice increases, with a reciprocal decrease in the concentration of chloride (Figure 51–4). These latter effects on the composition of the pancreatic juice are mediated predominantly by the endocrine mediator, secretin.

Factors Causing Secretin Release The S cells can be considered to act functionally as pH meters, sensing the acidity of the luminal contents (Figure 51–5). As the pH decreases, due to the entry of gastric acid, secretin is released into the blood and binds to receptors on pancreatic duct cells. These cells, in turn, secrete bicarbonate, thus causing an increase in pH that will eventually shut off secretin release.

pH 7.2

The threshold for secretin release appears to be a luminal pH of less than 4.5. The mechanism by which the S cells sense the change in luminal acidity is currently unclear. Nevertheless, subjects who are unable to secrete gastric acid also fail to release secretin postprandially no matter what type of meal is given.

CELLULAR BASIS OF PANCREATIC SECRETION ACINAR CELLS Pancreatic acinar cells synthesize the proteinaceous components of pancreatic juice and package them into zymogen granules that are stored in the apical pole of the cell. The contents of these granules are discharged into the lumen of the acinus via a process of compound exocytosis. The pancreatic enzymes are then rapidly resynthesized and repackaged into granules, with

pH 8.0

Concentration (mEq/L)

160 Na+ HCO3

140 120 100

Stomach

Acid

−

80 60 Duodenum

40 Cl

20 0

K+ 0.2

0.4

0.6 0.8 1.0 Flow rate (mL/min)

1.2

1.4

HCO3− Pancreatic ducts

Secretin

FIGURE 51–4 Ionic composition of the pancreatic juice as a function of its flow rate. Note that the pancreatic juice becomes alkaline at high rates of secretion. (Reproduced with permission from Barrett

FIGURE 51–5 Function of secretin. Secretin is released from the duodenum in response to reduced pH, and travels through the bloodstream to evoke bicarbonate secretion from the pancreatic ducts (as well as from the biliary ducts and the duodenal mucosa, not shown), thereby neutralizing gastric acid in the duodenal lumen.

KE: Gastrointestinal Physiology. New York: Lange Medical Books/McGraw-Hill, Medical

(Modified with permission from Barrett KE: Gastrointestinal Physiology. New York:

Pub. Division, 2006.)

Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2006.)

CHAPTER 51 Pancreatic and Salivary Secretion

521

Enzymes washed into duodenum by ductular secretion VIP cAMP Secretin Phosphorylation of structural and regulatory proteins GRP Ca++ ACh m3 CCK

Fusion of granules with apical membrane and discharge of contents

CCK−A

FIGURE 51–6 Receptors of the pancreatic acinar cell and the regulation of secretion. The block arrow indicates that calcium-dependent signaling pathways play the most prominent role in enzyme secretion. VIP, vasoactive intestinal polypeptide; GRP, gastrin-releasing peptide; ACh, acetylcholine; CCK, cholecystokinin. (Reproduced with permission from Barrett KE: Gastrointestinal Physiology. New York: Lange Medical Books/McGraw-Hill, Medical

BASOLATERAL

APICAL

the process taking less than an hour, leaving the cell ready to respond to the next meal. Evidence exists that the synthetic process is regulated by CCK and also by other hormones, such as insulin. In the long term, moreover, the rate of synthesis of specific classes of enzymes can be regulated in response to changes in the diet. For example, an increase in carbohydrates will eventually result in increased expression of amylase as a proportion of the total pancreatic enzymes. Corresponding changes occur in the hydrolytic enzymes responsible for digestion of each of the major classes of nutrients (carbohydrates, fats, and proteins) in response to increased or decreased ingestion. On their basolateral membranes, acinar cells express receptors for CCK as well as for neural regulators of secretion, including ACh, GRP, and vasoactive intestinal polypeptide (VIP) (Figure 51–6). All of the receptors are G protein–coupled receptors, and link to various downstream effectors such as phospholipase C and adenylyl cyclase. In general, the phospholipase C-dependent pathway, which is utilized by the receptors for CCK, ACh, and GRP and results in increases in cytoplasmic calcium, is the most quantitatively significant for acinar secretion, with cAMP-dependent signaling playing a subsidiary role.

DUCTULAR CELLS In contrast to acinar cells that secrete their characteristic products via exocytosis, the ductular cells are classical polarized epithelial cells that conduct vectorial ion transport. As seen elsewhere in the gastrointestinal tract, while exocytic secretion predominantly involves calcium-dependent signaling with cAMP playing a modulatory role, the membrane transport events that underlie ductular secretion are predominantly driven by cAMP, with calcium playing the subsidiary role. The primary stimulus of duct cell secretion is secretin, which binds to a basolateral receptor that links to adenylyl cyclase. The primary target is protein kinase A, which phosphorylates the cystic fibrosis transmembrane conductance regula-

Pub. Division, 2006.)

tor (CFTR) chloride channel localized to the apical membrane of the cell. This channel allows outflow of chloride ions, which can exchange for bicarbonate across an apical chloride/ bicarbonate exchanger to provide for movement of bicarbonate ions into the duct lumen (Figure 51–7). Water and sodium ions follow paracellularly. CFTR itself may also be permeable to bicarbonate ions under certain circumstances. The bicarbonate required for the transport mechanism derives from two sources. Some is generated intracellularly via the activity of carbonic anhydrase. Other bicarbonate ions are taken up from the bloodstream via a basolateral sodium–bicarbonate cotransporter (NBC). Circulating bicarbonate is derived from the “alkaline tide” that is a byproduct of gastric acid secretion. The bicarbonate transported by the duct cells, along with the fluid secretion that this transport mechanism drives, is important to wash the proteinaceous components of the gastric juice into the intestinal lumen. Moreover, the alkaline nature of this secretion is critically important in neutralizing gastric acid. The pancreatic digestive enzymes are optimally active at neutral pH, as opposed to the acidic pH optimum of gastric pepsin.

PANCREATIC PATHOPHYSIOLOGY The hydrolytic enzymes secreted by the pancreas are produced in quantities that are vastly in excess of those needed to digest a normal intake of nutrients. It has been calculated that pancreatic enzyme output needs to decrease below 10% of normal levels before effects on nutrient absorption are observed. Thus, pancreatic insufficiency is not common. However, under specific conditions, it can occur, manifesting as maldigestion and malabsorption. Fat absorption is usually the first affected by alterations in pancreatic output of enzymes and bicarbonate, perhaps due to a relatively limited supply of lipase and because pancreatic lipase is most sensitive to inactivation by low pH. Thus, steatorrhea, or fat in the stool, may be an early sign of pancreatic dysfunction.

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SECTION VIII GI Physiology

Duct lumen

Basolateral CO2 + H2O

−

H+

C.A

−

NHE-1

−

HCO3 + H+

HCO3 −

Cl /HCO3 Exchanger

Na+ − 2HCO3

NBC

Na+ 3Na+

FIGURE 51–7

Ion transport pathways present in pancreatic duct cells. C.A, carbonic anhydrase; NHE-1, sodium/hydrogen exchanger-1; NBC, sodium–bicarbonate cotransporter. (Adapted with permission from Barrett KE: Gastrointestinal Physiology. New York: Lange Medical

2K

Cl− +

+

Na+, K+ ATPase

K+ channel cAMP

CFTR

Books/McGraw-Hill, Medical Pub. Division, 2006.)

BASIC PRINCIPLES OF SALIVARY SECRETION We consider salivary secretion here because of analogies between this process and that of pancreatic secretion (Figure 51–8). Thus, a primary salivary secretion arises in acini, and is modified as it flows through ducts. Thus, it is instructive to compare and contrast these two processes, and an understanding of one permits understanding of the other.

ROLE AND SIGNIFICANCE

(known as a bolus) that is suitable for swallowing. However, it also performs additional roles. For example, the ability of saliva to solubilize molecules in the meal allows these to diffuse to taste buds on the tongue, affecting appetite and food intake. Salivary secretion can also begin the digestive process and plays important roles in host defense. It contains a variety of antibacterial substances that serve to protect the oral cavity from microbial colonization. Saliva is also slightly alkaline. This property is important in clearing any refluxed gastric acid from the esophagus, thus acting to prevent esophageal erosions and injury. Finally, saliva aids in speech.

SALIVARY SECRETORY PRODUCTS

Saliva plays a number of roles in gastrointestinal physiology (Table 51–2). Its primary function is to lubricate ingested food, and to thereby permit formation of a smooth, rounded portion

The protein components of saliva include digestive enzymes. Saliva begins the digestion of carbohydrates via the action of Smell Taste Sound Sight

Higher centers Parotid gland

ACh

Otic ganglion

Pressure in mouth Parasympathetics

Submandibular gland

FIGURE 51–8 Regulation of salivary secretion by the parasympathetic nervous system. ACh, acetylcholine. (Adapted with permission from Barrett KE: Gastrointestinal Physiology. New York: Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2006.)

Increased salivary secretion via effects on • Acinar secretion • Vasodilation

ACh Submandibular ganglion

Salivatory nucleus of medulla − Sleep Fatigue Fear

CHAPTER 51 Pancreatic and Salivary Secretion

523

Constituent

Functions

salivary glands also receive extensive sympathetic and parasympathetic innervation. Sympathetic efferents originate in the salivatory center adjacent to the dorsal vagal complex, whereas parasympathetics come from the salivatory nuclei.

Water

Facilitates taste and dissolution of nutrients; aids in swallowing and speech

ACINAR CELLS

TABLE 51–2 Constituents of saliva and their functions.

Bicarbonate

Neutralizes refluxed gastric acid

Mucins

Lubrication

Amylase

Starch digestion

Lysozyme, lactoferrin, IgA

Innate and acquired immune protection

Epidermal and nerve growth factors

Assumed to contribute to mucosal growth and protection

salivary amylase. This latter enzyme is not required for adequate digestion of starch in healthy adults, but may assume greater importance in neonates, where there is a developmental delay in the expression of pancreatic amylase. Salivary enzymes are “backups” that are only required for digestion if other sources are reduced. In patients with pancreatic insufficiency, for example, salivary enzyme synthesis may be modestly increased. Salivary lysozyme and other antibacterial peptides limit colonization of the oral cavity by microbes. Lactoferrin sequesters iron, thereby inhibiting the growth of bacteria that require this substance. Saliva also contains significant quantities of secretory IgA, which contribute to immune defense. In terms of the lubricating and solubilizing functions of saliva, the most important constituents are mucins and water. Mucin molecules are large glycoproteins with viscoelastic properties. Water is the main component of saliva and is secreted at very high rates. At maximal rates of secretion, the volumes produced by salivary glands can exceed 1 mL/min/g of gland tissue, necessitating high rates of blood flow to supply this fluid. In an adult, approximately 500 mL of saliva is produced daily. Saliva also contains a variety of inorganic solutes, including calcium and phosphate, that are important for tooth formation and maintenance. The primary secretion from the salivary acini has an ionic composition that is comparable to plasma. However, as the secretion moves along the ducts, the composition is modified by active transport processes as will be described later.

The salivary glands are heterogenous in their specific structure and function. The acini of the parotid glands, which drain into the upper part of the mouth via the parotid duct, consist entirely of serous cells, and thus are responsible for providing the protein constituents of saliva. The sublingual gland, under the tongue, has predominantly mucous acini responsible for secreting mucus and water, but also a scattering of serous acini as well. The submandibular gland, below the jaw, has a mixture of serous and mucous acini.

DUCTULAR CELLS As the saliva makes its way out of the acini, it passes through a ductular system. The intercalated ducts, linked directly to the acini, serve predominantly to convey the saliva out of the acinus and to prevent backflow. Cells of the striated intralobular ducts, on the other hand, are polarized epithelial cells with specialized transport functions. The epithelial cells of the intralobular ducts, moreover, have well-developed intercellular tight junctions that significantly limit the permeability of this segment of the gland relative to the leaky acinus.

REGULATION OF SALIVARY SECRETION NEURAL REGULATION The salivary glands are unusual in the gastrointestinal system in that their regulation appears to be exclusively mediated by neurocrine pathways and not by gastrointestinal hormones, at least in the short term. The salivary glands are also unusual in that they are positively regulated by both the parasympathetic and sympathetic branches of the autonomic nervous system. However, quantitatively, the predominant regulation of secretory rate and composition is via parasympathetic pathways with sympathetic efferents playing only a modifying role.

SALIVARY GLAND ANATOMY Like the pancreas, the salivary glands are made up of grapelike clusters of acini that drain into a system of intercalated and intralobular (striated) ducts, and eventually into interlobular ducts that drain into the oral cavity. The individual acini and associated ducts are also surrounded by a sheath of myofibroblasts, which are contractile cells that may be important in providing a hydrostatic force that expels saliva from the gland, thereby contributing to high rates of secretion. The

Parasympathetic and Sympathetic Regulation The parasympathetic nervous system initiates salivary secretion and sustains secretion at high rates. The nerves originate in the salivatory nucleus of the medulla, and receive input from higher centers interpret the need for changes in salivary secretion under both physiological or pathophysiological circumstances Conditioned reflexes, such as smell and taste, as

SECTION VIII GI Physiology

well as pressure reflexes transmitted from the oral cavity markedly stimulate parasympathetic outflow, whereas fatigue, sleep, fear, and dehydration suppress neurotransmission. Nausea also strongly stimulates salivation, presumably to protect the oral cavity and esophagus from the injurious effects of vomited gastric acid and other intestinal contents. Parasympathetic input to the salivary glands is mediated by ACh acting at muscarinic receptors. In addition to effects on the acinar cells and ducts of the glands, parasympathetic innervation causes dilation of the blood vessels supplying the gland, thereby providing both the fluid and metabolic requirements needed to sustain high rates of secretion. Efferents of the sympathetic nervous system passing through the superior cervical ganglion also terminate at the salivary glands. These nerves are not thought to be capable of initiating or sustaining secretion independently, but can potentiate the effects of parasympathetic regulation via the release of norepinephrine and beta-adrenergic receptors.

160 140 Concentration (mEq/L)

524

120 100

Na+

80 HCO3−

60

Cl−

40

K+

20 0

1

2

3

4

Flow of saliva (mL/min)

FIGURE 51–9 Ionic composition of saliva as a function of its flow rate. Note that saliva becomes less hypotonic as flow rates increase. (Reproduced with permission from Barrett KE: Gastrointestinal Physiology. New York: Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2006.)

CELLULAR BASIS OF SALIVARY SECRETION ACINAR CELLS Acinar cells release their protein and mucus contents via a process of exocytosis, analogous to enzyme release from the pancreatic acini. These responses involve mobilization of intracellular calcium downstream of the muscarinic receptor for ACh. Acinar cells also actively secrete chloride, bicarbonate, and potassium ions into the primary salivary secretion. Because the acini are relatively leaky, sodium and water follow paracellularly via the tight junctions and the initial secretion has an ionic composition comparable to plasma.

DUCTULAR CELLS As we learned for the pancreas, the duct cells in the salivary glands modify the composition of the saliva as it passes by them. The ionic composition of saliva changes as its flow rate increases (Figure 51–9). At low rates of secretion, saliva is hypotonic with respect to plasma and has higher concentrations of potassium than sodium, the opposite of the situation in plasma. The chloride concentration is also much lower than that found in plasma. These changes in ionic content are brought about by active transport events taking place in the duct cells (Figure 51–10). Sodium and chloride are reabsorbed across the apical membrane, in exchange for protons and bicarbonate, respectively. Protons are recycled to transfer potassium into the duct lumen. At the basolateral membrane, the driving force for sodium uptake is provided by a sodium–potassium ATPase, and a potassium channel supplies potassium for secretion into the saliva. Because the ductular epithelium has a low passive permeability, water cannot flow across the tight junctions fast enough at moderate rates of salivary secretion to

keep pace with the active reabsorption of sodium and chloride, and thus saliva becomes hypotonic. Moreover, due to secretion of bicarbonate into the lumen without an accompanying proton, the pH of saliva increases progressively to approximately 8 as the saliva enters the mouth. At very high rates of salivary secretion, the concentrations of sodium and potassium more closely resemble those in plasma. The concentration of chloride also increases as the flow rate of saliva increases. These changes in composition are due to the fact that the residence time of the saliva in the ducts is too short for the cells to be able to modify salivary composition significantly.

CLINICAL CORRELATION A Caucasian couple brings their two-month old infant to a pediatrician for a well-baby check. It is noted that the baby is underweight, and his mother notes frequent coughing, some episodes of vomiting after feeding, and a salty taste to the child’s skin. After administering the muscarinic agonist, pilocarpine, to stimulate secretion by the sweat glands, chloride concentrations in the sweat are found to be markedly increased. Genetic testing later reveals that both parents are heterozygous for a mutation that results in the deletion of the phenylalanine residue at position 508 of CFTR, and a diagnosis of cystic fibrosis is made. The child’s condition improves with supplementation of the diet with an oral preparation of pancreatic enzymes as well as physical therapy designed to dislodge thickened respiratory secretions, but recurrent lung infections often require antibiotic therapy. Respiratory complications due to failure to clear the thickened mucus from the airways, are usually the most significant cause of morbidity and mortality in cystic fibrosis. Pancreatic

CHAPTER 51 Pancreatic and Salivary Secretion

DUCT LUMEN

525

BASOLATERAL

Cl− channel

Cl−/HCO3− Exchanger

HCO3−

Cl−

Cl− Na+ NHE H+

3Na+ 2K+

Na+, K+ ATPase

H+ K+

H+/K+ Exchanger

K+

K+ channel

H2O

FIGURE 51–10 Ion transport pathways in salivary duct epithelial cells. NHE, sodium/ hydrogen exchanger (Reproduced with permission from Barrett KE: Gastrointestinal Physiology. New York: Lange

Tight junctions restrict osmotic reabsorption of water

function can also be altered in the genetic disorder of cystic fibrosis, where mutations lead to abnormal function of the CFTR chloride channel. Indeed, the disease was named for characteristic cystic histological abnormalities observed in the pancreas in affected patients. Although pancreatic enzyme synthesis and secretion are normal in patients with cystic fibrosis, the relative inability of the ducts to secrete bicarbonate and water means that the enzymes cannot be flushed properly from the organ, and limited quantities reach the intestinal lumen. Moreover, the enzymes that do reach the lumen are inactive because of the failure to neutralize gastric acid. These findings underscore the role of the duct cells in normal pancreatic function. In fact, in patients with severe CFTR mutations causing a marked reduction in channel function, the exocrine pancreas may be largely destroyed during fetal life, due to the action of retained proteolytic enzymes that become inappropriately activated and damage the tissue. Such patients are said to have pancreatic insufficiency and are treated with oral supplements of pancreatic enzymes, along with antacids, to allow for adequate nutrition. Patients with milder mutations may retain some degree of pancreatic function, at least early in life, but are then at greater risk for the development of inflammation of the pancreas (pancreatitis) with aging.

CHAPTER SUMMARY ■ ■

■

Pancreatic secretion provides for digestion of meals. Pancreatic acini supply enzymes, whereas ducts supply fluid; major regulators of each cell type are CCK and secretin, respectively. Pancreatic secretion is initiated during the cephalic phase, but is most prominent when the meal is in the duodenum.

Medical Books/McGraw-Hill, Medical Pub. Division, 2006.)

■ ■ ■

The pancreas has several lines of defense to protect against autodigestion. When these lines fail, pancreatitis results. Salivary secretion shares several parallels with pancreatic secretion. Salivary secretion is predominantly mediated by parasympathetic input arising from higher brain centers. Hormonal regulation is much less important.

STUDY QUESTIONS 1. A 4-year-old boy is brought to the pediatrician for an evaluation because of failure to thrive and frequent diarrhea characterized by pale, bulky, foul-smelling stools. Sweat chloride concentrations are measured and found to be elevated. Diminished secretion of which pancreatic product is most likely to be the primary cause of the patient’s apparent fat malabsorption? A) lipase B) procolipase C) monitor peptide D) cholecystokinin E) bicarbonate 2. In an experiment, recordings are made of electrical activity in afferent nerves originating in the small intestinal mucosa during sequential luminal perfusion with saline, a solution of hydrolyzed protein, and a solution of intact protein. Rates of neuronal firing were shown to increase markedly during the period when intact protein was infused compared with the other two. Firing in these nerves was most likely stimulated by an increase in the mucosal concentration of which of the following? A) gastrin B) secretin C) somatostatin D) ACh E) cholecystokinin

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SECTION VIII GI Physiology

3. A 50-year-old man with a history of alcohol abuse presents at the emergency room with severe, colicky abdominal pain and a fever. A blood test reveals increased levels of serum amylase and an endoscopic imaging procedure reveals a narrowed pancreatic duct. Pain in this patient is likely predominantly ascribable to premature activation of pancreatic enzymes capable of digesting which of the following nutrients? A) triglyceride B) phospholipids C) protein D) starch E) nucleic acids 4. A researcher conducts a study of the regulation of salivary secretion in a group of normal volunteers under various conditions. Which of the following conditions was associated with the lowest rates of secretion? A) chewing gum B) undergoing a mock dental exam C) sleep D) exposure to a nauseating odor E) resting control conditions

5. A 50-year-old female patient who has suffered for several years from severe dryness of her eyes due to inadequate tear production is referred to a gastroenterologist for evaluation of chronic heartburn. Endoscopic examination reveals erosions and scarring of the distal esophagus just above the lower esophageal sphincter. Reduced production of which of the following salivary components most likely contributed to the tissue injury? A) lactoferrin B) mucus C) IgA D) bicarbonate E) amylase

52 C

Water and Electrolyte Absorption and Secretion Kim E. Barrett

H A

P

T

E

R

O B J E C T I V E S ■ ■ ■ ■ ■ ■ ■ ■

Understand the physiological significance of the regulation of luminal water content and daily fluid balance. Describe the functional anatomy of the intestinal epithelium that permits it to function as a regulator of fluid movement. Define the pathways via which electrolytes can be transferred across epithelial barriers. Describe how a limited collection of membrane transport pathways is arranged to assemble transepithelial transport mechanisms. Identify the major electrolyte transport pathways of the small and large intestines and their intracellular mechanisms of regulation. Identify how subepithelial elements and other regulatory systems impact on epithelial transport function. Understand how transport function is integrated with intestinal motility. Define major pathogenic alterations in intestinal electrolyte transport and their consequences.

BASIC PRINCIPLES OF INTESTINAL FLUID TRANSPORT

this is exceeded that excessive water loss to the stool occurs, seen clinically as diarrhea.

ROLE AND SIGNIFICANCE

ELECTROLYTES INVOLVED

Control of the amount of fluid in the intestinal lumen is critical for normal intestinal function. This fluid environment permits contact of digestive enzymes with food particles, and in turn the diffusion of digested nutrients to their eventual site of absorption. The fluidity of the intestinal contents also provides for their transit along the length of the gastrointestinal tract without damage to the lining epithelium. Large volumes of fluid are handled by the intestine during the digestion and absorption of meals. Most of this fluid is supplied by the intestine and the organs that drain into it. The daily fluid load approximates 9 L in normal adults (Figure 52–1). In health, this large volume is later reclaimed by the intestine to avoid dehydration. Both the small and large intestines also have a large reserve capacity for absorption, and it is only when

Epithelial cells express several specialized properties that allow them to control fluid movement. Most important are the intracellular tight junctions that restrict the passive flow of solutes and backflow of these once either secreted or absorbed. Water is transported passively across the intestinal epithelium in response to osmotic gradients established by the active transport of electrolytes and other solutes. In common with those in other transporting epithelia, such as in the nephron, active electrolyte transport pathways share a number of defining characteristics (Table 52–1). These transport pathways move a solute across a single membrane in a polarized epithelial cell. Transepithelial transport mechanisms, in turn, move solutes across the entire epithelium. Furthermore, both absorption and secretion can occur simultaneously in any given segment of the intestinal

Ch52_527-534.indd 527

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TABLE 52–2 Small intestinal ion transport

Oral intake 2000 mL

mechanisms. Bicarbonate secretion Saliva 1500 mL

Sodium-coupled nutrient absorption Proton-coupled nutrient absorption

Gastric juice 2500 mL

Electroneutral NaCl absorption Chloride secretion Pancreatic juice 1500 mL

Bile 500 mL

Sodium-coupled bile acid absorption Calcium and iron absorptiona a

Not major determinants of fluid transport.

Intestinal secretion 1000 mL

ANATOMICAL CONSIDERATIONS AMPLIFICATION OF INTESTINAL SURFACE AREA

Small intestinal absorption 7000 mL (78%)

Colonic absorption 1900 mL (21%) Stool 100 mL (1%)

FIGURE 52–1 Daily water balance in the healthy adult human gastrointestinal tract. The amount of oral intake varies among individuals depending on the types of meals taken. Note that even in health there is a significant secretory flux of fluid from the intestine. (Modified with permission from Barrett KE. and Dharmsathaphorn K: Transport of water and electrolytes in the gastrointestinal tract: physiological mechanisms, regulation and methods for study. In: Maxwell and Kleeman’s Clinical Disorders of Fluid and Electrolyte Metabolism, 5th ed. Narins RG (editor). McGraw-Hill, New York, 1994.)

tract. This is primarily because most of the cells of the villi (or surface cells in the colon) are absorptive, whereas crypt epithelial cells are secretory. In general, absorptive mechanisms for fluid center on the active movement of sodium, whereas secretory fluxes of fluid in the intestine are driven mostly by the electrogenic movement of chloride ions, although bicarbonate secretion may assume significance in particular segments. Moreover, the transport mechanisms that are expressed in the small intestine and colon differ, due to the relative paucity of nutrients in the latter segment (Tables 52–2 and 52–3).

TABLE 52–1 Characteristics of active membrane transport pathways.

The capacity of the intestine for large volumes of water transport is related to its massively amplified surface area. In fact, the surface area of the adult small intestine alone exceeds that of a doubles tennis court. The intestine is not a simple cylinder, but instead is amplified first by folds in the mucosa, then by the presence of crypts and villi, and finally by the presence of microvilli on the apical poles of individual epithelial cells. Overall, the surface area is increased 600-fold by these physical structures. This amplification of the surface area not only allows for handling of the large volumes of fluids required for normal functioning of the intestine, but also provides the reserve capacity for fluid absorption in disease. However, the surface amplification, particularly in the crypts, also carries a liability in that there is a corresponding reserve capacity for intestinal fluid secretion. If such secretion is extensive and prolonged, it can rapidly lead to serious dehydration if left untreated.

INNERVATION AND REGULATORY CELLS As we learned in earlier chapters, the intestinal epithelium rests on a lamina propria that is a rich source of potential regulatory factors. In addition to endocrine regulators, epithelial electrolyte transport is controlled by paracrine mediators supplied by local enteroendocrine cells, immune mediators, and

TABLE 52–3 Colonic ion transport mechanisms. Electrogenic sodium absorption

Mediate uphill transport against an electrochemical gradient Electroneutral NaCl absorption Effective at low luminal concentrations Short-chain fatty acid absorption Demonstrate saturable kinetics Chloride secretion Require cellular energy Potassium absorption/secretiona Demonstrate high ionic specificity

a

Not a major determinant of fluid transport.

CHAPTER 52 Water and Electrolyte Absorption and Secretion neurocrines released from secretomotor efferent nerves originating predominantly in the submucosal plexus of the enteric nervous system. The epithelial cells themselves may also produce autocrine factors that regulate their transport function. The regulatory systems that mediate changes in epithelial transport do not act in isolation. Rather, there is significant crosstalk between the various modes of communication. For example, some immunologic mediators may have both direct effects on epithelial cells and others that are mediated secondarily via the activation of enteric nerves. Crosstalk between the various regulatory systems also provides for coordinated regulation of transport and motility functions.

REGULATION OF WATER AND ELECTROLYTE TRANSPORT REGULATORY STRATA Much of our knowledge of the control of intestinal fluid movement comes from studies of the factors that regulate fluid secretion, which is driven primarily by the secretion of chloride ions. Fluid absorption, particularly in the postprandial period, is more of a passive response that is driven by the presence of nutrients, and not highly subject to regulation by intracellular and intercellular mechanisms. On the other hand, in the absence of nutrients, the intestine absorbs fluid to balance secretory pathways via the absorption of sodium and chloride ions. These nutrientindependent pathways for fluid absorption are subject to both intracellular and intercellular regulation. In general, regulatory pathways that stimulate chloride secretion inhibit sodium chloride absorption, and vice versa. However, this does not apply to nutrient-coupled absorption, which can continue unopposed even under circumstances that lead to the stimulation of chloride secretion. This last point underlies the efficacy of so-called oral rehydration solutions, which are used to treat the dehydration accompanying severe diarrheal diseases, such as cholera, when intravenous fluids are not available.

Short and Long Reflexes Intestinal epithelial transport is regulated by neurotransmitters originating from nerve endings of the enteric nervous system. The most potent effectors in this regard include acetylcholine (ACh) and vasoactive intestinal polypeptide (VIP), both of which can directly stimulate epithelial cells to secrete chloride. Some neural input to the control of intestinal transport almost certainly originates in the central nervous system, and this input is then interpreted and integrated with local information to impinge ultimately on the activity of secretomotor neurons. In a similar fashion, vagovagal reflexes likely match intestinal transport function to conditions that result from the physical state of luminal contents, such as via the activation of stretch receptors. In addition to these “long” reflexes, however, “short” or local reflexes can be initiated by stroking the mucosa, which models

529

the local passage of a food bolus. In turn, this releases 5-hydroxytryptamine from local enterochromaffin cells, followed by activation of cholinergic efferents that stimulate a corresponding burst of chloride, and thus fluid, secretion. This reflex may be important in protecting the epithelium from physical damage by the passing meal components.

Humoral Control Although there appears to be a relatively limited role for classical endocrine hormones in mediating changes in intestinal transport function, at least in the short term, other soluble effectors have clear effects and are largely derived from paracrine or immune sources. For example, local production of prostaglandins, likely predominantly by subepithelial myofibroblasts, plays an important role in stimulating the secretion of both chloride and bicarbonate. Similarly, histamine, released by mast cells residing in the lamina propria, has been shown to be an effective chloride secretagogue, although its effect is transient. Indeed, immune effector cells that release substances capable of regulating the epithelium can be considered specialized “sensory” cells that alter transport function in response to specific conditions pertaining in the lumen, such as the presence of food substances to which an individual is allergic. These and other putative humoral regulators of intestinal secretion and/or absorption are listed in Table 52–4. Humoral regulators of intestinal transport typically bind to receptors localized to the basolateral pole of intestinal epithelial cells. It should be emphasized, however, that such effectors can alter epithelial function not only via such direct binding, but also via the secondary activation of other subepithelial elements. In this way, intestinal secretory and/or absorptive function can be better integrated with other physiological functions of the gut such as motility and blood flow. In turn, agonists that alter these latter functions may have indirect effects on intestinal secretion and absorption. The net rate of movement of any substance across the intestinal epithelium will reflect not only the “east–west” vector of absorption/secretion, but also the “north–south” vector of movement along the length of the gastrointestinal tract (Figure 52–2). Thus, if motility is increased, hastening the transit of substances along the intestine, there will be less time for absorption to take place (or, conversely, for active secretion to add to luminal fluid loads). If transit is slowed, absorption can catch up with the presented

TABLE 52–4 Major endogenous regulators of intestinal ion transport. Cyclic Nucleotide-dependent

Calcium-dependent

Vasoactive intestinal polypeptide (VIP)

Acetylcholine (ACh)

Prostaglandins

Histamine

Guanylin (cGMP)

5-Hydroxytryptamine

5′AMP/adenosine

Bile acids

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SECTION VIII GI Physiology

Oral

EAST-WEST VECTOR Influenced by surface area

pendent of the presence of a meal, notably as stimulated by input from the central nervous system at times of threat or stress. In either case, while both secretion and absorption occur simultaneously, in health, the absorptive vector predominates overall, and most of the fluid used for digestion and absorption is recycled (Figure 52–3). Neurotransmitters released from enteric secretomotor neurons, as well as paracrine effectors from local enteroendocrine cells or other subepithelial elements, alter the functional capacity of transporting epithelial cells to conduct transport across their apical and basolateral membranes. Acutely, second messenger pathways evoked by neurohumoral regulators alter the activation status of the transporters and/or redistribute transporters within the epithelial cells themselves. Delivery of additional, preformed transporters to the membrane will increase transport capacity, whereas endocytic retrieval will reduce it.

NaCl, nutrients Anal

NORTH-SOUTH VECTOR Influenced by motility → transit time

FIGURE 52–2 Integration of influences on fluid movement in the intestine. Overall fluid fluxes depend on the surface area available for ion transport and residence time in the lumen. (Modified

Villus

Health

with permission from Barrett KE: Gastrointestinal Physiology. New York: Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2006.)

fluid volume. This last principle underlies the efficacy of several antidiarrheal medications, and particularly opiate drugs such as loperamide.

Crypt

NaCl

Luminal Regulators The epithelium is also positioned to respond to substances present in the intestinal lumen, and expresses a number of apical receptors for such agents. Guanylin is a peptide regulator of epithelial chloride secretion that is synthesized by enteroendocrine cells and released into the lumen. The physiological role of this substance may be to coordinate salt handling by the small and large intestines with that of the kidneys. Bile acids, which are synthesized by the liver to aid in fat digestion and absorption, are also apical stimuli of chloride secretion in the colon. Under normal circumstances, however, bile acids are reabsorbed in the terminal ileum when they are no longer needed to solubilize the products of fat digestion, and so bile acid–induced diarrhea is only observed in the setting of disease.

ACUTE REGULATION Acute regulation of intestinal fluid and electrolyte transport occurs to match needs for luminal fluidity on a minute-tominute basis. Altered intestinal transport can also occur inde-

Cl−

Villus

Diarrheal disease

Crypt

Nutrient absorption largely normal Cl−

FIGURE 52–3 Balance between absorption and secretion in health and in secretory diarrheal disease. Note that small intestinal nutrient absorption is usually largely normal in the setting of secretory diarrhea. (Modified with permission from Barrett KE: Gastrointestinal Physiology. New York: Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2006.)

CHAPTER 52 Water and Electrolyte Absorption and Secretion

CHRONIC ADAPTATION The bowel is also capable of altering its ability to conduct water and electrolyte transport in a chronic fashion (over days to weeks), in order to adapt to changes in whole body electrolyte status. The hormone, aldosterone, is an important regulator of sodium transport in the intestine in addition to similar roles in the renal system (see Chapters 45 and 65). When the diet is low in salt, aldosterone is released and increases the expression of transporters required for sodium absorption in the colon. The net effect is active sodium retention by the colon. Analogous processes allow for increased or decreased intestinal retention of other important electrolytes. For example, a decrease in plasma calcium increases levels of 1,25-dihydroxyvitamin D, which stimulates the expression of proteins needed for calcium absorption in the small intestine. Conversely, levels of transporters involved in intestinal iron absorption are decreased in patients suffering from the disease of hemochromatosis, which is associated with overloading of the body’s stores of iron.

CELLULAR BASIS OF TRANSPORT ABSORPTIVE MECHANISMS Absorptive mechanisms expressed in the small intestine and colon are summarized in Tables 52–2 and 52–3. Throughout the length of the small intestine, sodium is taken up in conjunction with a variety of nutrients as exemplified by glucosecoupled sodium absorption (Figure 52–4). This, and related transport mechanisms such as those driven by specific amino acids, relies on the low intracellular sodium concentration established by the active, basolateral Na,K-ATPase. Apical

531

uptake of sodium and glucose (or galactose) is a coupled process that occurs via a cotransporter, SGLT-1. By tying the movement of glucose to that of sodium, glucose can be moved against its concentration gradient, even when luminal concentrations of this nutrient are low. Glucose thus absorbed is then utilized by the enterocyte, or is transported to the bloodstream via a facilitated diffusion pathway (GLUT-2). Anions (largely chloride) and water follow passively via the tight junctions. Sodium-coupled transport also allows for the active uptake of conjugated bile acids, although in this case the transport mechanism is restricted to the terminal ileum. In the colon, where luminal glucose is largely absent, a similar mechanism allows for the electrogenic uptake of sodium by replacing SGLT-1 with the epithelial sodium channel (ENaC) (Figure 52–5). Short peptides that are products of digestion of dietary proteins are absorbed via an apical transporter known as PepT1, coupled to proton uptake. PepT1 is a remarkable transporter in that it can accommodate a wide range of substrates, including dipeptides, tripeptides, and perhaps even tetrapeptides made up of various combinations of the 20 naturally occurring amino acids. As we will see in Chapter 58, some amino acids, including essential ones that cannot be synthesized by the body, are only efficiently absorbed in peptide form due to a relative lack of relevant amino acid transporters. Between meals, when nutrients are not available in the lumen, fluid absorption can still continue via a mechanism that involves the coupled absorption of both sodium and chloride (Figure 52–6). Coupled ion exchangers on the apical membrane carry sodium and chloride into the cell in exchange for protons and bicarbonate ions, respectively, and both exchange processes require the activity of the other. Notably, the NHE3 sodium–hydrogen exchanger isoform that participates in this transport mechanism is inhibited by cAMP; therefore, the overall transport process can likewise be inhibited by this second messenger.

Glucose GLUT-2

SGLT-1 2Na+

Glucose

2K+

3Na+ Na+,K+– ATPase

Cl–

FIGURE 52–4

Sodium-coupled nutrient absorption exemplified by the uptake of glucose from the intestinal lumen.

EN

aC

Na+

K+

2K+

3Na+ Na+,K+ ATPase Cl−

Kaplowitz N, Laine L, Owyang C, Powell DW (editors). Philadelphia, PA: Lippincott

FIGURE 52–5 Electrogenic sodium absorption in the colon. Sodium enters the epithelial cells via epithelial sodium channels (ENaC). (Reproduced with permission from Barrett KE, Barman SM, Boitano S, Brooks

Williams and Wilkins; 2003.)

H: Ganong’s Review of Medical Physiology, 23rd ed. McGraw-Hill Medical, 2009.)

(Used with permission from Montrose M.H. et al: Secretion and absorption: small intestine and colon. In: Textbook of Gastroenterology, 4th ed. Yamada T, Alpers DH,

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2K+ H+

NHE-3? NHE-2?

Na+

3Na+

Na+

_

2CI TR CF

Na+,K+ ATPase

Cl−

K+

NKCC1

Na+ 2K+

3Na+ +

HCO3–

CLD

Cl−

KCC1 ?

K+ Cl−

FIGURE 52–6 Electroneutral NaCl absorption in the small intestine and colon. NaCl enters across the apical membrane via the coupled activity of a sodium/hydrogen exchanger (NHE) and a chloride/bicarbonate exchanger (CLD). The route of basolateral chloride exit remains speculative. (Reproduced with permission from Barrett

+

Na , K ATPase

K+

KE, Barman SM, Boitano S, Brooks H: Ganong’s Review of Medical Physiology, 23rd ed.

FIGURE 52–7 Chloride secretion in the small intestine and colon. Chloride uptake occurs via the sodium/potassium/2 chloride cotransporter, NKCC1. Chloride exit is via the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel, as well as perhaps via additional chloride channels (not shown).

McGraw-Hill Medical, 2009.)

(Reproduced with permission from Barrett KE, Barman SM, Boitano S, Brooks H: Ganong’s Review of Medical Physiology, 23rd ed. McGraw-Hill Medical, 2009.)

The small intestine also absorbs iron and calcium in their ionic forms, although the small quantities of these ions that are handled do not contribute in a major way to fluid handling. Calcium absorption is possible along the length of the small intestine depending on whole body demands, whereas the majority of iron absorption occurs in the proximal small intestine due to specific expression of the membrane transporters required to facilitate iron movement. Dietary iron is also handled differently depending on whether it is in the form of heme (derived from meat), from which it is released by lysosomal enzymes following uptake of the intact heme molecule, or in its ionized form. The colon also conducts an additional absorptive transport process that reclaims an important byproduct of waste metabolism. Dietary fiber and other complex carbohydrates that cannot be digested by mammalian enzymes are degraded in the colon by the resident bacterial flora, and generate shortchain fatty acids such as acetate, propionate, and butyrate that are taken up by colonic epithelial cells.

SECRETORY MECHANISMS Secretory mechanisms in the gastrointestinal tract center around the active transport of chloride ions. The mechanism for secretion of chloride itself is depicted in Figure 52–7. Chloride is taken up across the basolateral membrane of crypt epithelial cells via a sodium/potassium/2 chloride cotransporter called NKCC1. This transporter conducts secondary active uptake of chloride into the cell cytosol by taking advantage of the favorable gradient for sodium movement established by the basolateral Na,K-ATPase. Potassium that is cotransported is recycled across the basolateral membrane via channels that may be activated by either cAMP or calcium. Chloride thus accumulates in the cytosol, ready to exit the cell across the apical membrane when chloride channels are opened in response to second messenger pathways. The quantitatively most significant path-

way for chloride exit is the CFTR channel; there is some evidence also to suggest an accessory role played by additional chloride channels. The net effect is the electrogenic movement of chloride from the bloodstream to the lumen; water and sodium follow passively via the tight junctions to maintain neutrality. In response to agonists such as VIP or prostaglandins, cAMP levels are increased in the crypt cell cytosol, which in turn result in activation of PKA. This enzyme can phosphorylate and thereby open the CFTR chloride channel, resulting in an initial burst of chloride secretion (Figure 52-8). cAMPdependent agonists of this process are additionally notable for the fact that they evoke sustained secretory responses. On the other hand, agonists such as ACh, histamine, and likely bile acids evoke chloride secretion by increasing cytosolic calcium concentrations. In this case, the primary locus for regulation is a basolateral potassium channel. As potassium leaves the cell, the driving force for chloride exit increases, allowing chloride to flow across the apical membrane via the small proportion of CFTR channels that may be open at any given time. The calcium-dependent chloride secretory response is smaller and more transient than that evoked by cAMP elevation. This may imply a physiological need to be able to call upon both brief and sustained secretory responses under specific circumstances during the digestion and absorption of a meal. Moreover, when crypt epithelial cells are simultaneously exposed to a combination of agonists acting via cyclic nucleotides and calcium, a synergistic enhancement of secretion results. The intestine is also capable of active bicarbonate secretion (Figure 52–9). This mechanism is particularly prominent in the proximal duodenum, which must defend itself from the potentially injurious effects of the acidic gastric juice, and is analogous to pancreatic secretion of this ion as discussed in the previous chapter. Like chloride secretion, the overall process of bicarbonate secretion can be stimulated by intracellular increases in cAMP, cGMP, or calcium, with prostaglan-

CHAPTER 52 Water and Electrolyte Absorption and Secretion

533

Cl− APICAL

Na+,K+– ATPase

R

CFT

Phosphorylation channel opening R C

P

Cl–

Cl– AE1? CLD?

C

Na+

cAMP

H+

3Na+

2K+ Na+,K+– ATPase

R?

Cytoskeleton

CFT

Vesicle trafficking

HCO3– Na+

Gs A.C. NKCC1 K+ Na+ 2Cl

BASOLATERAL

NHE-1

HCO3– + H+ CA CO2 + H2O

HCO3–

Protein kinase A

3Na+

2K+

CFTR

VIP PGE2

FIGURE 52–8

Regulation of chloride secretion by cAMPdependent agonists such as vasoactive intestinal polypeptide (VIP) and prostaglandins. These agonists activate adenylyl cyclase (A.C.) via a stimulatory G protein (Gs), leading to an increase in intracellular cAMP. This in turn activates the cAMP-dependent protein kinase (protein kinase A), causing dissociation of its catalytic (C) subunits from the regulatory (R) subunits. The catalytic subunits are thereby freed to phosphorylate CFTR leading to channel opening, and to stimulate the insertion of additional NKCC1 cotransporter molecules into the basolateral membrane. (Reproduced with permission from Barrett KE: Gastrointestinal Physiology.

HCO3– + H+ CA CO2 + H2O

NHE-1 H+

FIGURE 52–9 Bicarbonate secretion in the duodenum. The two models depicted differ in the pathway for bicarbonate exit across the apical membrane. Both models are likely to be important, although the anion exchanger involved in the upper mechanism has not been conclusively identified. CA, carbonic anhydrase; AE1/CLD, anion exchangers; NHE-1, sodium/hydrogen exchanger-1. (Used with permission from Montrose et al: Secretion and absorption: small intestine and colon. In: Textbook of Gastroenterology, 4th ed. Yamada T, Alpers DH, Kaplowitz N, Laine L, Owyang C, Powell DW (editors). Philadelphia: Lippincott, Williams and Wilkins; 2003.)

New York: Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2006.)

dins, guanylin, and ACh representing physiologically important secretagogues that utilize each respective second messenger. The primary physiological stimulus for duodenal bicarbonate secretion appears to be the presence of an acidic pH in the lumen.

CLINICAL CORRELATION Following a tsunami disaster in which the supply of clean drinking water is disrupted, hundreds of adults and children are brought to emergency medical personnel suffering from profuse, watery diarrhea. The children, in particular, show signs of severe dehydration. Because of the prevailing conditions and a lack of trained personnel, it is not possible to resuscitate patients with intravenous fluids. Instead, patients are placed on cots that allow fecal fluid losses to be measured over time. Many patients who

receive oral solutions of glucose and sodium chloride in volumes equivalent to their fecal losses recover from their acute diarrheal illness and survive. Later microbial analyses reveal that stool samples contain large numbers of a bacterial pathogen. Diarrhea can result when intestinal chloride secretion is stimulated excessively, and the resulting luminal fluid load exceeds the absorptive capacity of the small and large intestines (Figure 52–3). The prototypic disease state in which this occurs is cholera, in which Vibrio cholerae bacteria in the intestinal lumen secrete a toxin. The active subunit of this toxin translocates to the basolateral membrane of intestinal epithelial cells where it irreversibly activates the stimulatory Gs G-protein, resulting in a massive accumulation of cAMP and stimulation of downstream signaling pathways. This produces uncontrolled and sustained chloride secretion, inhibition of electroneutral NaCl absorption, and an outpouring of fluid into the

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lumen. Stool volumes of up to 20 L per day are not uncommon in this disorder, which can rapidly lead to death due to the complications of dehydration if left untreated. Active intestinal secretion may also underlie diarrhea caused by a number of other enteric pathogens, including rotavirus and Salmonella. Clostridium difficile is a pathogen that is often acquired in hospital settings, particularly in patients whose normal enteric flora has been disrupted by the administration of antibiotics. It secretes toxins that provoke chloride secretion via calcium-dependent pathways in addition to damaging the barrier function of the epithelium. Finally, the endogenous peptide regulator of chloride secretion, guanylin, shows homology to a heatstable toxin produced by certain strains of pathogenic E. coli, which is the major cause of traveler’s diarrhea. Secretory diarrhea can also occur in noninfectious settings. In particular, when the epithelium is exposed to a barrage of immune and inflammatory mediators, such as in the inflammatory bowel diseases of Crohn’s disease and ulcerative colitis, there is both a stimulation of chloride secretion and an inhibition of sodium and chloride absorption, seen clinically as diarrhea, which is the most frequent symptom of these conditions. Diarrheal diseases continue to represent a major public health problem, particularly in developing countries where sanitation is inadequate and represent an important cause of infant mortality in such countries, second only to respiratory infections. Diarrheal diseases also have a major impact in developed countries, though more frequently in terms of discomfort, inconvenience, and lost productivity than mortality. Nevertheless, thousands of deaths from diarrheal diseases occur each year even in the United States, and many of these take place even after the patient has reached a health facility due to an underappreciation of how rapidly diarrhea can cause dehydration and metabolic disturbances.

CHAPTER SUMMARY ■ ■ ■ ■ ■ ■ ■

The intestine handles large volumes of fluid in fulfilling its physiological functions. Dysfunction can rapidly impact whole body electrolyte homeostasis. Water is moved passively in response to active electrolyte transport. Transport mechanisms are heterogeneous along the length of the intestine and between crypt and villus cells. Transport mechanisms consist of the asymmetrical arrangement of a limited number of electrolyte transport pathways. Certain pathogens can cause diarrheal disease by hijacking normal cellular signaling pathways. Diarrheal disease remains a major health problem in both developed and developing countries.

STUDY QUESTIONS 1. Individuals housed in a camp in Southeast Asia following a natural disaster develop widespread watery diarrhea. Increased activity of which of the following transport proteins might be exploited therapeutically to reduce fluid losses? A) SGLT-1 B) CFTR C) NHE3 D) Na,K-ATPase E) NKCC1 2. A 50-year-old man on a business trip to a developing county develops severe diarrhea and begins taking the opiate drug Imodium (loperamide) in an attempt to lessen his symptoms. Any relief he obtains can most likely be ascribed to an increase in which of the following? A) intestinal transit time B) mucosal blood flow C) chloride secretion D) peristalsis E) epithelial proliferation 3. A 30-year-old woman with Crohn’s disease undergoes a surgical resection of her terminal ileum. After recovering from the surgery, she develops chronic diarrhea, with a daily stool output 10× normal. Which of the following substances is/are most likely primarily responsible for her symptoms? A) prostaglandins B) inflammatory cytokines C) VIP D) bile acids E) short-chain fatty acids 4. An infant develops chronic diarrhea and failure to thrive. Tests reveal glucosuria (increased glucose in the urine). Further studies show that urinary excretion of a nondigestible disaccharide given orally, as well as uptake of oral alanine, is comparable to that seen in a normal child, whereas oral galactose absorption is markedly impaired. Diarrhea in this child is most likely due to a mutation in which of the following proteins? A) CFTR B) ENaC C) NHE3 D) PepT1 E) SGLT-1 5. In a healthy adult, the volume of fluid presented to the intestine on a daily basis is approximately 8 L. Assuming a normal diet, reabsorption of the bulk of this fluid in the small intestine is driven primarily by which of the following? A) nutrient-coupled electrogenic sodium absorption B) electroneutral NaCl absorption C) nutrient-coupled proton absorption D) potassium absorption E) electrogenic sodium absorption via ENaC channels

53 C

Intestinal Mucosal Immunology and Ecology Kim E. Barrett

H A

P

T

E

R

O B J E C T I V E S ■

■ ■ ■ ■

Understand the role played by the mucosal immune system in protecting the host from infections acquired via the oral route while not responding to innocuous antigens. Identify the cell populations that contribute to immunity in the gut and where they are located Describe the immune responses that occur to antigens encountered in the gut. Understand the origins, makeup, and physiological importance of microbial populations that exist in the normal intestine. Define the consequences of abnormal immune responses in the intestine.

BASIC PRINCIPLES OF MUCOSAL IMMUNOLOGY CONCEPT OF A MUCOSAL IMMUNE SYSTEM The surface of the gastrointestinal tract represents a vast frontier that can potentially serve as a portal of entry into the body. Indeed, the intestine is challenged to distinguish between potentially harmful microorganisms, against which it must defend itself, and the innocuous antigens that occur in food. This constant exposure has driven the development of a highly specialized branch of the immune system, referred to as the mucosal immune system, which encompasses the mucosa-associated lymphoid tissues, or MALT. In fact, the intestine represents the largest immunological compartment of the body, and has also evolved nonimmunological barriers to invasion by pathogens.

SPECIAL FEATURES OF THE IMMUNE SYSTEM OF THE INTESTINE The lymphocytes that traffic to mucosal sites encounter antigens in a controlled fashion. This is accomplished by limiting the uptake of particulate antigens predominantly to specific sites within the epithelial monolayer, via specialized epithelial

Ch53_535-542.indd 535

cells known as M cells. M cells overlie organized lymphoid aggregates known as Peyer’s patches. The lymphocytes in these structures are immunologically naive and represent the afferent arm of the mucosal immune system. After they have been stimulated by their cognate antigen, they traffic back to the lamina propria. During this migration, the lymphocytes mature and differentiate, and then represent an efferent arm of the system, capable of effector functions in the mucosa. In addition to T cells, the humoral aspects of mucosal immunity are predominantly served by secretory immunoglobulin (IgA) molecules, and the intestinal mucosa can also be considered to be constantly in a state of “physiological” inflammation, even in health. Presumably this reflects the constant stimulation the system receives, and renders the intestine armed and ready to respond rapidly at times of threat by pathogens.

FUNCTIONAL ANATOMY OF THE MUCOSAL IMMUNE SYSTEM CELLULAR MEDIATORS OF INNATE IMMUNITY The innate arm of the mucosal immune system is designed to mount rapid responses to pathogens, via the expression of pattern recognition receptors that recognize molecules that are 535

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important to broad classes of pathogenic microbes. These receptors are prominently expressed on macrophages as well as on cells not classically considered to be immune effector cells, such as those in the epithelium. Pattern recognition receptors include the Toll-like receptors, and proteins that may respond to pathogen molecules presented intracellularly such as Nod2. In general, activation of the innate immune response generates chemotactic molecules that stimulate the influx and activation of more inflammatory cells, including monocytes and neutrophils. Collectively, these cells can effect microbial killing.

CELLULAR MEDIATORS OF ADAPTIVE IMMUNITY Adaptive immunity involves the exquisitely specific recognition of literally millions of discrete antigenic sequences via specific receptors expressed on T and B cells. T cells recognize peptides derived from antigenic sequences via a heterodimeric, variable cell surface T-cell receptor. The peptides are presented bound to major histocompatibility complex (MHC) molecules on antigen-presenting cells. The binding of antigen to a specific T-cell receptor then drives the expansion of a clone of cells expressing that receptor; some of these differentiate into effector T cells; others remain as memory cells to jump-start an adaptive immune response if the same antigen is encountered again. T cells in the mucosal immune system can be subdivided into those expressing the differentiation marker CD4 and those expressing CD8. The former cell population recognizes extracellular antigens displayed on the surface of antigen-presenting cells, likely including components of pathogenic microorganisms. CD8-positive T cells, on the other hand, recognize abnormal intracellular proteins and provide important protection against potentially harmful intracellular events, such as viral infection or malignant transformation. Adaptive immunity is also mediated by B cells, which secrete antibodies specific for a given antigen under the influence of T cell–derived cytokines.

ORGANIZATION OF LYMPHOID TISSUES It is also important to appreciate how lymphoid tissues are organized in the intestine. As mentioned earlier, in the small intestine, the afferent arm of the system (i.e., the arm that responds initially to a threat) occurs in Peyer’s patches, as shown diagrammatically in Figure 53–1. In the colon, these aggregates of lymphocytes are more loosely organized, but analogous in function. Naive T and B cells from the bloodstream are targeted to migrate into Peyer’s patches because they recognize a specific type of endothelial cell that is found in these lymphoid structures. The other important components of the Peyer’s patch include the M cell, and dendritic cells and macrophages, which process and present antigens to the T and B cells. Once stimulated, activated T and B cells migrate out of the lymphoid follicle and eventually back to the lamina propria.

Follicle-associated epithelium M cell

T cell area

B cell area

FIGURE 53–1 Structure of a Peyer’s patch in the small intestinal mucosa. The follicle-associated epithelium contains M, or microfold, cells that have a subapical pocket in which antigens can be presented to immune cells. Lymphocytes are aggregated underneath the epithelium with T and B lymphocytes restricted to distinct areas. Peyer’s patches also contain dendritic cells (not shown) that can present antigens to lymphocytes. (Reproduced with permission from Barrett KE: Gastrointestinal Physiology. New York: Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2006.)

A final class of organized lymphoid cells in the intestine consists of lymphocytes anchored to the epithelial layer via specific adhesion molecules. These are called intraepithelial lymphocytes, and appear predominantly to consist of memory T cells capable of responding to only a subset of luminal antigens. They likely function primarily to secrete cytokines involved in the regulation of the epithelium, and may also participate in immune surveillance for emerging malignancies.

SECRETORY IgA SYSTEM Seventy to 90% of the B cells in the intestinal lamina propria secrete IgA, with the remainder largely making IgM, and a few cells making IgE. Very few cells in the lamina propria make IgG. In fact, given the large numbers of lymphocytes that normally reside in the gut, the daily synthesis of IgA exceeds that of all other immunoglobulins.

STRUCTURAL ASPECTS OF IgA IgA plasma cells in the lamina propria secrete two IgA molecules that are bound together by a short polypeptide sequence known as the J (or joining) chain. J chain is also a component of other polymeric immunoglobulins, such as IgM. The other critical component of secretory IgA that is found in the lumen of the intestine derives from intestinal epithelial cells (Figure 53–2). Thus, dimers of IgA plus J chain are taken up at the basolateral surface of the epithelium by binding to a structure known as the polymeric immunoglobulin receptor (pIgR). The complex of IgA plus pIgR is internalized and translocated across the epithelial cell. At the apical membrane, the IgA dimer is released into the lumen bound to a cleaved

CHAPTER 53 Intestinal Mucosal Immunology and Ecology

LUMEN

Secretory component

Secretory lgA

Lysosomal degradation

Epithelial cell

537

encounter vesicles bearing IgA bound to pIgR that are destined for the apical membrane. The IgA in these vesicles can bind the foreign antigen and traffic it back to the apical membrane, thus resulting in its elimination. Finally, some IgA molecules may function to sequester antigens that are able to penetrate to the lamina propria. IgA has an additional specialization relative to other antibody classes that particularly suits it to function in the gut. Thus, the antibody is not capable of fixing complement via the classical pathway, rendering it relatively noninflammatory on antigen binding. This is likely an important consideration given the vast antigenic load that is presented to the intestine, representing the combined influences of potentially antigenic food proteins along with microbial products.

PHYSIOLOGICAL FUNCTIONS

plgR J chain

Dimeric lgA lgA plasma cell

FIGURE 53–2 Secretion of IgA across the intestinal epithelium. IgA is secreted by plasma cells in the lamina propria as a dimer, with two IgA molecules linked by a J, or joining, chain. J chain is recognized by the polymeric immunoglobulin receptor (pIgR) expressed on the basolateral membrane of epithelial cells, and once bound, the complex is internalized and trafficked across the cytosol to the apical membrane. Apical proteases cleave the extracellular portion of pIgR, which remains associated with the IgA dimer as secretory component. The remnant of the pIgR is internalized and degraded. (Reproduced with permission from Barrett KE: Gastrointestinal Physiology. New York: Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2006.)

portion of pIgR, known as secretory component. Secretory component further stabilizes the IgA dimer against proteolytic cleavage by either the digestive juices or bacterial proteases.

MECHANISMS OF PROTECTIVE EFFECTS Secretory IgA exerts protection in the intestine via several mechanisms. In the lumen, it can bind microbial antigens, food antigens, and viruses to prevent their uptake by intestinal epithelial cells. There is also evidence for a second line of defense that takes place within epithelial cells themselves. Thus, if any antigens are internalized by these cells, they

The secretory IgA response protects the body from potentially injurious substances that might otherwise stimulate a more generalized immune/inflammatory reaction in the periphery. Note that the IgA system is not well developed in newborns. In the breast-fed infant, protection can be obtained via IgA antibodies in the mother’s milk. This is one benefit of the common mucosal immune system, discussed earlier, where lymphocytes activated by antigens encountered in the intestine also traffic to other mucosal sites, including the mammary glands. The IgA system becomes mature in the child by the age of 5–6 months.

IMMUNE RESPONSE TO ENTERIC ANTIGENS There are three potential outcomes when the adaptive immune system encounters an antigen in the intestine. The specific outcome that occurs depends, in part, on the type of antigen that is encountered and its quantity. A localized response can occur, such as the stimulation of antigen-specific IgA production. The antigen can also, at least theoretically, drive a systemic immune response with the production of circulating antibodies plus expansion of antigen-specific T cells. However, it is clear that this would be an undesirable outcome under normal circumstances, given the number of antigens encountered by the intestine on a daily basis and the deleterious consequences of systemic reactions to these. Thus, an additional response to orally delivered antigens has also evolved in the mucosal immune system, which limits these adverse consequences in the systemic immune system. This specialized response is referred to as oral tolerance.

ORAL TOLERANCE Oral tolerance refers to a mucosal immune response where local IgA is produced, yet there is no detectable immune response in

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the periphery. Oral tolerance is the most frequent outcome for antigens that are presumably innocuous, such as from food. The determination as to whether oral tolerance will occur depends on the type of antigen, the amount given, the frequency of exposure, and host factors, including the age of the recipient. The lack of response in the periphery apparently requires active suppressive mechanisms, and is highly specific, extending only to the substance that is fed and not to other antigens. The phenomenon of oral tolerance is being exploited for the experimental treatment of some systemic autoimmune diseases.

known as the enteric flora or microbiota. The species that make up this flora are referred to as commensal microorganisms.

IMMUNE RESPONSIVENESS

Indigenous Populations

Under different circumstances, it may be appropriate for the intestine to respond to an antigen and additionally for this response to spread to the periphery. This is particularly the case for immune responses to pathogens. Generalized immune responses to otherwise innocuous antigens can also be driven by administering these in the presence of an adjuvant. This latter approach might ultimately prove useful in exploiting the oral route to vaccinate people against disease-related antigens. Generalized immune responses can also be deleterious to the host under specific circumstances. For example, if the barrier function of the epithelium is compromised, it is possible to generate both local and systemic immune responses to the normal commensal flora of the gut, which in turn can lead to tissue injury.

AUTOIMMUNITY During the development of immunity, clones of T and B cells capable of reacting to self-antigens are actively deleted. However, even in healthy individuals, a few such lymphocytes are thought to remain in the mucosal immune system, and may be needed to respond to microbes that express antigens that resemble proteins of the host, in an attempt to evade immunity. Under normal circumstances, these autoreactive clones are likely held in check by active suppressive mechanisms, including those mediated by regulatory T cells and inhibitory cytokines. Likewise, self-antigens may be presented in the absence of appropriate costimulatory molecules, which results in anergy (the lack of an immune reaction) rather than an immune response. On the other hand, under pathologic conditions, this regulation may be lost with the resulting emergence of autoreactivity and tissue inflammation and injury. These mechanisms may be important in contributing to disease in conditions such as inflammatory bowel diseases (Crohn’s disease and ulcerative colitis), celiac disease, and atrophic gastritis.

INTESTINAL MICROECOLOGY The gastrointestinal tract also represents a unique body compartment with respect to the lifelong, reciprocally beneficial relationship it establishes with a resident microbial community,

DEVELOPMENT OF INTESTINAL MICROBIOTA At birth, the intestinal tract is sterile. However, by the age of 1 month, the infant acquires a rich flora, derived from the environment in an oral-to-anal direction.

The entire gastrointestinal tract can be shown to be colonized by bacteria, but the types of bacteria and their numbers vary along the gastrointestinal tract. The stomach and the majority of the small intestine contain relatively few bacteria, and lack anaerobes. On the other hand, beginning in the distal small intestine, the numbers of bacteria increase sharply, and anaerobes also appear. The largest numbers of bacteria, by far, occur in the colon, where anaerobes vastly outnumber aerobic bacteria (Table 53–1). The flora in the colon is complex, likely containing at least 400 different bacterial species. However, the precise proportions of each species tend to differ between individuals, while remaining relatively constant in a given individual over time in the absence of events that alter the flora (see later). This has led to the concept that the bacterial flora of a given subject is essentially equivalent to a “fingerprint,” representing the interplay between host and bacterial factors. The major anaerobic species include Bacteroides, bifidobacteria, clostridia, Eubacteria, and anaerobic streptococci. Likewise, important aerobes include enterobacteria such as E. coli, streptococci, and staphylococci.

Factors Controlling Microbiota The bacterial colonization of the upper gastrointestinal tract is kept in check by a number of physical and humoral factors. Many gastrointestinal secretions contain substances that are toxic to bacteria, including gastric acid, bile acids, small antimicrobial peptides known as defensins, and lysozyme. In the small intestine, moreover, the overall bacterial burden is kept

TABLE 53–1 Enteric bacterial populations. Stomach

Jejunum

Ileum

Cecum/ Colon

Total bacteria/g

0–103

0–104

104–108

1010–1012

Aerobes and facultative anaerobes/g

0–103

0–104

104–105

102–109

Anaerobes/g

0

0

103–108

1010–1012

pH

3

6–7

7.5

6.8–7.3

CHAPTER 53 Intestinal Mucosal Immunology and Ecology in check by the combined influences of motility (especially peristalsis) and the secretion of fluid and electrolytes that can wash bacteria out of the lumen. Secretion of IgA may also limit the growth of some commensals. In the colon, on the other hand, the relatively slow motility permits the growth of large numbers of bacteria. These are largely retained in the large intestine by the action of the ileocecal valve. Upwards of 1012 bacteria can be found per gram of colonic luminal contents, and the majority of the formed mass of the stool, after water, consists of dead bacteria. Indeed, the number of colonic bacteria in the average person is greater than the total number of cells in the human body. The makeup of the colonic flora is relatively insensitive to diet, although a diet rich in fiber, which constitutes a fuel for anaerobic bacteria, may result in an increase in overall bacterial numbers. Conversely, intestinal colonization can be dramatically reduced in patients taking broad-spectrum antibiotics. In this setting, there is sometimes also overgrowth of harmful bacteria that can cause disease, such as Clostridium difficile, commonly acquired in hospitals, because there are fewer commensals to compete with the harmful bacteria for nutrients.

PHYSIOLOGICAL FUNCTIONS OF THE MICROBIOTA Experiments in animals reveal that the intestinal microflora is not essential to life. Thus, animals that are raised in a totally sterile environment from birth are apparently healthy and reproduce normally. Nevertheless, the flora clearly has measurable effects on the host. First, in germ-free animals, the mucosal immune system is poorly developed, illustrating the critical role of luminal stimuli in driving the development and

maturation of intestinal lymphoid populations. Second, epithelial proliferation and differentiation are slowed. Colonic bacteria, in particular, also supply unique metabolic functions, divided into effects on endogenous substances and those on substances that originate outside the body. Colonic bacteria convert bilirubin, a product of heme metabolism that is secreted in the bile, into urobilinogen. This compound undergoes some passive absorption across the wall of the colon and appears in the urine. Bacterial dehydroxylases also act on primary bile acids to generate secondary bile acids that enter the enterohepatic circulation, and bacterial enzymes are also responsible for deconjugating any conjugated bile acids that escape active reabsorption in the terminal ileum, to then permit their passive reuptake across the colonic mucosa (Table 53–2). Bacterial enzymes also salvage nutrients that cannot be degraded by pancreatic or other digestive enzymes (Table 53–2). This is particularly important for dietary fiber, a form of carbohydrate that is resistant to breakdown by amylase. Breakdown of fiber occurs via a metabolic process known as fermentation, and requires a strict anaerobic environment. Fermentation can also break down any carbohydrates that escape digestion and absorption in the small intestine. The products of fermentation are the short-chain fatty acids, which can be absorbed by colonic epithelial cells and used as fuel. Fermentation also yields energy for the bacteria and the gases hydrogen, carbon dioxide, and methane. Bacteria can also act on other dietary components to yield byproducts, although these are usually quantitatively less significant than the products of carbohydrate fermentation. A final, and likely critical, role of the microflora is to increase the resistance of the intestinal mucosa to colonization by pathogenic microorganisms (Table 53–3). Germ-free animals are exquisitely sensitive to enteric pathogens, succumbing to infection with only a few pathogenic bacteria presented orally compared to the

TABLE 53–2 Metabolic effects of enteric bacteria. Substrate

Enzymes

Products

Disposition

Urea

Urease

Ammonia

Passive absorption or excretion as NH4+

Bilirubin

Reductases

Urobilinogen, stercobilins

Passive reabsorption Excreted

Primary bile acids

Dehydroxylases

Secondary bile acids

Passive reabsorption

Conjugated bile acids

Deconjugases

Unconjugated bile acids

Passive reabsorption

Carbohydrates (fiber)

Glycosidases

SCFAsa H2, CO2, CH4

Active absorption Expired in breath or excreted in flatus

Amino acids

Decarboxylases and deaminases

Ammonia, HCO3−

Reabsorbed or excreted (for ammonia) as NH4+

Cysteine, methionine

Sulfatases

Hydrogen sulfide

Excreted in flatus

Endogenous substrates

Exogenous substrates

a

SCFA, short-chain fatty acid.

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TABLE 53–3 Selected important intestinal pathogens and their pathophysiological mechanisms. Luminal (Toxigenic) Pathogens

Adherent Pathogens

Invasive Pathogens

Viral Pathogens

V. cholerae

Giardia

Salmonella spp.

Rotavirus

Enterotoxigenic E. coli

Enteropathogenic E. coli

Shigella

Norwalk virus

H. pylori

Campylobacter Listeria

millions needed to cause disease in a normal animal. Likewise, the enteric flora protects the host from overgrowth of bacteria that are innocuous when present in low numbers, but can cause disease if allowed to dominate the flora.

GENERATION OF GAS IN THE INTESTINE The intestinal flora is also the source of the majority of the gas that originates in the gastrointestinal tract. While large volumes of air may be swallowed with meals, most of this is expelled from the stomach by belching. That which remains is supplemented by carbon dioxide that is generated when gastric acid is neutralized by bicarbonate; the majority of the carbon dioxide can diffuse across the wall of the bowel and is excreted via the lungs. The gas that remains in the intestine is moved back and forth by motility patterns, resulting in bowel sounds— borborygmi—that can be heard through a stethoscope and sometimes even by the naked ear as a “rumbling stomach.” The absence of such bowel sounds is a reliable indicator that bowel motility has been inhibited, which happens commonly (and usually reversibly) after abdominal surgery. More distally, fermentation and other metabolic pathways promoted by bacterial enzymes in the colon result in the formation of large volumes of gas on a daily basis, even in normal individuals. The volume of gas produced by a healthy individual is likely to average 1 L per day. However, there is considerable variation among individuals, and the amount of gas also depends on the quantity of fermentable residues that depends, in turn, on the diet. Most of the gases present in flatus are nonodorous, with the majority consisting of nitrogen and hydrogen (Figure 53–3). The amount of methane produced varies considerably among individuals. On the other hand, the gases that are responsible for the odor of flatus are present in very small, or trace, amounts. These include hydrogen sulfide, indole, and skatole.

CLINICAL CORRELATION A 30-year-old woman is out for dinner with friends when she notices a tingling sensation in her mouth and around her lips. Initially, she ignores the symptoms, but when her face starts to swell and she begins to feel light-headed, her friends take her to a nearby emergency room. On arrival,

she is found to be hypotensive, with a red, itchy rash and severe laryngeal edema that is starting to impair her breathing. The physician immediately administers epinephrine as well as an antihistamine, and the symptoms begin to subside. As she starts to recover, she tells the physician that as a child she was unable to eat peanuts but thought she had grown out of the problem; one of her friends then points out that one of the dishes she had tried contained ground peanuts in the sauce. The physician discharges her with a prescription for an epinephrine self-injector, and advice to make an appointment with an allergist for further testing and to carefully avoid ingesting peanuts in the future. In certain individuals, likely as a result of a genetic predisposition, the intestinal immune system inappropriately generates IgE antibodies to food proteins or other components of the diet, such as nucleic acids. These antibodies bind to mast cells that reside in the lamina propria, which are then

Major gases

H2 20%

CO2 10% N2 65%

CH4 3% O2 2%

Trace gases: Hydrogen sulfide Odorous Indole Skatole (3-methyl indole)

FIGURE 53–3

Composition of normal intestinal flatus.

(Reproduced with permission from Barrett KE: Gastrointestinal Physiology. New York: Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2006.)

CHAPTER 53 Intestinal Mucosal Immunology and Ecology

said to be “sensitized.” The sensitization process also results in upregulation of pathways that permit transfer of the offending protein across intestinal epithelial cells. The net result is that the next time the person eats the protein in question, it is transferred rapidly across the epithelium and cross-links IgE antibodies on the surface of mast cells, causing cell activation and release of a host of potent chemical mediators. These mediators can increase intestinal chloride secretion and alter motility, which can be observed clinically as diarrhea. Stimulation of enteric nerve endings by mast cell mediators may further amplify these responses. In a seriously allergic subject, the antigen may also gain access to the circulation from which it can trigger reactions in extraintestinal sites, such as the skin and airways, or cause the generalized allergic reaction throughout the body known as systemic anaphylaxis. Food allergies can be life-threatening. Certain foods are more commonly seen as triggers of allergic responses, perhaps reflecting the relative stability of component proteins during the digestive process. Such foods include peanuts, eggs, certain fruits, and shellfish. Unless an individual is allergic to multiple foods, the best treatment for food allergy is to avoid the food in question, especially if very severe allergic reactions occur. However, it may not always be a simple matter to avoid a given food, particularly outside the home, and for this reason, those who are seriously affected by food allergies are usually advised to carry a self-injector containing epinephrine, which can counter serious symptoms.

CHAPTER SUMMARY ■

■ ■

■ ■

■

■

■ ■ ■

The mucosal immune system is uniquely specialized to protect the vast interface between the host and environment represented by the GI tract. Mucosal immune responses are shared among several mucosal sites beyond the intestine. The intestine can be considered to be “physiologically inflamed,” even in health, priming it to respond promptly to invaders. Secretory IgA provides important humoral protection against infections in the gut. Presentation of antigens via the oral route often leads to a response known as oral tolerance, where a local immune response exists in the face of systemic unresponsiveness. Oral tolerance may protect us from inappropriate reactions to food antigens. This response may also be exploited for therapeutic benefit in autoimmune diseases. The intestine maintains a lifelong, reciprocally beneficial relationship with a complex microflora that is predominantly contained in the colon. Colonic bacteria supply metabolic functions, especially fermentation, and contribute to intestinal gas production. Commensal bacteria may provide important protection against colonization by pathogens. Derangements in intestinal physiology occur when immune responses are inappropriately stimulated in the intestine, or when defenses fail to protect us from infection with pathogens.

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STUDY QUESTIONS 1. A scientist interested in gut ecology studies intestinal responses in germ-free mice. Compared with normally housed animals, what combination of findings would be expected in the colonic lumen?

sIgA

Secondary Bile Acids

Short-chain Fatty Acids

A)

Increased

Increased

Decreased

B)

Decreased

Decreased

Decreased

C)

Increased

Decreased

Increased

D)

Decreased

Increased

Increased

E)

Increased

Increased

Increased

2. A biotechnology company attempts to develop an oral vaccine for use in developing countries by expressing a viral protein in transgenic bananas. However, clinical trials reveal that consumption of the bananas fails to confer protective immunity against the viral infection. What immune response likely accounts for this failure? A) IgA secretion B) phagocytic uptake C) oral tolerance D) T-cell sensitization E) Toll-like receptor activation 3. In a diagnostic test conducted in a patient with suspected Giardia infection, fecal samples are screened for the presence of antibodies reactive with giardial antigens. Assuming such antibodies are found, what is their likely class? A) monomeric IgG B) monomeric IgA C) dimeric IgA D) monomeric IgM E) pentameric IgM 4. A patient with a severe lung infection is treated with a broadspectrum antibiotic. Shortly after beginning this treatment, she develops severe diarrhea. Stool samples are most likely to reveal evidence of overgrowth with which of the following organisms? A) Shigella dysenteriae B) Vibrio cholerae C) Lactobacillus acidophilus D) Campylobacter jejuni E) C. difficile 5. A scientist working to develop a new diagnostic test administers a solution of lactulose (a disaccharide that is not digested by host enzymes, but can be broken down by bacterial enzymes) orally to a group of volunteers as well as to a patient with symptoms of malabsorption. She then measures the concentration of hydrogen in expired breath from each group. Hydrogen is present in negligible amounts in both groups prior to lactulose administration, and increases in the control group only after a 1–2-hour lag period. However, in the patient, breath hydrogen levels begin to rise almost immediately. What is the most likely cause of this more rapid appearance? A) celiac disease B) cystic fibrosis C) Crohn’s disease D) small bowel bacterial overgrowth E) H. pylori infection

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54 C

Intestinal Motility Kim E. Barrett

H A

P

T

E

R

O B J E C T I V E S ■ ■ ■

■ ■ ■

■ ■ ■

Understand how the motility functions of the esophagus, stomach, and intestines contribute to the integrated response to a meal. Describe the functional anatomy of the esophagus, stomach, intestines, and related structures, and their innervation. Understand the roles played by the oral cavity, pharyngeal structures, esophagus, and esophageal sphincters in transferring food from the mouth to the stomach during swallowing. Describe receptive relaxation and mixing/grinding patterns of motility and their regulation. Understand how the stomach is emptied, and how this is coordinated with the function of downstream segments. Define the motility patterns that characterize movements of the small and large intestines under fed and fasted conditions and their control mechanisms. Distinguish between mixing patterns and those that propel contents along the length of the intestine. Describe reflexes that coordinate the motility functions of the small intestine and colon with the function of the stomach. Understand the process whereby undigestible residues of the meal are eliminated from the body.

This chapter reviews the processes that move the meal along the length of the gastrointestinal tract and provide for its dispersion, as well as mixing with digestive secretions. Because there are segmental differences in the types and functions of the motility processes of the alimentary tract, we will consider in turn the motility of the esophagus, stomach, small intestine, and colon. Each segment has a specific role to play in handling the meal, but all depend on the properties of the smooth muscle layers that surround the mucosa. It may therefore be helpful to review the basic properties of smooth muscle as explained in Chapter 11.

Ch54_543-558.indd 543

BASIC PRINCIPLES OF ESOPHAGEAL MOTILITY ROLE AND SIGNIFICANCE The esophagus is a muscular tube that transfers food from the mouth to the stomach. Under normal circumstances, food resides in the esophagus for only a few seconds. The movements of the esophagus and related oral and pharyngeal structures must also be carefully regulated to avoid misdirection of

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SECTION VIII GI Physiology

Swallowing center

Glossopharyngeal + vagal afferents Pharynx

(S) Upper esophageal sphincter

(S)

Striated muscle

Outflow: • Somatic nerves (S) regulate striated muscle directly • Autonomic nerves (A) regulate smooth muscle via enteric nervous system or directly

(A) Smooth muscle

(A)

FIGURE 54–1

Functional anatomy and innervation of the esophagus. Note that the mode of innervation differs between the portions of the esophagus made up of smooth versus striated muscle. (Reproduced with permission from Barrett KE:

Lower esophageal sphincter

Gastrointestinal Physiology. New York: Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2006.)

Stomach

the food into the respiratory tract, or inspired air into the digestive system. At rest, the esophagus is a relaxed structure that is closed off at both ends by sphincters—the upper esophageal sphincter and lower esophageal sphincter (LES). These sphincters not only cooperate in the act of swallowing, or deglutition, but also prevent backflow of gastric contents into the esophageal lumen or oral cavity. However, under specific circumstances, the esophagus does allow for retrograde movement. This occurs normally for air swallowed with the meal, in the process of belching, or abnormally during vomiting. During retrograde movement in humans and most mammals, the esophagus itself is a passive conduit, that is, there are no specific motility functions that propel vomitus or air along the length of the tube. Swallowing can be initiated voluntarily, but thereafter reflects an automatic reflex that involves, sequentially, impulses from the brainstem, processing of this information through vagal centers in the central nervous system, direct effects of parasympathetic vagal efferents on esophageal muscle layers, and relay of information via the enteric nervous system (Figure 54–1). Movement of materials along the length of the esophagus is aided by gravity, but predominantly depends on a coordinated series of muscle contractions and relaxations that make up the propulsive motility pattern known as peristalsis.

in a circular fashion and the outer oriented longitudinally. However, unlike the exclusive occurrence of smooth muscle in all more distal segments of the gastrointestinal tract, the esophagus contains striated (or skeletal) muscle in its upper third, both striated and smooth muscle in its middle third, and exclusively smooth muscle in its most distal third. The distinction between muscle types also corresponds approximately to different types of neural control, as discussed later. Other structures associated with the esophagus are important in swallowing and normal esophageal function. We have already mentioned the upper esophageal sphincter and LES, which occlude both ends of the esophagus at rest. The esophagus is situated within the low-pressure thorax, and thus the presence of these sphincters is important to prevent the entry of air and gastric contents. The pharynx, which connects the nose and mouth to both the esophagus and trachea, is also critically involved in swallowing. It segregates food and air as they pass through this region.

FUNCTIONAL ANATOMY OF THE ESOPHAGEAL MUSCULATURE MUSCLE LAYERS The esophagus is 18–25-cm long in adult humans. Like the remainder of the gastrointestinal tract, it is surrounded by two muscle layers: the innermost (i.e., closest to the lumen) oriented

INNERVATION The function of the pharynx is controlled by the central nervous system, via outflow from a region known as the central swallowing center (Figure 54–1). The pharynx thereby permits complex coordination of voluntary swallowing with functions such as respiration and speech. Central input also controls the contractile function of the upper one third of the esophagus. The somatic nerves that innervate these structures have motor end plates that terminate directly on the striated muscle fibers. They originate in brain regions of the medulla known as the nucleus retrofacialis and the nucleus ambiguus and release acetylcholine (ACh), which acts via nicotinic receptors.

CHAPTER 54 Intestinal Motility The smooth muscle of the esophagus is innervated predominantly by the vagus nerve. The vagal efferents synapse with myenteric neurons via ACh and with the smooth muscle directly via ACh and substance P. Sensory afferents located in the esophagus likewise project via the vagus to the brain region of the medulla known as the nucleus tractus solitarius in the dorsal vagal complex. Cell bodies in this region also project to the motor neurons in the nucleus ambiguus, which control a pattern generator for the oral and pharyngeal components of swallowing. This neural circuitry ensures that control of the muscle groups involved in deglutition is linked to the function of more distal regions of the esophagus, as well as to the regulation of opening of the LES. The esophagus is also richly supplied with enteric neurons. These clearly contribute to both sensing the presence and nature of esophageal contents and coordinating local reflexes that supplement central control of swallowing and esophageal peristalsis. This network of enteric neurons can produce secondary peristalsis of the smooth muscle portion of the esophagus even in the absence of vagal input.

FEATURES OF ESOPHAGEAL MOTILITY The motility functions consist of sequential movement of food from the mouth into the esophagus itself, propulsion along the length of the esophagus via peristalsis, and relaxation of the LES to permit entry of the food bolus into the stomach. In health, these components of deglutition are tightly integrated, but for simplicity we will consider each in turn here.

SWALLOWING Although the term swallowing can refer to the entire process required to move food from the mouth to stomach, here we will consider it to include only those motility events that move the bolus beyond the upper esophageal sphincter, as well as their regulatory controls. As noted earlier, swallowing is initiated when we sense that food particles in the mouth have been reduced in size sufficiently to permit their passage into the esophagus. While we consider this to be a voluntary response, during its course it in fact becomes an involuntary reflex involving significant input from a pattern recognition center in the brainstem. This recognizes a food bolus as suitable for swallowing and generates the required neuromuscular response. However, it is possible to override this recognition system voluntarily, such as in the case of swallowing a pill or capsule. But in either case, the subsequent events that contribute to swallowing are entirely involuntary. First, the tongue shapes and lubricates the bolus and moves it backward in the mouth. Subsequently, a rapid series of pharyngeal effects occur, initiated by mucosal mechanoreceptors in the pharynx that activate afferent nerves traveling via the glossopharyngeal nerve to the swallowing center. In turn, efferent motor nerves run through the vagi to control the

545

contractile state of the pharyngeal muscles. These events occur almost simultaneously, which is in contrast to the slower motility changes that occur more distally in the esophagus, as will be discussed later. First, the larynx and soft palate move upwards, closing off the airway and nasopharynx, respectively. Next, contraction of several muscles in the anterior portion of the pharynx causes forward displacement of the larynx and pharynx as well as helping to open the upper esophageal sphincter. Sphincter opening also depends on relaxation of the encircling cricopharyngeal muscle. This is accomplished by a suppression of impulses normally occurring to this region, coordinated by the swallowing center via the nucleus ambiguus. Longitudinal contractions of the pharynx also bring the upper esophageal sphincter close to the base of the tongue, whereupon a pressure gradient developed by the tongue and pharyngeal muscles serves to force the bolus through the sphincter. Finally, the posterior wall of the pharynx contracts in a transverse fashion to clear the area of any remaining food residues. These transverse contractions are propagated aborally (i.e., away from the mouth) and can be considered the harbinger of the peristaltic wave that later will carry the bolus through the esophagus and down into the stomach. The sequence of events involved in normal swallowing is shown diagrammatically in Figure 54–2.

PERISTALSIS Once the bolus has moved through the upper esophageal sphincter into the esophageal lumen, it is moved along the length of the tube via peristalsis (Figure 54–3). The sequencing and thus the direction of this propulsive process appears to be hardwired, with contraction of more distal segments occurring at longer latencies following the swallow than in those close to the pharynx. The striated muscle region contracts within 1–2 seconds after the swallow, the middle third of the esophagus within 3–5 seconds, and the lower third within 5–8 seconds. This means that the ability of the body to transfer food from the mouth to stomach is largely independent of body orientation—one can swallow food while hanging upside down. Nevertheless, gravity influences transit rate, particularly for liquids. The peristaltic wave requires up to 10 seconds, on average, to sweep solid esophageal contents along its length. This relatively slow transfer should be contrasted with the rapid events of swallowing itself. Peristalsis in the esophagus is stimulated by its distension. Mechanoreceptors on sensory afferents transmit impulses to the dorsal vagal complex, which in turn activates somatic and vagal efferents that terminate either directly on the striated muscle in the upper third of the esophagus or onto nerves of the enteric nervous system, respectively. The latter activate enteric nerves capable of releasing ACh (to induce contraction) above the location of bolus-induced distension, or nitric oxide (to induce relaxation) below the bolus (Figure 54–4). The net effect of the sequential contractions and relaxations is to move the bolus aborally. The primary wave of peristalsis along the length of the esophagus may also be followed by a

546

SECTION VIII GI Physiology

Hard palate

Soft palate

Pharynx

Food

Tongue

Epiglottis

Glottis Trachea

Esophagus

Upper esophageal sphincter

(a)

(b)

(c)

(d)

FIGURE 54–2 Movement of food through the pharynx and upper esophagus during swallowing. a) The tongue pushes the food bolus to the back of the mouth. b) The soft palate elevates to prevent food from entering the nasal passages. c) The epiglottis covers the glottis to prevent food from entering the trachea, and the upper esophageal sphincter relaxes. d) Food descends into the esophagus. (Reproduced with permission from Widmaier EP, Raff H, Strang KT: Vander’s Human Physiology, 11th ed. McGraw-Hill, 2008.)

secondary wave restricted to the smooth muscle portion (Figure 54–5). Secondary peristalsis may clear a bolus that was not wholly expelled from the esophagus during the primary wave, or remove any gastric contents that reflux back

Swallow Pharynx

50 mm Hg 0

Upper esophageal sphincter

50 mm Hg 0

Striated muscle esophagus

into the lower esophagus. The response is triggered by distension, and involves both local reflexes within the enteric nervous system and vagovagal reflexes (Figure 54–6). Studies suggest that the presence of acid alone within the distal esophagus, in the absence of significant distension, may also be sufficient to generate a secondary peristaltic response. The esophagus also transmits information about its contents back to more proximal segments. Thus, the presence of water or, more potently, acid in the esophagus can be shown to increase the pressure of the upper esophageal sphincter. This response depends, at least in part, on vagovagal signaling. On

50 mm Hg 0

Dorsal vagal complex

50 mm Hg 0 Smooth muscle esophagus

Lower esophageal sphincter

Vagal efferents Vagal afferent Myenteric nerves

50 mm Hg 0

50 mm Hg 0

NO ACh

Bolus

5 sec

FIGURE 54–3

Orad contraction

Caudad distension

Primary peristalsis triggered by swallowing in the esophagus. Note that the pressure wave that moves down the esophagus is coordinated with opening of the lower esophageal sphincter. (Adapted with permission from Biancani P. et al: Esophageal motor function.

FIGURE 54–4 Control of peristalsis by vagovagal reflexes in the lower esophagus. ACh, acetylcholine; NO, nitric oxide.

In: Textbook of Gastroenterology, 4th ed. Yamada T, Alpers DH, Kaplowitz N, Laine L,

(Reproduced with permission from Barrett KE: Gastrointestinal Physiology. New York:

Owyang C, Powell DW (editors). Philadelphia: Lippincott Williams and Wilkins, 2003.)

Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2006.)

CHAPTER 54 Intestinal Motility

LES RELAXATION

Balloon inflated Pharynx

50 mm Hg 0

Upper esophageal sphincter

50 mm Hg 0 50 mm Hg 0

Striated muscle esophagus

50 mm Hg 0 50 mm Hg 0

Smooth muscle esophagus

50 mm Hg 0 Lower esophageal sphincter

50 mm Hg 0

5 sec

FIGURE 54–5 Secondary peristalsis triggered by distention in the smooth muscle portion of the esophagus. Contraction orad to the bolus is followed by a descending pressure wave that is coordinated with lower esophageal sphincter opening. (Adapted with permission from Biancani P. et al: Esophageal motor function. In: Textbook of Gastroenterology, 4th ed. Yamada T, Alpers DH, Kaplowitz N, Laine L, Owyang C, Powell DW (editors). Philadelphia: Lippincott Williams and Wilkins, 2003.)

the other hand, if air is present in the esophagus, it induces opening of the upper esophageal sphincter, which is critical to belching, or the retrograde movement of air that is swallowed along with food.

ROLE AND SIGNIFICANCE

Sensory neuron Myenteric plexus Excitatory motor neuron ACh

NO/VIP

Contraction of circular muscle

Relaxation of circular muscle

Distension low pH

CAUDAD

FIGURE 54–6 Control of peristalsis by the enteric nervous system. Peristalsis can be triggered when a sensory nerve detects distension or luminal acidity. Interneurons convey the signal to excitatory and inhibitory nerves above and below the site of stimulation, respectively. ACh, acetylcholine; NO, nitric oxide; VIP, vasoactive intestinal polypeptide. (Reproduced with permission from Barrett P. KE: Gastrointestinal Physiology. New York: Lange Medical Books/ McGraw-Hill, Medical Pub. Division, 2006.)

The final component of esophageal motility is relaxation of the LES, allowing the bolus to move into the stomach. Under resting conditions, the LES is tonically contracted. There is evidence to suggest that this tonic contraction is accounted for by a mechanism referred to as myogenic—that is, the contractile state of the muscle is independent of neural input, and increases intrinsically as it is stretched. Moreover, the tone of the sphincter can also be increased by neurohumoral agents released in concert with ingestion of a meal, including ACh and gastrin. The basal tone of the sphincter is critical to protect the lower portion of the esophagus from the corrosive effect of the gastric contents. When a food bolus is swallowed, relaxation of the LES is closely coordinated with the preceding motility events, such that it occurs just as the peristaltic wave reaches the end of the esophagus (Figures 54–3 and 54–5). The careful integration of peristalsis and sphincter relaxation is brought about by the combined activity of the vagus nerve and enteric nervous system, and is mediated by the release of nitric oxide from inhibitory nerves whose cell bodies lie in the myenteric plexus. Vasoactive intestinal polypeptide (VIP) within these nerves may also contribute to LES relaxation. In general, the contractile state of the LES at any given moment can be considered to reflect a summation of both positive and negative inputs. Even in healthy individuals, the LES relaxes transiently from time to time independent of either swallowing or secondary peristalsis. Such relaxations may be required to facilitate belching of swallowed air. However, in individuals with reflux disease, these transient relaxations occur more frequently and allow reflux of the gastric contents into the distal esophagus.

BASIC PRINCIPLES OF GASTRIC MOTILITY

Interneurons

ORAD

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As we have learned from previous chapters, the stomach is a segment of the gastrointestinal tract in which important aspects of digestion and secretory function are initiated. However, in addition to these functions, which are largely dependent on gastric secretion, the stomach also plays critical roles that depend on its motility properties. First, the stomach can be considered as a homogenizer, mechanically breaking down ingested food into an emulsion of small particles with a vastly increased total surface area, thereby amplifying the effects of digestion. Second, the stomach matches food delivery to the digestive and absorptive capacity of more distal segments of the gut. Under normal circumstances, the stomach allows the delivery of approximately 200 kcal/h into the small intestine. To accomplish its reservoir function, the stomach exhibits remarkable pressure/volume characteristics, which accommodate the volume of the meal without allowing significant reflux of the gastric contents back into the esophagus,

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SECTION VIII GI Physiology

or forcing them prematurely into the duodenum. Distention of the stomach also delivers important information to downstream segments of the gastrointestinal tract, as well as contributing to the signaling of satiety. Finally, the stomach possesses distinct motility functions during the fasted state. The migrating motor complex (MMC), a “housekeeping” motility pattern, sweeps undigested materials or ingested foreign objects along the length of the entire gastrointestinal tract, beginning at the stomach.

FUNCTIONAL ANATOMY OF THE GASTRIC MUSCULATURE The stomach is a highly distensible muscular sac with the largest caliber of any intestinal segment. It can be divided into two functional regions for considerations of motility (Figure 54–7). The proximal stomach, consisting of the cardia, fundus, and proximal portion of the body (corpus) of the stomach, serves primarily as a reservoir and to move gastric contents to the distal stomach. Tonic contractions of the proximal stomach are additionally important in gastric emptying. The distal stomach, on the other hand, consisting of the distal portion of the body and the antrum, serves predominantly to grind and pulverize the meal. Finally, the pylorus acts as a sphincter that controls the amount and size of food particles that can exit the stomach in the fed state. Conversely, full relaxation of the pylorus is critical during the housekeeping MMC.

MUSCLE LAYERS As elsewhere in the gastrointestinal tract, the muscle layers of the stomach consist of a circular layer of smooth muscle

arranged circumferentially, and closer to the lumen, and a longitudinal layer that is oriented along the length of the organ. However, because the stomach is shaped as a sac rather than a simple tube, these different muscle layers may assume greater or lesser importance in the different functional regions of the stomach, likely also important for specific motility patterns. Thus, circular muscle is prominent throughout the stomach, although it is notable that it is largely electrically isolated from the circular muscle in the small intestine because of the presence of a connective tissue septum at the level of the pylorus. On the other hand, longitudinal muscle is more prominent in the distal stomach, and these muscle fibers are mostly continuous with those of the duodenum. There is also a small region of obliquely oriented muscle fibers in the lesser curvature of the stomach that is continuous with the gastroesophageal junction, and restricted to the cardia. Finally, the pylorus represents a specialized region of circular muscle at the point where the caliber of the gastric lumen is sharply reduced prior to entry into the duodenum; it serves as a mechanical barrier to food exit that is also enhanced by a folded, redundant mucosa. The smooth muscle cells of the different functional regions of the stomach also display distinctive contractile properties. Most important for our discussion is the distinction between phasic and tonic contractions. Some smooth muscles contract and then relax in a matter of seconds, known as phasic contractions, which are prominent in the distal stomach. Tonic contractions, on the other hand, are sustained contractions that are prominent in the proximal stomach, and may persist for many minutes. Each type of contraction is important in mediating the specific motility properties that are needed for the function of each region of the stomach.

INNERVATION Lower esophageal sphincter

Fundus Reservoir (Tonic contractions) Body

Pacemaker region

Antrum

Pylorus

Antral pump (Phasic contractions)

FIGURE 54–7 Regions of the stomach involved in motility responses, and location of the gastric pacemaker. (Reproduced with permission from Barrett KE: Gastrointestinal Physiology. New York: Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2006.)

The stomach is richly endowed with both intrinsic and extrinsic neural inputs. The major extrinsic pathways are parasympathetic and contained within the vagus nerve. Most vagal efferents that terminate in the stomach are stimulatory, cholinergic nerves although a few nerves with high thresholds for activation are inhibitory, releasing VIP and nitric oxide as their major neurotransmitters. Mechanosensitive and chemosensitive vagal afferents are also critical for the control of motility functions. These activate sites in the nucleus tractus solitarius of the dorsal motor nucleus in the brain. In a more limited fashion, sympathetic innervation arrives at the stomach by way of the splanchnic nerve, and these nerves release noepinephrine as a postganglionic inhibitory neurotransmitter at the level of enteric ganglia. The physiological role of sympathetic innervation to the stomach is relatively unclear, but presumed to be minor compared with vagal influences. On the other hand, sympathetic influences may contribute to a decrease in gastric motility during times of threat. Intrinsic innervation via the enteric nervous system is also critically important to the full expression of gastric motility

CHAPTER 54 Intestinal Motility responses. Indeed, many of the stereotypical motility responses of the stomach are largely, if not wholly, independent of central input. Myenteric neurons of the stomach also provide for coordination of gastric motility functions with those of the more distal segments of the gut, particularly during fasting periods. These nerves also communicate with the pacemaker cells of the intestine, known as interstitial cells of Cajal, located within the circular muscle layers of the stomach and proximal gut. This communication establishes the maximal rate at which contractions of the tissue can occur if an additional excitatory signal is also received, which is known as the basal electrical rhythm (BER).

549

whereas the duodenum has a BER of 12 cpm. This presumably reflects the presence of dominant and separate pacemakers in each distinct segment, which then relay electrical information throughout the segment that they control via the remaining network of interstitial cells of Cajal.

RECEPTIVE RELAXATION The ability of the stomach to relax as its volume increases is essential to its reservoir function. The process—receptive relaxation—results in a drop in gastric pressure immediately after eating that persists until all solids have been emptied from the stomach. The process involves vagal input coincident with food intake, vagovagal reflexes, and intrinsic reflexes mediated wholly within the wall of the stomach (Figure 54–9). Vagovagal and intrinsic reflexes are triggered by the activation of mechanosensitive nerve endings within the stomach wall. In turn, ACh released by vagal pathways acts presynaptically to release additional neurotransmitters that actively relax the gastric smooth muscle layers, particularly in the proximal part of the stomach. Both VIP and nitric oxide have been implicated in this response. Gastric tone may also be affected by feedback signals coming from more distal segments of the gastrointestinal tract. For example, distension of the duodenum or colon, or an increase of fat or protein in the duodenum or ileum, results in a decrease in the tone of the gastric fundus. In this way, gastric emptying is retarded until the duodenum is able to process additional nutrients. The response involves reflexes of the enteric nervous system, as well as CCK by binding to CCK-A receptors expressed on vagal sensory afferents. Gastric distension, conversely, signals forward to more distal segments to ready them for the arrival of the meal. Probably the best known of these reflexes is the gastrocolic reflex, which may induce the need to defecate shortly after ingesting a meal.

FEATURES OF GASTRIC MOTILITY BASAL ELECTRICAL RHYTHM The BER refers to waves of rhythmic depolarization of intestinal smooth muscle cells, which originate at a specific point and then are propagated along the length of the gastrointestinal tract. The pacemaker potentials originating in this region determine the contractile parameters of the stomach as a whole—namely, the maximal frequency of contractions, their propagation velocity, and the direction in which they propagate. For the stomach, the waves appear to begin at a point in the body along the greater curvature of the stomach, and then sweep across the stomach toward the pylorus (Figure 54–7). It should also be emphasized that the BER represents only the maximal rate of contraction of the stomach or indeed of any other segment of the gastrointestinal tract. The waves of depolarization that occur in response to the pacemaker activity of the network of interstitial cells of Cajal are not of sufficient magnitude to initiate action potentials in the smooth muscle. Rather, it is only when the release of stimulatory neurotransmitters from enteric nerve endings is superimposed on these waves of depolarization that an action potential may occur, leading in turn to contraction of the smooth muscle (Figure 54–8). Various patterns of motility can thus be accomplished depending on whether the stomach is filled with a meal, or is in the fasted state. The BER differs in the various intestinal segments. For example, in the stomach the BER is approximately 3 cycles/min (cpm),

MIXING AND GRINDING The primary motility pattern of the distal portion of the stomach during the fed state consists of rapid phasic contractions that occur circumferentially, and which can even

Stimulated 0

Resting BER

Membrane potential (mV) −70 5 Tension (g)

20 s

FIGURE 54–8 Basal electrical rhythm established by the gastric pacemaker. Note that waves of depolarization initiated by the pacemaker are insufficient to trigger contractions unless these are superimposed with a contractile stimulus. (Modified with permission from Barrett KE: Gastrointestinal Physiology. New York: Lange Medical Books/McGraw-Hill, Medical

0

Pub. Division, 2006.)

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SECTION VIII GI Physiology occlude the lumen (Figure 54–10). The contractions proceed from the gastric pacemaker region and move toward the pylorus in a peristaltic pattern. As these waves of contraction begin, they force the gastric contents toward the outlet of the stomach. However, as the velocity of the peristaltic wave increases, it overtakes all but the smallest particles in the gastric lumen, and thus the majority of the meal is forced backwards (retropulsion), mixing the gastric contents with the gastric juice and mechanically reducing the size of the food particles.

DVC

Vago-vagal reflex NO VIP

VIP NO Relaxation

GASTRIC EMPTYING AND THE ROLE OF THE PYLORUS ACh

St re

tc h

When the stomach is filled with a meal, the pylorus remains closed for prolonged periods with only intermittent openings that allow small food particles (less than 1–2 mm) to enter the duodenum. The pylorus is regulated by both inhibitory and excitatory vagal pathways as well as ascending and descending intrinsic reflexes, and its function is clearly regulated independently of contractions of the gut segments on either side. Nitric oxide has been identified as a key mediator of pyloric relaxation, arising from both vagal and intrinsic pathways, whereas opioids released from vagal efferents and CCK have been implicated in contractions. The presence of nutrients, hypertonicity, or acid in the duodenum also causes the pylorus to close, with ACh and 5-hydroxytryptamine identified as mediators. Emptying of the stomach involves both tonic contractions of the proximal region and phasic distal contractions. Extrinsic innervation, working together with the enteric nervous system, is vital for normal emptying, with 5-hydroxytryptamine

Stretch Fat Protein CCK

FIGURE 54–9 Intrinsic and vagovagal reflexes involved in receptive relaxation of the stomach. The figure indicates that signals triggered by nutrients in the duodenal lumen, or duodenal distension, also result in relaxation of the gastric fundus. ACh, acetylcholine; NO, nitric oxide; VIP, vasoactive intestinal polypeptide; CCK, cholecystokinin; DVC, dorsal vagal complex. (Reproduced with permission from Barrett KE: Gastrointestinal Physiology. New York: Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2006.)

1

FIGURE 54–10 Gastric motility patterns contributing to mixing, grinding, and sieving of gastric contents. 1) A circumferential contraction, A, sweeps toward the pylorus resulting in anterograde and retrograde propulsion of material. 2) As contraction A subsides, a second contraction, B, mixes contents further. 3) Contraction B is sufficient to cause transient and partial opening of the pylorus, allowing particles smaller than 1 mm to exit the stomach. Larger particles are propelled back into the stomach to be further dispersed by contraction C. 4) Further cycles of contraction against a closed pylorus continue mixing and grinding until all of the meal is emptied from the stomach. (Reproduced with permission from Barrett KE: Gastrointestinal Physiology. New York: Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2006.)

2

Gastric contents

Pylorus

Pylorus Gastric contents

Contraction B Contraction A

Contraction A

Pylorus

3

4 Pylorus Contraction C

Contraction D

Contraction B Contraction C

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Some aspects of neurohumoral control of the MMC are understood. For example, the onset of phase III activity is independent of either parasympathetic or sympathetic input, but rather is correlated with levels of plasma motilin (Figure 54–11). However, the trigger for cyclical release of this hormone from the duodenal mucosa is not known, other than the fact that release is suppressed by feeding. Nevertheless, it enhances propulsive motility via both direct and indirect actions, the latter involving the release of ACh, 5-hydroxytryptamine, and nitric oxide. Moreover, while phase III can occur in the absence of vagal input, impulses from the vagus can amplify the response. Similarly, phase II of the MMC is abolished by vagotomy. The MMC is also reduced during sleep, and slowed by stress.

GASTRIC MOTILITY DURING FASTING

VOMITING

In the period in between meals, the stomach, in common with more distal segments of the gastrointestinal tract, undergoes the stereotypical pattern of motility known as the MMC. In the absence of feeding, cycles of motility lasting approximately 100 minutes, and consisting of three phases, begin in the stomach and are propagated aborally (Figure 54–11). Phase I is characterized by quiescence. During phase II, contractile activity increases, but with irregular contractions that fail to propel luminal contents. Finally, phase III involves a 5–10-minute period of intense, luminally occlusive contractions that sweep from the body of the stomach to the pylorus, and from there move into the duodenum. During this time, the pylorus opens fully in normal subjects, allowing any indigestible residues to be cleared. This housekeeping function is important for intestinal health, since in its absence, large quantities of indigestible materials called bezoars may accumulate and even obstruct the lumen, particularly in the stomach.

Vomiting primarily results in evacuation of the gastric contents, and reflects the coordinated interaction of neural, humoral, and muscular phenomena. Vomiting may be prompted by both central and peripheral triggers (Figure 54–12), but pivotally requires the involvement of central brain regions to coordinate the responses required. A chemoreceptor trigger zone, located in the area postrema of the medulla, receives input from cortical, oral, vestibular, and peripheral afferents. In addition, the blood/brain barrier in this region is relatively leaky. This means that the chemoreceptor trigger zone can sample chemical constituents of both the blood and cerebrospinal fluid. Various stimuli can lead to both nausea (the sensation that vomiting is imminent) and actual vomiting, such as endocrine changes in pregnancy, noxious odors, visual stimuli, somatic pain, or unpleasant tastes. Peripheral afferents can also trigger a vomiting response, such as when irritants are present in the gastric lumen, or if the intestine is obstructed. Some vagal afferents originating in the

800 Feeding 600 400 200

0 Gut motor pattern

Plasma motilin concentration, pg/ml

being identified as a key mediator. 5HT1 receptors have been implicated in delaying gastric emptying while 5HT3 receptors increase it. CCK also delays gastric emptying. The rate of gastric emptying also depends on both the physical state of the contents and their chemical characteristics. Inert liquids empty most rapidly. If the liquid contains nutrients, a rapid initial phase is followed by slowed exit, apparently reflecting feedback from the small intestine. The rate of emptying also depends on the caloric density and osmolarity of the contents. Emptying of solids from the stomach is slower yet, with a halftime of approximately 1–2 hours. Moreover, emptying of solids from the stomach does not begin immediately, but occurs only after a lag phase of up to 1 hour during which retropulsion and mixing take place.

Gastric antrum Upper jejunum Mid-intestine

FIGURE 54–11 The migrating motor complex as assessed in a dog, followed by the motility pattern in the fed state. Each antral phase III complex is accompanied by an increase in plasma motilin, whereas motilin release is suppressed after feeding. (Adapted from Itoh Z, et al. Changes in plasma motilin concentration and gastrointestinal contractile activity in conscious dogs.

Time intervals, 1 hr

Am J Dig Dis. 1978;23(10):929–935.)

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Pharyngeal stimulation

Programmed vomiting response

Glossopharyngeal nerve

Higher centers

Brain stem vomiting center

Nucleus tractus solitarius

Vagus nerve

Neural pathways leading to the initiation of vomiting in response to various stimuli. (Reproduced with

McGraw-Hill Medical, 2009.)

Cerebellum

Drugs eg, opiates, chemotherapy

FIGURE 54–12

Brooks H: Ganong’s Review of Medical Physiology, 23rd ed.

Area postrema chemoreceptor trigger zone

Labyrinth

Gastric mucosa

permission from Barrett KE, Barman SM, Boitano S,

Pain Sights Anticipation

Hormones eg, pregnancy

Motion Vertigo

Ipecac Cytotoxic drugs Irritants

stomach, and presumably linked to chemoreceptors, project to the area postrema. A second brain region, the nucleus tractus solitarius, also contributes to the emetic cascade, particularly following vagal activation (Figure 54–12). This region receives inputs from the area postrema, abdominal vagus, and labyrinths, and in turn coordinates the motor responses required, which are a stereotypical program of somatic muscle actions. First, the thoracic, diaphragmatic, and abdominal muscles contract concurrently against a closed glottis, resulting in the phenomenon of retching. The high positive intra-abdominal pressure also forces the gastric contents into the esophagus. The brain then coordinates the synchronous contraction of inspiratory and expiratory muscles, resulting in a reversal of the thoracic pressure gradient. This high positive thoracic pressure acts in turn to drive expulsion of the vomitus. Simultaneously, respiration is suppressed, and movement of laryngeal and pharyngeal structures prevents aspiration and, usually, passage of vomitus into the nasal cavity. Intestinal motility is also regulated during vomiting. The BER is suspended and replaced by bursts of electrical activity that propagate orally. These result in a motility pattern referred to as a retrograde giant contraction, or the retroperistaltic contractile complex, that moves the gastric contents up and out of the esophagus. Despite the autonomy of the enteric nervous system in producing normal patterns of gastric and esophageal motility, the retrograde propulsion seen during emesis is

entirely dependent on input from extrinsic nerves, coordinated by the brain centers that also regulate the functions of somatic muscles that support vomiting, as described earlier.

BASIC PRINCIPLES OF INTESTINAL MOTILITY ROLE AND SIGNIFICANCE IN THE SMALL INTESTINE The primary role of the small intestine is to digest the various components of the meal and to absorb the resulting nutrients into the bloodstream or lymphatic system. The motility patterns observed in the small intestine are profoundly altered by eating, with the duration of such changes depending on the caloric load. During the fed state, the motility patterns in the small intestine are not designed primarily to propel the intestinal contents aborally, but rather to mix them with digestive secretions and prolong their exposure to the absorptive epithelium. The speed with which the contents are propelled also varies along the length of the small intestine. Movement is fastest in the duodenum and jejunum, providing for rapid mixing and propulsion of the contents both orally and aborally. Motility then slows in the ileum, providing additional time for the absorption of slowly

CHAPTER 54 Intestinal Motility permeable nutrients, and particularly, lipids. Then, once the meal is digested and absorbed, the small intestine converts to the MMC to expel undigested residues through the small intestine and into the colon.

ROLE AND SIGNIFICANCE IN THE COLON The functions of the colon are quite distinct from those of the small intestine, serving primarily to extract and reclaim water from the intestinal contents, and process the feces for elimination. As a result, even in the fasted state, the motility functions of the colon are considerably more biased toward mixing the contents and retaining them for prolonged periods, and the colon does not participate in the MMC. On the other hand, periodically, large propulsive contractions sweep through the colon, transferring its contents to the rectum and ultimately promoting the urge to defecate.

FUNCTIONAL ANATOMY MUSCLE LAYERS The layer of circular muscle found closest to the mucosa, overlaid by a longitudinal muscle layer, produces the stereotypical motility patterns of the small intestine. A thin layer of muscle sandwiched between the mucosa and submucosa, the muscularis mucosa, also confers specific motility functions on mucosal structures, such as the villi. The functions of the circular and longitudinal muscle layers are closely integrated by electrical coupling through gap

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junctions, and by the activity of interstitial cells of Cajal. These latter pacemaker cells undergo rhythmic cycles of depolarization, and dictate the BER, or slow waves, that ultimately control the rate and locations of phasic contractions of the smooth muscle. The large intestine also contains both circular and longitudinal muscle layers that regulate its motility, but the anatomic arrangement of these differs somewhat from that seen in the small intestine. In the ascending, transverse, and descending colon, the circular muscle layer is overlaid by three long nonoverlapping bands of longitudinal muscle oriented at 120° to each other, known as the taenia coli. Electrical coupling between the circular muscle and taenia coli is less effective than that between the corresponding muscle layers in the small intestine, which likely contributes to less effective propulsive motility in the colon. The circular muscle layer is also contracted intermittently to divide the colon into functional segments known as haustra. Note that the haustral segments are not permanent structures, however, and thus they can be smoothed out to permit propulsion of the colonic contents. In the sigmoid colon and rectum, the intestine becomes completely enveloped by longitudinal muscle that is important to the specialized functions of this region, which include serving as a reservoir and participating in defecation. The lumen of the rectum is also partially occluded by transverse folds, again formed by muscular contraction, which act as shelves to retard the passage of fecal material (Figure 54–13). Finally, the most distal portion of the gastrointestinal tract, the anal canal, is a specialized region that contains both smooth and striated muscles in its walls.

Sigmoid colon

Rectosigmoid junction

Rectum

Rectal valves

Muscle layers making up internal and external anal sphincters

Internal anal sphincter External anal sphincter

FIGURE 54–13 Anatomy of the rectum and anal canal. (Reproduced with permission from Barrett KE: Gastrointestinal Physiology. New York: Lange Medical Books/

Anal canal

McGraw-Hill, Medical Pub. Division, 2006.)

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ENTERIC NERVOUS SYSTEM The primary determinant of motility function in both the small and large intestines derives from the activity of intrinsic neural circuits. The number of intrinsic nerves vastly exceeds that of extrinsic inputs, and the role of the latter is normally felt to be restricted largely to modulating motility patterns established by the “little brain” of the enteric nervous system. Enteric nerves are responsible for both contraction and relaxation. The major stimulatory neurotransmitters include ACh, neurokinin A, and substance P, whereas the inhibitory nerves express VIP and also produce nitric oxide on activation. There is also an abundant supply of sensory afferents that respond to the physicochemical characteristics of the luminal contents. Modulatory influences of extrinsic nerves derive from a variety of sources depending on the intestinal segment in question. The vagus (parasympathetic) and splanchnic (sympathetic) nerves innervate the small intestine, ileocecal valve, and proximal colon. The pelvic nerves, on the other hand, are the conduits of extrinsic input to the remainder of the colon and the internal anal sphincter. Finally, the pudendal nerves provide input from the sacral region of the spinal cord to the external anal sphincter and the muscle layers of the pelvic floor. In fact, unlike the other gastrointestinal regions discussed earlier, voluntary input to these latter structures is vital to their function. The ability to contract the external anal sphincter and pelvic floor muscles, a behavior learned during toilet training, allows the deferral of defecation until a time when it is socially convenient.

SPHINCTERS The passage of contents along the length of the small intestine and colon is also regulated by sphincters. The ileocecal valve, or junction, reflects activity of the circular muscle layer. The primary function of the ileocecal valve is to limit reflux of colonic contents into the ileum. The elimination of waste matter from the colon is under the control of the internal and external anal sphincters. The internal anal sphincter consists of a thickened band of gastrointestinal circular muscle (Figure 54–13). This sphincter supplies approximately 70–80% of the tone of the anal canal at rest, and its regulation is entirely autonomous. If the rectum is suddenly distended, the sphincter relaxes and then contributes only 40% of anal tone, with the remainder supplied by the external anal sphincter (which is composed of striated muscle). At the same time, the external anal sphincter pressure is increased. This rectoanal inhibitory reflex, initiated by rectal distension, thus allows for efficient defecation while preventing accidental leakage. After a short period of time, however, the internal anal sphincter accommodates to the new rectal volume and regains its tone, unless defecation can conveniently be completed.

FEATURES OF INTESTINAL MOTILITY FED VERSUS FASTED PATTERNS OF MOTILITY For the small intestine, there is a marked distinction between motility observed in the postprandial versus fasting periods; however, colonic motility has far less temporal association with the ingestion of a meal. These differences are mirrored by the times taken for luminal contents to transit these two intestinal segments. In the small intestine, substances move from the mouth to the ileocecal valve in a little under 2 hours in healthy adults, on average, with transit occurring most rapidly proximally. Transit is slowed in proportion to the number of calories presented to the intestine. In the colon, on the other hand, transit from the cecum to the rectum may take 1–2 days on average, with considerable interindividual variability. During fasting, the small intestine exhibits the MMC. When the meal has emptied from the small intestine, the MMC resumes with its characteristic three phases (Figure 54–14). As in the stomach, the purpose of the MMC, and of phase III in particular, appears to be to sweep the intestine clear of any remaining residues of the meal. The MMC may additionally play a role in limiting reflux of colonic contents into the ileum since it does not propagate into the colon in humans. After a meal is ingested, motility events in the small intestine become more frequent. The fed pattern of motility rests on the BER, generated by the intestinal pacemaker and propagated to surrounding smooth muscle cells. As in the stomach, however, the basal rhythm supplies only the nodes at which contractions can occur at any given moment, because the rhythmic changes in membrane potential that are induced in

D1

D2

J1 J2 J3 30 min

FIGURE 54–14 Migrating motor complexes in the duodenum and jejunum as recorded from a fasting human subject by manometry. D1, D2, J1, J2, and J3 indicate recording points along the length of the duodenum and jejunum. Note that the intense contractions occurring rhythmically during phase III propagate aborally. (Reproduced with permission from Soffer EE et al: Prolonged ambulatory duodeno-jejunal manometry in humans: normal values and gender effect. Am J Gastroenterol 1998;93:1318–1323. Copyright American College of Gastroenterology.)

CHAPTER 54 Intestinal Motility the muscle cells are insufficient to cause contraction. Rather, it is only when the effects of neurotransmitters are superimposed on this rhythm that action potentials can take place. The result is a series of intermittent phasic contractions occurring along the length of the small intestine, peaking 10–20 minutes after eating. ACh from the enteric nervous system is a critical mediator of such effects, with any role for hormonal mediators much less clear.

MIXING AND SEGMENTATION During the fed state, the primary motility events serve to mix the contents, and to propel them slowly, if at all. An isolated contraction in the absence of others either proximal or distal to it will have the effect of mixing the contents of the lumen in the immediate vicinity of the contraction (Figure 54–15). Another common pattern is referred to as segmentation. Segmenting contractions serve to move intestinal contents back and forth within a short segment of bowel. The complex patterns of motility in the small intestine after a meal are the result of the almost autonomous effects of the enteric neural circuitry, and presumably reflect a stereotypical “programmed” response to a given set of physiological conditions.

PERISTALSIS Peristalsis produces aboral propulsion in both the small intestine and colon. It is a motility response that occurs in response to deformation of the mucosa, either via the mechanical effects

Isolated contraction

Segmentation

Peristalsis

Contraction Relaxation

FIGURE 54–15 Patterns of intestinal mixing and propulsion. An isolated contraction moves contents both orally and aborally. Segmentation mixes contents over a short length of intestine, as indicated by the time sequence from left to right. In the diagram on the left, the vertical arrows indicate the points at which the next set of contractions is initiated. Finally, peristalsis, which involves both a contraction and a relaxation, propels the luminal contents aborally. (Reproduced with permission from Barrett KE, Barman SM, Boitano S, Brooks H: Ganong’s Review of Medical Physiology, 23rd ed. McGraw-Hill Medical, 2009.)

555

of passage of the food bolus along the wall of the gut or secondary to intestinal distension. Rapid stretch of the intestine is most effective in triggering peristalsis. As in the esophagus, where peristalsis is important in moving the bolus from mouth to stomach, intestinal peristalsis involves the influences of both an ascending contraction and a descending relaxation (Figure 54–15). Activation of stretch and possibly other mechanoreceptors in the mucosa secondarily induce the release of 5-HT and calcitonin gene–related peptide. On the proximal side of the bolus, the circular muscle shortens and the longitudinal muscle relaxes, pushing the bolus forward. These responses have been attributed to the action of ACh and substance P from enteric nerve endings. On the distal side, the bolus is received by a segment of intestine of increased caliber, brought about by shortening of the longitudinal muscle and relaxation of the circular muscle. These responses relate to the activity of VIP and nitric oxide.

COLONIC MOTILITY The motility patterns of the colon are primarily concerned with mixing the contents and retaining them for a sufficient period to allow optimal salvage of the fluid utilized during the digestive process. The colon has the capacity to reabsorb even unusually large quantities of fluid, provided adequate contact time with the mucosa occurs. However, periodically the colon also engages in a propulsive motility pattern that essentially moves the majority of the colonic contents into the rectum. In turn, this induces the need to defecate, which will be dealt with later. During mixing, the colon shuttles contents back and forth between its haustra, and progressively propels contents from one haustra to the next in a motility pattern referred to as segmental propulsion. These patterns are accomplished by two types of contraction that have been characterized in the colon, short- and long-duration contractions. Short-duration contractions arise in the circular muscle, and are stationary pressure waves lasting approximately 8 seconds on average, which effect local mixing. Long-duration contractions, on the other hand, last for 20–60 seconds and may be stationary or may propagate for a short distance, and are attributed to contraction of the longitudinal muscles of the taenia coli. Propagating contractions account for segmental propulsion. High-amplitude propagating contractions are distinct from the motility patterns just described. They propagate exclusively aborally, and provide for mass movement of the feces over long distances. While they precede the urge to defecate, they in fact occur about 10 times per day, and are associated with rising in the morning and with eating. These contractions originate in the cecum and sweep throughout the colon to the rectum, also resulting in relaxation of the internal anal sphincter. The propagation of these contractions is likely mediated by both cholinergic and neurokinin-dependent pathways.

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DEFECATION Defecation is the process of elimination of solid wastes from the gastrointestinal tract, and it involves several structures in and around the rectum and anus. Filling of the rectum causes relaxation of the internal anal sphincter via the release of VIP and nitric oxide from intrinsic nerves in the rectoanal inhibitory reflex, but this response is offset by a simultaneous action to increase the tone of the external anal sphincter. Overall, this reflex can permit efficient defecation while preventing leakage. The portion of rectal contents that enters the anal canal is also identified as being gaseous, solid, or liquid, thereby initiating appropriate activity of the external anal sphincter to retain each of these, or to permit voluntary expulsion. When defecation is desired, on the other hand, adopting a sitting or squatting position changes the relative orientation of the intestine and surrounding muscular structures to straighten the pathway for fecal exit. This is also assisted by relaxation of the puborectalis muscle, which results in a less acute rectoanal angle. Rectal contraction then produces the propulsive force to move the feces out of the body. Evacuation is enhanced by simultaneous contraction of the rectus abdominus, diaphragm, and other levator ani muscles, which increases intra-abdominal pressure. All of these events occur whether solid (in health) or liquid (in disease) feces are expelled, although less force is obviously needed to evacuate liquid feces. On the other hand, the voluntary expulsion of flatus involves the contractile functions listed, but the puborectalis muscle does not relax and there is no change in the rectoanal angle. This allows the flatus gas to be forced past the acutely angled anorectum without the simultaneous loss of feces.

CLINICAL CORRELATION A 90-year-old, bedridden male resident in a nursing home is given his daily oral medications (pills). He later regurgitates a bedtime snack and complains of a feeling that the pill “did not go all the way down,” so is taken to the emergency room. On physical examination, he is found to be somewhat underweight, agitated, and clearly distressed. He is also coughing and retching. The aide that accompanied him reports that this situation has occurred previously. A gastroenterologist is called and performs an upper endoscopy, whereupon the pill can be seen lodged in the mid-esophagus. It is removed via the esophagus and the patient’s symptoms slowly subside. The gastroenterologist advises the nursing home aide that the patient should be given only semisolid food in future, and that any needed pills should be crushed and mixed with apple sauce to administer them to the patient. Despite these measures, the patient’s problems worsen, and he is eventually admitted to the hospital suffering from pneumonia.

Difficulty in swallowing is referred to as dysphagia, and can result from abnormalities in any of the components of the swallowing reflex or the anatomic structures involved. For example, abnormalities of the tongue can result in dysphagia because the bolus cannot be propelled backward toward the pharynx with sufficient force. In general, dysphagia can be considered as arising from either the oropharynx and striated muscle region of the esophagus or the smooth muscle portion of the esophagus, corresponding to the different innervation and mechanisms of sensation and control in these two areas. Likewise, dysphagia can result from either structural or functional causes. Dysphagia is a common medical problem that is especially frequent in the elderly, and associated with much distress, as well as the risk of aspiration, choking, and malnutrition. It is estimated that up to 13% of hospitalized patients and as many as 60% of nursing home residents have feeding problems, most of which are the result of oropharyngeal dysphagia. All patients with dysphagia will experience problems with solid food, and may have varying degrees of difficulty swallowing liquids as well, depending on the severity of the underlying cause. Structural causes of dysphagia extend to diverticula, or outpouchings of the pharyngeal or esophageal wall in which food can become trapped, or to various forms of obstruction. The latter include mucosal or muscular rings that circumferentially occlude a portion of the esophageal lumen. These can occur in response to long-standing tissue injury secondary to gastroesophageal reflux disease (GERD); the inflammation eventually leads to scarring and fibrosis that may occlude the lumen. Esophageal tumors can also impede passage of esophageal contents. Functional causes of dysphagia relate to either neurological control of the oropharyngeal phase of swallowing, peristalsis, and esophageal sphincter relaxation or defects in the muscle layers themselves. Treatment of dysphagia depends on the underlying cause. When there are structural abnormalities, surgery to repair diverticula, cut overly tight muscles, or remove an obstructing tumor can often bring some relief. Mechanical dilation of a stricture (abnormal narrowing) is also attempted, with varying degrees of success. In the case of functional disorders, on the other hand, effective therapy usually depends on whether treatment is available for the underlying disorder, and surgery is much less helpful.

CHAPTER SUMMARY ■

■

Regulation of swallowing involves somatic neurotransmission in the upper third of the esophagus, composed of striated muscle, and autonomic regulation via the vagus and enteric nervous system in the lower two thirds, composed of smooth muscle. Swallowing is initiated voluntarily, but thereafter reflects a complex integration of regulatory influences coordinated by the swallowing center in the brain. Two sphincters, normally closed, regulate the movement of the bolus into and out of the esophagus. The upper esophageal

CHAPTER 54 Intestinal Motility

■

■

■ ■

■

■

■

■

■

sphincter is opened in concert with pharyngeal motility. The LES opens to allow the bolus to enter the stomach, coordinated with esophageal motility. The stomach serves to receive the meal from the esophagus, and it displays motility functions that both initiate the process of digestion and control the delivery of nutrients to more distal segments. Receptive relaxation of the proximal stomach allows the stomach to function as a reservoir and ensures that the pressure within the stomach changes little as its volume expands to receive the meal. The distal stomach uses phasic contractions to grind the meal, moving only the smallest particles to the pylorus. Emptying of the stomach involves tonic contractions of the proximal portions, and depends on both the physical and chemical characteristics of the meal. Liquids empty most rapidly; solids empty only after a lag phase. Nutrients and the osmolarity of the meal feed back to retard gastric emptying once they reach the small intestine via both neural and humoral mechanisms. Phase III of the MMC results in large contractions that propagate aborally, while the pylorus relaxes maximally, allowing the exit of even large particles. This phase of the MMC is related to release of the GI hormone motilin. Motility patterns in the small and large intestines serve not only to propel intestinal contents, but also to mix them with enzymes and other digestive juices, and to retain them in a given segment long enough for optimal absorption to occur. The colon serves predominantly salvage and reservoir functions, with slow transit of contents along its length and marked dehydration of luminal contents. Movement of colonic contents out of the body is controlled by the internal and external anal sphincters, under involuntary and voluntary control, respectively. Periodically, large propulsive contractions sweep through the colon and precede the urge to defecate.

STUDY QUESTIONS 1. In a study of the control of esophageal motility, a scientist instills a small amount of dilute hydrochloric acid into the upper third of the esophagus of a human volunteer, using an endoscope. This treatment is most likely to produce which of the following responses? A) peristalsis B) retroperistalsis C) esophageal spasm D) relaxation of the upper esophageal sphincter E) no response

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2. A 50-year-old man who is markedly overweight comes to his primary care physician complaining that he suffers nightly from a burning sensation in his chest after retiring, which is made worse if he has had a snack close to bedtime. Which of the following would be the most appropriate treatment for this patient if his symptoms are not resolved by weight loss and eliminating nighttime meals? A) cholinergic agonist B) smooth muscle relaxant C) nitric oxide donor D) nicotinic agonist E) proton pump inhibitor 3. In an experiment, a balloon is inserted into the stomach of a human volunteer and gradually inflated while intraluminal pressures are monitored. Although the volume of the balloon increases considerably, pressures remain relatively constant. This remarkable pressure–volume relationship is thought to involve release of which of the following patterns of neurotransmitters?

Acetylcholine

Vasoactive Intestinal Polypeptide

Nitric Oxide

A)

Yes

Yes

Yes

B)

Yes

Yes

No

C)

No

Yes

Yes

D)

No

Yes

No

E)

Yes

No

Yes

4. A mother brings her 2-year-old child to the emergency room, distressed because he has swallowed a quarter while the family was eating dinner at a restaurant. The physician reassures her that the quarter, which can be plainly seen in the stomach by fluoroscopy, will eventually pass in the stool. What physiological condition or response will be required to permit exit of the quarter from the stomach? A) receptive relaxation B) fasting C) eating another meal D) mixing and grinding by the stomach E) relaxation of the LES

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5. Four medical students studying for their physiology final develop headaches and take either regular or enteric-coated aspirin with either milk or water (enteric-coated pills will not dissolve until the pH is neutral). Assuming headache relief is proportional to blood aspirin concentrations, place the following conditions in order of headache relief (from fastest to slowest): 1. regular aspirin with water; 2. enteric-coated aspirin with water; 3. regular aspirin with milk; 4. enteric-coated aspirin with milk. A) 1 > 2 > 3 > 4 B) 4 > 3 > 2 > 1 C) 1 > 3 > 2 > 4 D) 2 > 4 > 1 > 3 E) 2 > 4 > 3 > 1

6. Which of the following substances is not involved in mediating the fed pattern of intestinal motility? A) ACh B) VIP C) 5-hydroxytryptamine (serotonin) D) nitric oxide E) motilin

55 C

Functional Anatomy of the Liver and Biliary System Kim E. Barrett

H A

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Understand the role of the liver in whole body homeostasis and the structural features that subserve its functions. Understand the functions of bile secretion and the anatomy of the biliary system. Describe the unusual circulatory features of the liver and the relationship of blood flow to bile flow. Identify the parenchymal and nonparenchymal cell types of the liver, their anatomic relationships, and their respective functions.

OVERVIEW OF THE LIVER AND BILIARY SYSTEMS AND THEIR FUNCTIONS The liver is the largest organ in the body, and conducts a myriad of vital metabolic and excretory functions. In addition, by virtue of its circulatory relationship to the absorptive surface of the gastrointestinal tract, the liver is the initial site where most ingested nutrients, and other substances entering via the gastrointestinal tract, are processed by the body. Thus, the liver is a gatekeeper that can process useful substances while detoxifying orally absorbed substances that are potentially harmful.

METABOLISM AND DETOXIFICATION The liver contributes in a pivotal way to the biochemical status of the body as a whole. It is beyond the scope of this text to provide a comprehensive analysis of all of the metabolic functions of the liver. Instead, we will focus our discussion on broad categories of metabolic functions of the liver that are relevant to the function of the gastrointestinal system, or are of particular importance to whole body homeostasis. First, the liver performs four specific functions in carbohydrate metabolism: glycogen storage, conversion of galactose and fructose to glucose, gluconeogenesis, and the formation of

Ch55_559-564.indd 559

many important biochemical compounds from the intermediate products of carbohydrate metabolism. Many of the substrates for these reactions derive from the products of carbohydrate digestion and absorption that travel directly to the liver from the gut, as will be described in more detail in Chapter 58. As a consequence, the liver plays a major role in maintaining blood glucose concentrations within normal limits, particularly in the postprandial period (see Chapter 69). The liver removes excess glucose from the blood and returns it as needed, in a process referred to as the glucose buffer function of the liver. The liver also contributes in a major way to fat metabolism. While many aspects of lipid biochemistry are common to all cells of the body, others are concentrated in the liver. Specifically, the liver supports an especially high rate of oxidation of fatty acids to supply energy for other body functions. Likewise, the liver converts amino acids and two-carbon fragments derived from carbohydrates to fats that can then be transported to adipose tissue for storage. Finally, the liver synthesizes most of the lipoproteins required by the body, as well as large quantities of cholesterol and phospholipids. The liver also serves to detoxify the blood of substances that originate from the gut or elsewhere in the body. It is highly active in removing particulates from the portal blood, such as small numbers of colonic bacteria that cross the wall of the intestine under normal circumstances. The majority of this “blood cleansing” is provided for by specialized cells related to blood macrophages, known as Kupffer cells. These are highly effective phagocytes that are strategically located to be exposed to the majority of the blood flow 559

11/26/10 10:29:27 AM

SECTION VIII GI Physiology

Heart Vena cava

ic

700 mL/min

ar

t

Liver

Celiac artery Spleen

EXCRETION OF LIPID-SOLUBLE WASTE PRODUCTS

Stomach Pancreas Aorta

The liver handles excretion of lipophilic molecules that do not enter the renal filtrate, and excretes them in the bile. In turn, the biliary system is designed to convey these substances out of the liver and into the intestinal lumen, where they undergo little, if any, reabsorption and thus can be eliminated from the body in the feces.

1300 mL/min

500 mL/min er y *

Hepatic veins

Portal vein

The liver is also critical for protein metabolism, and the body cannot dispense with the liver’s capacity to contribute to protein processing for more than a few days. The liver contributes the following important aspects of protein metabolism: deamination of amino acids, formation of urea as a means to dispose of blood ammonia, formation of plasma proteins, and interconversion of various amino acids, as well as conversion of amino acids to other intermediates important in the body. Likewise, the liver can synthesize all of the nonessential amino acids that need not be supplied in the diet in their native form (as will be discussed in more detail in Chapter 58). The liver also synthesizes proteins that are critical to the circulatory system. With the exception of the immunoglobulins produced by cells of the immune system, the liver provides most of the plasma proteins. Likewise, the liver is also the major site of synthesis of proteins that contribute to blood clotting.

t

PROTEIN METABOLISM AND SYNTHESIS

may increase to almost 90% in the period immediately after a meal. A schematic diagram of the splanchnic circulation is provided in Figure 55–1. At a microscopic level, blood perfuses the liver via a series of sinusoids, which are low-resistance cavities that receive blood supply both from branches of the portal vein and from the hepatic artery. At rest, many of these sinusoids are collapsed, whereas as portal blood flow to the liver increases coincident with ingestion and absorption of a meal, sinusoids are gradually recruited to allow the perfusion of the liver with a much greater volume per unit time but only a minimal increase in pressure. The liver also has a distinctive morphologic organization that underpins its functions. This organization is based on the so-called hepatic triad of branches of the portal vein, the hepatic artery, and the bile ducts. Blood flows into a branch of the portal vein in the center of portal areas, which are linked by anastomosing cords of cuboidal hepatocytes to a central venule that in turn drains into the hepatic vein. Branches of the hepatic artery likewise run close to the bile ducts, and likely play an important role in supplying energy

pa

originating from the gut. Other detoxification functions of the liver are biochemical in nature. Hepatocytes express large numbers of cytochrome P450 and other enzymes that can convert xenobiotics (foreign chemicals) to inactive, less lipophilic metabolites that can subsequently be excreted into the bile and thereby eliminated from the body. In addition to the metabolism of xenobiotics, the liver is responsible for the metabolism and excretion of a wide variety of hormones and other endogenous regulators that circulate in the bloodstream. In particular, the liver is responsible for metabolism of the steroid hormones.

He

560

700 mL/min Superior mesenteric artery

Small intestine Colon

400 mL/min

ENGINEERING CONSIDERATIONS Inferior mesenteric artery

BLOOD SUPPLY Hepatic Macrocirculation and Microcirculation The liver is unusual in that it receives the vast majority of its blood supply in the form of venous blood, especially in the postprandial period. Even at rest, blood flow to the liver via the portal vein is at a rate of 1,300 mL/min, compared with only 500 mL/min supplied by the hepatic artery. Moreover, the proportion of blood flow supplied to the liver by the portal vein

Rest of body *Branches of the hepatic artery also supply the stomach, pancreas and small intestine

FIGURE 55–1 Schematic of the splanchnic circulation under fasting conditions. Note that even during fasting, the liver receives the majority of its blood supply via the portal vein. (Reproduced with permission from Barrett KE, Barman SM, Boitano S, Brooks H: Ganong’s Review of Medical Physiology, 23rd ed. McGraw-Hill Medical, 2009.)

CHAPTER 55 Functional Anatomy of the Liver and Biliary System

Central vein

Hepatic artery

561

Liver

Portal vein Bile ducts

Sinusoids Gallbladder Duodenum Bile duct

Portal vein Terminal ileum

Portal vein

Bile duct

Hepatic artery

FIGURE 55–2 Arrangement of blood vessels, bile ducts, and hepatocytes to form the liver lobule. Branches of the portal vein and hepatic artery run parallel to bile ducts in the so-called portal triads. Blood percolates through sinusoids arranged between the hepatocytes, to be collected eventually in the central vein. (Reproduced with permission from Ross MH, Reith EJ: Histology. A Text and Atlas. New York: Harper and Row, 1985.)

and nutrients to the bile duct epithelial cells to support their transport functions. A diagram showing the interrelationships of the various cell types that make up the liver is shown in Figure 55–2.

Enterohepatic Circulation

FIGURE 55–3 Schematic of the enterohepatic circulation of conjugated bile acids. Bile acids secreted by hepatocytes enter the bile and flow through the biliary system to the duodenum. Conjugated bile acids are selectively reabsorbed in the terminal ileum, and flow through the portal vein back to the liver to be reabsorbed by hepatocytes and resecreted. (Reproduced with permission from Barrett KE: Gastrointestinal Physiology. New York: Lange Medical Books/ McGraw-Hill, Medical Pub. Division, 2006.)

Hepatocytes Hepatocytes are the metabolic “factories” of the liver, and are responsible for most of its characteristic functions. They are highly specialized polarized epithelial cells. Their apical membranes are in the form of grooves between adjacent cells, known as canaliculi (Figure 55–4). The canaliculi form a SINUSOIDAL LUMEN Stellate cell Tight junction

The circulatory features of the liver are also notable for the fact that some substances circulate continuously between the liver and intestine, in the enterohepatic circulation. This involves passage of solutes through three different environments—the portal vein and the sinusoids into which it empties, the biliary system, and the intestinal lumen (Figure 55–3). Most notably, this occurs for bile acids that are utilized during intestinal lipid digestion and absorption. The physiological significance of this circuit is that it permits the secretion rate to greatly exceed the synthesis or input rate.

Bile canaliculus

Hepatocyte

Endothelium Kupffer cell SINUSOIDAL LUMEN

HEPATIC PARENCHYMA AND SINUSOIDS The most prevalent cell type in the liver is the hepatocyte (80% of total cells, approximately 100 billion in an adult human liver), whereas the nonparenchymal cell types include the stellate cells, sinusoidal endothelial cells, and previously mentioned Kupffer cells. In this section, we will review how their properties contribute to the physiological functions of the liver.

Space of Disse

FIGURE 55–4 Interrelationships of the major cell types making up the liver. Hepatocytes are arranged in plates joined by tight junctions, and their apical membranes make up the bile canaliculi. They are segregated from the blood-filled sinusoids by fenestrated endothelial cells without a basement membrane, and by a loose connective tissue layer known as the space of Disse. Kupffer cells reside in the sinusoidal lumen, whereas stellate cells are found in the space of Disse. (Reproduced with permission from Barrett KE: Gastrointestinal Physiology. New York: Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2006.)

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continuous network that drains eventually into the bile ductules. On the opposing pole of the hepatocyte, the basolateral membrane faces the bloodstream in the form of the hepatic sinusoids. The apical and basolateral membranes of hepatocytes are separated by tight junctions that define the canaliculi. These junctions are relatively permeable, however, permitting the passage of glucose and other small solutes.

From liver Right and left hepatic ducts from liver Cystic duct Common hepatic duct Common bile duct Gallbladder

Pancreatic duct

Kupffer Cells Kupffer cells arise from the macrophage lineage, and line the sinusoidal epithelium on the bloodstream side (Figure 55–4). They are presumed to play a major role in host defense. Their location is such that they are exposed to virtually all of the portal blood flow. Kupffer cells also express cell-surface receptors for altered proteins, such as Fc immunoglobulin receptors that can be used to internalize foreign proteins or microorganisms that have been coated with host antibodies.

Sinusoidal Endothelium The endothelial cells that line the hepatic sinusoids have two characteristic properties that distinguish them from endothelial cells in other organs of the body. First, they are perforated by large intracellular pores known as fenestrae, which are 100–200 nm in diameter. These are designed to permit the passage of even quite large macromolecules out of the blood, including albumin with bound ligands. Second, sinusoidal endothelial cells in the healthy liver do not have a basement membrane. In total, therefore, the sinusoidal endothelium presents virtually no barrier to the efflux of albumin and other similarly sized molecules from the vascular space.

Space of Disse The space of Disse (pronounced Diss-eh) is a layer of loose connective tissue that lies between the sinusoidal endothelium and the basolateral membrane of hepatocytes. It is notably highly permeable to the bidirectional exchange of solutes between the sinusoidal blood flow and hepatocytes.

Hepatic Stellate Cells Hepatic stellate cells, previously also referred to as Ito cells, are star-shaped cells that reside in the space of Disse. They play an important role in the normal liver by storing a variety of lipids. In addition, these cells are contractile, and may be involved in the regulation of sinusoidal diameter. Stellate cells also play a critical role in liver injury by producing extracellular matrix materials, such as collagen. This collagen is deposited in the space of Disse and impairs hepatic function.

BILIARY TRACT AND GALLBLADDER The third functional division of the liver is concerned with the production and transport of bile out of the liver and into the gastrointestinal lumen. The functional anatomy of the biliary

Sphincter of Oddi Duodenum

FIGURE 55–5

Functional anatomy of the biliary system.

(Modified with permission from Barrett KE: Gastrointestinal Physiology. New York: Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2006.)

system is depicted in Figure 55–5. Bile drains from the liver via the right and left hepatic ducts that join to form the common hepatic duct. A cystic duct diverts bile for storage into the gallbladder. The anastomosis of the common hepatic duct and the cystic duct forms the common bile duct, which transfers bile to the sphincter of Oddi. At a functional level, the biliary system can be divided into four components. First, the canaliculi, which are composed of the adjacent apical membranes of hepatocyte couplets, form the initial biliary secretion. This secretion is then modified as it flows along the biliary ductules, which are analogous to pancreatic ducts. The ductules are made up of columnar epithelial cells (cholangiocytes), and both absorb and secrete various substances into and out of the bile. The ductules are perfused by a capillary network arising from the hepatic artery, rather than from the sinusoids. The majority of this periductular capillary plexus drains into the sinusoids. Flow in the periductular capillary plexus is in the opposite direction to bile flow. The larger bile ductules dilute and alkalinize the bile, again analogous to the function of the pancreatic ducts. The bile ducts serve simply as conduits for the bile without modifying its composition significantly, other than by adding mucus. Mucus secretion presumably serves to protect the ductular epithelium from potentially injurious surfactant effects of the bile itself. Finally, bile is stored in the gallbladder between meals, which is a blind sac lined by highly absorptive epithelial cells linked by well-developed tight junctions. The gallbladder serves not only to store bile, but also to concentrate it. However, the gallbladder is not essential to life and can be removed without compromising nutrition.

CLINICAL CORRELATION A 70-year-old veteran is seen in the primary care clinic of the VA hospital. He complains that his girth has increased progressively over a period of several months, despite attempts

CHAPTER 55 Functional Anatomy of the Liver and Biliary System

to lose weight. His ankles are also noted to be edematous. His history is notable for service in Korea, where he reports that he was diagnosed with acute “liver disease” that subsequently resolved. A needle is inserted into his peritoneal cavity and several liters of tan-colored fluid drain out. A blood test reveals evidence of past exposure to the hepatitis C virus. He is placed on interferon therapy, and told to return to the GI clinic in 6 weeks for follow-up, but 4 weeks later he presents at the emergency room vomiting bright red blood. An emergency endoscopic examination reveals a ruptured blood vessel bleeding into his esophagus. Hemostasis is obtained by placing a band around the bleeding vessel. Portal hypertension refers to conditions where the resistance to blood flow through the liver is increased, which can have several causes and results in a variety of problems. As we have already discussed, the liver has a very lowresistance vasculature in health, and pressures increase little as flow increases since additional sinusoids can be recruited. However, in several liver diseases, inflammatory responses trigger hepatic stellate cells to increase collagen production, reducing permeability across the sinusoidal endothelium and space of Disse and impairing liver function due to the associated fibrosis. The hardening of the liver impedes flow through the sinusoids. Some of the sinusoids and liver parenchyma may also be destroyed and replaced by fibrous tissue, further impairing liver function. The most obvious clinical consequence of portal hypertension is a condition known as ascites. Because the hepatic sinusoids and space of Disse are very permeable and allow albumin to pass, large quantities of lymph are produced by the liver even in health, and are collected by a series of lymph ducts that eventually return the fluid to the blood via the thoracic duct. However, when portal hypertension develops, plasma transudation increases and overwhelms the hepatic lymphatics, which may themselves be compromised by liver fibrosis. The resulting fluid, which contains almost as much albumin as the plasma, weeps from the surface of the liver and accumulates in the peritoneal cavity. In advanced liver disease, many liters of fluid may be found. Another consequence of portal hypertension is the development of collateral blood vessels to surrounding structures. These form in an attempt to bypass the blockage to portal flow posed by the hardened liver, and reconnect to the systemic circulation. If the collateral vessels link to the esophagus, they are referred to as esophageal varices and are vulnerable to erosion and rupture, particularly if their internal pressure is high. Rupture of such varices represents a major medical emergency due to the challenges involved in reestablishing hemostasis. Ruptured varices are also at high risk for rebleeding. Variceal pressures can be reduced by constructing a surgical shunt between the portal vein and the systemic circulation, although doing so diverts portal blood from any remaining functional liver parenchyma, and thus increases complications associated with the loss of the detoxifying functions of hepatocytes.

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CHAPTER SUMMARY ■

■

■

■

■ ■

■

■

Functions of the liver and biliary system include glucose storage and release, protein synthesis, detoxification of xenobiotics and ammonia, metabolism of endogenous hormones, initial handling of substances absorbed from the intestine, and excretion of lipophilic molecules and heavy metals in the bile. Functions of the liver are facilitated by its unique circulatory features. Blood arrives at the liver via two routes: the portal vein, which drains blood from the intestine, and the hepatic artery. Blood percolates through the liver via a low-resistance system of sinusoids that maximize exposure of hepatocytes to the blood’s contents. The functions of the liver are also subserved by specific cell types that assume specific geometric relationships. Hepatocytes conduct the majority of the metabolic functions of the liver and produce the initial biliary secretion. Kupffer cells line the sinusoids and cleanse the blood of particulates, such as bacteria. The endothelial cells of the liver have large fenestrations that allow small proteins and other molecules to leave the circulation, but retain blood cells and intact chylomicrons. Hepatic stellate cells are contractile and likely regulate sinusoidal caliber. In disease, they play an important role in generating fibrosis. Liver failure due to damage to the liver cells or to the biliary system, or blockade of biliary drainage, results in a host of systemic problems.

STUDY QUESTIONS 1. In a patient with end-stage liver disease, which of the following combinations of findings would be expected in the plasma? Albumin

Glucose

Ammonia

A)

Increased

Increased

Increased

B)

Decreased

Decreased

Decreased

C)

Increased

Decreased

Increased

D)

Decreased

Increased

Decreased

E)

Decreased

Decreased

Increased

2. A 60-year-old man comes to his physician complaining of a progressive increase in girth over several months, despite attempts to diet. He is suffering from jaundice (yellowing of the skin and sclera) and also complains of nausea and malaise. When a large needle is inserted into his abdomen, several liters of tan fluid drain out. An increase in which of the following does not account for this accumulation of fluid? A) portal pressure B) hepatic collagen C) plasma albumin D) stellate cell activity E) plasma transudation

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3. The liver is responsible for removing the small numbers of bacteria that enter the portal circulation from the intestines. Which cell type fulfills this function? A) sinusoidal epithelial cells B) cholangiocytes C) hepatocytes D) Kupffer cells E) stellate cells 4. A gallstone lodged in which of the following sites will result in increased bile acid flux through the hepatocytes making up only the left side of the liver? A) cystic duct B) common hepatic duct C) right hepatic duct D) left hepatic duct E) common bile duct

5. What structure in the liver permits protein-bound metabolic products to access the basolateral membranes of hepatocytes? A) canaliculi B) sinusoidal fenestrae C) Kupffer cells D) bile ducts E) tight junctions

56 C

Bile Formation, Secretion, and Storage Kim E. Barrett

H A

P

T

E

R

O B J E C T I V E S ■ ■ ■ ■ ■

■

Understand the physiologic functions of bile as a route for excretion and in aiding in the digestion and absorption of dietary lipids. Understand how bile acids are formed from cholesterol, how they are modified during gut passage, and their role in driving bile secretion. Describe the major biliary lipids and how they are transported into the canaliculus. Describe how the composition of bile is modified as the bile moves through the biliary ductules. Understand the role of the gallbladder in concentrating bile and coordinating its secretion with ingestion of a meal, and how contraction of the gallbladder is regulated. Explain why the gallbladder is vulnerable to the formation of cholesterol gallstones.

BASIC PRINCIPLES OF BILIARY EXCRETION AND SECRETION ROLE AND SIGNIFICANCE The liver fulfills its excretory function by producing bile, a lipid-rich solution designed to promote the elimination of hydrophobic solutes. Bile consists of a micellar solution in which bile acids, cholesterol metabolites produced by hepatocytes, form mixed micelles with phosphatidylcholine. These mixed micelles solubilize molecules that would otherwise have minimal aqueous solubility, such as cholesterol itself and a variety of xenobiotics. Bile also plays an important role in the digestion and absorption of dietary lipids. While bile acids are not essential for the uptake of most fatty acids, which have appreciable aqueous solubility, they do markedly increase the efficiency of this process. On the other hand, insoluble dietary lipids, such as saturated long-chain fatty acids and fat-soluble vitamins, are almost entirely dependent on micellar solubilization for absorption.

Ch56_565-574.indd 565

BILE ACID METABOLISM Bile secretion in the liver is driven by the active, ATP-dependent efflux of conjugated bile acids out of the hepatocyte into the canaliculus. In this section, we will consider how bile acids are synthesized, and subsequent modifications to their structure that promote their role as biological detergents.

FORMATION OF BILE ACIDS FROM CHOLESTEROL Bile acids are amphipathic end products of cholesterol metabolism. The term amphipathic refers to the fact that bile acids have both a hydrophobic and a hydrophilic face, and form micelles. Synthesis of bile acids from cholesterol occurs in the hepatocyte. Changes to both the steroid nucleus of cholesterol and its alkyl side chain are required to convert the highly insoluble cholesterol to the water-soluble bile acid product. The initial, and rate-limiting, step in bile acid formation is the hydroxylation of cholesterol at the 7 position of

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the steroid nucleus via the enzyme cholesterol 7α-hydroxylase (Figure 56–1). Note that cholesterol already contains a hydroxyl group at the 3 position, and this is retained in all of the bile acids. However, the 3-hydroxyl group in cholesterol is in the β-orientation, and this is converted to the α-position by a process known as epimerization. After these initial reactions, downstream pathways diverge to yield the two primary bile acids of humans, chenodeoxycholic acid and cholic acid. Note that all of the hydroxyl groups in the mature bile acids are in the form of α-epimers, and are thus oriented to the same face of the molecule. Cholesterol is a flat molecule, insoluble, and a major membrane constituent. In contrast, bile acids are kinked molecules that are highly water soluble when ionized. Bile acid synthesis in healthy humans is at a rate of approximately 200–400 mg per day. Synthesis is subject to feedback inhibition at the level of the 7α-hydroxylase enzyme.

lithocholic acid from chenodeoxycholic acid, and deoxycholic acid from cholic acid. Trace amounts of a third secondary bile acid, ursodeoxycholic acid (so called because it is a prominent bile acid in bears), are also generated in humans by epimerization of the 7α-hydroxyl group. Although only very little ursodeoxycholic acid is formed in humans, it is important to know about this compound because it is used therapeutically. The secondary bile acids are less water soluble than the primary bile acids. Lithocholic acid, in particular, is cytotoxic if present at high concentrations, and physiologic mechanisms have developed to limit its toxicity.

BILE ACID CONJUGATION Both primary and secondary bile acids are further modified in the hepatocyte by conjugating them to the amino group of either glycine or taurine in a stable amide linkage (Figure 56–2). It is these conjugated bile acids that are the substrates for active transport across the canalicular membrane. Conjugation also renders the bile acids more water soluble, and alters other physicochemical properties. In addition to bacterial conversion of primary to secondary bile acids, bacteria can deconjugate both primary and secondary bile acids, making them more lipophilic. Unconjugated bile

PRIMARY AND SECONDARY BILE ACIDS When the primary bile acids enter the distal small intestine or the colon, they can be acted on by bacterial enzymes to yield secondary bile acids. The most important conversion is dehydroxylation of the 7 position of the steroid nucleus, to yield

Cholesterol OH 7α−hydroxylase OH 12α−hydroxylase

HO

OH

Primary bile acids

C27 dehydroxylase

C27 dehydroxylase OH

COOH

permission from Barrett KE: Gastrointestinal Physiology. New York: Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2006.)

Secondary bile acids

Structures of primary and secondary bile acids and their precursors. Primary bile acids are synthesized in the liver, whereas secondary bile acids are produced in the colon by bacterial enzymes. (Modified with

COOH

Chenodoxycholic acid

HO

Cholic acid

OH

Bacteria

FIGURE 56–1

OH

HO

HO

OH

Bacteria

Bacteria

OH COOH

COOH

HO

HO

COOH

OH HO

Lithocholic acid

Ursodeoxycholic acid

Deoxycholic acid

CHAPTER 56 Bile Formation, Secretion, and Storage

567

Charged side chain C O

C O

OH Unconjugated bile acid pKa = 5.0

O

N

CH2

H

C

OH group

O−

O

Simple micelle

Bile acid monomers

Glycine conjugate pKa = 3.9

O C O

O

N

(CH2)2

H

S

O−

O

Mixed micelle

Taurine conjugate pKa < 1

FIGURE 56–2 Conjugation of bile acids with either glycine or taurine reduces their pKa. (Modified with permission from Barrett KE: Gastrointestinal Physiology. New York: Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2006.)

acids can be passively absorbed across the wall of the intestine. They then travel through the portal vein back to the liver, where they are reconjugated in the hepatocyte. Thus, all bile acids secreted by the hepatocyte are in their conjugated forms. Special handling applies to the potentially toxic bile acid, lithocholic acid. In addition to conjugation with glycine or taurine, lithocholic acid can be sulfated, particularly if present in abnormally high concentrations. This increases the hydrophilicity of the molecule and reduces its cytotoxic effects. The sulfated conjugates of lithocholic acid also cannot be absorbed by the intestine, which results in their elimination from the pool of bile acids that circulate enterohepatically.

PHYSICOCHEMICAL PROPERTIES OF BILE ACIDS The amphipathic character of bile acids is vital to the physiologic function of these molecules. Above a certain concentration called the critical micellar concentration (CMC), bile acid molecules are spontaneously self-associated into structures known as micelles, in which the hydrophobic faces are masked from the surrounding aqueous environment (Figure 56–3). However, simple micelles composed of bile acids alone do not exist in bile or intestinal content. In bile, bile acids form mixed micelles with phosphatidylcholine. In turn, these mixed micelles can serve as the “solvent” for hydrophobic waste products. Conjugated bile acids are present in both bile and intestinal contents as anions because they have a lower pKa than the

Phosphatidylcholine Cholesterol

FIGURE 56–3 Physical forms adopted by bile acids in solution. Micelles are shown in cross-section, and are actually thought to be cylindrical in shape. Mixed micelles of bile acids present in hepatic bile also incorporate cholesterol and phosphatidylcholine. (Adapted with permission from Barrett KE: Gastrointestinal Physiology. New York: Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2006.)

unconjugated forms. Due to this charge, conjugated bile acids are incapable of crossing cell membranes by passive means, needing instead an active transport mechanism for their secretion or uptake (Figure 56–4). This allows enterohepatic circulation of bile acids to be coordinated with the period when they are needed to help digest the meal.

BILE COMPOSITION CANALICULAR BILE The secretion of bile begins when bile acids are actively secreted across the canalicular membrane. Because the bile acids are osmotically active, canalicular bile is transiently hyperosmotic. However, the canalicular tight junctions are relatively permeable, and so water is drawn into the canaliculus to balance this, along with plasma cations to maintain electrical neutrality. Other secondary solutes also enter bile passively from the plasma, including glutathione, glucose, amino acids, and urea.

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SECTION VIII GI Physiology phatidylcholine from their normal position in the inner leaflet of the canalicular membrane, and specifically ejects them into the canalicular lumen as vesicles. These vesicles then fuse with secreted bile acids to form mixed micelles. Cholesterol is also secreted into the bile, particularly in humans, at a ratio of approximately 0.3 to the amount of phosphatidylcholine (or one tenth of the amount of bile acids). Such secretion appears to be mediated by a heterodimer of the transporters ABC5 and ABC8. Canalicular bile, in health, also contains conjugated bilirubin, which gives bile its characteristic brown color, and a variety of other organic anions and cations that arise from the biotransformation of xenobiotics and endogenous hormones. The membrane transporters that allow these various molecules to enter the bile are listed in Table 56–1.

Hepatocyte

Tight junction

Canaliculus Active secretion • Bile acids • Phosphatidylcholine • Conjugated bilirubin • Xenobiotics

DUCTULAR BILE Passive permeation • Water • Glucose • Calcium • Glutathione • Amino acids • Urea

FIGURE 56–4 Pathways for solute entry into bile by either active secretion or passive permeation through the tight junctions linking adjacent hepatocytes. (Reproduced with permission from Barrett KE: Gastrointestinal Physiology. New York: Lange Medical Books/ McGraw-Hill, Medical Pub. Division, 2006.)

The composition of canalicular bile is also modified by the active secretion of additional factors from the hepatocytes. Phosphatidylcholine, a component of the hepatocyte membrane, enters the bile and forms mixed micelles with the bile acids. The ratio of phosphatidylcholine to bile acids is approximately 0.3. Although phosphatidylcholine is only one of the phospholipids present in the hepatocyte plasma membrane, it is selectively secreted into bile. This is mediated by multidrug resistance protein 3 (MDR3), which “flips” molecules of phos-

As the bile moves out of the canaliculi, it is transferred to the smallest bile ductules via structures known as the canals of Hering. The bile ductules are lined by cholangiocytes, which are columnar epithelial cells specialized to modify bile composition. The tight junctions linking the cholangiocytes are much less permeable than those linking hepatocytes. They are freely permeable to water, but are only selectively permeable to electrolytes and impermeable to larger solutes. Because of their permeability to water, bile rapidly becomes isotonic. The ductules also serve to scavenge solutes that were filtered into the bile at the leaky canaliculus. In particular, glucose is actively reabsorbed. Likewise, glutathione is hydrolyzed to its constituent amino acids by the apically fixed enzyme, gamma-glutamyl transpeptidase (GGT). The function of the bile ductules is also coordinated with ingestion of a meal. In particular, the cholangiocytes secrete bicarbonate in response to secretin, via a process involving the coupled activity of the CFTR chloride channel and chloride/bicarbonate exchange at the apical membrane. Sodium ions follow paracellularly to maintain electrical neutrality, in turn drawing additional water into the bile and increasing its volume and flow. Thus, bile becomes slightly alkaline. Finally, the ductules secrete IgA molecules into the bile that contribute to host defense.

TABLE 56–1 Hepatocyte transporters. Name

Location

Substrate/Function

Sodium taurocholate cotransporting polypeptide (NTCP)

Basolateral membrane

Uptake of conjugated bile acids from blood

Organic anion transporting protein (OATP)

Basolateral membrane

Uptake of bile acids and xenobiotics from blood

Bile salt export pump (BSEP)

Canalicular membrane

Secretion of conjugated bile acids into bile

Multidrug resistance protein 3 (MDR3)

Canalicular membrane

“Flippase” that adds phosphatidylcholine to bile

Multidrug resistance protein 1 (MDR1)

Canalicular membrane

Secretion of hydrophobic cationic drugs into bile

ABC5/ABC8

Canalicular membrane

Secretion of cholesterol into bile

Multiple organic anion transport protein (cMOAT, MRP2)

Canalicular membrane

Secretion of sulfated lithocholic acid and conjugated bilirubin into bile

CHAPTER 56 Bile Formation, Secretion, and Storage

HEPATIC BILE Hepatic bile emerges from the liver in the common hepatic duct, prior to further modification by gallbladder storage. The large bile ducts are thought to have little ability to modify bile composition, other than by adding mucus. Hepatic bile is isoosmotic with plasma, slightly alkaline, and contains appreciable quantities of IgA but essentially no glucose or amino acids.

ENTEROHEPATIC CIRCULATION OF BILE ACIDS Unlike the digestive enzymes arising from the pancreas, which contribute to nutrient digestion catalytically, bile acids contribute to lipid digestion and absorption by mass action. This means that considerable quantities of bile acids are needed to solubilize the quantities of products of fat digestion that are derived from a typical diet on a daily basis. The liver synthesizes 200–400 mg of bile acids per day. However, the concentration of bile acids in the small intestinal lumen during digestion is much higher than would be predicted, because bile acid secretion with a meal is about 2,000–3,000 mg/h. This is achieved by recycling the majority of the bile acids secreted during a meal, such that a large pool (about 2,000 mg) of these molecules is constantly cycling between the intestine and liver (Figure 56–5).

INTESTINAL UPTAKE MECHANISMS Bile acids secreted into the gut lumen are initially in conjugated form. Because these bile acids are ionized, they cannot Hepatic synthesis Sphincter of Oddi Spillover from liver into systemic circulation

Gallbladder Active ileal uptake Return to liver

Small intestine

Large intestine

cross the wall of the intestine passively. Rather, there is a specific, sodium-coupled transporter known as the apical sodium-dependent bile salt transporter (asbt) that recognizes bile acid conjugates and reabsorbs them. The expression of asbt in the intestine is limited to epithelial cells in the terminal ileum. Thus, conjugated bile acids remain with the meal in the lumen until the nutrients are absorbed, whereupon they are reclaimed from the lumen and enter the portal circulation via a second bile acid transporter, OST, to be returned to the liver. Only a minor portion of the bile acid pool spills over into the colon in health. Moreover, conjugated bile acids that enter the colon are deconjugated by the resident bacteria. Deconjugated bile acids are largely nonionized and can be absorbed passively. The amount of bile acids found in the feces balances daily synthesis at steady state (Figure 56–5).

HEPATOCYTE TRANSPORT MECHANISMS Bile acids return to the liver bound to albumin, leave the portal circulation in the sinusoids, and then are specifically and efficiently taken up across the basolateral membrane of the hepatocytes via a variety of specific transporters (Table 56–1). Probably the best characterized is the sodium taurocholate cotransporting polypeptide (NTCP), a sodium-coupled transporter for the taurine conjugate of cholic acid that shares homology with asbt. Other bile acids are apparently transported by members of the organic anion transporting polypeptide (OATP) family, which are sodium-independent. Unconjugated bile acids are reconjugated with either taurine or glycine, and overall the recycled bile acids are handled in much the same way as bile acids that have been newly synthesized, being actively transported into the bile canaliculus via the bile salt export pump (BSEP). The only exception applies to secretion of the sulfated forms of conjugated lithocholic acid, which enter the bile via the multiple organic anion transporter (MOAT), also referred to as MRP2.

REGULATION OF BILE ACID SYNTHESIS AND TRANSPORT

Spillover into colon

Passive uptake of deconjugated bile acids from colon Fecal loss ( = hepatic synthesis)

FIGURE 56–5 Quantitative aspects of the circulation of bile acids. The majority of the bile acid pool circulates between the small intestine and liver. A minority of the bile acid pool is in the systemic circulation (due to incomplete hepatocyte uptake from portal blood) or spills over into the colon and is lost to the stool. Fecal loss is equivalent to hepatic synthesis of bile acids at steady state. (Adapted with permission from Barrett KE: Gastrointestinal Physiology. New York: Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2006.)

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The enterohepatic cycling of bile acids also controls the rate at which they are synthesized and transported. Bile acids exert feedback inhibition on cholesterol 7α-hydroxylase, such that when return of bile acids from the intestine is high, the synthesis of new primary bile acids is reduced. Conversely, interruption of the enterohepatic circulation of bile acids for any reason will relieve this feedback inhibition, increasing the rate at which cholesterol is converted to bile acids. Normal rates of bile acid synthesis can increase 10–20-fold under these conditions. This increased synthetic rate may or may not be sufficient to maintain the size of the circulating bile acid pool, depending on fecal losses.

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FUNCTIONAL ANATOMY OF THE GALLBLADDER

Dietary cholesterol 0.2 g/day

Hepatic and extrahepatic synthesis 0.8−1 g/day

Body cholesterol pools

Bile acid pools

Intact cholesterol 0.8 g/day

Cholesterol excreted as bile acids 0.2−0.4 g/day

Fecal excretion = Input

FIGURE 56–6 Relationship of bile acid pools to whole body cholesterol homeostasis in health. The combined fecal excretion of cholesterol and bile acids is equivalent to input of cholesterol from the diet plus endogenous synthesis of cholesterol. (Modified with permission from the Undergraduate Teaching Project of the American

The gallbladder is a muscular sac with a capacity of approximately 50 mL in adult humans. It is linked to the biliary system via the cystic duct, a bidirectional conduit for bile flow. During periods of fasting, bile secreted by the liver is diverted into the gallbladder. On the other hand, when the gallbladder receives neurohumoral cues that fats are present in the small intestine, it contracts and bile flows out of the gallbladder and into the intestine.

EPITHELIUM The gallbladder has two functional layers. The inner of these, facing the bile, is a columnar epithelium that participates actively in bile concentration. The tight junctions that link adjacent epithelial cells are among the best developed anywhere in the body, making the epithelium highly resistant to the passive flux of solutes. This “tight” epithelium prevents the passive loss of bile acid molecules and thus is essential to the ability of the gallbladder to concentrate the bile.

Gastroenterological Association, Unit 11. Copyright 2002.)

MUSCULATURE Bile acid synthesis should also be considered in the context of whole body cholesterol metabolism (Figure 56–6). The cholesterol pools reflect hepatic and extrahepatic synthesis (as well as a small component derived from absorption of dietary cholesterol). At steady state, cholesterol input must be balanced by elimination. Cholesterol is lost from the body in two forms by being secreted intact into the bile or after conversion to bile acids. In either case, the sole excretory pathway is via the bile as no cholesterol or bile acids are excreted in urine in healthy individuals. Because it is possible to increase bile acid synthesis by interrupting the enterohepatic circulation, this represents a pharmaceutical approach to enhance cholesterol elimination.

The epithelial layers are underlaid by smooth muscle that can alter the caliber of the gallbladder lumen. The muscle cells

l ga Va rents e eff

BASIC PRINCIPLES OF GALLBLADDER FUNCTION ROLE AND SIGNIFICANCE The gallbladder serves to store and concentrate bile coming from the liver in the period between meals. Gallbladder function therefore permits coordination of the secretion of a bolus of concentrated bile with the entry of dietary lipids into the small intestine. The gallbladder is not essential to normal digestion and absorption of a meal. In the absence of a functioning gallbladder, the bile acid pool continues to cycle through the enterohepatic circulation, and the majority of the bile acid pool is stored in the small intestine.

Vagal afferent

ACh ACh and CCK Gallcause smooth muscle contraction bladder

CCK

Dorsal vagal complex

NO VIP

Sphincter of Oddi

Duodenum

Nutrients Via CCK bloodstream

CCK

FIGURE 56–7 Neurohumoral control of gallbladder contraction and biliary secretion. Nutrients in the duodenum lead to the release of cholecystokinin (CCK), which acts through both endocrine and neurocrine routes to activate gallbladder contraction and relax the sphincter of Oddi, resulting in the secretion of a bolus of concentrated bile into the duodenal lumen. Secondary neurotransmitters released by the enteric nervous system in response to a vagovagal reflex include the excitatory neurotransmitter acetylcholine (ACh) and the inhibitory transmitters vasoactive intestinal polypeptide (VIP) and nitric oxide (NO). (Reproduced with permission from Barrett KE, Barman SM, Boitano S, Brooks H: Ganong’s Review of Medical Physiology, 23rd ed. McGraw-Hill Medical, 2009.)

CHAPTER 56 Bile Formation, Secretion, and Storage receive cholinergic input from the vagus nerve. They also express receptors for CCK. CCK additionally activates nerves that innervate the gallbladder (Figure 56–7).

GALLBLADDER STORAGE OF BILE EFFECTS ON COMPOSITION Hepatic bile is isotonic with plasma, with sodium as its major cation and chloride as its major anion. After gallbladder storage, water is removed from the lumen and the concentration of bile acids is increased by approximately 10-fold, whereas chloride and bicarbonate concentrations decrease. On the other hand, the concentrations of all cations in the bile increase, although to a lesser degree than those of the bile acids, indicating that cations are also subject to net absorption by the gallbladder epithelium. A comparison of the compositions of hepatic and gallbladder bile is shown as Figure 56–8. Despite the dramatic increase in the sum of anions and cations during gallbladder storage of bile, bile remains isotonic. How is this possible? The answer lies in the fact that the majority of the bile acid molecules are physically in the form of mixed micelles that also contain cholesterol and phosphatidylcholine. Once the CMC is reached, the monomeric concentration of bile acids does not change. Any additional bile acid molecules are immediately incorporated into existing micelles. Each particle in a solution contributes the same amount of osmotic force, be it a molecule, ion, or micelle. This allows the osmolality of bile to remain constant despite its concentration. Bile also changes from being slightly alkaline (a result of bicarbonate secretion in the ductules) to slightly acidic.

Hepatic bile

300

Gallbladder bile

Na+

Concentration (mM)

150

Bile acid anions Cl−

100 HCO3− 50

0

1

2

3 4 Storage time (h)

5

6

FIGURE 56–8

Changes in bile composition during gallbladder storage. (Reproduced with permission from Barrett KE: Gastrointestinal Physiology. New York: Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2006.)

The solubility of cholesterol in bile depends on its concentration relative to that of bile acids and phosphatidylcholine. As bile is concentrated, bile acids cannot leave the gallbladder since they are too large to pass through the tight junctions linking adjacent epithelial cells, and they are also not actively transported by the gallbladder epithelium. Accordingly, the proportion of bile acids to cholesterol plus phosphatidylcholine does not change, or even increases slightly, because the gallbladder can absorb cholesterol. As a result, bile becomes slightly less saturated in cholesterol as it is stored. Gallstone disease is nevertheless quite prevalent in humans because we secrete relatively high concentrations of cholesterol in hepatic bile.

MECHANISM FOR BILE CONCENTRATION Bile is concentrated in the gallbladder via the active transport of ions across the tight gallbladder epithelium (Figure 56–9). Sodium in the bile is exchanged for protons via members of the NHE family of exchangers that we encountered in the gastrointestinal tract. Protons that are secreted into the stored bile react with bicarbonate ions, yielding CO2 and water. The CO2 diffuses out of the gallbladder lumen passively, and water can be reabsorbed. In addition to sodium absorption, moreover, chloride is also actively absorbed by the gallbladder epithelium. Finally, water leaves across the gallbladder epithelium to follow the osmotic effect of absorbed sodium chloride.

MOTOR FUNCTIONS OF THE GALLBLADDER AND BILIARY SYSTEM GALLBLADDER CONTRACTION Postprandial gallbladder contraction coincides with gastric emptying. The entry of the meal into the duodenum triggers the release of a series of neurohumoral messengers that increase gallbladder tone (Figure 56–7). Cholecystokinin (CCK) released from cells lining the duodenal lumen travels through the bloodstream, and binds directly to CCK-A receptors on gallbladder smooth muscle cells. In addition, CCK activates vagal afferents in the wall of the duodenum, and these in turn initiate a vagovagal reflex that releases ACh at gallbladder synapses, further increasing contractile activity.

250 200

571

SPHINCTER OF ODDI FUNCTION Even if the gallbladder contracts fully, this does not allow for bile secretion into the duodenum if pressure at the sphincter of Oddi remains high. Therefore, relaxation of the sphincter is normally coordinated with gallbladder contraction. The

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SECTION VIII GI Physiology

LUMEN

BLOODSTREAM

CO2 + H2O Na+

CA NHE

FIGURE 56–9 Mechanism of bile concentration by gallbladder epithelial cells. Sodium is reabsorbed via a sodium/hydrogen exchanger on the apical membrane (NHE), in exchange for protons generated intracellularly by carbonic anhydrase (CA).The pathway for chloride absorption is less well characterized, but may involve the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel and/or a chloride/bicarbonate exchanger (not shown). Gallbladder epithelial tight junctions have extremely low permeability, and resist the passage of bile acid anions (BA−) out of the lumen. (Reproduced with permission from Barrett KE: Gastrointestinal Physiology. New York: Lange Medical

H+

3Na+

H+ + HCO3−

2K+

H+ + HCO3−

H2O + CO2 CFTR? Cl−

?

Cl−

?

Reabsorbed BA−

Books/McGraw-Hill, Medical Pub. Division, 2006.)

reduction in sphincter of Oddi tone is primarily brought about by CCK. CCK activates predominantly a neural mechanism to initiate this physiologic response, transmitted through the enteric nervous system. The final mediators acting at the level of the sphincter smooth muscle are VIP and nitric oxide, released from sphincter of Oddi nerve ganglia.

CLINICAL CORRELATION A 43-year-old woman who is a mother of three comes to her primary care physician complaining of sharp, colicky abdominal pain, usually when she enjoys a pepperoni pizza or other large, fatty meals. Recently, she has had pain with any meal. Her physical examination is unremarkable other than a finding that she is overweight. Nevertheless, having ruled out any cardiac disease, her physician refers her for an imaging study of her gallbladder. This reveals several stones. The patient undergoes a laparoscopic removal of her gallbladder (cholecystectomy) and her symptoms subside, other than the fact that she still cannot tolerate pepperoni pizza or fatty meals without some discomfort and bloating. The formation of stones in the gallbladder is a common disease that has afflicted humans for millennia. More than 20 million Americans have gallstones. Gallstone-related symptoms and complications are among the most common gastroenterologic disorders requiring hospitalization, at great cost to the health care system. Gallstones are of two types, related to the deposition of either cholesterol (cholesterol stones) or bilirubin (pigment stones). Choles-

terol stones account for the majority of gallstones in most Western countries. Human bile is unusually rich in cholesterol. In cholesterol gallstone disease, the balance between the normal ratios of cholesterol to the other biliary lipids is disrupted, either due to cholesterol hypersecretion, relative hyposecretion of bile acids or phospholipids, or some combination of these. Obesity, the use of oral contraceptives, estrogen, old age, sudden weight loss, and genetic factors may lead to cholesterol hypersecretion. Conversely, a diminished bile acid pool can occur if the enterohepatic circulation is interrupted. In either case, patients are at risk for supersaturation of cholesterol and thus for the development of gallstones. Supersaturation is not necessarily sufficient for stone formation, however, since nucleation must also occur. Some patients may be genetically predisposed to secrete proteins that can act as nucleating agents, whereas other proteins in bile may retard nucleation. Two thirds of patients with gallstones will have no associated symptoms. Others present with episodic pain in the epigastric region. In most patients, the pain is biliary colic, thought to reflect a tonic spasm resulting from transient obstruction of the cystic duct by a stone, and sometimes precipitated by eating a large meal. Biliary colic, while severe, usually subsides within a few hours, which serves to distinguish it from acute cholecystitis, where obstruction of the cystic duct leads to inflammation of the gallbladder. In some patients, acute inflammation may progress to chronic cholecystitis, resulting in a thickened and fibrotic gallbladder. The definitive treatment for symptomatic gallstone disease is cholecystectomy, which is usually simple, safe, and curative, particularly with the advent of laparoscopic approaches.

CHAPTER 56 Bile Formation, Secretion, and Storage

CHAPTER SUMMARY ■

■

■ ■

■

■

■ ■ ■

Bile is secreted by the liver as a vehicle to excrete lipid-soluble waste products of metabolism as well as xenobiotics, and it also aids in fat digestion and absorption. The major solutes driving the primary secretion of bile are the bile acids, which are amphipathic molecules synthesized from cholesterol in the hepatocyte. Bile acids are actively secreted into the bile canaliculus in conjugated forms by an energy-dependent transporter. Bile also contains cholesterol and phosphatidylcholine, which are actively transported into the primary secretion, as well as solutes filtered from the plasma, such as calcium and glucose. Bile acids recycle several times daily from the intestine to the liver in the enterohepatic circulation; in their conjugated forms, they are actively reabsorbed in the terminal ileum, thereby generating a recycling pool of bile acids. The gallbladder serves to store bile between meals and to coordinate the release of a concentrated bolus of bile with the presence of the meal in the duodenum. Gallbladder storage of bile results in changes in its composition, such that bile acids become the dominant anions. Bile remains isotonic during this process as bile acid monomers are rapidly incorporated into mixed micelles. Concentration of bile results from active transport processes taking place in the lining epithelial cells.

STUDY QUESTIONS 1. A patient with Crohn’s disease undergoes surgical resection of her diseased terminal ileum. After recovering from the surgery, she is noted to have moderate steatorrhea. What level of bile acid synthesis by the patient’s hepatocytes would be expected compared with a normal individual? A) 10-fold higher B) 10% higher C) unchanged D) 10% less E) 10-fold less

573

2. The composition of bile is modified as it flows through the biliary ductules. Which of the following is expected to increase in concentration during this transit? A) glucose B) bile acid monomers C) alanine D) glutathione E) IgA 3. A scientist studying the enterohepatic circulation measures the portal concentration of conjugated bile acids in rats treated with various drugs. An inhibitor of which of the following ion transport proteins would be expected to reduce the uptake of sodium taurocholate from the small intestinal lumen? A) Na+,K+-ATPase B) CFTR C) ENaC D) NKCC1 E) chloride/bicarbonate exchanger 4. Compared with hepatic bile, bile that has been stored in the gallbladder for several hours would be expected to display which of the following changes in concentration? Cholesterol

Base Equivalents

Calcium

A)

Increased

Increased

Increased

B)

Decreased

Decreased

Decreased

C)

Increased

Decreased

Increased

D)

Decreased

Increased

Decreased

E)

Decreased

Decreased

Increased

F)

Increased

Increased

Decreased

5. Sphincter of Oddi relaxation is normally coordinated with gallbladder contraction to allow bile outflow into the duodenum. Which of the following mediators circulates through the bloodstream to mediate this coordination when the meal is in the duodenum? A) gastrin B) motilin C) acetylcholine D) cholecystokinin E) nitric oxide

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57 C

Handling of Bilirubin and Ammonia by the Liver Kim E. Barrett

H A

P

T

E

R

O B J E C T I V E S ■ ■ ■ ■ ■

Understand the origins of bilirubin in the plasma, the need to excrete this substance, and how it is transported through the body. Describe the pathway of bilirubin handling, and further metabolic modifications that occur. Define the contributors to the level of ammonia in the circulation, and explain why a mechanism for disposal of this metabolite is needed. Describe the metabolic steps involved in the conversion of ammonia to urea in the hepatocyte. Understand the routes for eventual disposal of urea.

BASIC PRINCIPLES OF BILIRUBIN METABOLISM

PATHWAYS OF BILIRUBIN SYNTHESIS AND METABOLISM

Bilirubin is a metabolite of heme, a compound that serves to coordinate iron in various proteins. Very recently, bilirubin has been shown to possess important functions as an antioxidant, but it also serves simply as a means to excrete unwanted heme, derived from various heme-containing proteins such as hemoglobin, myoglobin, and various P450 enzymes. Bilirubin and its metabolites are also notable for the fact that they provide color to the bile and stool, as well as, to a lesser extent, the urine.

Bilirubin derives from two main sources. The majority (80%) of the bilirubin formed in the body comes from the heme released from senescent red blood cells. The remainder originates from various heme-containing proteins found in other tissues, notably the liver and muscles.

ROLE AND SIGNIFICANCE It is important for the body to be able to excrete bilirubin as it is potentially toxic. Excessive levels of bilirubin in the bloodstream can lead to accumulation of bilirubin in the brain due to its ability to cross the blood–brain barrier, a condition known as kernicterus (meaning “stained nuclei”). The development of this condition impairs brain function and can be fatal if untreated. Bilirubin is also notable for its yellow coloration. Accumulation of this substance in the blood is the basis for jaundice, or a yellow discoloration of the skin and eyes, which is a common symptom of liver diseases. Thus, measurement of bilirubin in the plasma can be a useful marker of such conditions.

Ch57_575-582.indd 575

CELLULAR HEME METABOLISM Bilirubin is produced by a two-stage reaction that occurs in cells of the reticuloendothelial system, including phagocytes, the Kupffer cells of the liver, and cells in the spleen and bone marrow. Heme is taken up into these cells and acted on by heme oxygenase, liberating the chelated iron from the heme structure and releasing an equimolar amount of carbon monoxide, which is eliminated via the lungs. The reaction yields a green pigment known as biliverdin (Figure 57–1). Biliverdin is then acted on by the enzyme biliverdin reductase, producing the yellow bilirubin. Bilirubin is almost insoluble in aqueous solutions at neutral pH. Thus, after its release into the plasma, it is taken up by albumin and transported throughout the body. The binding affinity of unconjugated bilirubin for albumin is extremely

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SECTION VIII GI Physiology

COO−

COO−

CH3

H3C N

N

Heme

Fe N

N

H2 C

CH3 CH2

CH3

NADPH + O2 Heme oxygenase CO + Fe3+ + NADP+

M

V

M

P

P

M

M

V Biliverdin

N H

O

N H

N

V

M

P

O

NADPH

Biliverdin reductase

M

N H

NADP+

P

M

M

V Bilirubin

O

N H

N H

H

H

N H

N H

O

FIGURE 57–1 Conversion of heme to bilirubin is a two-step reaction catalyzed by heme oxygenase and biliverdin reductase. M, methyl; P, proprionate; V, vinyl. (Modified with permission from Barrett KE: Gastrointestinal Physiology. New York: Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2006.)

high; there is usually very little free unconjugated bilirubin in the plasma. When the bilirubin-laden albumin reaches the liver, the high permeability of the hepatic microcirculation, as discussed in Chapter 55, allows the complex to enter the space of Disse such that it encounters the basolateral aspect of hepatocytes. At this site, bilirubin is taken up by a specific transport mechanism to enter the hepatocyte. However, this process is relatively inefficient, with the first-pass clearance of bilirubin being only about 20%.

HEPATIC TRANSPORT MECHANISMS The transporter responsible for uptake of the bilirubin into the hepatocyte is thought to be a member of the organic anion transporting polypeptide (OATP) family (Figure 57–2).

Once inside the hepatocyte, bilirubin requires special handling to maintain its solubility and traffic it appropriately. Thus, it is believed to bind to a variety of intracellular proteins, including fatty acid–binding proteins that direct the molecule to the microsomal compartment for conjugation. These proteins are likely also responsible for vectorial transport of the conjugated bilirubin to the canalicular membrane for transport into the bile. Following its conjugation, bilirubin exits the hepatocyte into the bile via a membrane transport protein known as MRP2. While this transporter has a relatively broad specificity, transporting additional metabolic products as well as some drug conjugates, it appears that its main physiological substrate is conjugated bilirubin. Insights into the role and significance of this transporter have been gained from a genetic disorder known as Dubin–Johnson syndrome, where mutations in the MRP2 gene lead to the absence of the transporter. However, even in health, transport of either unconjugated or conjugated bilirubin through the hepatocyte cytosol is not entirely efficient, and some escapes back into the plasma where it binds once more to albumin and can be transported around the body. On the other hand, only conjugated bilirubin is able to enter the bile via MRP2. It is primarily present in the aqueous fraction of the bile and is not believed to associate to any significant extent with the mixed micelles formed by the biliary lipids. Conjugated bilirubin is also neither further metabolized nor absorbed during its passage along the biliary tree.

HEPATOCYTE CONJUGATION The hepatocyte plays an important role in bilirubin handling by conjugating the molecule to glucuronic acid. This reaction is catalyzed by UDP glucuronyl transferase (UGT), and results in the sequential esterification of two glucuronide moieties to the propionic acid side chains of bilirubin (Figure 57–2). Under normal conditions, most molecules of bilirubin are modified with two glucuronide groups, forming bilirubin diglucuronide. Conjugation has several important effects on the physicochemical properties of bilirubin. First, it markedly increases its water solubility, allowing it to be transported in the bile without a protein carrier. Second, as a result of this increase in hydrophilicity, and increased molecular size, conjugated bilirubin cannot be passively reabsorbed from the intestinal lumen. There are also no specific transporters for the uptake of conjugated bilirubin in the intestine. Thus, conjugation serves to promote the elimination of this metabolic waste product. Finally, conjugation modestly decreases the affinity of bilirubin for albumin. Normal levels of total serum bilirubin are approximately 1–1.5 mg/dL in human adults, consisting of approximately 90% unconjugated and 10% conjugated bilirubin. The relative proportions of conjugated and unconjugated bilirubin in disease states provide important clues about the level of any dysfunction in the bilirubin export pathway.

CHAPTER 57 Handling of Bilirubin and Ammonia by the Liver

Alb

577

BILIRUBIN HOMEOSTASIS

B Reflux to plasma

BACTERIAL METABOLISM

Alb + B

In the small intestine, there appears to be little deconjugation or additional metabolism of bilirubin in the healthy gut. However, when conjugated bilirubin enters the colon, it can be rapidly deconjugated by the enteric flora, releasing it for further metabolism by anaerobic bacteria (Figure 57–3). Bilirubin is extensively metabolized in this site, producing molecules known as urobilinogens and stercobilinogens. These are further metabolized to urobilins and stercobilins, which give color to the stool. Urobilinogen, which is able to cross the colonic epithelium passively, also enters the enterohepatic circulation. In turn, it can be conjugated by the hepatocyte and secreted into bile.

e

Space of Diss

OATP

B UDP glucuronyl transferase

UDP-G UDP

BG BG2

MRP2

BG BG2

Canaliculus

Hepatocyte

FIGURE 57–2

Handling of bilirubin by hepatocytes. Albumin (Alb)-bound bilirubin (B) enters the space of Disse, and bilirubin is selectively transported into the hepatocyte, where it is either monoconjugated or diconjugated with glucuronic acid (G).The conjugates are secreted into bile via the multidrug resistance protein 2 (MRP2). Some unconjugated and conjugated bilirubin may also reflux into the plasma. OATP, organic anion transporting polypeptide. (Reproduced with permission from Barrett KE, Barman SM, Boitano S, Brooks H: Ganong’s Review of Medical Physiology, 23rd ed. McGraw-Hill Medical, 2009.)

Bilirubin

URINARY ELIMINATION Even under conditions of hyperbilirubinemia, little, if any, unconjugated bilirubin is able to enter the urine because of its tight binding to albumin. Urobilinogen, on the other hand, has appreciable aqueous solubility, and a small fraction (typically less than 5% of the urobilinogen pool) is lost to the urine on a daily basis, and is thought to contribute to the color of urine.

UroB Liver

Systemic circulation

BG2

UroBG2

Small

UroB

Urine (1−3%)

B

ne intesti

Enterohepatic circulation

Bacteria

UroB Colon Fecal urobilins and stercobilins (97−99%)

FIGURE 57–3 Cycling of bilirubin and its products through the liver, intestines, portal and systemic circulations, and kidneys. B, bilirubin; UroB, urobilinogen; G, glucuronide. Most UroB reabsorbed from the colon is taken up by the liver, but a small portion (indicated by the dashed arrow) spills over into the systemic circulation, from where it can be excreted by the kidneys. (Adapted with permission from Barrett KE: Gastrointestinal Physiology. New York: Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2006.)

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SECTION VIII GI Physiology

Jaundice

Bilirubin in urine

FIGURE 57–4 Differential diagnosis of jaundice depending on whether bilirubin is or is not present in the urine. (Reproduced with permission from Barrett KE: Gastrointestinal Physiology. New York: Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2006.)

Genetic defects in excretion

No bilirubin in urine

Hepatobiliary disease

Extrahepatic cholestasis

HYPERBILIRUBINEMIA Hyperbilirubinemia simply refers to excessive levels of bilirubin in the blood. This can be detected during clinical examination by the yellowish coloration it imparts to the skin (jaundice), and is an important marker of several disease states, some of which center on the liver. It is important to distinguish whether the plasma contains increased levels of conjugated bilirubin, unconjugated bilirubin, or both, in order to define the mechanism of disease. This can be assessed directly, but clues can also be provided by the presence of bilirubin in the urine, which imparts a brown coloration. Because of its less avid binding to albumin, an increase in urinary bilirubin reflects almost exclusively the conjugated molecule. In general, because conjugated bilirubin can be excreted in the urine, increases in its plasma levels represent a less serious state than those associated with severe unconjugated hyperbilirubinemia. An algorithm for the differential diagnosis of hyperbilirubinemia that takes account of these factors is presented in Figure 57–4.

Overproduction

Intrahepatic cholestasis

Impaired conjugation

Impaired hepatic uptake

AMMONIA FORMATION AND DISPOSITION Ammonia in the circulation originates in a number of different sites. A diagram showing the major contributors to ammonia levels is shown in Figure 57–5. Note that the liver is efficient in taking up ammonia from the portal blood in health, leaving only approximately 15% to spill over into the systemic circulation.

INTESTINAL PRODUCTION The major contributor to plasma ammonia is the intestine, supplying about 50% of the plasma load. Intestinal ammonia is derived via two major mechanisms. First, ammonia is

BASIC PRINCIPLES OF AMMONIA METABOLISM Ammonia (NH3) is a small metabolite that results predominantly from protein degradation. It is highly membrane permeable and readily crosses epithelial barriers in its nonionized form.

ROLE AND SIGNIFICANCE Ammonia is important clinically because it is highly toxic to the nervous system. Because ammonia is being formed constantly from the deamination of amino acids, it is important that mechanisms exist to provide for its timely and efficient disposal. The liver is critical for ammonia catabolism because it is the only tissue in which all elements of the urea cycle, also known as the Krebs–Henseleit cycle, are expressed, providing for the conversion of ammonia to urea. Ammonia is also consumed in the synthesis of nonessential amino acids, and in various facets of intermediary metabolism.

Intestinal production (mostly colonic) 50%

Renal production 40%

Red blood Muscle 5% cells 5%

FIGURE 57–5

Sources of ammonia production. (Reproduced

with permission from Barrett KE: Gastrointestinal Physiology. New York: Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2006.)

CHAPTER 57 Handling of Bilirubin and Ammonia by the Liver

579

Net reaction 2NH3 + CO2 = Urea + H2O

Hepatocyte NH3

NH3+

O ATP HCO3− ADP

H2N C NH (CH2)3 Citrulline

P O

O

1 H2N C O P O− 1 Carbamoyl O− Mitochondrion phosphate +

NH4

COO−

Aspartate

2 AMP COO−

NH2+

OOC CH2 CH NH Arginine succinate Ornithine

CH

C

NH3+

NH (CH2)3 CH COO−

3

NH3+

Fumarate

+

−

H3N

(CH2)2 CH COO

NH2+

NH3+

H2N C NH (CH2)3 CH COO− Arginine Urea cycle H 2O 4 O Cytosol

H2N C Urea

NH2

To circulation 1

FIGURE 57–6

Carbamoyl synthetase

2

Arginosuccinate synthetase

3 Arginine succinate lyase

4

Arginase

Whole body ammonia homeostasis in health. The majority of ammonia produced by the body is excreted by the kidneys in

the form of urea. (Reproduced with permission from Barrett KE, Barman SM, Boitano S, Brooks H: Ganong’s Review of Medical Physiology, 23rd ed. McGraw-Hill Medical, 2009.)

liberated from urea in the intestinal lumen by enzymes known as ureases. Ureases are not expressed by mammalian cells, but are products of many bacteria, and convert urea to ammonia and carbon dioxide. Second, after proteins are digested by either host or bacterial proteases, further breakdown of amino acids generates free ammonia. Ammonia in its nonionized form crosses the intestinal epithelium freely, and enters the portal circulation to travel to the liver; however, depending on the pH of the colonic contents, a portion of the ammonia will be protonated to ammonium ion. Because the colonic pH is usually slightly acidic, the ammonium is thereby trapped in the lumen and can be eliminated in the stool.

EXTRAINTESTINAL PRODUCTION The second largest contributor to plasma ammonia levels is the kidney. You will recall from renal physiology that ammonia transport by tubular epithelial cells is an important part of the response to whole body acid–base imbalances (see Chapter 47). Ammonia is also produced in the liver during the deamination of amino acids. Minor additional components of plasma ammonia derive from adenylic acid metabolism in muscle cells, as well as glutamine released from senescent red blood cells.

UREA CYCLE The most important site for ammonia catabolism is the liver, where the elements of the urea cycle are expressed in hepatocytes. A depiction of the urea cycle is provided in Figure 57–6. Ammonia is converted in the mitochondria to carbamoyl phosphate, which in turn reacts with ornithine to generate citrulline. Citrulline, in turn, reacts in the cytosol with aspartate, produced by the deamination of glutarate, to yield sequentially arginine succinate, and then arginine itself. The enzyme arginase then dehydrates arginine to yield urea and ornithine, the latter of which returns to the mitochondria and can reenter the cycle to generate additional urea. The net reaction is the combination of two molecules of ammonia with one of carbon dioxide, yielding urea and water.

UREA DISPOSITION A “mass balance” for the disposition of ammonia and urea is presented in Figure 57–7. As a small molecule, urea can cross cell membranes readily. Likewise, it is filtered at the glomerulus and enters the urine. While urea can be passively reabsorbed across the renal tubule as the urine is concentrated, its permeability is less than that of water such that only approximately half of the filtered load can be reabsorbed. Because of

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Systemic circulation 15%

P o rt

a l c ir c u l a ti o

n

85%

cu cir

Urea

n latio

Syste

mi c

NH3

25% 75%

Urea

Proteins + Amino acids Urinary excretion as urea

+ NH3 H

NH4+

Fecal excretion as ammonium ion

FIGURE 57–7 The urea cycle, which converts ammonia to urea, takes place in the mitochondria and cytosol of hepatocytes. (Reproduced with permission from Barrett KE, Barman SM, Boitano S, Brooks H: Ganong’s Review of Medical Physiology, 23rd ed. McGraw-Hill Medical, 2009.)

this, the kidney serves as the site where the majority of the urea produced by the liver is excreted. However, some circulating urea may also passively back diffuse into the gut, where it is acted on by bacterial ureases to again yield ammonia and water. Some of the ammonia generated is excreted in the form of ammonium ion; the remainder is again reabsorbed to be handled by the liver once more.

CLINICAL CORRELATION A 55-year-old homeless man is brought to the emergency room by the police because he has been found unresponsive in the street. His friends state that he has been drinking heavily. On physical examination, he is found to show signs of malnutrition, and his skin and the sclera of his eyes have a yellowish coloration. His abdomen is markedly distended, and palpation shows that his liver is enlarged. Over the next hour, he regains consciousness, but still shows signs of significant confusion, and cannot supply his name, or identify the day of the week or the current President. A counselor comes to see him to discuss the likely adverse outcomes of continued alcohol ingestion, and he is referred to a shelter and a treatment program. Chronic ingestion of excessive quantities of alcohol can have insidious effects on hepatic function, as fibrotic hard-

ening of the liver alters several aspects of structure and function. Indeed, alcohol abuse is one of the most important causes of chronic liver disease, and cirrhosis (irreversible deposition of excess collagen in the liver) accounts for the majority of all medical deaths among alcoholics. Most ingested ethanol is metabolized rapidly in the liver. Products of ethanol metabolism, most notably acetaldehyde, impair several aspects of hepatocyte metabolic function, as well as producing oxidative stress and forming protein adducts that may trigger adverse immune reactions that lead to cell death. In its initial stages, alcoholic liver disease involves the accumulation of fat in the liver. Ultimately, hepatic stellate cells are activated to produce collagen, and this occurs chronically if ingestion of excessive amounts of alcohol continues. In a subset of patients, hepatitis and fibrosis will progress to cirrhosis, characterized by fibrous bands connecting the portal triads with central veins, and small, regenerative nodules. Patients with alcoholic liver disease that has progressed at least to hepatitis and fibrosis present with a spectrum of symptoms of chronic liver failure, including jaundice, nausea, and malaise. Male patients may have hypogonadism and feminization, ascribable to both the direct toxic effects of ethanol on testicular Leydig cells and effects on estrogen production and reduced estrogen breakdown. In severe cases, there can be a collection of fluid in the abdominal cavity known as ascites that may become infected (see Chapter 55), hepatic encephalopathy, renal failure, and eventually death. The primary treatment is to secure abstinence from alcohol, although some liver changes may be irreversible even after drinking has stopped. When ammonia degradation is reduced, it can accumulate in the plasma to levels that become toxic to the central nervous system. Remember that ammonia, as a small, neutral molecule, is relatively permeable across cell membranes and can easily traverse the blood–brain barrier. Patients will experience a gradual decline in mental status with confusion and dementia, followed eventually by coma if the condition is untreated. The increase in plasma ammonia in liver disease occurs by two mechanisms. First, if hepatocyte function is compromised, there is less capacity to degrade ammonia coming from the intestine and extraintestinal sites. Second, if blood flow through the liver is impaired by cirrhosis and portal hypertension has set in (see also Chapter 55), collateral blood vessels may form that shunt the portal blood flow around the liver, bypassing the residual capacity of the liver to degrade ammonia. It is likely that both mechanisms contribute to the rise in plasma ammonia in the setting of long-standing liver disease. Because the intestine supplies the largest load of ammonia to the circulation, treatments for hepatic encephalo– pathy focus primarily on reducing the delivery of ammonia into the portal circulation. A common technique is to give a sugar, lactulose, which cannot be degraded by mammalian digestive enzymes but is broken down by bacteria in

CHAPTER 57 Handling of Bilirubin and Ammonia by the Liver

the colon to form short-chain fatty acids. In turn, the pH of the colonic lumen is decreased, and more of the ammonia being formed in that site is protonated and “trapped” as ammonium ion to be lost to the stool. Similarly, patients can be given a nonabsorbable antibiotic such as neomycin that reduces the level of bacterial colonization in the intestine, thereby reducing ammonia production. Finally, patients with liver disease are often advised to follow a lowprotein diet, again in an effort to reduce ammonia production in the intestine. Ultimately, however, the only lasting treatment for hepatic encephalopathy is a liver transplant, and mental symptoms often are reversible if they have not been too long-standing. Nevertheless, transplantation remains controversial in alcoholic patients.

CHAPTER SUMMARY ■

■

■

■

■

■

■

■

Bilirubin is a highly insoluble antioxidant produced by the metabolism of heme. It is derived mostly from senescent red blood cells and circulates with albumin. Bilirubin is taken up into hepatocytes, conjugated with glucuronide, and transported across the bile canaliculus by MRP2. Conjugation increases the solubility of bilirubin and prevents its reuptake from the intestinal lumen. Only conjugated bilirubin is transported into the bile, but both conjugated and unconjugated bilirubin may regurgitate from the hepatocyte into the plasma. Bilirubin is deconjugated and further metabolized by colonic bacteria; some of the products may circulate enterohepatically— notably urobilinogen, which also enters the urine. Hyperbilirubinemia can arise from an increase in the plasma levels of conjugated bilirubin, unconjugated bilirubin, or both, and often reflects liver disease. Ammonia in plasma is derived from protein degradation and deamination of amino acids, as well as from metabolism of urea by bacterial ureases. The intestine supplies the majority of plasma ammonia. Excessive amounts of ammonia in the circulation are toxic to the central nervous system, so circulating levels are carefully regulated in health. The liver is the site of ammonia catabolism via the Krebs– Henseleit, or urea, cycle. The urea produced is mostly excreted by the kidneys.

STUDY QUESTIONS 1. A newborn infant is noted to be suffering from mild jaundice, but no bilirubin is found in the urine. The child’s symptoms are most likely attributable to a developmental delay in the expression or establishment of which of the following? A) colonic bacterial colonization B) MDR2 C) UGT D) heme oxygenase E) biliverdin reductase

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2. A 2-year-old boy is brought to the pediatrician because his mother has noted a persistent, dark brown coloration of his urine. He is otherwise healthy, and his mother notes that a cousin displayed similar symptoms. Tests reveal conjugated hyperbilirubinemia. Bile produced by this child would be expected to display which of the following changes in composition compared with that of a normal child? Bilirubin

Urobilinogen

Bile Acids

A)

Decreased

Decreased

Decreased

B)

Increased

Increased

Increased

C)

Decreased

Increased

Decreased

D)

Increased

Decreased

Increased

E)

Decreased

Decreased

Unchanged

F)

Increased

Increased

Unchanged

3. In health, ammonia formed in the colon is partially excreted in the stool. Which of the following allows for this excretion? A) limited diffusion of ammonia across colonocytes B) short-chain fatty acid production C) active secretion of ammonia by colonocytes D) absorption of ammonium ions E) uptake by bacteria 4. A 70-year-old man with long-standing alcoholic liver disease is noted to have progressively worsening confusion and disorientation. Loss of the function of which cell type accounts for his altered mental state? A) Kupffer cells B) hepatocytes C) colonocytes D) vascular endothelial cells E) stellate cells 5. A patient with severe portal hypertension is noted to have bulging veins that protrude into his esophagus (esophageal varices) on endoscopic examination. He is treated surgically by the placement of a shunt connecting the portal vein to the vena cava. Which of the following will pertain after the surgery compared with before? Risk of Encephalopathy

Risk of Variceal Bleeding

A)

Increased

Decreased

B)

Decreased

Decreased

C)

Unchanged

Decreased

D)

Increased

Increased

E)

Decreased

Increased

F)

Unchanged

Increased

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58 C

Digestion and Absorption of Carbohydrates, Proteins, and Water-soluble Vitamins Kim E. Barrett

H A

P

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O B J E C T I V E S ■ ■

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Understand the barriers to assimilation of water-soluble macromolecules into the body. Describe dietary sources of carbohydrates, and the pathways involved in the digestion and absorption of carbohydrate polymers, dietary disaccharides, and monosaccharides. Compare and contrast protein assimilation with that of carbohydrates. Identify essential amino acids, and understand why they must be provided in the diet. Describe pathways involved in the digestion and absorption of proteins, peptides, and amino acids. Understand how protein assimilation is regulated. Define how key water-soluble vitamins are taken up into the body.

BASIC PRINCIPLES OF CARBOHYDRATE AND PROTEIN ASSIMILATION ROLE AND SIGNIFICANCE Carbohydrates and proteins are water-soluble macromolecules of nutritional significance. Together with lipids, discussed in the next chapter, they represent the major sources of calories in the diet, and each supplies specific building blocks for molecules needed for the physiologic function of the body as a whole. Dietary carbohydrates are the major exogenous source of glucose, which is utilized by cells as an energy source. Nutritionally significant carbohydrates include both large polymers and disaccharides (Table 58–1). Proteins supply amino acids, which are resynthesized into new proteins needed by the body.

Ch58_583-592.indd 583

TABLE 58–1 Nutritionally important carbohydrates. Starch Amylose Amylopectin Disaccharides Sucrose Lactose Monosaccharides Glucose Galactose Fructose Dietary fiber

While the body can synthesize glucose de novo from a variety of substrates, some amino acids (essential amino acids) cannot be synthesized by the body.

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BARRIERS TO THE ASSIMILATION OF WATER-SOLUBLE MACROMOLECULES Due to their hydrophilicity, proteins and carbohydrates are “at home” in the aqueous environment of the intestinal lumen. However, neither they nor the water-soluble end products of their digestion can readily traverse the membranes of the epithelial cells that line the small intestine. Moreover, intact dietary polymers are too large to be transported into cells. Thus, an ordered series of chemical reactions breaks down both proteins and carbohydrate polymers to their component monomers or short oligomers. Digestion of both carbohydrates and proteins takes place in two sites. First, enzymes secreted into the intestinal lumen begin the digestive process. Second, membrane-bound hydrolases localized to the microvillous membrane (“brush border”) of the epithelial cells lining the villus tips in the small intestine mediate the next stage of digestion. The epithelium is only capable of transporting monosaccharides, so even dietary disaccharides must be digested at the brush border before they can be absorbed. For proteins, on the other hand, the epithelium expresses transporters that can take up short peptides, as well as those specific for monomeric amino acids. Thus, peptides taken up into the enterocytes undergo a third stage of digestion in the cytosol, mediated by intracellular hydrolases.

CARBOHYDRATE ASSIMILATION SOURCES OF CARBOHYDRATE IN THE DIET Carbohydrates represent a major component of most human diets, and assume particular importance in specific populations (Table 58-1). There are three main forms of carbohydrate that have nutritional significance—starch, sucrose, and lactose. Starch is the name given to a complex mixture of dietary polymers of glucose derived from plant sources, such as cereals and starchy vegetables. There are two different types of glucose polymers in starch, which is significant because they require different enzymes to digest them fully. About 25% of starch consists of amylose, which is composed of simple, straight-chain polymers of glucose (Figure 58–1A). The remainder of the nutritional portion of starch consists of amylopectin, which is composed of complex, branched polymers of glucose (Figure 58–1A). Sources of starch also supply other carbohydrate polymers, as well as noncarbohydrate polymers, that collectively are known as dietary fiber. Fiber is characterized by the fact that constituent polymers cannot be degraded by mammalian digestive enzymes. It is critical for intestinal health because, being indigestible in the small intestine, it remains in the lumen and provides bulk to the stool, retaining fluid and aiding passage of the fecal material through the colon. Fiber has additional nutritional significance in that, although it is not

subject to digestion by mammalian enzymes, it can be broken down by hydrolases expressed by certain colonic bacteria. These reactions generate short-chain fatty acids, which are important energy sources for colonocytes.

LUMINAL DIGESTION OF CARBOHYDRATE Salivary Digestion Digestion of carbohydrates begins in the mouth. Saliva contains a 56-kd amylase enzyme that is closely related to the 55-kd amylase that is secreted into the pancreatic juice. As its name implies, salivary amylase is capable of digesting amylose, the straight-chain component of starch. Salivary amylase is not essential for the normal digestion of carbohydrates, since all of the enzymes in the pancreatic juice are present in considerable excess of requirements. However, the salivary enzyme likely does assume an important role in infants, where there is a developmental delay in the production of pancreatic enzymes, and as a backup in patients with pancreatic insufficiency, such as in those with cystic fibrosis. Salivary amylase is quite sensitive to acidic pH. However, its activity can be protected if its substrate occupies the active site of the enzyme. Thus, while starch is present in the gastric lumen, it is likely that its digestion mediated by salivary amylase can continue, until the task is assumed by pancreatic amylase. The latter is also sensitive to acid, but acts in an environment where gastric juices have been neutralized by duodenal, pancreatic, and biliary bicarbonate secretion. The synthesis and secretion of salivary amylase in the serous cells of the salivary glands are regulated by neurohumoral signals coincident with ingestion of a meal. Interestingly, in common with the pancreatic isoform, the synthesis of salivary amylase is upregulated by carbohydrate ingestion. Thus, the substrate controls the availability of the means of its digestion.

Intestinal Digestion In health, the majority of starch digestion likely involves the 55-kd amylase that is secreted as an active enzyme into the pancreatic juice by pancreatic acinar cells (see Chapter 51). Both the pancreatic and salivary enzymes act rapidly to cleave starch into a mixture of products, depending on whether amylose or amylopectin is the substrate. The amylase enzymes target internal α-1,4 bonds of both molecules, but the terminal bonds, as well as the α-1,6 bonds that provide for the branchedchain structure of amylopectin, are resistant (Figure 58–1A). This means that while the action of amylase is rapid, none of the products it generates can immediately be absorbed by the enterocytes, since the epithelium can only transport monosaccharides. By the time the meal reaches the proximal small intestine, therefore, digestion of starch will generate a mixture of maltose (a dimer of glucose), maltotriose (a trimer of glucose), and α-limit dextrins, which are the simplest structures that can be derived from the branch points in amylopectin.

CHAPTER 58 Digestion and Absorption of Carbohydrates, Proteins, and Water-soluble Vitamins A Glucose

585

B

α1,4 bond

1

Maltose Maltotriose

Amylose Glucoamylase Sucrase Isomaltase Amylase α1,6 bond

Amylopectin

2 α-limit dextrin

Glucoamylase Maltose Maltotriose

+

Glucose oligomers Isomaltase + α-limit dextrin

Glucoamylase Sucrase Isomaltase

FIGURE 58–1 A) Structure of amylose and amylopectin, which are polymers of glucose (indicated by circles). These molecules are partially digested by the enzyme amylase, yielding the products shown at the bottom of the figure. B) Brush border hydrolases responsible for the sequential digestion of the products of luminal starch digestion. Glucose monomers are indicated by circles. Panel 1 depicts the digestion of linear oligomers of glucose; panel 2 shows the final steps in digestion of α-limit dextrins. (Reproduced with permission from Barrett KE, Barman SM, Boitano S, Brooks H: Ganong’s Review of Medical Physiology, 23rd ed. McGraw-Hill Medical, 2009.)

Both maltose and maltotriose are resistant to amylase as they contain only terminal, and no internal, α-1,4 bonds.

BRUSH BORDER DIGESTION OF OLIGOSACCHARIDES AND DISACCHARIDES The products of luminal starch digestion, as well as dietary disaccharides, then are acted on by specific hydrolases present on the enterocyte brush border. Brush border digestion is an essential component of the pathways leading to assimilation of all dietary carbohydrates, with the exception of glucose. Brush border hydrolysis of carbohydrates, as well as other dietary components, likely increases the efficiency of carbohydrate absorption because the monosaccharides generated are produced in close proximity to the transporters that are then required for their uptake. Likewise, this may also sequester digested monosaccharides from the limited numbers of small intestinal bacteria. Brush border hydrolysis is catalyzed by a series of enzymes that are synthesized in the enterocytes as they differentiate

along the crypt–villus axis, with highest expression in the villus tips as well as in the proximal part of the small intestine. The enzymes are trafficked specifically to the apical membrane of the cells in these sites and anchored in the membrane by a single transmembrane segment. Brush border hydrolases are also heavily glycosylated. This may protect them, to some degree, from proteolysis. The enzymatic activities involved in brush border hydrolysis include sucrase, isomaltase, glucoamylase, and lactase. Sucrase and isomaltase activities are actually encoded in a single polypeptide chain with two distinct active sites, and thus the complete protein is referred to as sucrase-isomaltase. Overall, the brush border hydrolases cooperate to facilitate the complete digestion of dietary carbohydrates and the products derived from their luminal digestion.

Glucose Oligomers and α-Limit Dextrins The final digestion of these products of amylose and amylopectin digestion involves the concerted action of several brush border enzymes (Figure 58–1B). Glucoamylase, sucrase, and isomaltase activities are all capable of digesting the bonds

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SECTION VIII GI Physiology

1

Sucrose

Sucrase

Isomaltase

Na+

Brush border membrane

SGLT-1

GLUT5

Cytosol Glucose Fructose

Lactose

2 Lactase

Na+ SGLT-1

FIGURE 58–2

Brush border digestion and assimilation of the disaccharides sucrose (panel 1) and lactose (panel 2). SGLT-1, sodium-glucose cotransporter-1. (Reproduced with permission from Barrett KE, Barman SM, Boitano S, Brooks

Cytosol Glucose

H: Ganong’s Review of Medical Physiology, 23rd ed. McGraw-Hill Medical, 2009.)

contained in linear, short-chain (2–9 sugar units) oligomers of glucose, which include maltose and maltotriose. However, isomaltase is critical for the full digestion of starch, since it is unique among the listed activities in being able to cleave not only the α-1,4 bonds of linear glucose oligomers, but also the α-1,6 bonds of the α-limit dextrins. Glucose uptake is then mediated by SGLT-1, the sodium/glucose cotransporter. This cotransporter takes advantage of the low intracellular sodium concentration established by the basolateral Na,KATPase to accumulate glucose in the cytosol against a concentration gradient (i.e., uphill transport).

Sucrose Sucrose (table sugar) is a prominent carbohydrate in many Western diets and requires no luminal digestion because it is a simple disaccharide consisting of glucose and fructose. Rather, it is specifically digested at the level of the brush border by the enzyme sucrase, yielding the respective monosaccharides (Figure 58–2). Expression of sucrase-isomaltase is usually in excess of the requirements for this enzyme, at least in Western populations that emphasize sucrose in the diet. This means that the rate-limiting step for sucrose assimilation is not its hydrolysis, but rather the uptake of the released products

Galactose

across the apical membrane of the enterocyte. This is particularly the case for fructose, which enters the cytosol not via the SGLT-1 transporter, but rather via a sodium-independent, facilitated diffusion pathway (GLUT5).

Lactose Lactose is an important nutrient in those who consume large quantities of milk, such as infants. It is a disaccharide that consists of glucose and galactose and is broken down at the brush border by lactase, an enzyme that contains two identical active sites within a single polypeptide chain. The products of this hydrolysis reaction are, in turn, both substrates for SGLT-1 and thus can be accumulated against a concentration gradient (Figure 58–2). Lactose assimilation is limited in two important ways. First, there is a developmental decline in lactase expression, meaning that levels of this enzyme in adulthood may be inadequate to hydrolyze all of the substrate presented to them. Thus, lactose hydrolysis, rather than transport of the products of this reaction, is usually rate limiting for assimilation. Second, the activity of lactase is inhibited by glucose, in a process known as “endproduct inhibition.” If glucose levels increase in the vicinity of the enzyme, breakdown of lactose will further be inhibited.

CHAPTER 58 Digestion and Absorption of Carbohydrates, Proteins, and Water-soluble Vitamins

MONOSACCHARIDE UPTAKE PATHWAYS The final steps in carbohydrate assimilation involve specific membrane transport pathways that permit uptake of these hydrophilic molecules across the enterocyte apical membrane, as well as mediating their transfer out of the enterocyte across the basolateral membrane and thence into the portal circulation. We have already discussed two of these transporters, SGLT-1 and GLUT5. SGLT-1 is synthesized by villus enterocytes but not by those in the crypts, likely as a result of transcriptional regulatory mechanisms that parallel those involved in establishing brush border hydrolase expression. It exists in the membrane as a homotetramer, which appears to be important for its function. The protein mediates the ordered transfer of both sodium and glucose across the membrane. Sodium binds first to an extracellular site on the transporter, followed by glucose, which triggers a conformational change in the protein. This transfers these substrates to the cytoplasmic face of the membrane, where first glucose, and then sodium, can dissociate into the cytosol. Transporters of the GLUT family also play important roles in carbohydrate assimilation. The portion of absorbed glucose that is not needed for immediate energy needs of the enterocyte exits the cell across the basolateral membrane via a facilitated diffusion pathway (GLUT2). GLUT2 is sodium-independent, and thus the movement of glucose through this transporter will depend only on the relative concentrations of the sugar inside and outside the cell. It is also expressed in many other cell types throughout the body, where it participates in glucose uptake. A related molecule, GLUT5, provides for the brush border uptake of the fructose that is generated from the hydrolysis of sucrose (Figure 58–2). GLUT5 is also present in the basolateral membrane and thus can mediate transfer of fructose to the bloodstream, although there is evidence that fructose is additionally a substrate for GLUT2.

REGULATION OF CARBOHYDRATE ASSIMILATION Developmental In humans, the machinery for brush border digestion and absorption of carbohydrates is all in place before birth. However, the capacity for luminal digestion of carbohydrates is regulated in the postnatal period. Expression of pancreatic amylase is low in infants below the age of 1 and is gradually induced as starch is added to the diet. Conversely, lactase levels in the brush border decline after weaning. However, both of these responses likely do not reflect strict developmental regulation, but rather are appropriate adaptive responses to the appearance or disappearance of the relevant substrates in the normal diet.

Dietary The various components of the systems involved in carbohydrate assimilation are regulated by the diet in both the short

587

and long terms. Acutely, brush border hydrolases on the surface of enterocytes are degraded at the end of the meal, when dietary protein is no longer available to compete for the activity of pancreatic proteases. These enzymes are then resynthesized by the enterocyte to ready the epithelium to handle carbohydrates in the next meal. This cycle of degradation and resynthesis is not specific for the enzymes involved in carbohydrate digestion, but occurs for the entire complement of brush border proteins needed for nutrient assimilation. On the other hand, and on a longer time scale, if carbohydrates are specifically withheld from the diet, there is a gradual decline in the expression of the hydrolases and transporters that are involved in the assimilation of this class of nutrients, and likely also in the expression of amylase. All of these components are, in turn, upregulated if carbohydrate is then returned to the diet. These long-term changes are specific for the nutrient withdrawn from the diet. There are also hormonal influences on the expression of brush border hydrolases and transporters that match the capacity for carbohydrate assimilation with the body’s needs. Insulin, in particular, appears to suppress the levels of these molecules, meaning that glucose assimilation can be enhanced in the setting of type I diabetes mellitus.

PROTEIN ASSIMILATION COMPARISON WITH CARBOHYDRATE ASSIMILATION The digestion and absorption of proteins and carbohydrates shares many similar features, since both are water-soluble macromolecules, including a role for both luminal and brush border digestion and the presence of specific transporters in the apical membranes of enterocytes that take up the products of these digestion reactions. However, there are also important differences. First, the 20 naturally occurring amino acids, compared with the 3 nutritionally significant monosaccharides, mean that proteins represent a significantly more diverse set of substrates and require a broader spectrum of peptidases and transporters to mediate their digestion and uptake. Second, the intestine is capable of transporting not only single amino acids, but also short oligomers, encompassing dipeptides, tripeptides, and perhaps even tetrapeptides. In fact, some amino acids are absorbed much more efficiently in the form of peptides than as the single molecules. Finally, the existence of peptide transport in the intestine implies that these molecules must eventually be digested to their component amino acids in order for them to be useful to other body tissues. This final stage of protein digestion takes place in the cytosol of the enterocyte.

Essential Amino Acids Another important concept when considering protein assimilation is that of the essential amino acid. While the body (principally the liver) is able to convert one amino acid to another,

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Amino acids

Basic Arg Lys , His

Neutral

FIGURE 58–3

Naturally occurring amino acids organized on the basis of their physicochemical properties. Residues that are boxed are essential amino acids that must be obtained from dietary sources by humans. (Reproduced with permission from Barrett KE: Gastrointestinal Physiology. New York: Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2006.)

Acidic Glu, Gln Asp, Asn

Aliphatic Gly, Ala

Aromatic Tyr

Hydroxyl Ser

Sulfur Cys

Val , Leu , Ile

Phe , Try

Thr

Met

nine of the naturally occurring amino acids cannot be synthesized de novo, and therefore must be obtained from the diet and absorbed either as the amino acid itself or in peptide form (Figure 58–3). Proteins derived from animal sources contain all of the essential amino acids. However, proteins from vegetable sources are “incomplete,” meaning that they lack one or more of the essential amino acids.

LUMINAL PROTEOLYSIS Gastric Digestion of dietary proteins begins in the stomach—there are no nutritionally significant proteolytic enzymes found in the saliva. As we learned in Chapter 50, on the other hand, the chief cells of the gastric glands synthesize and store pepsinogens, inactive precursors of pepsins, which are a group of related proteolytic enzymes especially suited to action in the stomach. At low pH, there is autocatalytic cleavage of an N-terminal peptide from pepsinogen that yields the active form. Pepsins preferentially cleave dietary proteins at neutral amino acids, with a preference for large aliphatic or aromatic side chains. They are also sensitive to the pH of their environment, and are inactivated above a pH of 4.5. This means that gastric pepsins are quickly inactivated once they enter the small intestine, which may be important to prevent digestion of the epithelium. Because of the relatively limited specificity of pepsins, gastric proteolysis results in incomplete digestion with only a few free amino acids; the products are mostly large, nonabsorbable peptides. And in common with other aspects of the gastrointestinal system that are either redundant or present in excess, gastric proteolysis does not appear to be essential for normal levels of protein assimilation.

Intestinal The bulk of proteolysis occurs in the small intestinal lumen. This is a highly ordered process mediated by two families of pancreatic proteases, the secretion of which we discussed in Chapter 51. Endopeptidases cleave proteins and peptides at internal amide bonds. Ectopeptidases cleave at the terminal amino acid. All of the ectopeptidases secreted by the pancreas are carboxypeptidases—that is to say, they cleave off the

Imino Pro Hydroxypro

amino acid located at the C-terminus. Despite their various specificities, however, all of the pancreatic peptidases have one important feature in common. They are all stored in the pancreatic acinar cells as inactive precursors, which apparently is important to prevent autodigestion of the pancreas. How then are these inactive enzymes converted to their active forms only when they are in small intestinal lumen? The answer lies in yet another proteolytic enzyme—enterokinase— expressed on the apical membrane of small intestinal epithelial cells. When the pancreatic juice is secreted into the intestine, it comes into contact with enterokinase, which cleaves an N-terminal hexapeptide from trypsinogen, yielding active trypsin. Trypsin, in turn, can then activate additional trypsin molecules as well as all of the other inactive pancreatic peptidases only once they are in the intestinal lumen (Figure 58–4). The pathways of luminal proteolysis are shown in diagrammatic form in Figure 58–5. Large peptides derived from gastric proteolysis are sequentially cleaved by the endopeptidases (trypsin, chymotrypsin, and elastase). These reactions yield shorter peptides with either neutral or basic amino acids at their C-termini, which can be acted on in turn by carboxypeptidase A or carboxypeptidase B, respectively. Thus, the products of proteolysis in the intestinal lumen consist of free basic and neutral amino acids as well as short peptides that cannot be cleaved further due to the lack of an appropriate amino acid at their C-terminus. Approximately 60–70% of dietary protein is in the form of small oligopeptides following luminal hydrolysis; the remainder is in the form of amino acids.

BRUSH BORDER HYDROLYSIS Like carbohydrate assimilation, the degradation of proteins in the lumen is incomplete and they also undergo a process of brush border hydrolysis. However, because of the diversity of possible substrates, there is the requirement for a much larger number of brush border hydrolases. These membrane-bound enzymes comprise both endopeptidases and ectopeptidases, and are expressed by villus, but not crypt, enterocytes. The activity of these enzymes yields free amino acids in the vicinity of the enterocyte apical membrane, although some peptides remain relatively resistant to hydrolysis, and are taken up in their unhydrolyzed form.

CHAPTER 58 Digestion and Absorption of Carbohydrates, Proteins, and Water-soluble Vitamins

589

Pancreatic juice

Enterokinase

Trypsinogen Trypsin Trypsinogen

Trypsin

Chymotrypsinogen

Chymotrypsin

Proelastase

Elastase

Procarboxypeptidase A

Carboxypeptidase A

Procarboxypeptidase B

Carboxypeptidase B

FIGURE 58–4 Mechanism to avoid activation of pancreatic proteases until they are in the duodenal lumen. Trypsinogen is cleaved by the enzyme enterokinase, which is expressed on the apical membrane of duodenal epithelial cells (depicted as the pair of scissors).The trypsin that is thereby liberated can activate all of the other pancreatic proteases. (Reproduced with permission from Barrett KE, Barman SM, Boitano S, Brooks H: Ganong’s Review of

Epithelium

Lumen

UPTAKE MECHANISMS FOR OLIGOPEPTIDES AND AMINO ACIDS Peptide Transporters Perhaps the most fascinating aspect of protein assimilation is its dependence, in part, on a remarkable peptide transporter designated as peptide transporter 1 (PEPT1) (Figure 58–6). This protein is expressed on the apical membrane of enterocytes, and mediates the proton-coupled uptake of a broad variety of short peptides. What makes PEPT1 so intriguing is its extremely broad

Medical Physiology, 23rd ed. McGraw-Hill Medical, 2009.)

substrate specificity, accommodating peptides of various sizes and charges. Moreover, the stoichiometry of proton coupling can change, depending on the net charge of the peptide being transported. On the other hand, transport is strictly stereospecific— transport of peptides comprised of d-amino acids is negligible. The activity of this transporter is nutritionally significant, because it mediates the uptake of peptides resistant to brush border hydrolysis and thus increases the efficiency of protein assimilation from the gut. Indeed, certain amino acids are much more effectively absorbed in peptide form than when presented as individual molecules, especially glycine and proline.

Ser Chymotrypsin Elastase

Carboxypeptidase A

Peptide with C-terminal neutral AA

Large peptides

Arg Ser Short peptides free neutral and basic AA’s

Trypsin Carboxypeptidase B Arg Peptide with C-terminal basic AA

FIGURE 58–5 Luminal digestion of peptides resulting from partial proteolysis in the stomach. Individual amino acid residues are shown as squares. (Reproduced with permission from Barrett KE, Barman SM, Boitano S, Brooks H: Ganong’s Review of Medical Physiology, 23rd ed. McGraw-Hill Medical, 2009.)

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SECTION VIII GI Physiology

3Na+

Na+ NHE

2K+

H+ H+

Cytosolic digestion

PEPT1

Di-, tripeptides

Basolateral amino acid transporters

FIGURE 58–6 Disposition of short peptides in intestinal epithelial cells. Peptides are absorbed together with a proton supplied by an apical sodium/hydrogen exchanger (NHE) by the peptide transporter 1 (PEPT1). Absorbed peptides are digested by cytosolic proteases, and any amino acids that are surplus to the needs of the epithelial cell are transported into the bloodstream by a series of basolateral transport proteins. (Reproduced with permission from Barrett KE, Barman SM, Boitano S, Brooks H: Ganong’s Review of Medical Physiology, 23rd ed.

and amino tripeptidases. A cytosolic propeptidase, which hydrolyzes absorbed proteins that contain proline, has also been identified. Recall that peptides containing proline (and glycine) are relatively resistant to luminal or brush border hydrolysis.

REGULATION OF PROTEIN ASSIMILATION Many of the factors that regulate carbohydrate assimilation have analogous effects on protein assimilation. For example, brush border hydrolases, peptide transporters, and amino acid transporters can be degraded by proteolytic enzymes; these molecules are then resynthesized by the enterocyte to participate in the digestion and absorption of the next meal. Similarly, the membrane proteins involved in protein assimilation are expressed in gradients along the proximal to distal and crypt to villus axes.

McGraw-Hill Medical, 2009.)

Amino Acid Transporters Despite the significance of peptide uptake in the intestine, many amino acids are absorbed predominantly in molecular form. The physiology of amino acid transport in the intestine was at one time a complex topic, given the diversity of transporters that had been defined only functionally as well as some overlapping specificities. Moreover, some, but not all, amino acid transporters are sodium-dependent, analogous to SGLT-1 that we considered earlier for glucose uptake as well as the sodium-dependent bile acid transporter that recovers these molecules in the distal ileum. Others, analogous to PEPT1, may transport specific amino acids in concert with one or more protons. Finally, some amino acid transporters clearly have properties that classify them as facilitated diffusion pathways or even channels. More recently, some clarity has been brought to this field by molecular cloning of a large number of amino acid transport proteins from the gut, and their organization into families. We now know that there are multiple transport systems for neutral, cationic, and anionic amino acids, with each system being distinct but exhibiting overlapping specificity. However, it is beyond the scope of an introductory course in physiology to discuss all of these transporters in detail.

CYTOSOLIC PROTEOLYSIS Peptides absorbed into the enterocyte cytosol are further degraded before passing into the portal circulation. A portion of the released amino acids, as well as those taken up in molecular form, may also be utilized locally for the enterocyte’s own needs for protein synthesis. Peptide breakdown is mediated by a series of cytosolic peptidases that act to cleave N-terminal amino acids from these molecules, such as amino dipeptidases

WATER-SOLUBLE VITAMIN ASSIMILATION Vitamins are molecules that cannot be synthesized by the body, but which are essential to normal metabolism. Many act as cofactors for specific biochemical reactions, or play other critical roles in the body. Like essential amino acids, most vitamins must be obtained from dietary sources. We will consider here the uptake of two key water-soluble vitamins, since this process is analogous to the assimilation of the end products of carbohydrate and protein digestion. Lipid-soluble vitamins will be discussed in the next chapter.

VITAMIN C Vitamin C (ascorbic acid) acts as an antioxidant in the body as well as participates in a number of hydroxylation reactions. It is obtained from a variety of dietary sources, including citrus fruits and several vegetables. Having a pKa of 4.2, it is ionized at the pH of the small intestinal lumen and thus its passive diffusion across the epithelium is negligible. Thus, specific transport mechanisms exist to ensure its assimilation. Uptake of vitamin C is predominantly localized to the ileum. Ascorbic acid is transported across enterocyte apical membranes via a family of sodium-coupled cotransporters (SVCT1 and SVCT2), and uptake is controlled by intracellular signals. Vitamin C uptake is also regulated by its own levels in the body. Thus, supplementation with this vitamin, either orally or via injection, leads to a decrease in intestinal capacity for its transport. This finding implies that, unlike nutrient uptake, the intestine displays a capacity to allow for “vitamin homeostasis,” maintaining whole body levels of vitamins at a relatively stable level.

CHAPTER 58 Digestion and Absorption of Carbohydrates, Proteins, and Water-soluble Vitamins

VITAMIN B12 (COBALAMIN) Another water-soluble vitamin of note is vitamin B12, which is utilized by all cells in its coenzyme form in various metabolic reactions. Unlike vitamin C, whose uptake occurs via a simple, sodium-coupled mechanism, the uptake of cobalamin is more complex, and requires the participation of a specific binding factor secreted by parietal cells, known as intrinsic factor. Intrinsic factor secretion is triggered in the stomach by the same neurohumoral cues that result in gastric acid secretion. Intrinsic factor then binds to dietary cobalamin and later provides for the uptake of this vitamin. In an analogous fashion, cobalamin in the circulation is bound to a separate protein, plasma transcobalamin II (TC II). Specific receptors exist to mediate the endocytosis of cobalamin bound to each of these carrier proteins. Here, of course, we are chiefly concerned with the processes mediating cobalamin uptake from the intestinal lumen (Figure 58–7). In the gastric lumen, cobalamin is released from

Food-bound Cbl

Cbl bound Acid pH Biliary Cbl

Cbl free R R-Cbl + IF

Proteolytic degradation of R protein

R∗

Parietal cells secrete IF

Pancreatic proteases

Cbl

Cbl released IF-Cbl +IF after R protein degradation IF-Cbl complex forms IF-Cbl lleal enterocyte with receptor for IF-Cbl complex

Enterocyte

FIGURE 58–7 Sequential steps in the gastrointestinal absorption of vitamin B12 (cobalamin, Cbl). In the stomach, Cbl binds salivary R protein and intrinsic factor (IF) secreted by parietal cells. Proteolytic degradation of the R protein in the intestinal lumen yields a complex of only Cbl and IF, which then binds to a specific receptor located in the apical membrane of epithelial cells lining the terminal ileum. (Reproduced with permission from Halsted CH, Lonnerdal BL: Vitamin and mineral absorption. In: Textbook of Gastroenterology, 4th ed. Yamada T, Alpers DH, Kaplowitz N, Laine L, Owyang C, Powell DW (editors). Philadelphia: Lippincott Williams and Wilkins, 2003.)

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dietary proteins and binds initially to the R-binding protein (also known as haptocorrin), forming a complex that is stable at the acidic pH at this site. R-binding protein derives predominantly from the salivary glands. Intrinsic factor cannot bind to cobalamin at low pH. Rather, it follows the cobalamin–R-binding protein complex into the duodenum, where the R-binding protein is degraded by pancreatic proteases and the cobalamin is transferred to intrinsic factor at the increased pH that is brought about as gastric secretions are neutralized. The N-terminus of intrinsic factor also contains a binding sequence recognized by an apical receptor for this molecule that is expressed by enterocytes, known as the intrinsic factor-cobalamin receptor (IFCR). IFCR is highly expressed in the terminal ileum. When the complex of intrinsic factor and cobalamin binds to IFCR, the receptor plus the bound ligand is internalized, and these are then directed to a vesicular pathway for sorting and trafficking. Intrinsic factor is degraded, and the released cobalamin is then bound to TC II, synthesized by the enterocyte. In turn, this new complex is trafficked to the basolateral membrane, and released into the circulation in this form. Cobalamin bound to TC II can in turn be taken up via the specific receptor for this complex that is ubiquitously expressed throughout the body.

CLINICAL CORRELATION An 18-year-old, Asian American college freshman is living away from home for the first time. Having been brought up in a household that emphasized a traditional Chinese diet, and having been forbidden by his parents from indulging in snacks and junk food, he is particularly excited by the broad range of dishes to choose from in the cafeteria. He becomes particularly enamored of cheese pizza and chocolate ice cream. However, 2 weeks after the start of term, he comes to the student health center complaining of frequent diarrhea, gas, and bloating. A physical exam reveals that he is otherwise healthy and well nourished, and the patient denies any fever or bloody stools. Based on his history and symptoms, a diagnosis of lactose intolerance is made. A deficiency in the ability to assimilate dietary lactose is a common disorder, particularly in specific ethnic groups such as African-Americans and Asians who have not traditionally emphasized milk as a component of the adult diet. Lactose intolerance arises secondary to the normal developmental decline in lactase-phlorizin hydrolase levels that occurs after weaning, which occurs to a greater extent in some people than in others. In susceptible individuals, ingestion of lactose in dairy products overwhelms the capacity of the brush border lactase-phlorizin hydrolase to digest this disaccharide, leaving the undigested material in the small intestinal lumen from where it passes to the colon. In the colon, commensal bacteria are highly active in degrading lactose as an energy source, leading to symptoms of abdominal pain and bloating from the hydrogen and

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CO2 gases that are produced. The delayed production of hydrogen (or labeled CO2) in the breath following lactose ingestion can accordingly be used as a test for the presence of lactose intolerance. Patients with lactose intolerance who wish to consume dairy products can do so without major discomfort if they also take oral supplements of a lactase enzyme derived from bacteria. This supplemental lactase is resistant to degradation by gastric acid, and thus is available in the small intestinal lumen to cleave dietary lactose into its component monosaccharides, which can then be absorbed by the small intestine.

CHAPTER SUMMARY ■ ■

■

■

■ ■ ■ ■

Carbohydrates and proteins are water-soluble polymers that are important sources of nutrition. The end products of digestion are hydrophilic, and thus specific transporters are needed to translocate them across the plasma membrane of enterocytes. Both carbohydrates and proteins, with the exception of glucose monomers, must be digested to allow for their uptake across the intestinal epithelium. Only monosaccharides can be absorbed by the intestine, whereas the intestine can assimilate short peptides in addition to free amino acids. Digestion of both carbohydrates and proteins occurs in an ordered series of distinct stages. Both luminal and brush border hydrolysis are important; the latter may increase efficiency. Absorbed peptides also undergo cytosolic digestion in the enterocyte. Water-soluble vitamins also undergo selective transport across the intestinal epithelium.

STUDY QUESTIONS 1. Digestive enzymes can be secreted by the pancreas in active or inactive forms. Enzymes capable of digesting which of the following nutrients are only secreted as inactive precursors? A) starch B) nucleic acids C) proteins D) triglyceride E) cholesterol esters

2. An infant with diarrhea is given a glucose and electrolyte solution orally. What membrane protein accounts for the ability of this solution to provide rapid hydration? A) sucrase-isomaltase B) SGLT-1 C) CFTR D) chloride–bicarbonate exchanger E) lactase-phlorizin hydrolase 3. Glucose–galactose malabsorption is a rare disorder caused by mutations in SGLT-1. Infants with this disorder develop severe osmotic diarrhea if they consume certain carbohydrates. Of the following, which would not be expected to cause symptoms in these patients? A) sucrose B) glucose C) amylopectin D) lactose E) fructose 4. A child is brought to the pediatrician because of severe failure to thrive, diarrhea, and edema of the extremities. Blood tests reveal that he has low plasma protein concentration (hypoproteinemia). Duodenal aspirates are obtained at endoscopy after intravenous administration of cholecystokinin, and are found to be incapable of protein hydrolysis at neutral pH unless a small amount of trypsin is added. The patient is likely suffering from a congenital lack of which of the following? A) pepsinogen B) PEPT1 C) trypsinogen D) carboxypeptidases E) enterokinase 5. A 75-year-old woman comes to her physician complaining of progressively worsening fatigue and numbness in her fingers. A blood test reveals that she is anemic, despite adequate iron intake. Her symptoms resolve following a series of vitamin injections. Her symptoms are consistent with an age-related decline in synthesis of which of the following proteins? A) haptocorrin B) intrinsic factor C) transcobalamin D) SVCT1 E) PEPT1

59 C

Lipid Assimilation Kim E. Barrett

H A

P

T

E

R

O B J E C T I V E S ■ ■ ■ ■ ■ ■

Understand the special barriers to absorption of lipids supplied in the diet. Describe the phases of lipid digestion. Describe events at the level of the intestinal epithelium that govern uptake of different classes of lipids. Understand how the products of lipolysis cross the brush border. Delineate pathways for lipid processing in the enterocyte. Describe how chylomicrons are formed and their eventual disposition.

GENERAL PRINCIPLES OF LIPID ASSIMILATION

dispersed surface area to allow for lipolysis at the oil/water interface. Additional phase transitions allow for efficient trafficking of lipids to the enterocyte surface, where they can be absorbed.

ROLE AND SIGNIFICANCE Lipids are organic substances that are hydrophobic, and thus are more soluble in organic solvents (or cell membranes) than in aqueous solutions. They form an important part of most human diets. First, they are denser in calories than either proteins or carbohydrates, increasing the nutritional content of a given meal. Second, the fat-soluble vitamins are lipids. Third, many of the compounds that account for the flavor and aroma of foods are volatile hydrophobic molecules, meaning that lipids serve as an important vehicle to render food palatable.

BARRIERS TO ASSIMILATION OF HYDROPHOBIC MOLECULES The products of lipid digestion (lipolysis) are, in large part, readily able to cross cell membranes to allow for absorption into the body. However, lipids are not “at home” in the aqueous milieu of the intestinal contents. Likewise, they must interact with lipolytic enzymes that are themselves soluble proteins. Finally, the products of lipolysis must arrive at the brush border at a sufficient rate to allow for uptake before being propelled along and out of the gut. Systems therefore exist to maintain lipids in suspension in the gut contents with a sufficiently

Ch59_593-600.indd 593

DIETARY AND ENDOGENOUS SOURCES OF LIPIDS IN INTESTINAL CONTENT Lipids represent a major source of calories in most Western diets, with an average of 120–150 g consumed daily by a typical adult. On a daily basis, the intestine is also presented with 40–50 g of endogenous lipids arising from the biliary system. Despite their hydrophobicity, the process of lipid assimilation has evolved to be highly efficient, with significant reserve capacity also present. The ready availability of lipid-rich foods in developed countries is an important contributor to the burgeoning problem of obesity. Lipids in the diet as well as in endogenous pools are composed of several distinct molecular classes. The majority of lipid in the diet is in the form of long-chain triglycerides (i.e., fatty acids with at least 12 carbon atoms each, esterified to glycerol). Phospholipids, which are components of cell membranes, are also significant contributors. Other, more minor sources of dietary lipids include plant sterols (whose absorption may be inefficient) and cholesterol, another membrane constituent that is present in the diets of all except vegans. However, even vegans will encounter cholesterol in the intestinal contents because it is secreted into the bile, along with the 593

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other biliary lipid, phosphatidylcholine. In fact, the endogenous secretion of cholesterol of 1–2 g per day usually exceeds dietary intake of 200–500 mg that is typical of most individuals. While fat-soluble vitamins are only present in trace amounts, their absorption is critical for a variety of body processes. The fat-soluble vitamins are A, D, E, and K. Vitamin A (retinoic acid) is an important regulator of gene transcription. The active metabolite of vitamin D (calciferol) regulates calcium and phosphate absorption by the intestine, and homeostasis of these ions throughout the body (see Chapters 48 and 64). Vitamin E (tocopherol) is a vital antioxidant. Finally, vitamin K is utilized by the liver to catalyze the posttranslational modification of several blood clotting factors. The fat-soluble vitamins, as a group, have negligible aqueous solubility.

1

Gastric lipase H2O O CH2

O

C O

CH

O

C O

CH2

O

C Fatty acid plus diglyceride

2

Pancreatic lipase H2O

INTRALUMINAL DIGESTION Like in the assimilation of protein and carbohydrate, the initial stages of lipid assimilation take place in the intestinal lumen. Luminal events include dispersion of the lipid, which is liquid at body temperature, into an emulsion, thereby maximizing the area of the oil/water interface at which lipolysis occurs. Luminal events also include lipolysis, mediated by a series of pancreatic and other enzymes, and uptake of the products of lipolysis into micelles that can then transfer these molecules to the epithelial surface. Indeed, there is an ordered series of phase transitions that facilitate lipid assimilation. Oil droplets are converted to lamellar, vesicular, and liquid crystalline product phases, and finally to micelles that contain the products of lipolysis together with bile acids.

O CH2

O

C O

CH

O

C O

CH2

O

C Fatty acids plus monoglyceride

H2O Pancreatic lipase

FIGURE 59–1 Positional specificity of gastric (1) and pancreatic (2) lipases. Both enzymes can digest triglycerides but the products differ. (Modified with permission from Barrett KE: Gastrointestinal Physiology. New York: Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2006.)

GASTRIC DIGESTION Digestion of the lipid components of the diet begins in the stomach. Gastric peristalsis and mixing patterns provide a shearing action that disperses triglyceride and phospholipids into a fine emulsion. The oil droplets can then be acted upon by gastric lipase, which binds to the surface of the oil droplets where it can act on triglyceride molecules to generate free fatty acids and diglycerides. However, at the low pH of the gastric lumen, the fatty acids become protonated and move into the center of oil droplets. Thus, overall, gastric lipolysis is incomplete, and fails to generate products that are free to diffuse to the mucosal surface. In general, 10–30% of overall lipolysis takes place in the stomach in a healthy adult, and gastric digestion of lipids is not essential to their normal uptake. Gastric lipase, the enzyme that initiates digestion in the lumen of the stomach, is specialized for activity in the unique conditions that pertain in this segment of the gastrointestinal tract. Most notably, the enzyme displays a pH optimum consistent with that of the gastric contents—4.0–5.5. The enzyme is also relatively resistant to the action of pepsin. Further, gastric lipase is independent of the presence of any specific cofactors, but is inhibited by bile acids in the duodenum. Finally, gastric lipase acts preferentially to hydrolyze the fatty acid linked to

the first position of triglyceride (Figure 59–1) and is subject to end-product inhibition such that gastric lipolysis is largely incomplete because the triglyceride molecule is not fully broken down to its component parts.

INTESTINAL DIGESTION As the pH increases in the small intestine, the fatty acids that were liberated by gastric lipase become ionized and orient themselves to the outside of the oil droplets. This surrounds the droplet with a layer of ionized fatty acids that stabilizes the fat emulsion. Because even long-chain fatty acids have some solubility in water, some will dissociate from the droplet and traverse the lumen to the intestinal epithelium. Fatty acids are potent stimuli of cholecystokinin (CCK) release. CCK has a number of actions that are pertinent to lipid digestion and absorption. First, it causes an increase in secretion of pancreatic enzymes. Second, it relaxes the sphincter of Oddi, allowing outflow of the pancreatic juice into the intestinal lumen, and finally, it contracts the gallbladder, providing a bolus of concentrated bile that contains the bile acids needed eventually to dissolve the products of lipolysis in mixed micelles.

CHAPTER 59 Lipid Assimilation

Enzymes and Other Factors Involved in Digestion

3

TABLE 59–1 Mediators of intestinal lipolysis. Protein

Source

Activity

Comments

Pancreatic lipase

Pancreatic acinar cells

Hydrolyzes 1 and 3 positions of triglyceride

Inhibited by bile acids

Colipase

Proform secreted by pancreatic acinar cells

Cofactor for lipase

Binds to lipase and to bile acids

Secretory Proform secreted phospholipase by pancreatic A2 acinar cells

Hydrolyzes fatty acid in 2 position of phospholipids

Requires calcium for activity

Cholesterol esterase

Broad substrate specificity— cholesterol and vitamin esters; 1, 2, and 3 positions of triglyceride

Requires bile acids for activity

Related to cholesterol esterase

Important in neonates

Breast milk lipase

Mammary gland

C

L

3 Fatty acids released

Pancreatic acinar cells secrete a number of proteins that are important in fat digestion (Table 59–1). The first of these is pancreatic lipase. This enzyme is functionally related to gastric lipase, but it displays a number of important differences. First, it has a different positional specificity, acting on both the 1 and 3 positions of the glycerol molecule to liberate esterified fatty acids (Figure 59–1). Thus, the products of pancreatic lipase are fatty acids and monoglycerides. Second, it displays a pH optimum in the neutral range. However, both gastric and pancreatic lipases share the property of being inhibited by bile acids. This is not a major issue in the stomach, which is proximal to the entry of bile. How to solve this conundrum, on the other hand, for pancreatic lipase? The answer lies in the presence of a second product of pancreatic acinar cells, colipase. Colipase is synthesized as an inactive precursor (procolipase) that is secreted in approximately equimolar amounts with lipase, and is activated by proteolytic cleavage in the intestinal lumen. Colipase is capable of binding to both bile acids and lipase, which stabilizes the presence of lipase on the surface of oil droplets. The significance of this interaction is shown in Figure 59–2. If lipase alone is present, it adsorbs to the surface of the oil droplets and generates free fatty acids. With addition of bile acids, however, these array themselves on the surface of the oil droplets and displace lipase, halting its enzymatic activity. However, if colipase is also present, it can anchor lipase to the oil droplet, and thus lipolytic action is restored. Additional pancreatic exocrine products also contribute to lipid digestion. Phospholipase A2 is also stored in pancreatic acinar cells as an inactive proform that is activated by proteolytic cleavage once it reaches the intestinal lumen. Because phospholipids are the major constituent of cell membranes,

Pancreatic acinar cells

595

2 Bile acids added

Bile acids L

2

1

Colipase added

1 Fat droplet

L

Time

FIGURE 59–2 Role of colipase in promoting lipase activity in the intestinal lumen. Lipase (L) can absorb to the surface of fat droplets (1), but is displaced by the binding of amphipathic bile acids that arrange themselves around the exterior of the oil droplet (2). Colipase (C) can bind to both bile acids and lipase, again bringing lipase in proximity to its substrates in the oil droplet (3). (Modified with permission from Barrett KE: Gastrointestinal Physiology. New York: Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2006.)

including those of pancreatic duct cells, this delayed activation of the enzyme is important in the prevention of autodigestion of the pancreas. Phospholipase A2 breaks down dietary phospholipids by cleaving the fatty acid located in the 2 position of glycerol, as well as degrading (and thereby reclaiming) the phosphatidylcholine that is present in biliary secretions. The activity of this enzyme is dependent on luminal calcium. A final lipolytic enzyme in the pancreatic juice is cholesterol esterase, also referred to as nonspecific esterase. This enzyme is capable of degrading not only esters of cholesterol derived from dietary sources, but also the esters of vitamins A, D, and E. Likewise, the broad specificity of this enzyme renders it capable of complete digestion of triglycerides, since it is capable of hydrolyzing the 2-position fatty acid that is left untouched by both the gastric and pancreatic lipases. Cholesterol esterase acts in the lumen as a tetramer, and, interestingly, the formation of this complex depends on the presence of bile acids, distinguishing this enzyme from both acid (i.e., gastric) and pancreatic lipases. It is also important to note that an enzyme closely related to cholesterol esterase, known as breast milk lipase, is produced in the mammary gland of lactating females. This enzyme may “predigest” the lipid components of breast milk, increasing the efficiency of their uptake in the neonatal period. Breast milk lipase shares the broad specificity of cholesterol esterase.

Phase Transitions Involved in Product Solubilization Not only must dietary and endogenous lipids be digested by enzymes to allow for their assimilation into the body, but they must also be trafficked across the intestinal lumen. This is

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accomplished in the first instance by “phase transitions” that move the products of lipolysis from the oil droplets where they are generated to the epithelial surface. The phases involved in lipid absorption can actually be visualized by mixing an emulsion of fat with lipase, colipase, and bile acids on a microscope slide. The products of lipolysis that are released from the surface of the oil droplet form a lamellar phase similar to the lipid bilayer that surrounds cells. Vesicles bud off from this lamellar phase, which can be observed under the microscope as a liquid crystalline phase that is clearly distinct from the oil droplets. Eventually, micelles are formed, or a true solution of lipids in water. The phase transitions in the small intestine are directed to a single end—to transfer the products of lipolysis ultimately to the absorptive epithelium.

ROLE OF BILE ACIDS/MICELLES As the gallbladder contracts, the meal encounters a bolus of concentrated bile. The bile acids have an important role in solubilizing the end products of lipolysis and promoting their transfer to the absorptive epithelium. As the ratio of bile acids to lipolytic products increases, the relatively insoluble lipids are incorporated into mixed micelles. The formation of these structures is dependent on the physicochemical properties of bile acids. Likewise, micelle formation depends on the concentration of bile acids in the lumen, since these structures cannot form unless bile acid concentrations exceed the “critical micellar concentration” (CMC). Lipolytic products that are captured in micelles are truly in solution, compared with the emulsion of oil droplets that has been their physical form hitherto. The micelles that form in small intestinal content are pivotally dependent on the amphipathic nature of bile acids, with both a hydrophilic and a hydrophobic face. The structure of the mixed micelles in the intestine is analogous to that of the biliary mixed micelles we discussed in Chapter 56 (Figure 56–3). The bile acids assemble such that their hydrophilic faces are opposed to the aqueous environment. At the same time, the hydrophobic faces of the bile acid molecules can sequester the products of lipolysis such that their solubility is measurably increased. The resulting mixed micelles carry fatty acids and other lipolytic products through the aqueous lumen, markedly increasing their rate of diffusion. Indeed, the rate-limiting step for lipid assimilation is the ability to present lipid molecules at a sufficient concentration at the brush border to provide for uptake. While bile acids increase the efficiency of uptake of the products of lipolysis, the majority of such products are not dependent on micellar solubilization for their assimilation into the body. Fatty acids and monoglycerides have measurable aqueous solubility and can diffuse in molecular form to the brush border, where they can then be absorbed. This raises the concept of the “anatomic reserve” of the small intestine. The normal surface area of the small intestine, and its length, is sufficient to provide for molecular uptake of fatty acids and monoglycerides even if micelles are absent, although transport rates are slower. On the other hand, some dietary lipids have

such limited aqueous solubility that they are essentially incapable of absorption unless dissolved in micelles. This is the case for cholesterol, fat-soluble vitamins, and plant sterols.

EPITHELIAL EVENTS IN LIPID ASSIMILATION BRUSH BORDER EVENTS Mechanisms of Absorption of Lipolytic Products In theory, the products of lipolysis have sufficient hydrophobicity that they should be able to passively “flip” across the enterocyte apical membrane by simply partitioning into the lipid bilayer. Such a mechanism may indeed contribute to the intestinal uptake of the various products of the mixed micelle, with the exception of conjugated bile acids, which are exclusively absorbed via an active transport mechanism localized to the terminal ileum. However, there are likely also to be carrier-mediated mechanisms that assist in transporting the products of lipid digestion across the microvillous membrane. Uptake of plant sterols from the diet is inefficient. At least part of the reason for this was revealed by studying the disease known as sitosterolemia, in which patients accumulate abnormally high levels of plant sterols in the plasma. This disease is caused by mutations in two transporters, ABCG5 and ABCG8. Together, these proteins normally come together to form an efflux pump that transports any plant sterols that are taken up into the enterocyte back out into the intestinal lumen (Figure 59–3). The transporter so formed also can export cholesterol, albeit with less efficiency, explaining why the absorption of either dietary or biliary cholesterol is incomplete. Enterocytes also express at least one specific pathway for cholesterol uptake, known as the Niemann–Pick C1-like 1 (NPC1L1) gene product (Figure 59–3). In summary, uptake of the products of lipolysis appears to involve a combination of passive transfer across the brush border membrane, as well as facilitated diffusion for some lipids that is mediated by specific protein carriers. Intestinal absorption of at least some lipids is additionally compromised by pumps that can efflux lipid substrates from the enterocyte cytosol, limiting their ability to enter the body.

Special Considerations for Medium-chain Fatty Acids Fatty acid chain length, likely via effects on aqueous solubility, also appears to have an important influence on the molecular mechanisms that govern uptake of these molecules. Importantly, medium-chain fatty acids, with 6–12 carbon atoms, have increased water solubility, and this means that they have measurable absorption via the paracellular route. Mediumchain fatty acids therefore appear to bypass the intracellular processing events that are encountered by the long-chain fatty

CHAPTER 59 Lipid Assimilation

Cholesterol

NPC1L1

ABC G8

ATP

ABC G5

LUMEN

ADP

Utilized by enterocyte

Chylomicron assembly

Exocytosis

FIGURE 59–3 Intestinal handling of cholesterol. Cholesterol in the intestinal lumen is taken up via the NPC1L1 transporter. Absorbed cholesterol can be effluxed back out of the cell via the ABCG5/ABCG8 efflux pump at the expense of ATP hydrolysis, can be retained for use in the enterocyte, or can be packaged with other absorbed lipids into chylomicrons, which leave the epithelial cell via exocytosis. (Modified with permission from Barrett KE: Gastrointestinal Physiology. New York: Lange Medical Books/McGraw-Hill, Medical Pub. Division, 2006.)

acids that predominantly enter the enterocyte cytosol, discussed in greater detail later. As a result, such fatty acids also follow a different route out of the gut, being exported chiefly via the portal circulation rather than the lymphatic route used by other lipids.

prior to export to the systemic circulation. Long-chain fatty acids and monoglycerides are reesterified into triglyceride in the smooth endoplasmic reticulum; phospholipids, cholesterol, and fat-soluble vitamins are also selectively trafficked and reesterified. Approximately 75% of absorbed fatty acids is reassembled into triglyceride; the remainder is retained within the enterocyte for local needs. The various reassembled lipids are then coated with proteins known as apoproteins for export from the enterocyte (Figure 59–4). Apoproteins are synthesized in the rough endoplasmic reticulum, and undergo glycosylation in the Golgi apparatus where they also encounter the reesterified lipids taken up from the intestinal lumen. The particles that are formed via this process are referred to as chylomicrons, and have a core of triglyceride surrounded by phospholipids, cholesterol esters, and the apoproteins. The chylomicron is the structure used to transport dietary lipids to other locations in the body. Approximately 80–90% (w/w) of the chylomicron is composed of triglyceride, with 8–9% phospholipids and trace amounts of cholesterol, fatsoluble vitamins, and protein. The resulting structure is exported across the basolateral membrane by exocytosis.

LYMPHATIC UPTAKE OF ABSORBED LIPID The physical form of lipid exported from the enterocyte determines the subsequent route this nutrient can take to leave the gut. Chylomicrons range in size from 750 to 5,000 Å in diameter. They are therefore too large to cross the intercellular junctions linking capillary endothelial cells. This means that the only way for them to leave the intestine is via the lymphatics, which have leakier junctions. However, eventually these chylomicrons will enter the systemic circulation via the thoracic

Smooth ER

INTRACELLULAR PROCESSING

Chylomicron Formation Unlike the products of protein and carbohydrate digestion, which are exported to the body in their digested forms, the products of lipid digestion are reassembled in the enterocyte

FA/MG TG

Synthesis of TG and phospholipids Synthesis of apolipoproteins

Role of Fatty Acid Binding Proteins The small intestinal epithelium expresses a family of low-molecular-weight binding proteins that are capable of binding fatty acids and other dietary lipids. The best studied of these are the ileal-fatty acid binding protein (I-FABP) and the liver-type (hepatic) FABP. These and related proteins participate in the directed trafficking of absorbed lipids to the smooth endoplasmic reticulum, which is the site of intracellular lipid processing.

597

Rough ER

Golgi

Apolipoprotein glycosylation Exocytosis

Chylomicrons

FIGURE 59–4 Secretion of chylomicrons by intestinal epithelial cells. Absorbed fatty acids (FA) and monoglycerides (MG) are reesterified to form triglyceride (TG) in the smooth endoplasmic reticulum. Apolipoproteins are synthesized in the rough endoplasmic reticulum and glycosylated, and then coated around lipid cores and secreted from the basolateral pole of the enterocyte via a mechanism of exocytosis. (Reproduced with permission from Barrett KE, Barman SM, Boitano S, Brooks H: Ganong’s Review of Medical Physiology, 23rd ed. McGraw-Hill Medical, 2009.)

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duct. The lipid-bearing chylomicrons serve to carry lipids to various body tissues. They are too large to exit the bloodstream across the fenestrae of hepatic endothelial cells, and thus are retained in the plasma, although components may leave the chylomicron as needed at this and other body sites. Eventually, the chylomicrons are reduced to remnants that are small enough to pass into the space of Disse, and can finally have their remaining components recycled by hepatic metabolism.

ABSORPTION OF FAT-SOLUBLE VITAMINS Despite their importance, relatively little is understood about the specific molecular basis of the absorption and handling of fat-soluble vitamins by intestinal epithelial cells. It is known that such vitamins are reesterified in the enterocyte, and incorporated into the developing chylomicron. Presumably this is the form in which they are trafficked to sites of need. Trafficking of fat-soluble vitamins to the brush border membrane is essentially entirely dependent on micelles. A failure to form micelles in the intestinal lumen will almost inevitably be followed by deficiencies in fat-soluble vitamins in the body as a whole, which may manifest clinically as rickets and osteomalacia (see Chapter 64), night blindness (see Chapter 15), or an inability to effectively clot the blood, among others. Many fat-soluble vitamins are now available in more water-soluble forms that can be used to treat such problems, such as prior to elective surgery.

ileum, the situation will be complicated further by a decrease in the bile acid pool, in the absence of an anatomic reserve that might otherwise compensate for this. Short bowel syndrome is usually the consequence of surgery— either to remove segments of necrotic bowel in a pediatric condition known as necrotizing enterocolitis, which may have an infectious pathogenesis in some cases, or in patients who have undergone resections for extensive Crohn’s disease. Eventually, small bowel transplantation may offer hope that such patients will be able to dispense with parenteral nutrition, although problems with conserving bowel in a viable state prior to transplantation, as well as the usual problems of rejection, have not yet fully been resolved. Likewise, some exciting experimental treatments that employ growth factors to increase mucosal mass may hold promise, but concerns that these therapies might predispose to intestinal malignancies must be resolved. This is particularly the case in inflammatory bowel disease, where the risk of intestinal malignancy is already increased.

CHAPTER SUMMARY ■ ■

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CLINICAL CORRELATION A 30-year-old woman suffering from inflammation of the ileum (Crohn’s disease) undergoes a surgical resection of a long segment of her small bowel, including the terminal ileum. The remaining proximal segment of small bowel is connected directly to the ileocecal valve. After recovering from her surgery and resuming oral feeding, she notes that diarrheal symptoms have returned, and fears a recurrence of her bowel inflammation. However, in contrast to the bloody diarrhea with cramping that she experienced previously, now her stools are large, bulky, and foulsmelling, but with no blood. She also experiences some abdominal bloating. Examination of a fecal smear under the microscope reveals prominent lipid droplets. Short bowel syndrome is defined as being present in a patient who no longer has sufficient mucosal area for the adequate uptake of nutrients via the enteric route, and thus such patients may require parenteral nutritional support (i.e., via the intravenous route). Even if sufficient bowel remains for absorption of the majority of nutrients, if the segment of missing bowel includes the terminal

■ ■

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Lipids are important constituents of most diets, make food more palatable, and are energy-dense. Lipid digestion and absorption involves a complex series of events designed to emulsify, digest, and solubilize these hydrophobic dietary constituents. Biliary excretion of cholesterol may substantially exceed dietary intake. Micelles increase the efficiency of absorption of the products of triglyceride digestion, but they are not required for this process in healthy individuals. Absorption of fat-soluble vitamins and cholesterol is entirely dependent on micellar solubilization. Absorbed lipids are esterified and repackaged in the enterocyte into a structure known as a chylomicron, which then traffics absorbed lipids around the body, initially bypassing the portal circulation. Chylomicrons consist predominantly of resynthesized triglyceride, but apoproteins are essential components. Lipid digestion is a highly efficient process and significant excess capacity exists in the system.

STUDY QUESTIONS 1. A patient with obstructive jaundice who is scheduled for gallbladder surgery is found to have an increased prothrombin time, which indicates an increase in blood clotting time. This laboratory finding is most likely due to malabsorption of which of the following vitamins? A) A B) B12 C) D D) E E) K

CHAPTER 59 Lipid Assimilation 2. A patient is treated for hypercholesterolemia with cholestyramine, a resin that binds bile acid molecules. Absorption of which of the following is likely to be abnormal in this patient? A) long-chain triglyceride B) medium-chain triglyceride C) starch D) vitamin D E) vitamin C 3. A mouse was constructed in which the expression of NPC1L1 was knocked out by genetic targeting. Assimilation of which of the following substances from the diet would be expected to be abnormal in this animal? A) triglyceride B) vitamin D C) vitamin E D) cholesterol E) phospholipids

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4. A patient with a long-standing history of mild cystic fibrosis notices that his stools are becoming bulky and oily. Laboratory tests confirm steatorrhea. Which of the following is not involved in the apparently decreased fat assimilation in this patient? A) lipase inactivation B) decreased pancreatic lipase output C) reduced pancreatic bicarbonate secretion D) loss of the anatomic reserve E) decreased colipase synthesis 5. An otherwise healthy child is found to have mild, intermittent steatorrhea but no evidence of malabsorption of fat-soluble vitamins. There are also no defects in protein or carbohydrate assimilation. His brother was similarly affected. Lack of which of the following is most consistent with the clinical picture? A) bile acid micelles B) cholesterol esterase C) L-FABP D) gastric lipase E) pancreatic lipase

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SECTION IX ENDOCRINE AND METABOLIC PHYSIOLOGY

60 C

General Principles of Endocrine Physiology Patricia E. Molina

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Contrast the terms endocrine, paracrine, and autocrine. Define the terms hormone, target cell, and receptor. Understand the major differences in cellular mechanisms of action of peptides, steroid, and thyroid hormones. Understand the role of hormone-binding proteins. Understand the feedback control mechanisms of hormone secretion. Explain the effects of secretion, degradation, and excretion on plasma hormone concentrations.

THE ENDOCRINE SYSTEM: PHYSIOLOGIC FUNCTIONS AND COMPONENTS Some of the key functions of the endocrine system include: • regulation of sodium and water balance and control of blood volume and pressure; • regulation of calcium and phosphate balance to preserve extracellular fluid concentrations required for cell membrane integrity and intracellular signaling; • regulation of energy balance and control of fuel mobilization, utilization, and storage to ensure that cellular metabolic demands are met; • coordination of the responses to stress; • regulation of reproduction, development, growth, and senescence. The endocrine system is an integrated network of multiple organs derived from different embryologic origins that release

Ch60_601-612.indd 601

hormones ranging from small peptides to glycoproteins, which exert their effects in either neighboring or distant target cells. This endocrine network of organs and mediators does not work in isolation, and is closely integrated with the central and peripheral nervous systems as well as with the immune systems, leading to currently used terminology such as “neuroendocrine” or “neuroendocrine–immune” systems for describing their interactions. Three basic components make up the core of the endocrine system: • Endocrine glands: The classic endocrine glands are ductless and secrete their chemical products (hormones) into the interstitial space from where they reach the circulation. Unlike the cardiovascular, renal, and digestive systems, the endocrine glands are not anatomically connected and are scattered throughout the body (Figure 60–1). Communication among the different organs is ensured through the release of hormones or neurotransmitters. • Hormones— Hormones are chemical products, released in very small amounts from the cell, that exert a biologic action on a target cell. Hormones can be released from 601

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Hypothalamus Releasing hormones: GHRH, CRH, TRH, GnRH Inhibitory hormones: Somatostatin, Dopamine Projecting to Posterior Pituitary: Antidiuretic Hormone Oxytocin

FIGURE 60–1 The classic endocrine system. Endocrine organs are located throughout the body, and their function is controlled by hormones delivered through the circulation or produced locally or by direct neuroendocrine stimulation. Integration of hormone production from endocrine organs is under regulation by the hypothalamus. Many other tissues are now known to produce hormones and can thus be considered part of the endocrine system. Examples include adipose tissue (e.g., leptin), the gastrointestinal tract (e.g., ghrelin), skeletal muscle (myokines), the kidneys (erythropoietin), and the heart (e.g., atrial natriuretic peptide). GHRH, growth hormone–releasing hormone; CRH, corticotropin-releasing hormone; TRH, thyrotropin-releasing hormone; GnRH, gonadotropinreleasing hormone; ACTH, adrenocorticotropic hormone; MSH, melanocyte-stimulating hormone; TSH, thyroid-stimulating hormone; FSH, follicle-stimulating hormone; LH, luteinizing hormone; T3, triiodothyronine; T4, thyroxine. (Modified with permission from Molina PE:

Thyroid gland T3, T4, & calcitonin

Adrenal glands Cortisol Aldosterone Adrenal androgens Epinephrine Norepinephrine

Pituitary gland Growth hormone, Prolactin ACTH, MSH TSH, FSH, & LH

Parathyroid glands Parathyroid hormone

Pancreas Insulin Glucagon Somatostatin

Ovaries Estrogens Progesterone

Testes Testosterone

Endocrine Physiology, 3rd ed. New York: McGraw-Hill Medical, 2010.)

the endocrine glands (i.e., insulin, cortisol); the brain (i.e., corticotropin-releasing hormone, oxytocin, and antidiuretic hormone); and other organs such as the heart (atrial natriuretic peptide), liver (insulin-like growth factor-I), and adipose tissue (leptin). • Target organ: The target organ contains cells that express hormone-specific receptors and that respond to hormone binding by a demonstrable biologic response.

HORMONE CHEMISTRY AND MECHANISMS OF ACTION Based on their chemical structure, hormones can be classified into proteins (or peptides), steroids, and amino acid derivatives (amines). Hormone structure, to a great extent, dictates the location of the hormone receptor, with amines and peptide hormones binding to receptors in the cell surface and steroid hormones able to cross plasma membranes and bind to intracellular receptors. An exception to this generalization is thyroid hormone, an amino acid–derived hormone that is transported into the cell in order to bind to its nuclear receptor. Hormone structure influences the half-life of the hormone as well, with peptides having shorter half-lives than steroid hormones.

PROTEIN OR PEPTIDE HORMONES Protein or peptide hormones constitute the majority of hormones. Most are synthesized as preprohormones and undergo posttranslational processing. They are stored in secretory granules before being released by exocytosis (Figure 60–2). Examples of peptide hormones include insulin, glucagon, and adrenocorticotropic hormone (ACTH). Some hormones in this category, such as the gonadotropic hormone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH), together with thyroid-stimulating hormone (TSH) and human chorionic gonadotropin (hCG), contain carbohydrate moieties, leading to their designation as glycoproteins.

STEROID HORMONES Steroid hormones are derived from cholesterol and are synthesized in the adrenal cortex, gonads, and placenta. They are lipid soluble, require binding proteins to circulate in plasma, and cross the plasma membrane to bind to intracellular cytosolic or nuclear receptors. Vitamin D and its metabolites are also steroid hormones.

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Endocrine cell

Granular endoplasmic reticulum

Synthesis Preprohormone Prohormone

Nucleus

Packaging Prohormone

Golgi apparatus

Hormone

Storage Secretory vesicles

Hormone

Plasma membrane

Secretion Hormone (and any "pro" fragments)

Cytosol

Ca2+

Interstitium

FIGURE 60–2 Peptide hormone synthesis. Peptide hormones are synthesized as preprohormones in the ribosomes and processed to prohormones in the endoplasmic reticulum (ER). In the Golgi apparatus, the hormone or prohormone is packaged in secretory vesicles, the contents of which are released from the cell in response to an influx of Ca2+. The increase in cytoplasmic Ca2+ is required for docking of the secretory vesicles in the plasma membrane and for exocytosis of the vesicular contents. The hormone and the products of the posttranslational processing that occurs inside the secretory vesicles are released into the extracellular space. Examples of peptide hormones are ACTH, insulin, growth hormone, and glucagon. (Modified with permission from Molina PE: Endocrine Physiology, 3rd ed. New York: McGraw-Hill Medical, 2010.)

AMINO ACID–DERIVED HORMONES Amino acid–derived hormones are synthesized from the amino acid tyrosine and include the catecholamines norepinephrine, epinephrine, and dopamine, as well as the thyroid hormones, derived from the combination of two iodinated tyrosine amino acid residues.

HORMONE EFFECTS The biologic effect of a hormone can be classified in many ways (Figure 60–3). The effect is endocrine when a hormone is released into the circulation and then travels in the blood to produce a biologic effect on distant target cells. The effect is paracrine when a hormone released from one cell produces a biologic effect on a neighboring cell, which is frequently a cell in the same organ or tissue. The effect is autocrine when a hormone pro-

duces a biologic effect on the same cell that released it, and intracrine when the hormone has an intracellular effect without first being released into the extracellular space.

HORMONE TRANSPORT Hormones released into the circulation can circulate either freely or bound to carrier proteins, also known as binding proteins. The binding proteins serve as a reservoir for the hormone and prolong the hormone’s half-life, the time during which the concentration of a hormone decreases to 50% of its initial concentration. The free or unbound hormone is the active form of the hormone, which binds to the specific hormone receptor. Hormone binding to its carrier protein serves to regulate the activity of the hormone by determining how much hormone is free to exert a biologic action. Most carrier proteins are globulins and are synthesized in the liver.

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Interstitial space Endocrine cell

Hormone Circulatory system

Paracrine signaling

Hormone-specific receptor Endocrine signaling

Autocrine signaling

Intracrine signaling

FIGURE 60–3 Mechanisms of hormone action. Depending on where hormones exert their effects, they can be classified into endocrine, paracrine, autocrine, or intracrine mediators. Hormones that enter the bloodstream and bind to hormone receptors in target cells in distant organs mediate endocrine effects. Hormones that bind to cells near the cell that released them mediate paracrine effects. Hormones that produce their physiologic effects by binding to receptors on the same cell that produced them mediate autocrine or intracrine effects. (Modified with permission from Molina PE: Endocrine Physiology, 3rd ed. New York: McGraw-Hill Medical, 2010.)

As a result, alterations in hepatic function may result in abnormalities in binding protein levels and may indirectly affect total hormone levels. The majority of amines, peptides, and protein (hydrophilic) hormones circulate in their free form. Steroid and thyroid (lipophilic) hormones circulate bound to specific transport proteins. The interaction between a given hormone and its carrier protein is in a dynamic equilibrium and allows adjustments that prevent clinical manifestations of hormone deficiency or excess. Secretion of the hormone is adjusted rapidly following changes in the levels of carrier proteins. For example, plasma levels of cortisol-binding protein increase during pregnancy. The increase in circulating levels of cortisol-binding protein leads to an increased binding capacity for cortisol (a steroid hormone produced in the adrenal glands), resulting in a decrease in free cortisol levels. This decrease in free cortisol stimulates the hypothalamic release of CRH, which stimulates ACTH release from the anterior pituitary and consequently

cortisol synthesis and release from the adrenal glands. This feedback mechanism restores free cortisol levels and prevents manifestation of cortisol deficiency. The half-life of a hormone is inversely related to its rate of removal from the circulation. Once hormones are released into the circulation, they can bind to their specific receptor in a target organ, they can undergo metabolic transformation by the liver, or they can undergo urinary excretion. In the liver, hormones can be inactivated through Phase I (hydroxylation or oxidation) and/or Phase II (glucuronidation, sulfation, or reduction with glutathione) reactions, and then excreted by the liver through the bile or by the kidney. In some instances, the liver can actually modify a hormone precursor, as is the case for vitamin D synthesis. Hormones can be degraded at their target cell through internalization of the hormone– receptor complex followed by lysosomal degradation of the hormone. Only a very small fraction of total hormone production is excreted intact in the urine and feces.

CHAPTER 60 General Principles of Endocrine Physiology

HORMONE CELLULAR EFFECTS The biologic response to hormones is elicited through binding to hormone-specific receptors at the target organ. Hormones circulate in very low concentrations (10−7 to 10−12 M), so the receptor must have high affinity and specificity for the hormone to produce a biologic response. Affinity is determined by the rates of association and dissociation for the hormone–receptor complex under equilibrium conditions. It is a reflection of how tight the hormone–receptor interaction is. Specificity is the ability of a hormone receptor to discriminate between hormones with related structures. The binding of hormones to their receptors is saturable, with a finite number of hormone receptors to which a hormone can bind. Abnormal endocrine function is the result of either excess or deficiency in hormone action. This can result from abnormal production of a given hormone (either in excess or in insufficient amounts) or from decreased receptor number or function. Hormone–receptor agonists and antag-

Amino acid derived: Epinephrine, norepinephrine

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onists are widely used clinically to restore endocrine function in patients with hormone deficiency or excess.

HORMONE RECEPTORS AND SIGNAL TRANSDUCTION Hormones produce their biologic effects by binding to specific hormone receptors in target cells, and the type of receptor to which they bind is largely determined by the hormone’s chemical structure. Hormone receptors are classified depending on their cellular localization, as cell membrane (Figures 60–4 and 60–5) or intracellular receptors (Figure 60–6).

CELL MEMBRANE RECEPTORS These receptor proteins are located within the phospholipid bilayer of the cell membrane of target cells (Figures 60–4 and 60–5). Functionally, cell membrane receptors can be divided

Peptide and protein: Glucagon, Angiotensin, GnRH, SS, GHRH, FSH, LH, TSH, ACTH

N E1

E2

E3

α I1

I2

I3

GDP

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β

γ

Ion channels, PI3Kγ, PLC-β, adenylate cyclases

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αq

αs

α12

GTP Adenylate cyclase cAMP

GTP PLC-β DAG Ca++ PKC

GTP Adenylate cyclase cAMP

GTP RhoGEFs Rho

Biological responses Proliferation, differentiation, development, cell survival, angiogenesis, hypertrophy, cancer

P

Gene expression regulation

P

Transcription factors

Nucleus

FIGURE 60–4 G protein–coupled receptors. Peptide and protein hormones bind to cell surface receptors coupled to G proteins. Binding of the hormone to the receptor produces a conformational change that allows the receptor to interact with the G proteins. This results in the exchange of guanosine diphosphate (GDP) for guanosine triphosphate (GTP) and activation of the G protein. The second-messenger systems that are activated vary depending on the specific receptor, the α-subunit of the G protein associated with the receptor, and the ligand it binds. Examples of hormones that bind to G protein–coupled receptors are shown. DAG, diacylglycerol; PLC, phospholipase C; cAMP, cyclic adenosine monophosphate; RhoGEFs, Rho guanine nucleotide exchange factors; PI3K, phosphatidyl-3-kinase; PKC, protein kinase C; GnRH, gonadotropinreleasing hormone; SS, somatostatin; GHRH, growth hormone–releasing hormone; FSH, follicle-stimulating hormone; LH, luteinizing hormone; TSH, thyroid-stimulating hormone; ACTH, adrenocorticotropin hormone. (Modified with permission from Molina PE: Endocrine Physiology, 3rd ed. New York: McGraw-Hill Medical, 2010.)

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N N

N

N

Growth factor Plasma membrane

Plasma membrane

Tyrosine kinase domain C

C

Nonreceptor tyrosine kinase

Cytosol

Kinase

ATP

PO4 JAK kinase

ADP Docking protein Docking protein

Protein

+ATP

Protein-PO4 + ADP

Protein activation

Recruitment & activation of proteins

FIGURE 60–5 Receptor kinase and receptor-linked kinase receptors. Receptor kinases are receptors that have intrinsic tyrosine or serine kinase activity that is activated by binding of the hormone to the amino terminal of the cell membrane receptor. The activated kinase recruits and phosphorylates downstream proteins producing a cellular response. An example of hormones that utilize this receptor pathway is insulin. Receptor-linked tyrosine kinase receptors do not have intrinsic activity in their intracellular domain. They are closely associated with kinases that are activated with binding of the hormone. Examples of hormones using this mechanism are growth hormone and prolactin. ATP, adenosine triphosphate; ADP, adenosine diphosphate; JAK, janus kinase. (Modified with permission from Cooper GM: The Cell: A Molecular Approach, 4th ed. Sinauer, 2007.)

Extracellular fluid Steroid

Cytoplasm

Steroid enters target cell by diffusion

Nucleus

Activated receptor dimer Gene transcription

Steroid receptor

Plasma membrane

DNA Steroid response element Nuclear envelope

FIGURE 60–6 Intracellular receptors. The general scheme for the mechanism of action of steroid receptors. The ligand (steroid) diffuses into the cell and binds to the cytosolic receptor. Once binding occurs, the receptors dimerize (pair up) and are translocated to the nucleus where they bind to a steroid response element on the DNA. This activates gene transcription to mRNA, and ultimately, through increased mRNA translation to specific proteins, results in a cellular response. Some intracellular receptors, rather than being in the cytosol in the unbound state, reside in the nucleus (e.g. thyroid hormone receptors), but their ultimate mechanisms of activation of gene transcription and translation are similar. (Reproduced with permission from Kibble J, Halsey CR: The Big Picture, Medical Physiology. New York: McGraw-Hill, 2009.)

CHAPTER 60 General Principles of Endocrine Physiology into ligand-gated ion channels and receptors that regulate activity of intracellular proteins.

Ligand-gated Ion Channels These receptors are functionally coupled to ion channels. Hormone binding to this receptor produces a conformational change that opens ion channels on the cell membrane, producing ion fluxes in the target cell. The cellular effects occur within seconds of hormone binding.

Receptors that Regulate Activity of Intracellular Proteins These receptors are transmembrane proteins that transmit signals to intracellular targets when activated. Ligand binding to the receptor on the cell surface and activation of the associated protein initiate a signaling cascade of events that activates intracellular proteins and enzymes and that can include effects on gene transcription and expression. The main types of cell membrane hormone receptors in this category are the G protein–coupled receptors (Figure 60–4) and the receptor protein tyrosine kinases (Figure 60–5). An additional type of receptor, the receptor-linked kinase receptor, activates intracellular kinase activity following binding of the hormone to the plasma membrane receptor. This type of receptor is used in producing the physiologic effects of growth hormone (Figure 60–5).

G protein–coupled receptors G protein–coupled receptors are transmembrane proteins coupled to heterotrimeric guanine-binding proteins (G proteins) consisting of three subunits: α, β, and γ. Hormone binding to the G protein–coupled receptor produces a conformational change that induces interaction of the receptor with the regulatory G protein, stimulating the release of guanosine diphosphate (GDP) in exchange for guanosine triphosphate (GTP), resulting in activation of the G protein (Figure 60–4). The activated G protein (bound to GTP) dissociates from the receptor followed by dissociation of the α from the βγ subunits. The subunits activate intracellular targets, which can be either an ion channel or an enzyme. Hormones that use this type of receptor include TSH, antidiuretic hormone or arginine vasopressin, and catecholamines. On the basis of the Gα subunit, G proteins can be classified into four families associated with different effector proteins. The signaling pathways of three of these have been extensively studied. The Gαs activates adenylate cyclase, Gαi inhibits adenylate cyclase, and Gαq activates phospholipase C; the second-messenger pathways used by Gα12 have not been completely elucidated. The interaction of Gαs with adenylate cyclase and its activation result in increased conversion of adenosine triphosphate to cyclic 3′,5′-adenosine monophosphate (cAMP), with the opposite response elicited by binding to Gαi-coupled receptors. The increase in intracellular cAMP activates protein kinase A, which in turn phosphorylates effector proteins, responsible for

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producing cellular responses. The action of cAMP is terminated by the breakdown of cAMP by the enzyme phosphodiesterase. In addition, the cascade of protein activation can also be controlled by phosphatases, which dephosphorylate proteins. Phosphorylation of proteins does not necessarily result in activation of an enzyme. In some cases, phosphorylation of a given protein results in inhibition of its activity. Gαq activation of phospholipase C results in the hydrolysis of phosphatidylinositol bisphosphate and the production of diacylglycerol (DAG) and inositol trisphosphate (IP3). DAG activates protein kinase C, which phosphorylates effector proteins. IP3 binds to calcium channels in the endoplasmic reticulum, leading to an increase of Ca2+ influx into the cytosol. Ca2+ can also act as a second messenger by binding to cytosolic proteins such as calmodulin. Binding of Ca2+ to calmodulin results in the activation of kinases, leading to a cascade of phosphorylation of effector proteins and cellular responses.

Receptor protein tyrosine kinases Receptor protein tyrosine kinases are usually single transmembrane proteins that have intrinsic enzymatic activity that is activated by hormone binding. This results in phosphorylation of tyrosine residues on the catalytic domain of the receptor itself, increasing its kinase activity. Phosphorylation outside the catalytic domain creates specific binding or docking sites for additional proteins that are recruited and activated, initiating a downstream signaling cascade. Hormone binding to cell surface receptors results in rapid activation of cytosolic proteins and cellular responses. Through protein phosphorylation, hormone binding to cell surface receptors can also alter the transcription of specific genes through the phosphorylation of transcription factors. An example of this mechanism of action is the phosphorylation of the transcription factor cAMP response element-binding protein (CREB) by protein kinase A in response to receptor binding and adenylate cyclase activation. This same transcription factor (CREB) can be phosphorylated by calcium–calmodulin following hormone binding to receptor tyrosine kinase and activation of phospholipase C. Therefore, hormone binding to cell surface receptors can elicit immediate responses when the receptor is coupled to an ion channel or through the rapid phosphorylation of preformed cytosolic proteins, and it can also activate gene transcription through phosphorylation of transcription factors.

INTRACELLULAR RECEPTORS Receptors in this category belong to the steroid receptor superfamily (Figure 60–6). These receptors are transcription factors that have binding sites for the hormone (ligand) and for DNA and function as ligand (hormone)-regulated transcription factors. Hormone–receptor complex formation and binding to DNA result in either activation or repression of gene transcription. Binding to intracellular hormone receptors requires that the hormone be hydrophobic and cross the

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plasma membrane. Steroid hormones and the active steroid derivative of vitamin D fulfill this requirement (Figure 60–6). Thyroid hormones must be actively transported into the cell. The distribution of the unbound intracellular hormone receptor can be cytosolic or nuclear. Hormone–receptor complex formation with cytosolic receptors produces a conformational change that allows the hormone–receptor complex to enter the nucleus and bind to specific DNA sequences to regulate gene transcription. Once in the nucleus, the receptors regulate transcription by binding, generally as dimers, to hormone response elements normally located in regulatory regions of target genes. In all cases, hormone binding leads to a nearly complete nuclear localization of the hormone– receptor complex. Unbound intracellular receptors may be located in the nucleus, as in the case of thyroid hormone receptors. The unoccupied thyroid receptor represses transcription of genes. Binding of thyroid hormone to the receptor activates gene transcription.

HORMONE–RECEPTOR REGULATION Hormones can influence responsiveness of the target cell by modulating receptor function. Target cells are able to detect changes in hormone signal over a very wide range of stimulus intensities. This requires the ability to undergo a reversible process of adaptation or desensitization, whereby a prolonged exposure to a hormone decreases the response to that level of hormone. This allows cells to respond to changes in the concentration of a hormone (rather than to the absolute concentration of the hormone) over a very wide range of hormone concentrations. Several mechanisms can be involved in desensitization to a hormone. Hormone binding to cellsurface receptors, for example, may induce their endocytosis and temporary sequestration in endosomes. Such hormoneinduced receptor endocytosis can lead to the destruction of the receptors in lysosomes, a process that leads to receptor downregulation. In other cases, desensitization results from a rapid inactivation of the receptors, for example, as a result of a receptor phosphorylation. Desensitization can also be caused by a change in a protein involved in signal transduction following hormone binding to the receptor or by the production of an inhibitor that blocks the transduction process. In addition, one hormone can downregulate or decrease the expression of receptors for another hormone and reduce that hormone’s effectiveness. Hormone receptors can also undergo upregulation. Upregulation of receptors involves an increase in the number of receptors for the particular hormone and frequently occurs when the prevailing levels of the hormone have been low for some time. The result is an increased responsiveness to the physiologic effects of the hormone at the target tissue when the levels of the hormone are restored or when an agonist to the receptor is administered. A hormone can also upregulate the receptors for another hormone, increasing the effectiveness of that hormone at its target tissue. An example of this type of interaction is the upregulation of cardiac myo-

cyte adrenergic receptors following sustained elevations in thyroid hormone levels.

CONTROL OF HORMONE RELEASE The secretion of hormones involves synthesis or production of the hormone and its release from the cell. In general, the discussion of regulation of hormone release in this section refers to both synthesis and secretion; specific aspects pertaining to the differential control of synthesis and release of specific hormones will be discussed in the respective chapters when they are considered of relevance. Plasma levels of hormones oscillate throughout the day, showing peaks and troughs that are hormone specific (Figure 60–7). This variable pattern of hormone release is determined by the interaction and integration of multiple control mechanisms, which include hormonal, neural, nutritional, and environmental factors that regulate the constitutive (basal) and stimulated (peak levels) secretion of hormones. The periodic and pulsatile release of hormones is critical in maintaining normal endocrine function and in exerting physiologic effects at the target organ. The hypothalamus plays an important role in control of hormone pulsatility. Although the mechanisms that determine the pulsatility and periodicity of hormone release are not completely understood for all the different hormones, three general mechanisms can be identified as common regulators of hormone release.

NEURAL CONTROL Control and integration by the central nervous system is a key component of hormonal regulation and is mediated by direct neurotransmitter control of endocrine hormone release (Figure 60–8). Neural control plays an important role in the regulation of peripheral endocrine hormone release. Endocrine organs such as the pancreas receive sympathetic and parasympathetic input, which contributes to the regulation of insulin and glucagon release.

HORMONAL CONTROL Hormone release from an endocrine organ is frequently controlled by another hormone. When the outcome is stimulation of hormone release, the hormone that exerts that effect is referred to as a tropic hormone, as is the case for most of the hormones produced and released from the anterior pituitary. One example of this type of hormone release control is the regulation of glucocorticoid release by ACTH. Hormones can also suppress another hormone’s release. An example of this is the inhibition of growth hormone release by somatostatin from the hypothalamus. Hormonal inhibition of hormone release plays an important role in the process of negative feedback regulation of hormone release, described below and in Figure 60–9. In addition, hor-

CHAPTER 60 General Principles of Endocrine Physiology

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Cortisol 600

Cortisol (nmoI/L)

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300

200

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25 20 15 10 5 0 09

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FIGURE 60–7 Patterns of hormone release. Plasma hormone concentrations fluctuate throughout the day. Therefore, plasma hormone measurements do not always reflect the function of a given endocrine system. Both cortisol and growth hormone show considerable variations in blood levels throughout the day. These levels can also be affected by sleep deprivation, light, stress, and disease, and are dependent on their secretion rate, rates of metabolism and excretion, metabolic clearance rate, circadian pattern, fluctuating environmental stimuli, and internal endogenous oscillators. Biologic influences include illness, night work, sleep patterns, changes in longitude, and prolonged bed rest. (Modified with permission from Molina PE: Endocrine Physiology, 2nd ed. New York: McGraw-Hill Medical, 2007.)

mones can stimulate the release of a second hormone in what is known as a feedforward mechanism.

NUTRIENT OR ION REGULATION Plasma levels of nutrients or ions can also regulate hormone release (Figure 60–9). In all cases, the particular hormone regulates the concentration of the nutrient or ion in plasma either directly or indirectly. Examples of nutrient and ion regulation of hormone release include the control of insulin release by

plasma glucose levels and the control of parathyroid hormone release by plasma calcium and phosphate levels. Release of one hormone can be influenced by more than one of these mechanisms. For example, insulin release is regulated by nutrients (plasma levels of glucose and amino acids), neural (sympathetic and parasympathetic stimulation), and hormonal (somatostatin) mechanisms. The ultimate function of these control mechanisms is to allow the neuroendocrine system to adapt to a changing environment, integrate signals, and maintain homeostasis. The responsiveness of target cells to hormonal action leading to regulation of hormone release constitutes a

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Preganglionic

Neuron

Neuron

ACh

Postganglionic SNS or PSNS

FIGURE 60–8 Neural control of hormone release. Endocrine function is under tight regulation by the nervous system, hence the term “neuroendocrine.” Hormone release by endocrine cells can be modulated by postganglionic neurons from the sympathetic nervous system (SNS) or parasympathetic nervous system (PSNS) using acetylcholine (ACh) or norepinephrine (NE) as neurotransmitters, or by preganglionic neurons using acetylcholine as a neurotransmitter. Therefore, pharmacologic agents that interact with the production or release of neurotransmitters affect endocrine function.

Neuron

ACh or NE

ACh

Endocrine cell

Adrenomedullary cell

(Modified with permission from Molina PE: Endocrine Physiology, 3rd ed. New York: McGraw-Hill Medical, 2010.)

feedback control mechanism. A dampening or inhibition of the initial stimulus is called negative feedback. Stimulation or enhancement of the original stimulus is called positive feedback (Figure 60–9). Negative feedback is the most common control mechanism regulating hormone release. The integrity of the system ensures that adaptive changes in hormone levels do not lead to pathologic conditions. Furthermore, the control mechanism plays an important role in short- and long-term adaptations to changes in the environment. Three levels of feedback can be identified: long loop, short loop, and ultrashort loop.

ASSESSMENT OF ENDOCRINE FUNCTION In general, disorders of the endocrine system result from alterations in hormone secretion or target cell responsiveness to hormone action. Alterations in target cell response can be due to increased or decreased biologic responsiveness to a particular hormone (Figure 60–10). The initial approach to assessment of endocrine function is measurement of plasma hormone levels.

Hormone release

Hormone release

INTERPRETATION OF HORMONE MEASUREMENTS Because of the variability in circulating hormone levels resulting from pulsatile release, circadian rhythms, sleep/wake cycle, and nutritional status, interpretation of isolated plasma hormone measurements should always be done with caution and with understanding of the integral components of the hormone axis in question. Some general aspects that should be considered when interpreting hormone measurements are as follows: • Hormone levels should be evaluated with their appropriate regulatory factors (e.g., insulin with glucose, calcium with parathyroid hormone, thyroid hormone with TSH, etc.). • Simultaneous increase of pairs (increase in both the hormone and the substrate that it regulates, such as increased plasma glucose and insulin levels) can indicate a hormone resistant state. • Urinary excretion of hormone or hormone metabolites over 24 hours may be a better estimate of hormone secretion

CHAPTER 60 General Principles of Endocrine Physiology

a. Negative feedback

A. Decreased hormone responsiveness 150 Hormone effect (%)

TSH

Anterior pituitary

Thyroid gland

100

Maximal response Effect produced by saturating dose of hormone

50

0

Thyroid hormone

Log [hormone]

b. Positive feedback

B. Decreased hormone sensitivity 150 Hormone effect (%)

LH

Hypothalamus Pituitary

611

Ovary

Estradiol

100 Sensitivity Hormone concentration required to elicit halfmaximal response

50

0 Log [hormone]

c. Product regulation PTH

Parathyroid gland

Bone

Ca++

FIGURE 60–9 Mechanisms regulating hormone release a. Negative feedback regulation. In some cases, the endocrine gland is itself a target organ for another hormone. In this case, endocrine cells from organ 1 produce a hormone that stimulates the target organ to produce another hormone (hormone 2). Hormone 2 decreases the production and release of the hormone that stimulated its release, also known as a tropic hormone. An example is the regulation of anterior pituitary release of thyroid-stimulating hormone (TSH) by thyroid hormones produced by the thyroid gland. b. Positive feedback regulation, occurs when the release of a hormone stimulates a second hormone that then stimulates the first hormone, resulting in a vicious cycle. An example is the stimulation of LH release by estradiol during the middle of the menstrual cycle. c. Product control of hormone release. The production and release of a hormone can be regulated by the circulating levels of the substrate that it controls. An example is the regulation of parathyroid hormone release from the parathyroid glands by the prevailing serum levels of Ca2+. (Modified with permission from Molina

FIGURE 60–10 Receptor function. A. Hormone responsiveness. Decreased responsiveness to hormone effects can be due to a decreased number of hormone receptors, a decreased concentration of enzyme activated by the hormone, an increased concentration of noncompetitive inhibitor, or a decreased number of target cells. When responsiveness is decreased, then no matter how high the hormone concentration is, a maximal response will not be achieved. B. Hormone sensitivity. A decrease in hormone sensitivity requires higher hormone concentrations to produce 50% of the maximal response. Decreased sensitivity can be due to decreased hormone–receptor affinity, decreased hormone–receptor number, increased rate of hormone degradation, and increased levels of antagonistic or competitive hormones. (Modified with permission from Molina PE: Endocrine Physiology, 3rd ed. New York: McGraw-Hill Medical, 2010.)

TABLE 60–1 Interpretation of hormone levels. Pituitary Hormone Level High

Target Hormone Level Low

Normal

Autonomous secretion of pituitary hormone or resistance to target hormone action

Primary failure of target endocrine organ

PE: Endocrine Physiology, 3rd ed. New York: McGraw-Hill Medical, 2010.)

Normal

than one-time plasma-level measurement. However, these measures rely on adequate renal function. • Target hormone excess should be evaluated with the appropriate tropic hormone. The possible interpretations of altered hormone and regulatory factor pairs are summarized in Table 60–1.

Low

High

Normal range Pituitary failure

Autonomous secretion by target endocrine organ

Reproduced with permission from Kibble J and Halsey CR: The Big Picture, Medical Physiology. New York: McGraw-Hill, 2009

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CHAPTER SUMMARY ■ ■ ■ ■ ■ ■

Hormones are classified into protein, amino acid derived, and steroid based on their chemistry. Binding proteins regulate hormone availability and physiologic function. Physiologic effects of hormones require binding to specific receptors in target organs. Hormone release is under neural, hormonal, and product regulation. Hormones can control their own release through feedback regulation. Interpretation of hormone levels requires consideration of hormone pairs or of the nutrient or factor controlled by the hormone.

STUDY QUESTIONS 1. Which of the following statements concerning a particular hormone is correct? A) It will bind to cell membrane receptors in all cell types. B) It is lipid soluble and has an intracellular receptor. C) It circulates bound to a protein, and this shortens its half-life. D) It is a small peptide; therefore, its receptor localization will be in the nucleus.

2. Which of the following would be expected to alter hormone levels? A) changes in mineral and nutrient plasma levels B) pituitary tumor C) transatlantic flight D) training for the Olympics E) all of the above 3. Which of the following statements concerning hormonal regulation is correct? A) A hormone does not inhibit its own release. B) The substrate a hormone regulates does not affect that hormone’s release. C) Negative feedback regulation occurs only at the level of the anterior pituitary. D) Feedback inhibition may be exerted by nutrients and hormones. 4. The structure of a newly discovered hormone shows that it is a large peptide with a glycosylated subunit. The hormone is likely to A) bind to DNA and affect gene transcription B) bind to adenylate cyclase and stimulate protein kinase C C) bind to a cell membrane receptor D) be secreted intact in the urine

61 C

The Hypothalamus and Posterior Pituitary Gland Patricia E. Molina

H A

P

T

E

R

O B J E C T I V E S ■ ■ ■ ■ ■ ■

Describe the physiologic and anatomic relationships between the hypothalamus and the anterior and the posterior pituitary. Understand the integration of hypothalamic and pituitary function, and identify the two different pathways used for hypothalamic–pituitary interactions. Identify the appropriate hypothalamic releasing and inhibitory factors controlling the secretion of each of the anterior pituitary hormones. Differentiate between the routes of transport of hypothalamic neuropeptides to the posterior and anterior pituitary. Identify the mechanisms that control the release of oxytocin and antidiuretic hormone (ADH; arginine vasopressin [AVP]). Understand the physiologic target organ responses and the cellular mechanisms of oxytocin and ADH action.

The hypothalamus is the region of the brain involved in coordinating the physiologic responses of different organs that together maintain homeostasis. It does this by integrating signals from the environment, other brain regions, and visceral afferents, and then stimulating the appropriate neuroendocrine responses. In doing so, the hypothalamus influences many aspects of daily function, including food intake, energy expenditure, body weight, fluid intake and balance, blood pressure, thirst, body temperature, and the sleep cycle. Most of these hypothalamic responses are mediated through hypothalamic control of pituitary function (Figure 61–1). This control is achieved by the following two mechanisms: (1) release of hypothalamic neuropeptides synthesized in hypothalamic neurons and transported through the hypothalamohypophysial tract to the posterior pituitary gland and (2) neuroendocrine control of the anterior pituitary through the release of peptides that mediate anterior pituitary gland hormone release (hypophysiotropic hormones) (Figure 61–2).

FUNCTIONAL ANATOMY The hypothalamus is the part of the diencephalon located below the thalamus and between the lamina terminalis and the mamillary bodies forming the walls and the floor of the

Ch61_613-622.indd 613

third ventricle. At the floor of the third ventricle, the two halves of the hypothalamus are rejoined to form a bridgelike region known as the median eminence (Figure 61–1). The median eminence is important because this is where axon terminals of hypothalamic neurons release neuropeptides involved in the control of anterior pituitary function. In addition, the median eminence is traversed by the axons of hypothalamic neurons ending in the posterior pituitary. The median eminence funnels down to form the infundibular portion of the neurohypophysis or posterior pituitary.

HYPOTHALAMIC NUCLEI In the hypothalamus, the neuronal bodies are clustered in nuclei with projections reaching other brain regions as well as ending in other hypothalamic nuclei. This intricate system of neuronal connections allows continuous communication between the hypothalamic neurons and other brain regions. Some of the neurons that make up the hypothalamic nuclei are neurohormonal in nature. Neurohormonal refers to the ability of these neurons to synthesize neuropeptides that function as hormones and to release these neuropeptides from axon terminals in response to neuronal depolarization. Two types of 613

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Small diame Hypothalamus

GnRH

TRH CRH

ter ne u

GHRH

rons

Somatostatin Dopamine

Hypothalamus Optic chiasm

PVN Mamillary body

Superior hypophyseal artery

SON

Preprooxyphysin Prepropressophysin

Optic chiasm

Mamillary body

Posterior pituitary Anterior pituitary

Oxytocin Anterior pituitary ACTH TSH GH FSH LH Prolactin

ADH Posterior pituitary Inferior hypophysial artery

FIGURE 61–1 Anatomic and functional relationship between the hypothalamus and the pituitary. The hypothalamus is anatomically and functionally linked with the anterior and posterior pituitary. They are closely related because of the portal system of blood supply. The superior, medial, and inferior hypophyseal arteries provide arterial blood supply to the median eminence and the pituitary. Magnocellular neurons of the supraoptic and paraventricular nuclei have long axons that terminate in the posterior pituitary. Antidiuretic hormone (ADH, also known as arginine vasopressin) and oxytocin are synthesized in magnocellular neurons as precursors (preprohormones), post-translationally processed, and released from the posterior pituitary into the blood. The axons of parvocellular neurons terminate in the median eminence where they release their neuropeptides. The long portal veins drain the median eminence, transporting the peptides from the primary capillary plexus to the secondary plexus that provides blood supply to the anterior pituitary. TRH, thyrotropin-releasing hormone; CRH, corticotropin-releasing hormone; GnRH, gonadotropin-releasing hormone, GHRH, growth-hormone releasing hormone; PVN, paraventricular nucleus; SON, supraoptic nucleus; ADH, antidiuretic hormone; ACTH, adrenocorticotropin; TSH, thyroid-stimulating hormone; GH, growth hormone; FSH, follicle stimulating hormone; LH, luteinizing hormone. (Reproduced with permission from Kibble J, Halsey CR: The Big Picture, Medical Physiology. New York: McGraw-Hill, 2009.)

FIGURE 61–2

Magnocellular neurons are larger in size and produce large quantities of neurohormones. Located predominantly in the paraventricular and supraoptic nuclei of the hypothalamus, their unmyelinated axons form the hypothalamohypophyseal tract that traverses the median eminence ending in the posterior pituitary. They synthesize the neurohormones oxytocin (OT), and antidiuretic hormone (ADH), and neurophysin (NP), that are transported in neurosecretory vesicles down the hypothalamohypophyseal tract and stored in varicosities at the nerve terminals in the posterior pituitary. Parvocellular neurons are small in size and have projections that terminate in the median eminence, brainstem, and spinal cord. They release small amounts of releasing or inhibiting neurohormones (hypophysiotropic hormones - CRH, TRH, GnRH, GHRH, SST, DA) that control anterior pituitary function (discussed in the next chapter). These are transported in the long portal veins to the anterior pituitary where they stimulate the release of pituitary hormones (ACTH, TSH, LH/FSH, GH, Prl) into the systemic circulation. (Modified with permission from Molina PE: Endocrine Physiology, 3rd ed. New York: McGraw-Hill Medical, 2010.)

Magnocellular neuron

Parvocellular neuron

Axonal transport

Axonal transport

Median eminence CRH, TRH, GnRH, GHRH, SST, DA Long portal veins Anterior pituitary

Posterior pituitary OT, ADH, NP ACTH, TSH, LH/FSH, GH, Prl

Systemic circulation

Systemic circulation

CHAPTER 61 The Hypothalamus and Posterior Pituitary Gland neurons are important in mediating the endocrine functions of the hypothalamus: the magnocellular and the parvocellular neurons (Figure 61–2). The magnocellular neurons are predominantly located in the paraventricular and supraoptic nuclei of the hypothalamus and produce large quantities of the neurohormones oxytocin and antidiuretic hormone (ADH) also known as arginine vasopressin (AVP). The unmyelinated axons of these neurons form the hypothalamohypophysial tract, the bridgelike structure that traverses the median eminence and ends in the posterior pituitary. Oxytocin and ADH are released from the posterior pituitary in response to an action potential. Parvocellular neurons have projections that terminate in the median eminence, brainstem, and spinal cord. These neurons release small amounts of releasing or inhibiting neurohormones (hypophysiotropic hormones) that control anterior pituitary function.

HYPOTHALAMIC NEUROPEPTIDES Two general types of neurons constitute the endocrine hypothalamus: the magnocellular neurons, with axons terminating in the posterior pituitary, and the parvocellular neurons, with axons terminating in the median eminence. Hypophysiotropic peptides released near the median eminence are transported down the infundibular stalk to the anterior pituitary, where they bind to specific cell membrane receptors in cells of the anterior pituitary, activating intracellular second-messenger cascades that result in the release of anterior pituitary hormones into the systemic circulation (Table 61–1). Peptides released from the anterior pituitary (adrenocorticotropic hormone [ACTH], prolactin, growth hormone [GH], luteinizing hormone [LH], follicle-stimulating hormone [FSH], and thyroid-stimulating hormone [TSH]) and the axons of magnocellular neurons terminating in the posterior pituitary (oxytocin and ADH) are transported in the venous blood draining the pituitary that enters the intercavernous sinus and the internal jugular veins to reach the systemic circulation.

615

REGULATION OF HORMONE RELEASE Because the hypothalamus receives and integrates afferent signals from multiple brain regions, it does not function in isolation from the rest of the central nervous system. Some of these afferent signals convey sensory information about the individual’s environment such as light, heat, cold, and noise. Among the environmental factors, light plays an important role in generating the circadian rhythm of hormone secretion. This endogenous rhythm is generated through the interaction between the retina, the hypothalamic suprachiasmatic nucleus, and the pineal gland through the release of melatonin. Melatonin is a hormone synthesized and secreted by the pineal gland at night that conveys information concerning the daily cycle of light and darkness to body physiology and participates in the organization of circadian rhythms. Its rhythm of secretion is entrained to the light/dark cycle. Other signals perceived by the hypothalamus are visceral afferents that provide information to the central nervous system from peripheral organs such as the intestines, the heart, the liver, and the stomach. The neuronal signals are transmitted by various neurotransmitters released from the afferent fibers, including glutamate, norepinephrine, epinephrine, serotonin, acetylcholine, histamine, γ-aminobutyric acid, and dopamine. In addition, circulating hormones produced by endocrine organs and substrates such as glucose can regulate hypothalamic neuronal function. Together, these neurotransmitters, substrates, and hormones influence hypothalamic hormone release. Therefore, hypothalamic hormone release is under environmental, neural, and hormonal regulation. The ability of the hypothalamus to integrate these signals makes it a center of command for regulating endocrine function and maintaining homeostasis. Hormones can signal the hypothalamus to either inhibit or stimulate hypophysiotropic hormone release. This control mechanism of negative (or positive) feedback regulation consists of the ability of a hormone to regulate its own cascade

TABLE 61–1 Key aspects of hypophysiotropic hormones. Hypophysiotropic Hormone

Predominant Hypothalamic Nuclei

Anterior Pituitary Hormone Controlled

Target Cell

Thyrotropin-releasing hormone

Paraventricular nuclei

Thyroid-stimulating hormone and prolactin

Thyrotroph

Gonadotropin-releasing hormone

Anterior and medial hypothalamus; preoptic septal areas

Luteinizing hormone and follicle-stimulating hormone

Gonadotroph

Corticotropin-releasing hormone

Medial parvocellular portion of paraventricular nucleus

Adrenocorticotropic hormone

Corticotroph

Growth hormone–releasing hormone

Arcuate nucleus, close to median eminence

Growth hormone

Somatotroph

Somatostatin or growth hormone– inhibiting hormone

Anterior paraventricular area

Growth hormone

Somatotroph

Dopamine

Arcuate nucleus

Prolactin

Lactotroph

The six recognized hypophysiotropic factors and the predominant locations of their cells of origin are listed in the left columns. The right columns list the anterior pituitary hormone that each hypophysiotropic factor regulates and the cell that releases the specific hormones.

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of release (see Figure 60–9). For example, cortisol produced from the adrenal gland can inhibit the release of CRH, thus inhibiting the production of proopiomelanocortin and ACTH and consequently decreasing adrenal gland synthesis of cortisol. This loop of hormonal control and regulation of its own synthesis is critical in maintaining homeostasis and preventing disease. A shorter loop of negative feedback inhibition also exists, which depends on the inhibition of hypophysiotropic neuropeptide release by the pituitary hormone that it stimulates. In this case, an example would be the ability of ACTH to inhibit CRH release by the hypothalamus. Some neuropeptides also possess an ultrashort feedback loop, in which the hypophysiotropic neuropeptide itself is able to modulate its own release. As an example, oxytocin stimulates its own release, creating a positive feedback regulation of neuropeptide release. This continuous regulation of hormonal release is dynamic; it is continuously adapting to changes in the environment and in the internal milieu of the individual. Throughout a given day, the hypothalamus integrates a multitude of signals to ensure that the rhythms of hormone release are kept in pace

with the needs of the organism. Disruption of these factors can alter the patterns of hormone release.

HORMONES OF THE POSTERIOR PITUITARY The neuropeptides produced by the magnocellular neurons, and consequently released from the posterior pituitary, are oxytocin and ADH. Oxytocin and ADH are closely related peptides consisting of nine amino acids with ring structures. They are synthesized as large precursor molecules in the magnocellular neurons and packaged into neurosecretory vesicles (Figure 61–3). Within the neurosecretory vesicles, the precursor hormone undergoes additional posttranslational processing during axonal transport, producing the biologically active peptides ADH and oxytocin as well as small peptide products of hormone processing called neurophysins. Following neuronal depolarization, neuropeptides released enter the systemic circulation through venous drainage of the posterior pituitary into the intercavernous sinus and internal

Nucleus Cell body

Pre-prohormone synthesis in ER followed by packaging into secretory granules in GA occurs in the cell body of magnocellular neurons.

Axon

FIGURE 61–3 Synthesis and processing of oxytocin and antidiuretic hormone. Oxytocin and antidiuretic hormone are synthesized in the endoplasmic reticulum (ER) of hypothalamic magnocellular neurons as preprohormones. In the Golgi apparatus (GA) they are packaged in secretory granules and are transported down the hypothalamohypophyseal tract. During their transport the precursor hormones are processed, yielding the final hormone and the respective neurophysins. The contents of the neurosecretory vesicles are released by exocytosis from the axon terminals in the posterior pituitary. Exocytosis is triggered by the influx of Ca2+ through voltage-gated channels that are opened during the neuronal depolarization. The rise in Ca2+ produces the docking of the secretory vesicles on the axonal plasma membrane and the release of the neuropeptides into the interstitial space. (Modified with permission from Molina PE: Endocrine Physiology, 3rd ed. New York: McGraw-Hill Medical, 2010.)

Neurosecretory vesicles are transported down the hypothalamo-hypophysial tract. Hormone processing occurs during this stage yielding hormone and neurophysins.

Contents of neurosecretory vesicles are released from nerve terminals in the posterior pituitary. Exocytosis is triggered by Ca2+ influx through voltage-gated channels opened during neuronal depolarization.

Mitochondria Synaptic vesicle

CHAPTER 61 The Hypothalamus and Posterior Pituitary Gland

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jugular vein. In the systemic circulation, oxytocin and ADH circulate unbound. They are rapidly cleared from the circulation by the kidney and, to a lesser extent, by the liver and brain. Their half-life is short and is estimated to range between 1 and 5 minutes.

The physiologic effects of oxytocin in the pregnant uterus are augmented by a dramatic increase in sensitivity to the hormone during the onset of labor, due to an increased density (upregulation) of oxytocin receptors in the uterine muscle, increased gap junction formation between smooth muscle cells, and by increased synthesis of prostaglandins.

OXYTOCIN

Control of Oxytocin Release

The neuropeptide oxytocin is released in response to sensory stimulation during breastfeeding (lactation) and childbirth (parturition) (Figure 61–4).

Physiologic Effects of Oxytocin The two main target organs for oxytocin’s physiologic effects are the lactating breast and the uterus during pregnancy (Figure 61–4). The physiologic effects of oxytocin are achieved by binding to cell membrane Gq/11 protein–coupled oxytocin receptors expressed in the uterus, mammary glands, and brain. In the lactating breast, oxytocin stimulates milk ejection by producing contraction of the myoepithelial cells that line the alveoli and ducts in the mammary gland. In the pregnant uterus, oxytocin produces rhythmic contractions to help induce labor and to promote regression of the uterus following delivery. Oxytocin analogs are used clinically during labor and delivery to promote uterine contractions and during the postpartum period to help decrease bleeding and return the uterus to its normal size (uterine involution) (Table 61–2).

The principal stimulus for oxytocin release is mechanical stimulation of the uterine cervix by the fetus near the end of gestation and by the forceful contractions of the uterus during the fetal expulsion reflex. In addition, oxytocin release is also triggered by stimulation of tactile receptors in the nipples of the lactating breast during suckling (Figure 61–4). The role of oxytocin in males is not clear, although recent studies have suggested that it may participate in ejaculation.

ANTIDIURETIC HORMONE ADH, also known as arginine vasopressin (AVP), is the other neuropeptide produced by magnocellular neurons of the hypothalamus and released from the posterior pituitary. The principal effect of ADH is to increase water reabsorption by enhancing permeability to water in the distal convoluted tubules and the medullary collecting ducts in the kidney (see Chapter 45). The result is the production of smaller volumes of concentrated urine. In addition, ADH increases vascular resistance. This function of ADH may be important during

PVN & SON Fear, pain, noise, fever

Stretch of cervix end of pregnancy

Posterior pituitary Oxytocin release Sucking of lactating breast Contraction of myoepithelial cells

Uterine contraction

FIGURE 61–4 Physiologic effects and regulation of oxytocin release. The release of oxytocin is stimulated by the distention of the cervix at term of pregnancy and by the contraction of the uterus during parturition. The signals are transmitted to the paraventricular nuclei (PVN) and supraoptic nuclei (SON) of the hypothalamus, where they provide a positive feedback regulation of oxytocin release. The increased number of oxytocin receptors, the increased number of gap junctions between smooth muscle cells, and the increased synthesis of prostaglandins enhance the responsiveness of the uterine muscle. Oxytocin release causes an increase in uterine contractility, aiding in the delivery of the baby, and involution of the uterus after parturition. Suckling of the nipple of the lactating breast also stimulates oxytocin release. The afferent sensory signals elicit a rise in oxytocin release into the circulation. Oxytocin produces contraction of the myoepithelial cells lining the breast ducts, resulting in milk ejection. (Modified with permission from Molina PE: Endocrine Physiology, 3rd ed. New York: McGraw-Hill Medical, 2010.)

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TABLE 61–2 Key aspects of posterior pituitary hormones. Oxytocin

Antidiuretic Hormone

Receptor

Gq/11 protein–coupled

G protein–coupled (V1R, Gq/11, V2R, Gs)

Second messenger

Phospholipase C ↑ [Ca2+]i

(V1R) Phospholipase C ↑ [Ca2+]i (V2R) Adenylate cyclase cAMP

Target organ or cells

Physiologic effects

Uterus

V2R: kidney collecting ducts

Mammary myoepithelial cells

V1R: smooth muscle cells

Uterine contraction

Increased H2O permeability

Milk ejection

Vasoconstriction

cAMP, cyclic adenosine monophosphate.

periods of severe lack of responsiveness to other vasoconstrictors, as may occur during severe blood loss (hemorrhagic shock) or systemic infection (sepsis).

Physiologic Effects of ADH The cellular effects of ADH are mediated by binding to G protein–coupled membrane receptors. Three ADH receptors have been characterized thus far, which differ in terms of where they are expressed as well as in the specific G proteins to which they are coupled and, thus, in the

second-messenger systems that they activate. The main effects of ADH are mediated through the V2R receptor. The main target site of ADH is the collecting duct in the kidney. Water permeability of the collecting duct can be dramatically increased (within a few minutes) through the production of cyclic adenosine monophosphate (cAMP) following ADH binding to V2 receptors in the basolateral membrane of the principal cells in the collecting duct (Figure 61–5). The increase in cAMP activates protein kinase A and subsequently the phosphorylation of an aquaporin (AQP2) leading Interstitial space

ADH H2O

H2O Adenylate cyclase

V2R

AQP3

AQP4 Basolateral membrane

α

βγ

α

FIGURE 61–5

Cellular mechanism of ADH water conservation. The principal function of antidiuretic hormone (ADH) is to increase water reabsorption and to conserve water. ADH binds to the V2 G protein–coupled receptor (V2R) in the principal cells of the distal tubule. This triggers the activation of adenylate cyclase and the formation of cAMP, leading to activation of protein kinase A (PKA). PKA phosphorylates the water channel aquaporin 2 (AQP2), leading to the insertion of AQP2 into the luminal cell membrane. The insertion of water channels into the membrane increases the permeability to water. Water reabsorbed through these water channels leaves the cell through aquaporins 3 (AQP3) and 4 (AQP4), which are constitutively expressed in the basolateral membrane of the principal cells. (Modified with

α ATP

cAMP

PKA

Principal cell distal tubule AQP2 AQP2

Apical membrane

AQP2 AQP2

H2O

permission from Molina PE: Endocrine Physiology, 3rd ed. New York: McGraw-Hill Medical, 2010.)

Cytosolic pool of AQP2

H2O

Lumen-collecting duct

CHAPTER 61 The Hypothalamus and Posterior Pituitary Gland

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TABLE 61–3 Key features of aquaporins. Aquaporin

Features

AQP1

Constitutively expressed in apical and basolateral membranes of epithelial cells of proximal tubules and descending limb of Henle’s loop. Involved in 90% of water reabsorption

AQP2

Exclusively expressed in the collecting ducts. The only aquaporin directly regulated by ADH. Binding to the V2 ADH (AVP) receptor stimulates insertion into the luminal membrane

AQP3, AQP4

Constitutively expressed in the basolateral membranes of epithelial cells in the collecting ducts. Enhance water reabsorption following AQP2 insertion into the luminal membrane

AQP, aquaporin; ADH, antidiuretic hormone; AVP, arginine vasopressin.

to its movement from cytoplasmic pools and its insertion in the luminal (apical) epithelial cell membrane of the collecting duct cells. The result is an increase in the number of functional water channels in the luminal membrane, making it more permeable to water. AQP2, one of the several members of the aquaporin family, is exclusively expressed in the collecting ducts of the kidney (Table 61–3). It is the only aquaporin that is directly regulated by ADH via the V2 ADH receptor. AQP3 and AQP4 are constitutively expressed in the basolateral membranes of the collecting ducts and contribute to the enhanced water reabsorption following AQP2 insertion into the luminal membrane. Water that enters the epithelial cell through AQP2 on the apical membrane leaves the cell through AQP3 and AQP4, located in the basolateral membranes of these cells, eventually entering the vasculature. ADH also binds the V1 receptor, found in the vascular smooth muscle, producing contraction and increasing peripheral vascular resistance. The

hormone is known as vasopressin because of these vasoconstrictor effects.

Control of ADH Release ADH is released into the circulation following either an increase in plasma osmolality or a decrease in blood volume (Figure 61–6). Under physiologic conditions, the most important stimulus for ADH release is the “effective” plasma osmolality detected by special osmoreceptor neurons located in the hypothalamus and in three structures associated with the lamina terminalis: the subfornical organ, the median preoptic nucleus, and the organum vasculosum lamina terminalis. The sensitivity of this system is quite high. That is, very small changes in plasma osmolality (as little as 1% change) above the osmotic threshold of 280–284 mOsm/kg water produce significant increases in ADH release.

Fluid loss Hemorrhage, vomiting, diarrhea

Plasma ADH (pg/ml)

10 MABP

8 10% blood loss 6

Baroreceptor stretch and firing

4 9th and 10th cranial nerve afferents

2 Thirst 0 270

280 290 300 310 Plasma osmolarity (mOsm/kg)

Plasma osmolarity

Shrinkage of osmoreceptors

Sympathetic tone

ADH release

Magnocellular neuron inhibition

Restore fluid balance

H2O reabsorption

FIGURE 61–6 Integration of signals that trigger ADH release. Release of ADH is stimulated by an increase in plasma osmolality and a decrease in blood volume. Small changes in plasma osmolality above a threshold of 280–284 mOsm/kg produce an increase in ADH release before the stimulation of thirst. A decrease in blood volume sensitizes the system and increases the responsiveness to small changes in plasma osmolality. Blood loss and a decrease in mean arterial blood pressure (MABP) greater than 10% signal the hypothalamus to increase the release of ADH. The afferent signals are transmitted by the 9th and 10th cranial nerves. These signals increase sympathetic tone, therefore decreasing magnocellular neuron inhibition and stimulating ADH release. (Modified with permission from Molina PE: Endocrine Physiology, 3rd ed. New York: McGraw-Hill Medical, 2010.)

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ADH secretion is also stimulated by a decrease in blood pressure of greater than 10%. Factors that reduce cardiac output, such as a decrease in blood volume greater than 8%, orthostatic hypotension, and positive pressure breathing, are all stimuli for ADH release. ADH secretion is far more sensitive to small changes in plasma osmolality than to changes in blood volume. The volume-induced sensitization of ADH release results in a more accentuated ADH response to changes in plasma osmolality. ADH is barely detectable below a certain plasma osmolality (287 mOsm/kg) threshold. Above this threshold, the plasma AVP concentration rises steeply in direct proportion to plasma osmolality.

Disorders of ADH Production Either excess or deficiency of ADH can result in clinical disease. The concentrations of ADH may be altered in various chronic pathophysiologic conditions, including congestive heart failure, liver cirrhosis, and nephrotic syndrome. A decrease in ADH release or action results in diabetes insipidus, a clinical syndrome in which the ability to form concentrated urine is reduced.

Diabetes insipidus Diabetes insipidus is characterized by the excretion of abnormally large volumes (up to 30 mL/kg of body weight per day for adult subjects) of dilute (<250 mmol/kg) urine and excessive thirst. Three basic defects have been identified in the etiology (only the first two pertain to alterations related to components of the ADH system itself): • Decreased ADH release: Neurogenic (central or hypothalamic) diabetes insipidus is due to a decrease in ADH release from the posterior pituitary, resulting from diseases affecting the hypothalamic-neurohypophysial axis. Three causes can be identified: traumatic, inflammatory or infectious, and cancer related. • Decreased renal responsiveness to ADH: Renal (nephrogenic) diabetes insipidus results from renal insensitivity to the antidiuretic effect of ADH. ADH production and release are not affected, but responsiveness at the distal tubule is impaired. Nephrogenic diabetes insipidus can be inherited or acquired and is characterized by an inability to concentrate urine despite normal or elevated plasma concentrations of ADH. About 90% of inherited cases are males with the X-linked recessive form of the disease who have mutations in the ADH type 2 receptor gene. A small number of cases of inherited nephrogenic diabetes insipidus are due to mutations in the AQP2 water channel gene. Acquired nephrogenic diabetes insipidus can result from lithium treatment, hypokalemia, and postobstructive polyuria. • Excess water intake: Finally, the third possible cause of diabetes insipidus is excess water intake. This cause does not involve dysfunction of the ADH system.

Syndrome of inappropriate ADH secretion An increase or excess in the release of ADH, also known as the syndrome of

inappropriate ADH secretion, may be the result of tumor production of ADH. The tumor can be located in the brain, but malignancies of other organs such as the lung have also been shown to produce high levels of ADH. The excess production of ADH results in the production of very small volumes of concentrated urine. Retention of water may lead to decreased plasma sodium (hyponatremia). Management of this condition entails fluid restriction and in some cases the use of saline solutions to restore adequate plasma sodium levels.

CLINICAL CORRELATION A head trauma patient on his third day in the surgical intensive care unit is reported to have an excessive urine output of 20 L in the past 24 hours. Laboratory findings show hypernatremia (high serum Na) and hypotonic urine. Withholding drinking water did not decrease urine output or increase urine osmolarity. Urine osmolarity increased in response to exogenous antidiuretic hormone (vasopressin) administration. He is diagnosed as having posttraumatic diabetes insipidus. Neurogenic diabetes insipidus is the result of decreased release of ADH characterized by polyuria (increased urine output) and hypernatremia. This can be the result of destruction of neurons that produce and release ADH resulting from inflammation, neoplasia, vascular abnormalities, or traumatic injury. Patients are treated with desmopressin, a synthetic analog of ADH, which binds to V2 receptors, increasing water reabsorption in the kidney, decreasing urine output, and restoring serum osmolarity.

CHAPTER SUMMARY ■

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The parvocellular neurons of the hypothalamus produce neuropeptides that are released at the median eminence and are transported to the anterior pituitary, where they regulate the release of anterior pituitary hormones. The hypothalamus integrates information from various brain regions, the environment, and peripheral organs and mediates systemic responses that help maintain homeostasis. The magnocellular neurons of the hypothalamus produce oxytocin and ADH, hormones that are released from the posterior pituitary into the systemic circulation. Prohormone posttranslational modification and processing of oxytocin and ADH occur inside the secretory granules during axonal transport. ADH binds to the V2 receptor and increases water reabsorption by stimulating the insertion of aquaporin 2 into the apical (luminal) membrane of tubular collecting duct epithelial cells. The release of ADH is more sensitive to small changes in plasma osmolality than to small changes in blood volume. Deficiency of ADH results in the production of large quantities of dilute urine.

CHAPTER 61 The Hypothalamus and Posterior Pituitary Gland

STUDY QUESTIONS 1. The renal effects of ADH (AVP) are mediated by A) binding to V2 G protein–coupled receptor, protein phosphorylation, and insertion of aquaporin 2 into luminal cell membrane in collecting duct B) binding to nuclear receptors, protein phosphorylation, and insertion of aquaporin 2 into basolateral membrane of collecting duct C) binding to V1 G protein–coupled receptor, protein phosphorylation, and insertion of aquaporin 1 into luminal cell membrane of collecting duct D) binding to nuclear receptors, protein phosphorylation, and insertion of aquaporin 2 into luminal cell membrane of collecting duct 2. On a hot summer day after profuse sweating, the release of ADH occurs A) when plasma osmolality is 270 mOsm/kg B) immediately following stimulation of thirst C) only after more than a 10% decrease in blood volume D) before stimulation of thirst 3. Which of the following can be manifestations of the syndrome of inappropriate ADH secretion? A) hypernatremia with high urine osmolality B) hyponatremia with high urine osmolality C) hypophosphatemia with low urine osmolality D) hyponatremia with low urine osmolality

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4. Oxytocin A) is released from the anterior pituitary during parturition B) is synthesized in the posterior pituitary and released during parturition C) is produced in the magnocellular neurons of the hypothalamus and released from the posterior pituitary during parturition D) is produced in the magnocellular neurons of the hypothalamus and released from the anterior pituitary during parturition 5. Uterine muscle responsiveness to oxytocin A) is not altered throughout pregnancy B) is prevented by high prostaglandin levels during pregnancy C) is decreased by lower gap junction formation during the third trimester D) is enhanced by increased oxytocin receptor density

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62 C

Anterior Pituitary Gland Patricia E. Molina

H A

P

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O B J E C T I V E S ■ ■ ■ ■

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Identify the three families of anterior pituitary hormones and their main structural differences. Understand the mechanisms that regulate anterior pituitary hormone production and describe the actions of tropic hormones on target organs. Diagram the short- and long-loop negative feedback control of anterior pituitary hormone secretion. Predict the changes in secretory rates of hypothalamic anterior pituitary and target gland hormones caused by oversecretion or undersecretion of any of these hormones or receptor deficit for any of these hormones. Explain the importance of pulsatile and diurnal hormone secretion.

The anterior pituitary plays a central role in the regulation of endocrine function through the production and release of tropic hormones (Figure 62–1). The function of the anterior pituitary, and thereby the production of tropic hormones, is under hypothalamic regulation by the hypophysiotropic neuropeptides released in the median eminence, summarized in Table 62–1. The tropic hormones produced by the anterior pituitary bind to specific receptors at their target organs to produce a physiologic response, most frequently involving the release of a hormone (Figure 62–2). The hormones produced by the target organs affect anterior pituitary function as well as the release of hypophysiotropic neuropeptides, maintaining an integrated feedback control system of endocrine function.

FUNCTIONAL ANATOMY The pituitary, or hypophysis, consists of an anterior and a posterior lobe that differ from one another in their embryologic origin, mode of development, and structure. The anterior lobe, also known as the adenohypophysis, is the remnant of Rathke’s pouch; it is a highly vascularized structure consisting of epithelial cells derived from the ectodermal lining of the roof of the mouth. The pituitary cells that line the capillaries produce the tropic (also known as trophic) hormones: adrenocorticotropic hormone (ACTH), thyroid-stimulating

Ch62_623-632.indd 623

hormone (TSH), growth hormone (GH), prolactin, and the gonadotropins [luteinizing hormone (LH) and folliclestimulating hormone (FSH)] (Figure 62–1). All of these hormones are released into the systemic circulation.

HYPOTHALAMIC CONTROL OF ANTERIOR PITUITARY HORMONE RELEASE The production of pituitary tropic hormones is under direct regulation by the hypothalamic neurohormones released from neuronal terminals in the median eminence. The responsiveness of the anterior pituitary to the inhibitory or stimulatory effects of hypophysiotropic neurohormones can be modified by several factors, including hormone levels, negative feedback inhibition, and circadian rhythms The release of anterior pituitary hormones is cyclic in nature, and this cyclic pattern of hormone release is governed by the nervous system. Most daily (circadian) rhythms are driven by an internal biologic clock located in the hypothalamic suprachiasmatic nucleus; this clock is synchronized by external signals such as light and dark periods. Both sleep and circadian effects interact to produce the overall rhythmic pattern of pituitary hormone release and the associated responses. Some of the 24-hour 623

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Artery Artery Anterior pituitary gland

Posterior pituitary gland

GH TSH

ACTH

Thyroid hormone

FIGURE 62–1 Anterior pituitary hormones, target organs, and physiologic effects. Thyroid-stimulating hormone (TSH) stimulates the thyroid gland to produce and release thyroid hormones that regulate growth, differentiation, and energy balance. Luteinizing hormone (LH) and follicle-stimulating hormone (FSH) stimulate gonadal production of sex steroids, which mediate reproductive function and behavior. Adrenocorticotropic hormone (ACTH) stimulates the adrenal glands to produce steroid hormones, which regulate water and sodium balance, inflammation, and metabolism. Prolactin (Prl) stimulates breast development and milk production. Growth hormone (GH) exerts direct effects on tissue growth and differentiation and indirect effects through the stimulation of insulin-like growth factor I production, which mediates some of the growth and differentiation effects of GH. (Modified with permission from Molina PE: Endocrine

Cortisol, aldosterone, & androgens

H2O & Na balance Inflammation & metabolism

Growth & differentiation Energy balance

Physiology, 3rd ed. New York: McGraw-Hill Medical, 2010.)

hormonal rhythms depend on the circadian clock (i.e., ACTH, cortisol, and melatonin) and some are sleep related (i.e., prolactin, GH, and TSH). For example, GH secretion is influenced by the first slow-wave sleep episode at the beginning of the night. Pulses of prolactin and GH are positively linked to increases in delta-wave activity, present during the deepest phases of sleep and occurring primarily during the first third of the night. Pulses of TSH and cortisol are related to superficial phases of sleep. Although the regulation of the patterns of hormone release is not well understood, it is clear that the respective patterns of anterior pituitary hormone release play a crucial role in achieving their physiologic effects and, thus, in maintaining homeostasis. The importance of this regulation has become evident because constant or continuous exogenous hormone

Insulin-like growth factor

LH & FSH

Growth & differentiation Prl

Estrogen, progesterone, & testosterone Reproductive function & behavior

Breast development Milk production

administration produces effects that differ from the hormone’s natural physiologic effects. These observations have highlighted the importance of trying to simulate as much as possible the endogenous cyclic patterns of hormone release when giving hormone replacement therapy to a patient.

HORMONES OF THE ANTERIOR PITUITARY The hormones of the anterior pituitary can be classified into three families: the glycoproteins, those derived from proopiomelanocortin (POMC), and those belonging to the GH and prolactin family.

CHAPTER 62 Anterior Pituitary Gland

TABLE 62–1 Anterior pituitary cell type, regulatory hypothalamic factor, and hormone product. Anterior Pituitary Cells

Hypothalamic Factor

Pituitary Hormone Produced

Lactotrophs

Dopamine (−)

Prolactin

Corticotrophs

CRH (+)

POMC: ACTH, β-LPH, α-MSH, β-endorphin

Thyrotrophs

TRH (+)

Thyroid-stimulating hormone

Gonadotrophs

GnRH (+)

LH and FSH

Somatotrophs

GHRH (+) and SST (−)

Growth hormone

(+), stimulatory factor; (−), inhibitory factor; CRH, corticotropin-releasing hormone; POMC, proopiomelanocortin; ACTH, adrenocorticotropic hormone; LPH, lipotropin; MSH, melanocyte-stimulating hormone; TRH, thyrotropinreleasing hormone; GnRH, gonadotropin-releasing hormone; LH, luteinizing hormone; FSH, follicle-stimulating hormone; GHRH, growth hormone– releasing hormone; SST, somatostatin.

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GLYCOPROTEINS Glycoprotein hormones are among the largest hormones known to date. They include TSH, FSH, LH, and human chorionic gonadotropin produced by the placenta. These hormones are heterodimeric glycoproteins consisting of a common α-subunit and a unique β-subunit, which confers the biologic specificity of each hormone.

Thyroid-stimulating Hormone TSH is a glycoprotein synthesized and secreted from thyrotrophs of the anterior pituitary gland. Thyrotrophs constitute approximately 5% of all adenohypophysial cells. They synthesize and release TSH in response to stimulation by thyrotropinreleasing hormone (TRH), which is synthesized in the hypothalamus and released from nerve terminals in the median eminence. TSH binds to a Gs protein–coupled

Hypothalamic Peptides TRH

GnRH

CRH

GHRH

Somatostatin

Dopamine

Median eminence

G protein−coupled receptors in anterior pituitary Thyrotroph

Gonadotroph

Corticotroph

PLC

PLC

AC

TSH

LH & FSH

ACTH

Somatotroph AC

AC

AC

AC,

GH

G protein−coupled receptors

AC

AC

Lactotroph K+ ,

Ca2+

Prl

Class 1 cytokine receptor Kinase activity

Kinase activity

Target organ physiologic response

FIGURE 62–2 Cellular signaling pathways involved in hypothalamo-pituitary hormone-mediated effects. All hypothalamic releasing and inhibiting factors mediate their effects predominantly via G protein–coupled receptors. Anterior pituitary hormones bind to either G protein–coupled receptors (thyroid-stimulating hormone [TSH], luteinizing hormone [LH], follicle-stimulating hormone [FSH], adrenocorticotropic hormone [ACTH]) or class 1 cytokine receptors (growth hormone [GH] and prolactin [Prl]). Most of the cellular responses elicited by anterior pituitary hormones that bind to G protein–coupled receptors are mediated by modulation of adenylate cyclase activity. The cellular responses evoked by anterior pituitary binding to class 1 cytokine receptors are mediated through protein kinase activation. TRH, thyrotropin-releasing hormone; GnRH, gonadotropin-releasing hormone; CRH, corticotropin-releasing hormone; GHRH, GH-releasing hormone; PLC, phospholipase C activity; AC, adenylate cyclase activity. (Modified with permission from Molina PE: Endocrine Physiology, 3rd ed. New York: McGraw-Hill Medical, 2010.)

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receptor in the thyroid gland, and stimulates all the events involved in thyroid hormone synthesis and release. In addition, it acts as a growth factor for the thyroid gland. The release of TSH from the anterior pituitary gland is under negative feedback inhibition by thyroid hormones.

Gonadotropins (FSH and LH) The gonadotropic hormones LH and FSH are synthesized and secreted by gonadotrophs of the anterior pituitary in response to stimulation by gonadotropin-releasing hormone (GnRH). Gonadotrophs constitute about 5–10% of the pituitary cells. Most of the gonadotrophs (60%) produce both LH and FSH. The remainder of the gonadotroph population produces LH (18%) or FSH (22%) exclusively. GnRH is synthesized and secreted by the hypothalamus in a pulsatile manner. FSH and LH exert their physiologic effects on multiple cells of the reproductive system by binding to Gαs protein–coupled receptors and activation of adenylate cyclase. Among the target cells for gonadotropins are ovarian granulosa cells, theca interna cells, testicular Sertoli cells, and Leydig cells. The physiologic responses produced by the gonadotropins include stimulation of sex hormone synthesis (steroidogenesis), spermatogenesis, folliculogenesis, and ovulation. Therefore, their central role is the control of reproductive function in both males and females. GnRH controls the synthesis and secretion of both FSH and LH by the pituitary gonadotroph cell. Gonadotropin synthesis and release, as well as differential expression, is under both positive and negative feedback control by gonadal steroids and gonadal peptides. Gonadal hormones can decrease gonadotropin release both by decreasing the frequency and amplitude of pulses of GnRH release from the hypothalamus and by affecting the ability of GnRH to stimulate gonadotropin secretion from the pituitary itself.

PROOPIOMELANOCORTINDERIVED HORMONES Proopiomelanocortin (POMC) is a precursor prohormone produced by the corticotrophs of the anterior pituitary. Corticotrophs account for 10% of the secretory cells of the anterior pituitary. The production and secretion of POMCderived hormones from the anterior pituitary are regulated predominantly by corticotropin-releasing hormone (CRH) produced in the paraventricular nucleus of the hypothalamus and released in the median eminence. CRH binds to Gs protein–coupled CRH receptors. POMC is posttranslationally cleaved to ACTH; β-endorphin, an endogenous opioid peptide; and α-, β-, and γ-melanocytestimulating hormones (MSH) (Figure 62–3). The biologic effects of POMC-derived peptides are largely mediated through melanocortin receptors (MCRs), of which five have been described. MC1R, MC2R, and MC5R have defined roles in the skin, adrenal steroid hormone production, and thermoregulation, respectively. MC4R is expressed in the brain and

has been implicated in feeding behavior and appetite regulation. The role of MC3R is not well defined.

Adrenocorticotropic Hormone The main hormone of interest produced by the cleavage of POMC is ACTH. The release of ACTH is stimulated by psychological and physical stressors such as infection, hypoglycemia, surgery, and trauma and is considered critical in mediating the adaptive response of the individual to stress. ACTH is released in pulses, with the highest concentrations occurring in the morning and the lowest concentrations around midnight. ACTH released into the systemic circulation binds to a Gαs protein–coupled receptor at the adrenal cortex and stimulates the production and release of glucocorticoids (cortisol) and, to a lesser extent, mineralocorticoids (aldosterone). The release of cortisol follows the same diurnal rhythm as that of ACTH. The feedback inhibition of ACTH and of CRH release by cortisol is mediated by glucocorticoid receptor binding in the hypothalamus and in the anterior pituitary.

Melanocyte-stimulating Hormone α-MSH is produced by the proteolytic cleavage of POMC, mainly in the pars intermedia of the pituitary gland (Figure 62–3). Only small amounts of α-MSH are produced in the human pituitary under normal conditions. Melanocortin peptides exert their effects through MC1R found in melanocytes, which are key components of the skin’s pigmentary system, endothelial cells, monocytes, and keratinocytes.

β-Endorphin β-Endorphin, the most abundant endogenous opioid peptide, is another product of POMC processing in the pituitary (Figure 62–3). The physiologic effects of this opioid peptide are mediated by binding to opiate receptors, expressed in multiple cell types in the brain as well as in peripheral tissues. The physiologic actions of endorphins are not well understood, but may include analgesia, behavioral effects, and neuromodulatory functions.

GROWTH HORMONE & PROLACTIN FAMILY Growth Hormone GH is a 191–amino acid peptide hormone, with a molecular weight of approximately 22 kd and structural similarity to prolactin and chorionic somatomammotropin (human placental lactogen), a placental-derived hormone. GH is released from the somatotrophs, an abundant (50%) cell type in the anterior pituitary. It is released in pulsatile bursts, with the majority of secretion occurring nocturnally in association with slow-wave sleep (see Figure 60–7). The basis of the pulsatile release of GH and the function of this pattern are not fully

CHAPTER 62 Anterior Pituitary Gland

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Pro-opiomelanocortin Signal peptide COOH

NH2 β-LPH

N-terminal

ACTH

γ-LPH

ACTH receptor γ-MSH

β-end

β-MSH α-MSH

CLIP

Melanocortin receptor

Opiate receptor

FIGURE 62–3 Proopiomelanocortin (POMC) processing. Corticotropin-releasing hormone stimulates the production, release, and processing of POMC, a preprohormone synthesized in the anterior pituitary. POMC is posttranslationally cleaved to adrenocorticotropic hormone (ACTH); β-endorphin, an endogenous opioid peptide; and α-, β-, and γ-melanocyte-stimulating hormones (MSH). The cellular effects of these peptides are mediated via melanocortin (ACTH and MSH) or opiate (β-end) receptors. LPH, β-lipotropin; CLIP, corticotropin-like intermediate lobe peptide. (Modified with permission from Molina PE: Endocrine Physiology, 3rd ed. New York: McGraw-Hill Medical, 2010.) understood; however, nutritional, metabolic, and age-related sex steroid mechanisms, adrenal glucocorticoids, thyroid hormones, and renal and hepatic functions are all thought to contribute to the pulsatile release of GH and appear to be essential in achieving optimal biologic potency of the hormone.

Regulation of GH release The two principal hypothalamic regulators of GH (somatotropin) release from the anterior pituitary are growth hormone-releasing hormone (GHRH) and somatostatin (SST), which exert stimulatory and inhibitory influences, respectively, on the somatotrophs (Figure 62–4). GH release is also inhibited by insulin-like growth factor-I (IGF-I), the hormone produced in the periphery, particularly in the liver, in response to GH receptor stimulation, in a classic negative feedback mechanism of hormone control. More recently, ghrelin has been identified as an additional GH secretagogue. Ghrelin is a peptide released predominantly from stomach.

The overall contribution of ghrelin to regulation of GH release in humans is still not fully elucidated.

Other regulators In addition to regulation by GHRH and SST, GH is regulated by other hypothalamic peptides and neurotransmitters, which act by regulation of GHRH and SST release, as summarized in Table 62–2. Catecholamines, dopamine, and excitatory amino acids increase GHRH and decrease SST release, resulting in an increase in GH release. Hormones such as cortisol, estrogen, androgens, and thyroid hormone can also affect somatotroph responsiveness to GHRH and SST and consequently GH release. Metabolic signals such as glucose and amino acids can affect GH release. Decreased blood glucose concentrations (hypoglycemia) stimulate GH secretion in humans. Glucose and nonesterified fatty acids decrease GH release, whereas amino acids, particularly arginine, increase GH release. Consequently, arginine administration is also an effective challenge to elicit an increase in GH release in the clinical setting.

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SECTION IX Endocrine and Metabolic Physiology

Sleep Hypoglycemia (+) Stress

(–)

Aging (–) Disease Glucose GHRH (+) SST (–)

(–)

Adipose tissue Glucose uptake Lipolysis

(–) (–) GH

Muscle Glucose & AA uptake Protein synthesis Chondrocytes AA uptake Protein synthesis DNA & RNA synthesis Chondroitin sulfate Collagen Cell size & number

IGF-I

FIGURE 62–4 Growth hormone release and effects. Growth hormone release from the anterior pituitary is modulated by several factors, including stress, exercise, nutrition, sleep, and growth hormone itself. The primary controllers of GH release are growth hormone–releasing hormone (GHRH) that stimulates both the synthesis and secretion of growth hormone and somatostatin (SST) that inhibits growth hormone release in response to GHRH and to other stimulatory factors such as low blood glucose concentration. Growth hormone secretion is also part of a negative feedback loop involving IGF-1. High blood levels of IGF-1 lead to decreased secretion of growth hormone not only by directly suppressing the somatotroph, but also by stimulating release of somatostatin from the hypothalamus. Growth hormone also feeds back to inhibit GHRH secretion and probably has a direct (autocrine) inhibitory effect on secretion from the somatotroph. Integration of all the factors that affect growth hormone synthesis and secretion leads to a pulsatile pattern of release. GH effects in peripheral tissues are mediated by GH binding to its receptor and through the synthesis of insulin-like growth factor 1 (IGF-1) by the liver and at the tissue level. The overall effects of GH and IGF-I are anabolic. (Modified with permission from Molina PE: Endocrine Physiology, 3rd ed. New York: McGraw-Hill Medical, 2010.) GH is released from the anterior pituitary into the systemic circulation. The half-life of the hormone averages 6–20 minutes. GH is degraded in the lysosomes following binding to its receptor and internalization of the hormone–receptor complex.

TABLE 62–2 Factors that regulate growth hormone release. Stimulation of GH Release

Inhibition of GH Release

GHRH

Somatostatin

Dopamine

IGF-I

Catecholamines

Glucose

Excitatory amino acids

FFA

Thyroid hormone GHRH, growth hormone–releasing hormone; IGF-I, insulin-like growth factor-I; FFA, free fatty acids.

Physiologic effects of GH GH can have direct effects on cellular responses, by binding to the GH receptor at target tissues, and, indirectly, by stimulating the production and release of IGF-I, a mediator of several of growth hormone’s effects at target tissues. IGF-I is a small peptide (about 7.5 kd) structurally related to proinsulin that mediates several of the anabolic and mitogenic effects of GH in peripheral tissues. The most important physiologic effect of GH is stimulation of postnatal longitudinal growth. GH also plays a role in regulation of substrate metabolism, adipocyte differentiation; and maintenance and development of the immune system.

GH receptor In the peripheral tissues, GH binds to specific cell surface receptors belonging to the class 1 cytokine receptor superfamily (see Figure 60–5) that includes the receptors for prolactin, erythro-

CHAPTER 62 Anterior Pituitary Gland poietin, leptin, interferons, granulocyte colony–stimulating factor, and interleukins. GH receptors are present in many biologic tissues and cell types, including liver, bone, kidney, adipose tissue, muscle, eye, brain, heart, and cells of the immune system. The GH molecule exhibits two binding sites for the GH receptor, resulting in dimerization of the receptor, a step that is required for biologic activity of the hormone.

GH effects at target organs • Bone: GH, both directly and indirectly through circulating and localized production of IGF-I, stimulates longitudinal growth by increasing the formation of new bone and cartilage. The growth effects of GH are not critical during the gestational period, but begin gradually during the first and second years of life and peak at the time of puberty. Before the epiphyses in long bones have fused, GH and IGF-1 stimulate chondrogenesis and widening of the cartilaginous epiphysial plates, followed by bone matrix deposition. In addition to its effects on linear growth stimulation, GH plays a role in regulating the normal physiology of bone formation in the adult by increasing bone turnover, with increases in bone formation and, to a lesser extent, bone resorption. • Adipose tissue: GH stimulates release and oxidation of free fatty acids, particularly during fasting. These effects are mediated by a reduction in the activity of lipoprotein lipase, the enzyme involved in clearing triglyceride-rich chylomicrons and very-low-density lipoprotein particles from the bloodstream. Thus, GH favors the availability of free fatty acids for adipose tissue storage and skeletal muscle oxidation. • Skeletal muscle: GH and IGF-I have anabolic actions on skeletal muscle tissue mediated through stimulation of amino acid uptake and incorporation into protein, cell proliferation, and suppression of protein degradation. • Liver: GH stimulates hepatic IGF-I production and release. It stimulates hepatic glucose production. Overall, GH counteracts the action of insulin on lipid and glucose metabolism, by decreasing skeletal muscle glucose utilization, increasing lipolysis, and stimulating hepatic glucose production. Key aspects of GH physiology can be summarized as follows: • GH is produced and stored in somatotrophs in the anterior pituitary. • The production of GH is pulsatile, mainly nocturnal, and is controlled mainly by GHRH and SST. • Circulating levels of GH increase during childhood, peak during puberty, and decrease with aging. • GH stimulates lipolysis, amino acid transport into cells, and protein synthesis. • GH stimulates the production of IGF-I, which is responsible for many of the activities attributed to GH.

Insulin-like Growth Factors Many of the growth and metabolic effects of GH are mediated by the IGFs, or somatomedins. The importance of this

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hormone in linear growth is clearly demonstrated by the severe growth failure in children with congenital IGF-I deficiency. These small peptide hormones are members of a family of insulin-related peptides including relaxin, insulin, IGF-I, and IGF-II. The IGFs are synthesized primarily by the liver and act as a mitogen, stimulating DNA, RNA, and protein synthesis. IGF-I circulates in blood either free (halflife is about 15–20 minutes) or bound to one of the several specific binding proteins that prolong the half-life of the peptide.

IGF receptor IGF-I and IGF-II bind specifically to two high-affinity membrane-associated receptors that are tyrosine kinases and belong to the same family of receptors as insulin. The insulin and IGF-I receptors, although similar in structure and function, play different physiologic roles in vivo. The insulin receptor is primarily involved in metabolic functions, whereas the IGF-I receptor mediates growth and differentiation. The separation of these functions is controlled by several factors, including the tissue distribution of the respective receptors, the binding with high affinity of each ligand to its respective receptor, and the binding of IGF to plasma insulin-like growth factor binding proteins (IGFBPs).

Prolactin Prolactin is a polypeptide hormone synthesized and secreted by lactotrophs in the anterior pituitary gland. The lactotrophs account for approximately 15–20% of the cell population of the anterior pituitary gland, and this increases dramatically in response to elevated estrogen levels, particularly during pregnancy. Prolactin levels are higher in females than in males, and the role of prolactin in male physiology is not completely understood. Plasma concentrations of prolactin are highest during sleep and lowest during the waking hours in humans.

Regulation of prolactin release Prolactin release is predominantly under tonic inhibition by dopamine derived from dopaminergic (D2) neurons of the hypothalamus. D2 inhibition of lactotroph release of prolactin is mediated by D2 Gαi protein–coupled receptors. Prolactin release is affected by a large variety of stimuli provided by the environment, and the internal milieu, the most important being suckling, increased levels of ovarian steroid hormones, primarily estrogen. The release of prolactin in response to suckling is a classical neuroendocrine reflex also referred to as a stimulus-secretion reflex (Figure 62–5). This surge in prolactin release in response to a suckling stimulus is mediated by a decrease in the amount of dopamine released at the median eminence, relieving the lactotroph from tonic inhibition. Estrogen stimulates growth of the lactotrophs during pregnancy as well as prolactin gene expression and release. Several neuropeptides have been identified as potential prolactin-releasing factors. These include TRH,

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SECTION IX Endocrine and Metabolic Physiology

Hypothalamus Dopamine Dopamine release

Pituitary

Prolactin Breast differentiation Duct proliferation and branching Glandular tissue development Milk protein synthesis Lactogenic enzyme synthesis

• Mammary gland development • Milk production

FIGURE 62–5 Physiologic effects of prolactin. Prolactin plays an important role in the normal development of mammary tissue and in milk production. Prolactin release is predominantly under negative control by hypothalamic dopamine. Suckling stimulates the release of prolactin. Prolactin inhibits its own release by stimulating dopamine release from the hypothalamus. (Modified with permission from Molina PE: Endocrine Physiology, 3rd ed. New York: McGraw-Hill Medical, 2010.)

oxytocin (OT), vasoactive intestinal peptide (VIP), and neurotensin (NT). Prolactin regulates its own secretion through a short-loop feedback mechanism by binding to prolactin receptors located in neuroendocrine D2 neurons; this binding leads to increased hypothalamic dopamine synthesis (Figure 62–5). When the concentration of dopamine in the hypothalamo-hypophysial portal blood increases, the release of prolactin from the lactotrophs is suppressed.

Physiologic effects of prolactin The physiologic effects of prolactin are mediated by the prolactin receptor found in the mammary gland and the ovary. The main physiologic effects of prolactin are stimulation of growth and development of the mammary gland, synthesis of milk, and maintenance of milk secretion (Figure 62–5). Prolactin stimulates glucose and amino acid uptake and synthesis of the milk proteins β-casein and α-lactalbumin, the milk sugar lactose, and milk fats by the mammary epithelial cells. During pregnancy, prolactin prepares the breast for lactation. The production of milk is prevented during pregnancy by the high progesterone levels. Additional effects of prolactin include inhibition of GnRH release, progesterone biosynthesis, and luteal cell hypertrophy during pregnancy. Prolactin also modulates reproductive and parental behavior.

DISEASES OF THE ANTERIOR PITUITARY Alterations in function of the anterior pituitary can be due to excess or deficient production of pituitary hormones or to altered responsiveness to hormone effects at the target organ.

HORMONE-PRODUCING PITUITARY ADENOMAS The most common cause of excess production of pituitary hormones is a hormone-producing pituitary adenoma, a usually benign neoplasm. Prolactinomas are the most common (40–45%) pituitary tumors, followed by somatotroph (20%), corticotroph (10–12%), gonadotroph (15%), and very rarely thyrotroph adenomas. Small pituitary adenomas can cause manifestations of excess tropic hormone production, whereas larger tumors can produce neurologic symptoms by mass effect in the sellar area. Patients with a prolactinoma present with elevated levels of prolactin (hyperprolactinemia), milk secretion (galactorrhea), and reproductive dysfunction. In males, prolactinomas may cause infertility by producing hypogonadism. In most cases, dopamine agonists are extremely effective in lowering serum prolactin levels, restoring gonadal function, decreasing tumor size, and improving visual fields decreased because of tumor compression of the optic chiasm. GH-secreting adenomas can be associated with acromegaly or bone and soft tissue overgrowth in adults, and with gigantism in children. ACTH-releasing adenomas are associated with excess cortisol production or Cushing syndrome; patients present with central obesity, proximal myopathy, hypertension, mood changes, dorsocervical fat pads, and hyperglycemia, among other clinical signs and symptoms. Gonadotroph pituitary adenomas are frequently inefficient in hormone production. Thyrotropin-secreting tumors are exceedingly rare and are frequently large when diagnosed.

HYPOPITUITARISM Hypopituitarism, or deficiency of anterior pituitary hormones, can be congenital or acquired. Pituitary insufficiency can result from trauma, such as that associated with surgery, penetrating injury, or automobile accidents, particularly involving head trauma. Severe blood loss and decreased blood flow (ischemia) of the pituitary can also lead to pituitary insufficiency. Ischemic damage to the pituitary gland or hypothalamic-pituitary stalk during the peripartum period leads to Sheehan syndrome, manifested as hypothyroidism, adrenal insufficiency, hypogonadism (failure to resume normal menses), and GH deficiency. GH deficiency and retarded growth may result from impaired release of GH from the pituitary gland because of diseases of the hypothalamus or pituitary gland or genetic predisposition.

CHAPTER 62 Anterior Pituitary Gland Alternatively, mutations in the gene for the GH receptor can cause insensitivity to GH and growth retardation with low serum IGF-I concentrations. GH insensitivity syndrome is also known as Laron syndrome and is characterized by failure to generate IGF-I and IGFBP-3. The typical manifestation is short stature or dwarfism, which can be prevented by IGF-I treatment.

EVALUATION OF ANTERIOR PITUITARY FUNCTION Measurements of anterior pituitary hormone concentrations and of the respective target gland hormone levels are used to assess the functional status of the system. For example, paired measures of TSH and thyroid hormone, FSH and estradiol, and ACTH and cortisol are used to evaluate the integrity of the respective systems. In addition, stimulation and inhibition tests can be used to assess the functional status of the pituitary gland. These tests are based on the normal physiologic feedback mechanisms that control tropic hormone release. For example, administration of the amino acid arginine can be used to elicit an increase in GH release in patients with suspected GH deficiency. In contrast, suppression tests can be used to diagnose Cushing syndrome, a clinical state resulting from prolonged, inappropriate exposure to excessive endogenous secretion of cortisol.

CLINICAL CORRELATION CASE A A mother of two school-age children still in her reproductive years consults her physician because she has had no menstrual periods for the past 6 months. A pregnancy test is negative, and she is not taking any medications. She also complains of problems with her peripheral (temporal) vision, and has also noted milky discharge from her nipples. An magnetic resonance image (MRI) scan of the brain reveals a pituitary mass. On physical examination, she is afebrile and has a normal blood pressure. Laboratory values are within normal ranges for serum glucose, Na+ and K+. Increased levels of prolactin are measured, with normal levels of all other pituitary hormones. She is diagnosed as having a prolactinoma. Prolactinomas account for 50% of functioning pituitary tumors and are more frequent in females than in males. Tumor size is correlated with prolactin levels. Women present with amenorrhea (lack of menses), galactorrhea (milk discharge from nipples), and infertility. Large tumors extending caudal to the pituitary are associated with visual defects due to compression of the optic chiasm. In males, presentation is impotence, loss of libido, and infertility as well as headaches and alterations in visual field. Initial treatment consists of administra-

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tion of dopamine agonists to reduce prolactin production. Tumors that do not shrink in size with medical treatment may require focused radiation therapy and/or surgical removal.

CASE B A middle-aged male patient consults his family physician because he has noticed that his hat and wedding ring are tight and his shoe size has increased one size during the past couple of years. He complains of joint aches and pains. He also states that he has noticed his voice getting deeper and his facial features being thicker and coarser when compared to his pictures of 10 years ago. Laboratory values show increased growth hormone and IGF-I levels and increased fasting plasma glucose. An intravenous infusion of glucose fails to decrease growth hormone levels. Brain MRI reveals a tumor localized to the pituitary. The patient is diagnosed with acromegaly resulting from a growth hormone–producing tumor. Acromegaly occurs as a result of growth hormone production in middle-aged adults. The symptoms of acromegaly develop slowly over many years, resulting in a frequent delay in diagnosis after the estimated onset of symptoms. The clinical manifestations result from soft tissue growth in response to growth hormone stimulation. This is evident in thickening of facial features, hands, and feet but is also associated with organomegaly (enlargement of internal organs). Because of growth hormone’s anti-insulin actions in adipose tissue, patients present with increased fasting plasma glucose levels or impaired glucose tolerance. Diagnosis is made by measurement of growth hormone release during the 2-hour period following a 75-g oral glucose load (similar to that used for the glucose tolerance test), as well as by measurement of peripheral IGF-I levels. Treatment consists of administration of long-acting somatostatin analogs such as octreotide and surgical removal of the tumor in cases that do not respond to medical treatment. There are also GH receptor antagonists currently available that can be used to treat the symptoms of GH excess.

CHAPTER SUMMARY ■ ■ ■ ■ ■

Anterior pituitary function is under regulation by the hypothalamus. Anterior pituitary hormone release is under feedback regulation by peripheral hormone levels. Pulsatile release of hypothalamic, pituitary, and target organ hormones plays an important role in endocrine function. Growth hormone exerts direct and indirect (IGF-I) effects on linear growth and metabolism. With the exception of dopamine inhibition of prolactin and SST inhibition of GH, adenohypophysial hormones are under stimulatory hypothalamic control.

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STUDY QUESTIONS 1. A female patient presents with milky discharge from both nipples and menstrual irregularity. The patient has no history of headache or visual abnormalities. A pregnancy test is negative, and her mammogram and breast exam are normal. She has a list of medications that her psychiatrist has recently prescribed. Which of the following could be responsible for the milky discharge? A) levodopa B) dopamine antagonist C) D2 agonist D) serotoninergic agonist 2. Damage to the axons passing through the pituitary stalk during an automobile accident could be expected to result in any of the following with the exception of A) decreased prolactin release B) decreased TSH release C) decreased LH and FSH release D) decreased GH release

3. A patient has been taking pharmacologic doses of a steroidal anti-inflammatory drug for a prolonged period for his asthma flare-ups. Which of the following is likely to occur to hypothalamic CRH release and plasma cortisol? A) low CRH and high cortisol B) high CRH and high cortisol C) low CRH and low cortisol D) high CRH and low cortisol 4. Growth hormone excess in an adult male can present with A) longitudinal growth of the extremities B) thickening of cartilaginous tissue C) hypoglycemia D) low IGFBP-3

63 C

Thyroid Gland Patricia E. Molina

H A

P

T

E

R

O B J E C T I V E S ■ ■ ■ ■ ■ ■ ■

Identify the steps and control factors of thyroid hormone biosynthesis, storage, and release. Describe the distribution of iodine and the metabolic pathway involved in thyroid hormone synthesis. Explain the importance of thyroid hormone binding in blood for free and total thyroid hormone levels. Understand the significance of the conversion of tetraiodothyronine (T4) to triiodothyronine (T3) and reverse T3 (rT3) in extrathyroidal tissues. Understand how thyroid hormones produce their cellular effects. Describe their effects on development and metabolism. Understand the causes and consequences of excess and deficiency of thyroid hormones.

Thyroid hormones play important roles in maintaining energy homeostasis and regulating energy expenditure. Their physiologic effects, mediated at multiple target organs, are primarily to stimulate cell metabolism and activity. The vital roles of these hormones, particularly in development, differentiation, and maturation, are underscored by the severe intellectual and developmental delay observed in infants with deficient thyroid hormone function during gestation. Thyroid hormones are derived from the amino acid tyrosine and are produced by the thyroid gland in response to stimulation by thyroid-stimulating hormone (TSH) produced by the anterior pituitary. TSH, in turn, is regulated by negative feedback by thyroid hormone and by the hypophysiotropic peptide thyrotropin-releasing hormone (TRH).

FUNCTIONAL ANATOMY The thyroid gland is a highly vascular, ductless gland located in the anterior neck in front of the trachea. The cellular composition of the thyroid gland is diverse, including the following: • follicular (epithelial) cells, involved in thyroid hormone synthesis;

Ch63_633-642.indd 633

• endothelial cells lining the capillaries that provide the blood supply to the follicles; • parafollicular or C cells, involved in the production of calcitonin, a hormone with a minor role in calcium homeostasis (discussed in Chapter 64); • fibroblasts, lymphocytes, and adipocytes.

THYROID FOLLICLE The main function of the thyroid gland is the synthesis and storage of thyroid hormone. The functional unit of the thyroid gland is the thyroid follicle, a spherical structure consisting of a layer of thyroid epithelial cells arranged around a large central cavity filled with colloid. Colloid makes up about 30% of the thyroid gland mass and contains a protein called thyroglobulin. Thyroglobulin plays a central role in the synthesis and storage of thyroid hormone. The parafollicular cells are in the spaces between follicles. Most parafollicular cells synthesize and secrete the hormone calcitonin, and therefore they are frequently referred to as C cells.

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REGULATION OF BIOSYNTHESIS, STORAGE, AND SECRETION OF THYROID HORMONES HYPOTHALAMIC REGULATION OF TSH RELEASE Thyroid hormone synthesis and release is under negative feedback regulation by the hypothalamic–pituitary–thyroid axis (Figure 63–1). TRH is a tripeptide synthesized in the hypothalamus, released from nerve terminals in the median eminence, and transported to the anterior pituitary where it stimulates release of TSH into the systemic circulation. The release of TSH is inhibited by the thyroid hormones triiodothyronine (T3) and tetraiodothyronine (T4, thyroxine). TSH is transported in the bloodstream to the thyroid gland, where it binds to the TSH receptor located on the thyroid follicular epithelial cells. The TSH receptor is an important antigenic site involved in thyroid autoimmune disease. Autoantibodies to the receptor may act as agonists mimicking the actions of TSH in Graves’ disease.

TSH receptor activation results in stimulation of all of the steps involved in thyroid hormone synthesis, including iodine uptake and organification, production and release of thyroid hormones from the gland, and promotion of thyroid growth. The biologic effects of TSH include stimulation of activity and production of the Na+/I− symporter, thyroglobulin, thyroid peroxidase, and T4 and T3. Both growth and function of the thyroid are stimulated by TSH stimulation. Therefore, continued stimulation of the TSH receptor causes hyperthyroidism and thyroid hyperplasia.

THYROID HORMONE SYNTHESIS Thyroglobulin is a glycoprotein synthesized in the thyroid follicular epithelial cells and secreted into the follicular lumen, where it is stored in the colloid. It undergoes major posttranslational modification during the production of thyroid hormones consisting of iodination of multiple tyrosine residues, followed by coupling of some of the iodotyrosine residues to form T3 and T4. A small amount of noniodinated thyroglobulin is also secreted into the circulation, and it can be increased in diseases such as thyroiditis and Graves’ disease.

Hypothalamus

TRH

(-)

Dopamine Somatostatin Glucocorticoids

(-) Pituitary

(-)

FIGURE 63–1 The hypothalamic–pituitary–thyroid axis. Thyrotropin-releasing hormone (TRH) is synthesized in parvocellular neurons of the paraventricular nucleus of the hypothalamus and released from nerve terminals in the median eminence, from where it is transported via the portal capillary plexus to the anterior pituitary. TRH binds to a G protein–coupled receptor in the anterior pituitary, leading to an increase in intracellular Ca2+ concentration, which in turn results in stimulation of exocytosis and release of thyroid-stimulating hormone (TSH) into the systemic circulation. TSH stimulates the thyroid gland to increase the synthesis and secretion of tetraiodothyronine (T4) and triiodothyronine (T3) into the circulation. T4 and T3 inhibit the secretion of thyrotropin (TSH) both directly and indirectly by inhibiting the secretion of TRH. Additional factors that inhibit TSH release are glucocorticoids, somatostatin, and dopamine. (Modified with permission from Molina PE: Endocrine Physiology, 3rd ed. New York: McGraw-Hill Medical, 2010.)

TSH

T4 T3

Thyroid

CHAPTER 63 Thyroid Gland The iodide required for thyroid hormone synthesis is readily absorbed from dietary sources, primarily from iodized salt, but also from seafood and plants grown in soil that is rich in iodine. Iodide is removed from the blood primarily by the thyroid and the kidneys.

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ease and toxic nodules, and to ablate thyroid tissue in the treatment of thyroid cancer. The iodination of thyroglobulin residues is a process that occurs at the apical membrane of the thyroid follicular cell. Thus, once inside the cell, iodide must leave the follicular cell through apical efflux via a chloride–iodide transporting protein (iodide channel). The uptake, concentration, and efflux of iodide are all functions of TSH-stimulated transepithelial transport of iodide. The transport of iodine through the Na+/I− symporter can be substituted by other substances including perchlorate and pertechnetate. Radiolabeled pertechnetate (Tc99m-pertechnetate) can be used for imaging of the thyroid gland that reflects the ability of specific regions of the thyroid to take up the iso-

REGULATION OF IODINE METABOLISM IN THE THYROID FOLLICULAR CELL Iodide is concentrated in thyroid epithelial cells by a sodium– iodide (Na+/I−) symporter (Figure 63–2). This ability of the thyroid gland to accumulate iodine allows therapeutic administration of radioactive iodine for the treatment of Graves’ dis-

Follicle lumen (colloid) Apical membrane

Follicular cell

Thyroid gland

Iodide

I–

2Na+/I – symporter Na+

P AD

K + ATP Na +

K+ Na +

3Na+/2K+ ATPase

Low intracellular Na

Iodide channel Colloid

Apical membrane

Basolateral membrane

FIGURE 63–2 Mechanism of iodide concentration by the thyroid gland. Iodide is transported into the cytosol of the follicular cell by active transport against a chemical and electrical gradient. The energy is derived from the electrochemical gradient of sodium. Two sodium ions are transported inside the thyroid follicular cell with each iodide molecule. Sodium moves down its concentration gradient, which is maintained by the Na+/K+-ATPase that constantly pumps sodium out of the cytoplasm of the thyroid follicular epithelial cell, maintaining the low intracytoplasmic concentration of sodium. Iodide must reach the colloid space, where it is used for organification of thyroglobulin. This process is achieved by efflux through the iodide channel. One of the early effects of TSH binding to its receptor is the opening of these channels, which facilitate the leakage of iodide into the extracellular space. This transcellular transport of iodide relies on the functional and morphologic polarization of the thyroid follicular epithelial cell. ATP, adenosine triphosphate. (Modified with permission from Molina PE: Endocrine Physiology, 3rd ed. New York: McGraw-Hill Medical, 2010.)

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1 Iodide trapping

BLOOD Na+

90% T4 10% T3

I–

5 Hormone secretion 2 Tg synthesis and secretion

I– pool

I– pool

T3 T4

MIT DIT Tg

MIT DIT T3 T4

REGULATION OF THYROID HORMONE RELEASE

Tg I–

Tg 4

I– iodine

Thyroid peroxidase

I° iodine

Tg

roglobulin yields monoiodinated tyrosine (MIT) and diiodinated tyrosine (DIT) residues that are enzymatically coupled to form T3) or T4 by the enzyme thyroid peroxidase. Because not all of the iodinated tyrosine residues undergo coupling, thyroglobulin stored in the follicular lumen contains MIT and DIT residues as well as formed T3 and T4. Iodine metabolism within the thyroid can also be regulated independently of TSH, particularly when plasma iodide levels are increased via an autoregulatory phenomenon known as the Wolff–Chaikoff effect. This effect lasts for a few days and is followed by the so-called “escape” phenomenon, at which point the organification of intrathyroidal iodine resumes and the normal synthesis of T4 and T3 returns.

Colloid uptake by endocytosis

3 MIT Iodination + conjugation Tg DIT T4 T3

THYROID COLLOID

FIGURE 63–3 Overview of thyroid hormone synthesis in the thyroid follicular epithelial cell. Thyroid hormone synthesis involves concentration of iodide by the Na+/I− symporter (1) and transport of iodide through the epithelial cell and into the extracellular compartment of the follicular cells, where it is oxidized to iodine by thyroid peroxidase (3) and is then used in the iodination of thyroglobulin (Tg) synthesized within the cell and released into the colloid (2). Iodine organification is an extracellular process that takes place inside the thyroid follicles at the apical membrane surface facing the follicular lumen. Iodine is bound to either carbon 3 or carbon 5 of the tyrosyl residues of thyroglobulin to form monoiodinated tyrosine (MIT) and diiodinated tyrosine (DIT). An MIT and a DIT, or two DITs are conjugated to form triiodothyronine (T3) and tetraiodothyronine (T4), respectively. Secretion of the hormone involves endocytosis of colloid containing thyroglobulin (4), followed by degradation of thyroglobulin and release of T4 and T3 (5). Some of the T4 produced is deiodinated in the thyroid follicle to T3, which is then released into the bloodstream. In addition, intracellular deiodination provides a mechanism for recycling iodide to participate in the synthesis of new thyroid hormone at the apical cell surface. A small fraction of thyroglobulin is released from the follicular epithelial cell into the circulation. (Reproduced with permission from Kibble J, Halsey CR:

TSH stimulates release of thyroid hormones from the thyroid gland. This process involves endocytosis of vesicles containing thyroglobulin from the apical surface of the follicular cell, lysosomal fusion of the vesicles, and proteolytic cleavage of thyroglobulin. As a result, the products of proteolytic cleavage include the thyroid hormones T4 and T3, which are released into the circulation, and the iodinated tyrosine residues (MIT and DIT) that are deiodinated intracellularly. With normal iodine intake, greater amounts of T4 than T3 are released (plasma concentrations of T4 are 40-fold higher than those of T3). Most of the T4 released is converted to T3 (the more active form of the hormone) in peripheral tissues by the removal of iodine from carbon 5 on the outer ring of T4. Key features of thyroid regulation and function are listed in Table 63–1.

TABLE 63–1 Key features of thyroid regulation and function. Key Features TSH

Binds to Gαs protein–coupled receptor on thyroid follicular cells. Main secondmessenger system is cAMP. Stimulates all steps involved in thyroid hormone synthesis: iodine uptake and organification, production and release of thyroid hormone, and promotion of thyroid growth

Thyroid gland

Can store 2–3-month supply of thyroid hormones in the thyroglobulin pool (colloid). Produces more T4 than T3

Thyroid hormone

Synthesis and release are under negative feedback regulation by the hypothalamic– pituitary–thyroid axis. T4 is converted to T3 in peripheral tissues. Biologic activity of T3 is greater than that of T4. Binds to nuclear receptors and modulates gene transcription

The Big Picture, Medical Physiology. New York: McGraw-Hill, 2009.)

tope and therefore to function normally. In the follicular lumen, tyrosine residues of thyroglobulin are iodinated by iodine (Io; formed by oxidation of I− by thyroid peroxidase) (Figure 63–3). This reaction requires hydrogen peroxide. Iodine bonds to carbon 3 or carbon 5 of the tyrosine residues on thyroglobulin in a process referred to as the organification of iodine. The iodination of specific tyrosines located on thy-

TSH, thyroid-stimulating hormone; cAMP, cyclic adenosine monophosphate; T4, tetraiodothyronine; T3, triiodothyronine.

CHAPTER 63 Thyroid Gland

TRANSPORT AND TISSUE DELIVERY OF THYROID HORMONES Once thyroid hormones are released into the circulation, most of them circulate bound to plasma proteins (thyroid-binding globulin [TBG], transthyretin, and albumin). This high percentage of protein-bound hormone significantly prolongs thyroid hormone half-life. A small fraction of each hormone circulates in the free form that is bioavailable and can enter the cell to bind to the thyroid receptor. Of the two thyroid hormones, T4 binds more tightly to binding proteins than T3 and thus has a lower metabolic clearance rate and a longer half-life (7 days) than T3 (1 day).

THYROID HORMONE METABOLISM Thyroid hormone peripheral metabolism is a sequential deiodination process catalyzed by tissue deiodinases, leading first to a more active form of thyroid hormone (T3) and finally to complete inactivation of the hormone (Figure 63–4). Approximately 40% of T4 is deiodinated at carbon 5 in the outer ring to yield the more active T3. In about 33% of T4, iodine is removed

Glucuronidation (T4G)

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from carbon 5 in the inner ring to yield reverse T3 (rT3). rT3 has little or no biologic activity. Following conversion of T4 to T3 or rT3, these are converted to T2, a biologically inactive hormone. This extrathyroidal progressive deiodination of thyroid hormones catalyzed by deiodinases plays a significant role in thyroid hormone metabolism and involves three deiodinases (type I, II, and II) that differ in their tissue distribution, catalytic profiles, substrate specificities, physiologic functions, and regulation outlined in Figure 63–4.

BIOLOGIC EFFECTS OF THYROID HORMONES Thyroid hormones are essential for normal growth and development; they control the rate of metabolism and hence the function of practically every organ in the body. Thyroid hormone receptors are expressed in most tissues and affect multiple cellular events. The following are some examples of the specific effects of thyroid hormone. Their effects are mediated primarily by the transcriptional regulation of target genes, and are thus known as genomic

Tetraiodothyronine (T4, thyroxine). NH2

Sulfation (T4S)

CH2

O

HO

Deiodinase I & II

CH

COOH

Deiodinase I & III

Outer ring deiodination (T3)

Inner ring deiodination (rT3)

O HO

O

CH2 CH C OH

O =

3 5

=

3'

HO

CH2 CH C OH

O

NH2

NH2 3,5,3' – Triiodothyronine (T3)

Reverse T3 (rT3)

Deiodinase I & III

Deiodinase I & II

=

O HO

O

CH2

CH NH2

C

OH

FIGURE 63–4 Thyroid hormone metabolism. Peripheral metabolism of thyroid hormones involves the sequential removal of iodine molecules, converting T4 into the more active T3 and inactivating thyroid hormones before their excretion. In addition, thyroid hormones can undergo conjugation in the liver, which increases their solubility and facilitates their biliary excretion. The type I iodothyronine deiodinase is expressed predominantly in liver, kidney, and thyroid. It catalyzes both outer- and inner-ring deiodination of thyroid hormones. It is the primary site for clearance of plasma rT3 and a major source of circulating T3. Type II deiodinase is expressed primarily in the human brain, anterior pituitary, and thyroid. It has only outer-ring deiodination activity and plays an important role in the local production of T3 in tissues that express this enzyme. The type III deiodinase is located predominantly in human brain, placenta, and fetal tissues. It has only inner-ring activity and catalyzes the inactivation of T3 more effectively than that of T4, thereby regulating intracellular T3 levels. (Modified with permission from Molina PE: Endocrine Physiology, 3rd ed.

Diiodothyronine (T2)

New York: McGraw-Hill Medical, 2010.)

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effects. Thyroid hormones enter cells by a carrier-mediated energy-, temperature-, and Na+-dependent process. The cellular actions of thyroid hormones are mediated by nuclear receptors. They bind thyroid hormones with high affinity and specificity, particularly for T3. Thyroid hormone receptors are DNA-binding transcription factors that function as molecular switches in response to hormone binding. The hormone receptor can activate or repress gene transcription, depending on the promoter context and ligand-binding status. The cellular events mediated by thyroid hormones are:

Liver

• transcription of cell membrane Na+/K+-ATPase, leading to an increase in oxygen consumption; • transcription of uncoupling proteins, enhancing fatty acid oxidation and heat generation without production of ATP; • protein synthesis and degradation, contributing to growth and differentiation; • epinephrine-induced glycogenolysis and gluconeogenesis, affecting insulin-induced glycogen synthesis and glucose utilization; • cholesterol synthesis and low-density lipoprotein receptor regulation.

Brain

ORGAN-SPECIFIC EFFECTS OF THYROID HORMONE Bone Thyroid hormone is important for bone growth and development through activation of osteoclast and osteoblast activities. Deficiency during childhood affects growth. In adults, excess thyroid hormone levels are associated with increased risk of osteoporosis.

Cardiovascular System Thyroid hormone has cardiac inotropic and chronotropic effects, increases cardiac output and blood volume, and decreases systemic vascular resistance. These responses are mediated through thyroid hormone changes in gene transcription of several proteins including Ca2+-ATPase, phospholamban, myosin, β-adrenergic receptors, adenylate cyclase, guanine nucleotide–binding proteins, Na+/Ca2+ exchanger, Na+/K+-ATPase, and voltage-gated potassium channels. The effect on β-adrenergic receptor expression accounts for the sympathomimetic effects of high levels of thyroid hormone.

Fat Thyroid hormone induces white adipose tissue differentiation, lipogenic enzymes, and intracellular lipid accumulation; stimulates adipocyte cell proliferation; stimulates uncoupling proteins; and uncouples oxidative phosphorylation. The induction of catecholamine-mediated lipolysis by thyroid hormones results from an increased β-adrenoceptor (AR) number and a decrease in phosphodiesterase (PDE) activity resulting in an increase in cAMP level and hormone-sensitive lipase (HSL) activity.

Thyroid hormone regulates triglyceride and cholesterol metabolism, as well as lipoprotein homeostasis. It also modulates cell proliferation and mitochondrial respiration.

Pituitary Thyroid hormone regulates the synthesis of pituitary hormones, facilitates growth hormone production, and inhibits TSH.

Thyroid hormone controls expression of genes involved in myelination, cell differentiation, migration, and signaling. It is necessary for axonal growth and development.

DISEASES OF THYROID HORMONE OVERPRODUCTION AND UNDERSECRETION The widespread distribution of thyroid hormone receptors and the multitude of physiologic effects that they exert are highlighted in cases of abnormal thyroid function (Table 63–2). Dysfunction can result from three factors: (1) alterations in the circulating levels of thyroid hormones, (2) altered metabolism of thyroid hormones in the periphery, and (3) resistance to thyroid hormone actions at the tissue level. An individual whose thyroid function is normal is said to be in a euthyroid state. The clinical state resulting from an alteration in thyroid function is classified as either hypothyroidism (low thyroid function) or hyperthyroidism (excessive thyroid function). Autoimmunity plays an important role in thyroid disease. Abnormal immune responses directed to thyroid-related proteins result in two opposite pathogenic processes: thyroid enlargement (hyperplasia) in Graves’ disease and thyroid inflammation and/or destruction in Hashimoto’s thyroiditis. The most common presentations of thyroid hormone abnormalities are summarized as follows.

HYPOTHYROIDISM Hypothyroidism is the condition resulting from insufficient thyroid hormone action. It has an incidence of 2% in adult women and is less common in men. Two main types are distinguished, primary and secondary hypothyroidism, although the former is more common.

Primary Hypothyroidism When the decrease in thyroid function occurs in utero, the result is severe intellectual and developmental delay or cretinism, underscoring the vital role that thyroid hormone plays in development and growth. Hypothyroidism may be associated with thyroid enlargement, resulting from inflammation as in

CHAPTER 63 Thyroid Gland

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TABLE 63–2 Clinical and laboratory manifestations of excess or deficient thyroid hormone function. Hypothyroidism

Hyperthyroidism

Clinical Presentation

Laboratory Values Clinical Presentation

Laboratory Values

In utero: Cretinism, mental and growth retardation, short limbs Adult onset: Tiredness, lethargy, constipation, decreased appetite, cold intolerance, abnormal menstrual flow, hair loss, brittle nails, dry coarse skin, hoarse voice Chronic: Myxedema, thickened features, periorbital edema, swelling of hands and feet without indentation, delayed muscle contraction and relaxation, delayed tendon reflexes, reduced stroke volume and heart rate, decreased cardiac output, enlarged heart, pericardial effusion, pleural and peritoneal fluid accumulation, slowing of mental function, impaired memory, slow speech, decreased initiative, somnolence, hypothermia

Primary: Low free T4; low or sometimes normal T3; high TSH Secondary: Low T4 and T3, normal or inappropriately low TSH

Primary: Low TSH; high T4 (2-fold) and T3 (3–4-fold). In Graves’ disease, elevated anti-TSH receptor antibody titers Secondary: High TSH, T4, and T3

Palpitations, exercise impairment, widened pulse pressure, tachycardia at rest and during exercise, increase in blood volume, palpable enlarged thyroid gland, infiltrative ophthalmopathy, nervousness, irritability, hyperactivity, emotional instability, tenseness, pounding of the heart, heat intolerance, weight loss despite increased food intake, decreased or absent menstrual flow, increased number of bowel movements, warm moist skin or velvety texture, proximal muscle weakness, fine hair, fine tremor, excessive sweating

T4, thyroxine; T3, triiodothyronine; TSH, thyroid-stimulating hormone.

Hashimoto’s thyroiditis and increases in TSH due to dietary iodine deficiency.

Secondary Hypothyroidism Secondary hypothyroidism is characterized by decreased TSH secretion and subsequently decreased thyroid hormone release, and is usually due to hypopituitarism (decreased anterior pituitary function).

HYPERTHYROIDISM Hyperthyroidism is excessive functional activity of the thyroid gland, characterized by increased basal metabolism and disturbances in the activity of the autonomic nervous system as a result of excess thyroid hormone production. The incidence is higher in women than in men. Several conditions can lead to hyperthyroidism, but the most common cause in adults is Graves’ disease.

Graves’ Disease Graves’ disease is an autoimmune condition leading to autonomous thyroid hormone secretion resulting from the stimulation of TSH receptor by TSH-like antibodies called thyroid-stimulating immunoglobulins (TSI). Clinically, about 40–50% of patients with hyperthyroidism present with protruding eyes (exophthalmos or proptosis) as a result of lymphocyte and fibroblast infiltration of the extraocular tissues and muscles, and accumulation of hyaluronate, a glycosaminoglycan produced by fibroblasts in the tissues and muscles. The majority (90%) of patients with thyroid ophthalmopathy have Graves’ hyperthyroidism.

TSH-secreting Adenomas Secondary hyperthyroidism is due to increased thyroid hormone release by the thyroid gland in response to increased TSH levels derived from TSH-secreting pituitary adenomas.

TSH-secreting adenomas represent a very small fraction (<1%) of all pituitary adenomas and result in a syndrome of excess secretion of TSH. The hormonal profile is characterized by the inability to suppress TSH despite increased levels of free thyroid hormones (T3 and T4).

ABNORMALITIES IN IODINE METABOLISM Iodine is an essential component of thyroid hormone, but both low and high iodine intake may lead to disease. Several drugs can interfere with the ability of the thyroid gland to concentrate iodide. Perchlorate is a contaminant that can be found in drinking and groundwater, and occasionally in cow’s milk. Ingestion of high levels, as with consumption of well water, can lead to inhibition of iodine transport into the follicular cells. Methimazole, the active form of carbimazole, inhibits iodide uptake and organification of iodine. Thiouracil and propylthiouracil inhibit iodine organification. Abnormalities in the metabolism or supply of iodine have particular importance in fetal development. Severe iodine deficiency of the mother may lead to insufficient thyroid hormone synthesis in both mother and fetus, resulting in developmental brain injury. Iodine deficiency is the leading cause of preventable mental retardation worldwide, although it is rare in the USA where table salt is supplemented with iodine. On the other hand, excess iodine given to the mother (e.g., use of an antiarrythmic iodine-containing drug called amiodarone or excess iodine supplementation) may inhibit fetal thyroid function, leading to hypothyroidism and goiter, or may precipitate hyperthyroidism (iodine toxicity).

Goiter Goiter is defined as an overall enlargement of the thyroid gland. It can be associated with either decreased (iodine

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deficiency or Hashimoto’s) or increased (Graves’ disease) thyroid function. Enlargement of the gland can be the result of increased TSH receptor stimulation leading to thyroid hyperplasia or of localized inflammatory and/or autoimmune processes.

Thyroiditis Thyroiditis, or inflammation of the thyroid gland, may lead to abnormalities in thyroid hormone state. This condition may be acute, subacute, or chronic. Chronic thyroiditis (Hashimoto’s thyroiditis, chronic lymphocytic thyroiditis, autoimmune thyroiditis) is an autoimmune disease of the thyroid gland characterized by lymphocyte infiltration and circulating autoimmune antibodies. These antibodies inhibit the Na+/I− symporter, preventing iodide uptake and consequently thyroid hormone synthesis. Hashimoto’s thyroiditis is the most common cause of adult hypothyroidism; it is more prevalent in women than in men, and peaks at the age of 30–50 years.

population, and is more frequent in females than in males. The excess production of thyroid hormone in Graves’ disease is the result of circulating IgG antibodies that bind to the TSH receptor on the thyroid gland, activating the G protein–coupled receptor. This excess stimulation of the receptor leads to follicular hypertrophy and hyperplasia, causing thyroid enlargement, as well as increases in thyroid hormone production. As a result of excess thyroid hormone production, the release of TSH is markedly suppressed via negative feedback. Clinical manifestations are the result of excess thyroid hormone activity. Treatment for Graves’ disease includes antithyroid drugs (inhibitors of thyroid hormone synthesis), radioiodine ablation of the thyroid tissue, and surgical removal of the thyroid gland.

CHAPTER SUMMARY

EVALUATION OF THE HYPOTHALAMIC–PITUITARY– THYROID AXIS

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TSH AND THYROID HORMONE LEVELS TSH levels are useful in evaluation of the patient because small changes in free thyroid hormone levels lead to greater changes in TSH levels. Serum TSH concentrations are considered the single most reliable test to screen for all common forms of hypothyroidism and hyperthyroidism, particularly in the ambulatory setting. Overt primary hyperthyroidism is accompanied by low serum TSH concentrations. Interpretation of abnormal TSH levels is best done with simultaneous measures of thyroid hormone levels.

CLINICAL CORRELATION A premenopausal woman presents with palpitations and a history of weight loss over the past 6 months. In addition, she complains of increased irritability and anxiety, inability to sleep, and heat intolerance. Physical examination reveals tachycardia (pulse of 120 beats/min), hypertension (a blood pressure of 139/80 mm Hg), and a diffusely enlarged nontender thyroid gland. In addition, she has infrequent blinking and characteristic stare, sweaty hands, and tremor. Her serum TSH level is low, and the level of free thyroxine is increased. She is diagnosed with Graves’ disease. Graves’ disease accounts for 50–80% of cases of hyperthyroidism, affects approximately 0.5% of the

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■ ■

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The thyroid gland is regulated by the hypothalamic–pituitary– thyroid axis. Dietary iodine is required for thyroid hormone synthesis. The thyroid gland produces thyroid hormones by a process of concentration of iodine in the thyroid, iodination of tyrosine residues of thyroglobulin in the colloid space of the follicle, and endocytosis of colloid followed by proteolytic release of thyroid hormones (T4 and T3). Thyroid hormones undergo metabolism in peripheral tissues, leading to the production of the more active T3 and deactivation of thyroid hormones. The presence of deiodinases and their substrate specificity play a central role in thyroid hormone function in target tissues. Thyroid hormone receptors are located intracellularly, bound to DNA, and alter gene transcription on binding by thyroid hormone. Thyroid hormone actions are systemic and vital for development, growth, and metabolism.

STUDY QUESTIONS 1. Which of the following blood laboratory values would be compatible with hyperthyroidism due to Graves’ disease? A) low TSH and T4 levels B) high TSH but low T4 levels C) low TSH and high T4 levels D) high T4 and low T3 levels 2. The following laboratory results are available before physical examination of a new patient: very low TSH levels, and increased T4 and T3. Which of the following signs and symptoms would you expect to find? A) heart rate of 45 beats/min, diarrhea, and weight gain B) sweaty hands, 40-g goiter, and constipation C) heat intolerance, irritability, and weight loss D) insomnia, delayed muscle relaxation, and diarrhea

CHAPTER 63 Thyroid Gland 3. Blood laboratory values that would be compatible with endemic goiter due to iodine deficiency include A) increased TSH, and decreased T4 and T3 levels B) increased free T4 levels and thyroid-stimulating Ig positive C) low TSH, T4, and T3 levels D) normal free T4 and low TSH levels

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4. A radioactive iodine scan revealed greater concentration of radioiodine when compared to that of other asymptomatic individuals. Subsequent laboratory values came back positive for serum titers of autoantibodies to the TSH receptor. The pathophysiology of disease in this patient involves A) increased deiodination of T4 to T3 in the liver B) decreased thyroid hormone–binding levels C) increased cAMP formation in the thyroid follicular cell D) downregulation of the Na+/I– symporter

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Parathyroid Gland and Calcium and Phosphate Regulation Patricia E. Molina

64 C

H A

P

T

E

R

O B J E C T I V E S ■ ■ ■

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Identify the origin, target organs and cell types, and physiologic effects of parathyroid hormone. Describe the functions of osteoblasts and osteoclasts in bone remodeling and the factors that regulate their activities. Describe the regulation of parathyroid hormone secretion, the role of the calcium-sensing receptor, and the negative feedback relationship between parathyroid hormone and the biologically active form of vitamin D. Identify the sources, biosynthetic pathway, and physiologic effects of vitamin D and its active metabolites. Describe the causes and consequences of excess or deficiency of parathyroid hormone and vitamin D. Describe the regulation of calcitonin release and the cell of origin and target organs for calcitonin action. Explain the hormonal regulation of plasma calcium concentration through bone resorption, renal excretion, and intestinal absorption. Explain the hormonal regulation of plasma phosphate concentration through exchange with bone, renal excretion, and dietary intake and absorption.

The regulation of plasma calcium levels is critical for normal cell function, neural transmission, membrane stability, bone structure, blood coagulation, and intracellular signaling. This regulation relies on the interactions between parathyroid hormone (PTH) from the parathyroid glands and dietary and endogenous vitamin D (Figure 64–1). PTH stimulates bone resorption and the release of calcium (and phosphate) into the circulation. In the kidney, PTH promotes Ca2+ reabsorption and inorganic phosphate excretion in the urine. In addition, PTH stimulates the hydroxylation of 25-hydroxyvitamin D (25(OH)D) at the 1-position, leading to the formation of 1,25-dihydroxyvitamin D (1,25(OH)2D), the active form of vitamin D. 1,25(OH)2D exerts its main effects through increased intestinal absorption of dietary calcium. In addition, and to a lesser degree, it contributes to renal reabsorption of filtered calcium and bone resorption. The overall result of the interactions between PTH and vitamin D is the maintenance of normal plasma calcium concentrations.

Ch64_643-654.indd 643

FUNCTIONAL ANATOMY The parathyroid glands are pea-sized glands located at the top and bottom posterior borders of the lateral lobes of the thyroid gland. The chief cells synthesize and secrete the polypeptide PTH, which plays a major role in bone remodeling, calcium homeostasis, renal excretion of phosphate, and activation of vitamin D.

REGULATION OF PTH RELEASE PTH is synthesized as a prepropeptide that is posttranslationally modified to yield PTH, an 84–amino acid polypeptide. PTH release is controlled in a tight feedback system by small changes in plasma calcium levels detected by the parathyroid calcium-sensing receptor, a G protein–coupled receptor located on the plasma membrane of the parathyroid chief cells; 643

11/30/10 3:30:58 AM

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SECTION IX Endocrine and Metabolic Physiology 1,25(OH)2D

FIGURE 64–1 Regulation of parathyroid hormone (PTH) release. A decrease in calcium (Ca2+) stimulates the release of PTH from the parathyroid gland. PTH increases the activity of 1α-hydroxylase in the kidney, leading to increased production of 1,25(OH)2D. In addition, PTH increases the reabsorption of calcium and decreases the reabsorption of inorganic phosphate (Pi). In bone, PTH stimulates bone resorption, increasing the plasma calcium levels. The increases in 1,25(OH)2D and plasma calcium levels exert negative feedback inhibition of PTH release. Increases in plasma phosphate (Pi) levels stimulate the release of PTH. (Modified with

Kidney: ↑Vitamin D activation ↑Ca2+ reabsorption ↓Pi reabsorption

Ca2+ ↑Ca2+

↓PTH release

↑PTH release ↑Pi ↓ Ca2+

permission from Molina PE: Endocrine Physiology, 3rd ed.

Bone: ↑Bone resorption

Ca2+

New York: McGraw-Hill Medical, 2010.)

it is also found in kidney tubule cells and thyroid C cells (Figure 64–2). An acute decrease in circulating calcium levels (hypocalcemia) triggers PTH release within seconds. In addition, increases in plasma phosphate levels increase PTH secretion. PTH release can be stimulated by a decrease in plasma Mg2+. The balance of magnesium is closely linked to that of calcium; magnesium depletion or deficiency is frequently associated with hypocalcemia. A combined decrease in Mg2+ and calcium leads to impairment in the individual’s ability to secrete PTH. Moreover, severe hypomagnesemia impairs not only the release of PTH from the parathyroid gland in response to hypocalcemia, but also prevents the responsiveness of bone to

PTH-mediated bone resorption. Table 64–1 lists the factors that regulate PTH release.

PTH TARGET ORGANS AND PHYSIOLOGIC EFFECTS The primary target organs for the physiologic effects of PTH are kidney and bone. The main physiologic response elicited by PTH is to increase plasma calcium levels by increasing renal calcium reabsorption, bone resorption, and intestinal calcium absorption indirectly (via 1,25(OH)2D, the active form

↓ [Ca++]

Activates Ca++ sensor

↑ [Ca++]

Relaxed Ca++ sensor

1,25(OH)2D

FIGURE 64–2

Parathyroid Ca2+sensing receptor and regulation of PTH release. PTH release is decreased by increased serum calcium (Ca2+) concentrations and by increased 1,25(OH)2D. PTH is increased by decreased calcium, decreased magnesium, and increased phosphate levels. Changes in calcium concentrations are sensed by a G protein–coupled receptor on the parathyroid chief cells. (Modified with permission

↓ PTH release

↑ PTH release Nucleus

↓ PTH synthesis

from Molina PE: Endocrine Physiology, 3rd ed. New York: McGraw-Hill Medical, 2010.)

↓ Magnesium

↑ Phosphate

CHAPTER 64 Parathyroid Gland and Calcium and Phosphate Regulation

peptide product of a different gene from that which encodes for PTH, and is expressed in multiple tissues. It binds to the PTHR1 in bone and kidney, resulting in elevated plasma calcium levels. PTHrP released from cancerous tissue is responsible for the hypercalcemia of malignancy. Therefore, PTHR1 not only mediates the physiologic effects of PTH, but also plays an important role in the pathophysiologic effects of PTHrP.

TABLE 64–1. Regulation of parathyroid hormone release. PTH Release is Increased by

PTH Release is Decreased by

Hypocalcemia

Hypercalcemia

Hyperphosphatemia

1,25(OH)2D

Catecholamines

Severe hypomagnesemia

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PTH, parathyroid hormone.

CELLULAR EFFECTS OF PTH

of vitamin D). PTH also increases renal 1α-hydroxylase activity and renal phosphate excretion. The effects of PTH are mediated through binding to G protein–coupled PTH receptors. At least three receptors have been identified, but the important physiologic effects of PTH are mediated by PTHR1. PTHR1 is expressed in bone osteoblasts and kidney, where it binds PTH and PTH-related protein (PTHrP). PTHrP is a

In the kidney, PTH directly stimulates calcium reabsorption, decreases the reabsorption of phosphate causing an increase in phosphate excretion, and stimulates the activity of 1α-hydroxylase, the enzyme responsible for formation of 1,25(OH)2D. PTH regulation of calcium reabsorption is mediated in the distal tubules (Figure 64–3). PTH stimulates the insertion and opening of the apical calcium channel, facilitating calcium reabsorption as discussed in Chapter 48. It

Ca2+

Distal tubule PTH

+ Ca2+ channel

Luminal membrane

Calbindin-D28K

+ 1,25(OH)2D

+ ATP ADP

3 Na+

Basolateral membrane

Ca2+/Na+

Ca2+ ATPase

exchanger Ca2+

Ca2+

Interstitial space

FIGURE 64–3 Parathyroid hormone (PTH) increases renal calcium reabsorption. The transcellular reabsorption of calcium (Ca2+) by the distal tubule is regulated by PTH and 1,25(OH)2D. PTH increases the insertion of calcium channels in the apical membrane and facilitates the entry of calcium. Inside the cell, calcium binds to calbindin-D28K, a vitamin D–dependent calcium-binding protein that facilitates the cytosolic diffusion of calcium from the apical influx to the basolateral efflux sites. Calcium transport out of the cell through the basolateral membrane into the interstitial space is mediated by a Na+/Ca2+ exchanger and a Ca2+-ATPase. 1,25(OH)2D contributes to the enhanced calcium reabsorption by stimulating the synthesis of calbindin and the activity of Ca2+-ATPase. ATP, adenosine triphosphate. (Modified with permission from Molina PE: Endocrine Physiology, 3rd ed. New York: McGraw-Hill Medical, 2010.)

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SECTION IX Endocrine and Metabolic Physiology

Proximal tubule 3Na+

Pi

PTH Luminal membrane

Type IIa

Type I

Type IIa

Type IIa

+

PTH • Internalization • Destruction

Lysosomes

A– Basolateral membrane

Type III Pi

Pi

Na+

Pi

Interstitial space

FIGURE 64–4

Parathyroid hormone (PTH) decreases renal inorganic phosphate (Pi) reabsorption. Renal reabsorption of phosphate occurs through apical sodium (Na+)/Pi cotransport. Three different Na/Pi cotransporters have been identified: types I, II, and III. Types I and II cotransporters are located in the apical membrane. Type II cotransporters are expressed in the renal proximal tubule (type IIa) and in the small intestine (type IIb). Type IIa cotransporters are the major target for PTH regulation and contribute to most (up to 70%) of proximal tubular Pi reabsorption. PTH acutely stimulates internalization of the type IIa cotransporters, directing them to the lysosomes for destruction, resulting in a decrease in Pi reabsorption as indicated by the dotted line. Type III cotransporters are most likely located at the basolateral membrane and play a general “housekeeping” role in ensuring basolateral Pi influx if apical Pi entry is insufficient to satisfy cellular requirements. Basolateral exit, which is necessary to complete transcellular Pi reabsorption, is not well defined. Several Pi transport pathways have been suggested including Pi cotransport, anion (A−) exchange, and even an “nonspecific” Pi channel. (Modified with permission from Molina PE: Endocrine Physiology, 3rd ed. New York: McGraw-Hill Medical, 2010.)

decreases the renal (and intestinal) reabsorption of phosphate by decreasing the expression of the type II Na+/phosphate cotransporters by stimulating their internalization via coated vesicles and subsequent lysosomal degradation (Figure 64–4). In the bone, PTH binds to receptors found in osteoblasts stimulating the activity of several proteins, including osteoclastdifferentiating factor (ODF), also known as receptor activator of nuclear factor-κβ ligand (RANKL) or osteoprotegerin ligand (Figure 64–5). In addition, PTH stimulates osteoblast expression of genes involved in degradation of the extracellular matrix and bone remodeling (collagenase-3), production of growth factors (insulin-like growth factor I), and stimulation and recruitment of osteoclasts (RANKL and interleukin-6).

PTH MOBILIZATION OF BONE CALCIUM The inorganic phase of bone matrix is composed mainly of hydroxyapatite, which functions as a reservoir of calcium and phosphate ions and plays a major role in the homeostasis of

these minerals. Bone remodeling involves the continuous removal of bone (bone resorption) followed by synthesis of new bone matrix and subsequent mineralization (bone formation). Osteoclastic activity induced by PTH is indirectly mediated through osteoblast activation. Osteoclastic bone resorption involves several steps, including recruitment and differentiation of osteoclast precursors into mononuclear osteoclasts (preosteoclasts) and fusion of preosteoclasts to form multinucleated functional osteoclasts (Figure 64–6). PTH stimulation of osteoblast synthesis of ODF (RANKL or osteoprotegerin ligand) facilitates recruitment and binding of osteoclast precursors expressing the ODF receptor (RANK). This interaction initiates the differentiation and activation of osteoclasts (Figures 64–5 and 64–6). Another protein that participates in this sequence of events is osteoprotegerin, a member of the TNF receptor superfamily, secreted by osteoblasts. Osteoprotegerin acts as a natural antagonist of RANKL, decreasing RANK–RANKL interaction and, as a result, bone resorption. Osteoclastic bone resorption involves the attachment of osteoclasts to the bone surface, generating an isolated extracellular

CHAPTER 64 Parathyroid Gland and Calcium and Phosphate Regulation

Osteoprotegerin

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Osteoclast precursor

RANKL RANK

+ PTH Osteoblast

Mature Osteoclast

Osteoblast Ca2+, Pi, alkaline phosphatase –

HCO3 Osteoclast

Cl– Osteoblast

Cl– H+ Cl– H+

Hydroxyapatite

Bone

FIGURE 64–5 PTH-mediated osteoclast differentiation. Upper Panel: PTH binds to PTHR1 in osteoblasts and stimulates the expression of receptor activator of nuclear factor-κβ ligand (RANKL) expression on the cell surface. RANKL binds to RANK, a cell surface protein on osteoclast precursors. Binding of RANKL to RANK activates osteoclast gene transcription and the differentiation into a mature osteoclast, characterized by the ruffled membrane under which bone resorption occurs. Lower Panel: Osteoclasts attach to the bone surface through β-integrins generating an isolated extracellular microenvironment. Hydrogen ions generated are delivered across the plasma membrane by H+-ATPases at the cell’s ruffled membrane. The acidification of this microenvironment to ~pH 4 favors the dissolving of hydroxyapatite and provides optimal conditions for the action of the lysosomal proteases including collagenase and cathepsins. The products of bone degradation (ionized Ca2+, inorganic phosphate [H2PO4−], and alkaline phosphatases) are endocytosed by the osteoclast and transported to and released at the cell’s antiresorptive surface. Osteoprotegerin, a soluble protein secreted by osteoblasts that serves as a decoy ligand for RANKL, prevents binding of RANKL to RANK, thereby inhibiting the process of osteoclastic bone resorption. As a result, there is a decreased differentiation of precursor cells into oscteoclasts and decreased bone resorption. Production of osteoprotegerin is increased by estrogen and decreased by glucocorticoids and PTH. Cl−, chloride; HCO3−, bicarbonate; H+, hydrogen ion. (Modified with permission from Molina PE: Endocrine Physiology, 3rd ed. New York: McGraw-Hill Medical, 2010.)

microenvironment between osteoclasts and the bone surface that in effect functions as a lysosome in which bone resorption takes place. The products of bone degradation (including calcium and phosphate), as well as intracellular enzymes such as alkaline phosphatase, are also released into the circulation.

CALCIUM HOMEOSTASIS The human body contains approximately 1,100 g of calcium, 99% of which is deposited in bones and teeth. The small amount found in plasma is divided into three fractions: ionized calcium (50%), protein-bound calcium (40%), and calcium complexed to citrate and phosphate forming soluble complexes (10%). The complexed and ionized calcium fractions (about 60% of total plasma calcium) can cross the plasma membrane. The majority (80–90%) of protein-bound calcium is bound to albumin, and this interaction is sensitive to changes in blood pH. Acidosis leads to a decrease in protein binding of

calcium and an increase in “free” or ionized calcium in the plasma. Alkalosis results in increased calcium binding and a decrease in ionized calcium in the plasma. A smaller fraction (10–20%) of protein-bound calcium is bound to globulins. Calcium is a key intracellular messenger, a cofactor for various enzymes, and has diverse extracellular functions (e.g., in the clotting of blood, maintenance of skeletal integrity, and modulation of neuromuscular excitability). Therefore, stable calcium levels are critical for normal physiologic function. For example, Na+ channel voltage gating is dependent on the extracellular calcium concentration. Decreased plasma calcium concentrations (hypocalcemia) reduce the voltage threshold for the action potential firing, resulting in neuromuscular hyperexcitability. This can result in muscle cramps or numbness and tingling of fingertips, toes, and the perioral region. Clinically, neuromuscular irritability can be demonstrated by mechanical stimulation of the hyperexcitable nerve leading to tetanic-like muscle contraction by eliciting Chvostek’s sign (ipsilateral contraction of facial muscles elicited by tapping the

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SECTION IX Endocrine and Metabolic Physiology

Bone remodeling Osteoblast

Growth hormone

Stromal vessels

Increase in insulin-like growth factor I

Stroma Trabeculae Circulating osteoblasts

Osteogenic cells in bone marrow

Chondrocytes

Endochondral bone formation

Systemic circulation Periosteum Osteoblast Osteoclast Periosteal appositional bone formation

Blood vessel PTH

Local factors

New lining cells

Lining cells Osteoblasts Osteoclasts

Osteoid New osteocytes

Microcrack

Osteocyte apoptosis

New bone Cement line Old bone

FIGURE 64–6 Bone remodeling involves bone formation by osteoblasts and bone resorption by osteoclasts. PTH stimulates both aspects of the process. Growth hormone, acting through insulin-like growth factor, also stimulates bone formation particularly during the linear growth phase in children. Bone remodeling ensures bone repair and is necessary to maintain calcium homeostasis. (Reproduced with permission from Canalis E, Giustina A, Bilezikian JP. Mechanisms of anabolic therapies for osteoporosis. NEJM. 2007;357:905-916. Copyright Massachusetts Medical Society. All rights reserved.)

skin over the facial nerve) or Trousseau’s sign (carpal spasm induced by inflation of the blood pressure cuff to 20 mm Hg above the patient’s systolic blood pressure for 3–5 minutes).

INTERACTION OF BONE, KIDNEY, AND INTESTINE IN MAINTAINING CALCIUM HOMEOSTASIS Plasma concentrations of calcium are mainly regulated by the actions of PTH and 1,25(OH)2D and three tissues: bone, kidney, and intestine.

Bone Calcium in bone is distributed in a readily exchangeable pool and a stable pool. The readily exchangeable pool is involved in maintaining plasma calcium levels by the daily exchange of approximately 550 mg of calcium between the bone and extracellular fluid. The stable calcium pool is involved in bone remodeling.

Kidney In the kidney, virtually all filtered calcium is reabsorbed, of which about 40% is under hormonal regulation by PTH.

CHAPTER 64 Parathyroid Gland and Calcium and Phosphate Regulation

Intestine The availability of dietary calcium is a critical determinant of calcium homeostasis. Dietary intake of calcium averages 1,000 mg per day, of which only 30% is absorbed in the intestinal tract. This percentage of dietary calcium that is absorbed is significantly enhanced by 1,25(OH)2D.

HORMONAL REGULATION OF CALCIUM HOMEOSTASIS A slight decrease in the calcium level results in an increased release of PTH. In bone, PTH increases resorption and the release of calcium and phosphate into the circulation. In the kidney, PTH promotes calcium reabsorption and phosphate excretion in urine. In addition, PTH stimulates the formation of 1,25(OH)2D. 1,25(OH)2D increases intestinal absorption of dietary calcium and, to a lesser extent, renal reabsorption of filtered calcium. In bone, 1,25(OH)2D increases bone turnover,

649

with a resulting increase in the release of calcium into the circulation. The increase in calcium levels decreases PTH release from the parathyroid gland, decreases activation of 25(OH)D in the kidney, and stimulates release of calcitonin from the parafollicular cells of the thyroid gland. At high pharmacological concentrations, calcitonin can inhibit osteoclast activity and increase renal calcium excretion. Overall, PTH and 1,25(OH)2D are the critical hormones that work together to maintain plasma calcium levels within a normal range.

ROLE OF VITAMIN D IN CALCIUM HOMEOSTASIS Synthesis and Activation of Vitamin D Vitamin D is a lipid-soluble vitamin synthesized either from dietary plant- and animal-derived precursors or through the action of sunlight on cholesterol-derived precursors found in the skin (Figure 64–7). Active vitamin D (calcitriol; 1,25(OH)2D)

Liver

UV light Cholecalciferol Provitamin D 7-dehydrocholesterol in skin

25(OH)Vitamin D Ergocalciferol (Vitamin D2) in diet

Kidney 24α-Hydroxylase

Ca

PTH 1α-Hydroxylase

24, 25 (OH)2 Vitamin D (Inactive form)

1, 25 (OH)2 Vitamin D (Active form)

Bone resorption

Ca absorption

Ca reabsorption

PTH synthesis

Plasma Ca2+ concentrations

FIGURE 64–7 Vitamin D metabolism and physiologic effects at target organs. Provitamin D (7-dehydrocholesterol) in the skin is converted to cholecalciferol by ultraviolet (UV) light. Cholecalciferol and ergocalciferol (from plants) are transported to the liver, where they undergo the first step in bioactivation, the hydroxylation at C-25 to 25-hydroxyvitamin D (25(OH)D), the major circulating form of vitamin D. The second hydroxylation step, at C-1, occurs in the kidney and results in the hormonally active 1,25(OH)2D. This activation step, mediated by 1α-hydroxylase, is under tight regulation by parathyroid hormone (PTH), calcium levels, and 1,25(OH)2D. The activity of 1α-hydroxylase is stimulated by PTH and inhibited by calcium and 1,25(OH)2D. Decreased activity of 1α-hydroxylase favors C-24 hydroxylation and formation of the less active 24,25(OH)2D. 1,25(OH)2D increases bone resorption, increases calcium absorption from the intestine (the major effect), increases renal calcium reabsorption, and decreases the production of PTH by the parathyroid glands. The overall effect of 1,25(OH)2D is to increase plasma calcium concentrations. (Modified with permission from Molina PE: Endocrine Physiology, 3rd ed. New York: McGraw-Hill Medical, 2010.)

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SECTION IX Endocrine and Metabolic Physiology

is the product of two consecutive hydroxylation steps. The first hydroxylation of the precursors cholecalciferol (D3, derived from skin or diet) and ergocalciferol (D2, derived from diet) takes place in the liver. Cholecalciferol is produced in the skin by ultraviolet radiation acting on 7-dehydrocholesterol, an inert precursor. Vitamin D circulates to the liver bound to vitamin D–binding protein. The precursors are hydroxylated at C-25 to the prehormone 25(OH)D. 25(OH)D is the major circulating and storage form of vitamin D, and circulates bound to vitamin D–binding protein. In the kidney, it is hydroxylated by 1α-hydroxylase resulting in 1,25(OH)2D. This second hydroxylation step is a tightly regulated process enhanced by PTH and under negative feedback regulation by plasma calcium levels. An increase in plasma calcium levels inhibits the hydroxylation at C-1 and favors hydroxylation at C-24, leading to the synthesis of an inactive metabolite of vitamin D (24,25(OH)2D).

Cellular Effects of Vitamin D 1,25(OH)2D mediates its effects through binding to a steroid receptor located in the intestines, bone, kidney, and parathyroid gland, where it stimulates intestinal calcium absorption, regulates bone turnover, increases renal calcium reabsorption, and suppresses the synthesis of PTH (Figure 64–7).

Abnormal Vitamin D Levels Vitamin D belongs to the class of vitamins that are lipid soluble (i.e., A, D, E, and K), and can be stored in tissues. Extremely high levels of vitamin D (vitamin D toxicity) may lead to problems such as calcinosis (calcification of soft tissues), deposition of calcium and phosphate in the kidney, and increased plasma calcium levels, resulting in cardiac arrhythmia. Deficiency of vitamin D is extremely common and can be the result of inadequate dietary intake or absorption, or lack of sunlight, resulting in decreased conversion of inactive precursors to the substrates used in the synthesis of 25(OH)D. Vitamin D

deficiency can result in bone deformities (rickets) when it occurs in children and decreased bone mass (osteomalacia) in adults. Vitamin D deficiency is associated with weakness, bowing of the weight-bearing bones, dental defects, and hypocalcemia.

ROLE OF CALCITONIN IN CALCIUM HOMEOSTASIS Calcitonin is a 32–amino acid peptide hormone produced by the parafollicular or C cells in the thyroid gland in response to total plasma concentrations greater than 9 mg/dL. The two target organs for calcitonin’s physiologic effects are bone and kidney. Calcitonin inhibits bone resorption, and increases urinary calcium excretion. The cellular effects of calcitonin are mediated through G protein–coupled receptors from the same receptor family as the PTH, PTHrP receptor superfamily. Calcitonin does not appear to be critical for the regulation of calcium homeostasis in humans; in fact, total removal of the thyroid does not produce major alterations in calcium homeostasis. However, calcitonin has been used therapeutically for the prevention of bone loss and for the short-term treatment of hypercalcemia of malignancy.

ADDITIONAL REGULATORS OF CALCIUM AND BONE METABOLISM PTH and vitamin D play central roles in the regulation of bone metabolism. However, additional hormones participate in this process (Table 64–2). Sex steroids (androgens and estrogens) decrease bone resorption through increased osteoprotegerin synthesis, osteoblast proliferation, expression of type I collagen and alkaline phosphatase, and modulation of the effects of growth hormone, vitamin D, progesterone, and PTH. Growth hormone and insulin-like growth factor-I stimulate proliferation

TABLE 64–2 Factors involved in the regulation of calcium and bone metabolism. Regulator

Action

PTH

Increases bone resorption and plasma calcium

1,25(OH)2D

Increases intestinal calcium absorption, bone resorption, and facilitates renal calcium reabsorption

Calcitonin

Decreases bone resorption and plasma calcium

Sex steroids (androgens and estrogens)

Increase 1α-hydroxylase activity Increase osteoprotegerin synthesis Net decrease in bone loss

Growth hormone and insulin-like growth factor

Stimulate bone synthesis and growth

Thyroid hormone

Increases bone resorption

Prolactin

Increases renal calcium reabsorption and 1α-hydroxylase activity

Glucocorticoids

Increase bone resorption, decrease bone synthesis

Inflammatory cytokines

Increase bone resorption

PTH, parathyroid hormone.

CHAPTER 64 Parathyroid Gland and Calcium and Phosphate Regulation and differentiation of osteoblasts, bone protein synthesis, and growth, and promote synthesis of type I collagen. Normal thyroid function is required for physiologic bone remodeling; yet, excess thyroid hormone levels result in increased bone resorption. Glucocorticoids increase bone resorption, decrease bone synthesis, and inhibit osteoprotegerin synthesis, together leading to decreased bone mass. The proinflammatory cytokines are potent stimulators of bone resorption in vitro and in vivo. The overall interaction of these various factors during health and disease plays an important role in maintaining bone mass.

REGULATION OF PHOSPHATE BALANCE Phosphorus in the form of phosphate accounts for more than 50% of bone mineral mass in the form of calcium phosphate. It plays numerous vital roles in cell function. Most food products, whether plant or animal, contain relatively abundant quantities of phosphorus. The skeleton contains 85% of the body’s phosphorus; the rest is distributed in the ECF and ICF. Total extracellular phosphorus is found in an ionized form and a nonionized form (organic and inorganic forms). The inorganic form may be found ionized or free in the form of phosphate (50%); complexed with calcium, Mg2+, and Na+ (35%); or bound to protein (15%). Phosphate homeostasis is maintained by intestinal absorption, renal excretion, balance of phosphate exchange in and out of the cells, and hormonal regulation. Most phosphate absorbed from the diet undergoes urinary excretion. Extracellular phosphate concentration is tightly regulated principally through urinary excretion. Alterations in extracellular phosphate concentrations lead to rapid adjustments in renal phosphate excretion and slower and less regulated adjustments in intestinal absorption. Phosphate excretion by the kidney is stimulated by PTH (Figure 64–4). 1,25(OH)2D stimulates phosphate intestinal absorption by stimulating the brushborder membrane Na+–HPO42− cotransport in the upper small intestine. Thus, PTH promotes phosphate excretion, whereas 1,25(OH)2D and insulin promote phosphate renal reabsorption and intestinal absorption. Vitamin D deficiency leads to increased phosphate renal excretion and decreased intestinal phosphate and calcium absorption, resulting in a severe loss of both calcium and phosphate from bone (the major site of both of these mineral stores) because of enhanced PTH activity, resulting in loss of bone mineral and osteomalacia. This is in contrast to osteoporosis induced by calcium deficiency.

HORMONAL REGULATION OF BONE METABOLISM Bone remodeling results from the interactions of multiple elements, including osteoblasts, osteoclasts, hormones, growth factors, and cytokines, the result being a dynamic maintenance

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of the bone architecture and systemic preservation of calcium homeostasis. In early life, a careful balance exists between bone formation by osteoblasts and bone resorption by osteoclasts. With aging, the process of coupled bone formation–resorption (turnover) is affected by the reductions in osteoblast differentiation, activity, and life span, which are further potentiated in the perimenopausal years by hormone deprivation (estrogen and dehydroepiandrosterone) and an increase in osteoclast activity. Decreased calcium intake below obligatory calcium loss (through the urine, feces, and skin) mobilizes calcium from the skeleton to maintain the ionized calcium concentration in the ECF, resulting in bone destruction. Vitamin D deficiency decreases the concentration of ionized calcium in the ECF (from loss of the calcemic action of 1,25(OH)2D on bone), resulting in stimulation of PTH release (secondary hyperparathyroidism), increased phosphate excretion (hypophosphatemia), and failure to mineralize new bone as it is being formed. Simple calcium deficiency is associated with compensatory increases in PTH and calcitriol, which together cause loss of whole bone, whereas true vitamin D deficiency reduces the mineral content of the bony tissue itself, leading to abnormal bone composition. However, these two nutritional deficiencies cannot be completely separated because calcium malabsorption is the first manifestation of vitamin D deficiency.

CHILDHOOD–ADULT Bone mass increases throughout childhood and adolescence. In girls, the rate of increase in bone mass decreases after menarche, whereas in boys, gains in bone mass persist up to 17 years of age and are closely linked to pubertal stage and androgen status. By age 17–23, the majority of peak bone mass has already been achieved in both sexes. Skeletal growth is achieved through the interaction between osteoblasts and osteoclasts, which work cooperatively under the influence of the mechanical strain placed on bone by skeletal muscle force such as that exerted during exercise. Decreased mechanical strain (such as that associated with prolonged bed rest or immobilization) leads to bone loss, whereas increased mechanical strain (weight-bearing exercise) stimulates osteoblastic activity and bone formation. Peak bone mass is attained in the third decade of life and is maintained until the fifth decade, when age-related bone loss begins in both men and women.

PREGNANCY AND LACTATION Overall requirements for calcium are significantly increased during pregnancy and lactation. The uptake and release of calcium from the skeleton are increased during pregnancy, and the rate of calcium mobilization continues to be increased during the early months of lactation, returning to prepregnancy rates during or after weaning. Calcium absorption, urinary calcium excretion, and bone resorption are higher during pregnancy than before conception or after delivery.

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TABLE 64–3 Measurements used frequently for the clinical evaluation of abnormalities in parathyroid hormone function or calcium homeostasis. Normal Range

Abnormality

Plasma calcium

8.5–10.5 mg/dL

Increased with ↑ PTH, vitamin D intoxication, ↑ bone resorption

Plasma phosphate

3–4.5 mg/dL

Decreased in hyperparathyroidism, vitamin D deficiency; increased in renal failure, hypoparathyroidism, vitamin D intoxication

Intact plasma PTH levels

10–65 pg/mL

Increased in hyperparathyroidism; decreased in hypoparathyroidism

Alkaline phosphatase

30–120 U/L

High levels indicate increased osteoblastic activity (bone turnover)

Bone-specific alkaline phosphatase

17–48 U/L

High bone turnover, useful marker of active bone formation

Osteocalcin (intact)

<1–23 ng/mL

Marker for skeletal bone turnover

PTH, parathyroid hormone.

MENOPAUSE The acute loss of bone that accompanies menopause involves most of the skeleton but particularly affects the trabecular component. The associated biochemical changes include increases in the complexed fraction of plasma calcium (bicarbonate), increases in plasma alkaline phosphatase and urinary hydroxyproline (representing increased bone resorption followed by a compensatory increase in bone formation), increased obligatory calcium loss in the urine, and a small but significant decline in calcium absorption (Table 64–3). These changes are ameliorated by hormone treatment with estrogen or selective estrogen receptor modulators (SERMs), calcium supplementation, thiazide diuretic administration (which reduces calcium excretion), and restriction of salt intake, which reduces obligatory calcium loss. In some cases of osteoporosis, calcium absorption is low, and high bone resorption can be suppressed by treatment with vitamin D that in turn leads to improvement in calcium absorption. The process of bone loss is progressive, starting at about the age of 50 in men and at menopause in women. Bone loss is faster in women than in men and affects some bones more than others; the consequences include decreased bone mineral density (BMD) and increased risk of fractures. Estrogen deficiency is a major pathogenic factor in the bone loss associated with menopause and the subsequent development of postmenopausal osteoporosis. In males, bone loss is not associated with a rise in bone resorption markers. Instead, bone loss in men is linked to an age-related decline in gonadal function and is due to a decrease in bone formation, not so much an increase in bone resorption.

Bone Density Bone density determines the degree of osteoporosis and the fracture risk. The main determinants of peak bone density are genetics, calcium intake, and exercise. The most common test for measuring bone density is dual-energy x-ray absorptiometry (DEXA) scanning. Additional approaches include computed tomography, radiologic techniques (morphometry or

densitometry), or bone biopsy. DEXA uses x-rays to measure bone density and provides two measures of how dense bone is: the T score and the Z score. The T score compares the person’s bone density with the average bone density of young healthy adults of the same sex, a time when bone density is at its peak. The Z score compares a person’s bone density with that of people of the same age, sex, and weight, and is less valuable in making predictions of risk of fracture or in making decisions about treatment.

Prevention of Osteoporosis The principal current approaches include: • Estrogen replacement therapy: Estrogen decreases bone loss in postmenopausal women by inhibiting bone resorption, resulting in a 5–10% increase in BMD over 1–3 years. Calcium supplements enhance the effect of estrogen on BMD. • Bisphosphonates: Bisphosphonates have a strong affinity for bone apatite and are potent inhibitors of bone resorption. These agents reduce the recruitment and activity of osteoclasts and increase their apoptosis. • Calcitonin: Calcitonin reduces bone resorption by direct inhibition of osteoclast activity. Intranasal calcitonin produces significant effects on BMD. Calcitonin is less effective in prevention of cortical bone loss than cancellous bone loss in postmenopausal women. • PTH: Intermittent administration of human recombinant PTH restores bone strength by stimulating new bone formation at the periosteal (outer) and endosteal (inner) bone surfaces, thickening the cortices and existing trabeculae of the skeleton, and perhaps increasing trabecular numbers and their connectivity. • SERMs: SERMs are compounds that exert estrogenic effects in specific tissues and antiestrogenic effects in others. Raloxifene competitively inhibits the action of estrogen in the breast and the endometrium and acts as an estrogen agonist on bone and lipid metabolism. In early postmenopausal women, raloxifene prevents postmenopausal bone loss at all skeletal sites, reduces markers of

CHAPTER 64 Parathyroid Gland and Calcium and Phosphate Regulation bone turnover to premenopausal concentrations, and reduces the serum cholesterol concentration and its lowdensity lipoprotein fraction without stimulating the endometrium. • Vitamin D analogs: Vitamin D analogs induce a small increase in BMD that seems to be limited to the spine. • Exercise: Physical activity early in life contributes to high peak bone mass. Walking, weight training, and high-impact exercises induce a small (1–2%) increase in BMD at some skeletal sites. These effects disappear if the exercise program is stopped. Load-bearing exercise is more effective for increasing bone mass than are other types of exercise.

DISEASES OF PTH PRODUCTION PRIMARY HYPERPARATHYROIDISM Excess PTH production is often due to parathyroid gland hyperplasia, adenoma, or carcinoma. The manifestations include increased PTH levels, increased plasma calcium levels (hypercalcemia), increased urinary calcium excretion (hypercalciuria) with increased formation of kidney stones (urolithiasis), and decreased plasma phosphate levels due to the large increase in urinary excretion. The increase in PTH results in increased bone resorption and further increases in extracellular calcium concentrations leading to increased filtered load of calcium in the kidney that exceeds the reabsorptive transport capacity, as discussed in Chapter 48.

SECONDARY HYPERPARATHYROIDISM Secondary hyperparathyroidism and hyperplasia of the parathyroid glands are complications that occur in patients with chronic renal failure. In early renal failure, a reduction in plasma 1,25(OH)2D and moderate decreases in ionized calcium contribute to greater synthesis and secretion of PTH. As renal disease progresses, parathyroid expression of receptors for vitamin D and calcium is reduced, making the parathyroid gland more resistant to both the 1,25(OH)2D and calcium negative feedback regulation of PTH release. Thus, for any increase in plasma calcium, the inhibition of PTH secretion is less efficient. As a result, for any particular plasma calcium concentration, secretion of PTH is enhanced, resulting in a shift in the calcium–PTH set point toward secondary hyperparathyroidism. Hyperphosphatemia independent of calcium and 1,25(OH)2D levels further enhances uremiainduced parathyroid gland hyperplasia and PTH synthesis and secretion, the latter by posttranscriptional mechanisms.

HYPOPARATHYROIDISM Hypoparathyroidism, resulting from impaired production of PTH, can be associated with other endocrine disorders and neoplasias or may result from surgical removal of the parathy-

653

roid glands. Because of the important role of PTH in the acute regulation of plasma calcium levels, an early manifestation of surgical removal of the parathyroid glands is hypocalcemic tetany. The classic clinical sign is known as the Chvostek’s sign, which is twitching or contraction of the facial muscles in response to tapping the facial nerve at a point anterior to the ear and above the zygomatic bone.

PSEUDOHYPOPARATHYROIDISM Pseudohypoparathyroidism—PTH resistance—is the result of a decreased response to PTH because of a congenital defect in the G protein associated with the PTHR1.

CLINICAL CORRELATION A postmenopausal patient is referred for asymptomatic hypercalcemia and history of repeated episodes of urolithiasis (kidney stones). Blood laboratory values reveal increases in intact PTH, 1,25(OH)2D, and markers of bone resorption. Neck ultrasound revealed a mass below the right lobe of the thyroid gland. Surgical removal and pathological examination of the excised gland led to the diagnosis of parathyroid adenoma. Parathyroid adenomas cause the majority (90%) of cases of primary hyperparathyroidism. Excess PTH release leads to increased bone resorption, increased hydroxylation of 25(OH)D, and increased intestinal calcium absorption. Urolithiasis results from increased concentrations of calcium in the glomerular filtrate. Increased bone resorption leads to increased release of bone proteins that are markers of bone resorption, such as osteocalcin and bone alkaline phosphatase. With measurement of total plasma calcium during routine laboratory testing, hypercalcemia in the absence of clinical manifestations is now a more frequent presentation of these adenomas.

CHAPTER SUMMARY ■ ■ ■

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PTH release is under negative feedback regulation by calcium and vitamin D. The main physiologic effects of PTH are mediated by the PTHR1 expressed in bone and kidney. PTHR1 binds PTH and PTHrP, a peptide responsible for the pathophysiologic elevation of plasma calcium in some malignancies. In the kidney, PTH increases renal calcium reabsorption, increases the activity of 1α-hydroxylase (which mediates the final activation step in the synthesis of vitamin D), and decreases phosphate reabsorption. In bone, PTH increases osteoclast-mediated bone resorption indirectly through stimulation of osteoblast activity.

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SECTION IX Endocrine and Metabolic Physiology Calcitonin decreases bone resorption and lowers plasma calcium levels. Synthesis of the active form of vitamin D (1,25(OH)2D; calcitriol) involves hydroxylation in the liver (C-25) and kidney (C-1). 1,25(OH)2D increases bone resorption, renal calcium reabsorption, and intestinal calcium absorption. Plasma calcium levels are tightly regulated through hormonemediated effects on bone. Bone mineral density and mass are under nutritional and hormonal control. Phosphate is regulated principally through effects on renal excretion.

STUDY QUESTIONS 1. A 43-year-old male is admitted to the emergency room for severe pain in his left flank, radiating to the groin. The pain is intermittent and initiated after running a marathon on a hot summer day. The patient is asked for a urine specimen and blood is detected in the urine. He is hydrated and additional diagnostic procedures are done. Laboratory values show an increased plasma calcium of 12 mg/dL, and increased plasma intact PTH values of 130 pg/mL. Which of the following findings would be predictable in this patient? A) increased plasma phosphate B) increased serum alkaline phosphatase C) increased intestinal calcium loss D) decreased urinary calcium excretion 2. In the patient described above, the mechanism underlying the abnormalities observed is A) increased calcitonin release B) decreased hepatic 25-hydroxylase activity C) increased osteoclast apoptosis D) increased bone resorption

3. A 73-year-old woman is admitted to the hospital following a bout of severe vomiting and generalized weakness. Initial laboratory values reveal increased plasma calcium levels. The referring physician tells you that she has breast cancer and her bone scan indicates metastasis to bone. Which of the following blood laboratory values would be compatible with this clinical scenario? A) low PTH and phosphate, and high alkaline phosphatase B) high PTH and phosphate, and low alkaline phosphatase C) low PTH and phosphate, and low alkaline phosphatase D) low PTH and phosphate, and normal alkaline phosphatase 4. The most likely cause of hypercalcemia in the patient described in Question 3 is A) increased PTH production B) increased responsiveness of the PTH receptor 1 C) increased PTHrP production D) increased calcitonin release 5. Hyperventilation usually leads to muscle cramping (tetanic contractions). What is the physiologic concept that explains what happens in that situation? A) hypercalcemia secondary to PTH-mediated bone resorption B) increased dissociation of protein-bound calcium C) decreased ionized plasma calcium levels D) increased renal calcium excretion

65 C

Adrenal Gland Patricia E. Molina

H A

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O B J E C T I V E S ■ ■

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Identify the functional anatomy and zones of the adrenal glands and the principal hormones secreted from each zone. Describe and contrast the regulation of synthesis and release of the adrenal steroid hormones (glucocorticoids, mineralocorticoids, and androgens) and the consequences of abnormalities in their biosynthetic pathways. Understand the cellular mechanism of action of adrenal cortical hormones and identify their major physiologic actions, particularly during injury and stress. Identify the major mineralocorticoids, their biologic actions, and their target organs or tissues. Describe the regulation of mineralocorticoid secretion and relate this to the regulation of sodium and potassium excretion. Identify the causes and consequences of overproduction and underproduction of glucocorticoids, mineralocorticoids, and adrenal androgens. Identify the chemical nature of catecholamines and their biosynthesis and metabolic fate. Describe the biologic consequences of sympathoadrenal medulla activation and identify the target organs or tissues for catecholamine effects along with the receptor types that mediate their actions. Describe and integrate the interactions of adrenal medullary and cortical hormones in response to stress. Identify diseases caused by oversecretion of adrenal catecholamines.

The adrenal glands contribute significantly to maintaining homeostasis through their role in the regulation of the adaptive response to stress, in the maintenance of body water, sodium, and potassium balance, and in the control of blood pressure. The main hormones produced by the human adrenal glands belong to two different families based on their structure; these are the steroid hormones including the glucocorticoids, mineralocorticoids, and androgens; and the catecholamines norepinephrine and epinephrine.

Ch65_655-670.indd 655

FUNCTIONAL ANATOMY AND ZONATION The adrenal glands are located above the kidneys and consist of two different components: the outer cortex derived from mesodermal tissue and the inner medulla derived from a subpopulation of neural crest cells (Figure 65–1). The cortex makes up the majority of the gland and synthesizes the adrenal

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Cortex

Zona glomerulosa

Aldosterone

Zona fasciculata

Cortisol and androgens

Medulla

Zona reticularis

Epinephrine and norepinephrine

Cortex Medulla

FIGURE 65–1 Adrenal glands. The adrenal glands are composed of a cortex and a medulla, each derived from a different embryologic origin. The cortex is divided into three zones: reticularis, fasciculata, and glomerulosa. The cells that make up the three zones have distinct enzymatic capacities, leading to a relative specificity in the products of each of the adrenal cortex zones. The adrenal medulla is made of cells derived from the neural crest; the adrenal cortex is made of cells derived from mesodermal tissue. (Reproduced with permission from Widmaier EP, Raff H, Strang KT [editors]: Vander’s Human Physiology: The Mechanisms of Body Function, 11th ed. McGraw-Hill, 2007.)

steroid hormones. The medulla synthesizes the catecholamines epinephrine and norepinephrine.

HORMONES OF THE ADRENAL CORTEX The adrenal cortex consists of three zones that vary in both their morphologic and functional features and, thus, the steroid hormones they produce (Figure 65–1): • The zona glomerulosa is the unique source of the mineralocorticoid aldosterone. • The zona fasciculata produces the glucocorticoids, cortisol and corticosterone, and the androgens, DHEA and DHEA sulfate (DHEAS). • The zona reticularis (which develops postnatally) produces glucocorticoids and androgens. The steroid hormones produced by the adrenal cortex are classified into three general categories: glucocorticoids, mineralocorticoids, and androgens. They share an initial

step in their biosynthesis (steroidogenesis), which is the conversion of cholesterol to pregnenolone (Figure 65–2). This step involves the release of cholesterol by the enzyme cholesterol esterase, the transfer of cholesterol from the outer mitochondrial membrane to the inner mitochondrial membrane by steroidogenic acute regulatory (StAR) protein (the rate-limiting step), and the conversion of cholesterol to pregnenolone by cytochrome P450 sidechain cleavage (SCC) enzyme (P450scc; or cholesterol SCC desmolase). Defects in the activity of specific enzymes involved in the pathway leading to production of steroid hormones can result in disease with various degrees of severity depending on the enzymatic step that is compromised. The key enzymes involved in steroid hormone synthesis and the consequences of their deficiency are described in Table 65–1. The severity of the manifestations ranges from death in utero as in the case of congenital deficiency of cholesterol SCC enzyme (P450scc) to abnormalities that become evident in adult life and that are not life threaten-

CHAPTER 65 Adrenal Gland

657

StAR

Cholesterol Cholesterol side chain cleavage Pregnenolone 3β-hydroxysteroid dehydrogenase Progesterone 21-hydroxylase

17α-hydroxylase/ 17,20 lyase

17-OH-Pregnenolone

17α-hydroxylase/ 17,20 lyase

DHEA

3β-hydroxysteroid dehydrogenase 17-OH-Progesterone

Androstenedione

21-hydroxylase Androgens

DOC Aldosterone synthase

11-Deoxycortisol 11β-hydroxylase

Corticosterone Aldosterone synthase

Cortisol

Glucocorticoid

Aldosterone

Mineralocorticoid

FIGURE 65–2 Overview of the zone-specific adrenal steroid hormone synthetic pathway. Steroidogenic acute regulatory (StAR) protein mediates cholesterol transfer into the mitochondria where cholesterol is converted to pregnenolone by cholesterol side-chain cleavage enzyme. Pregnenolone is converted to progesterone by 3β-hydroxysteroid dehydrogenase. These two initial steps are shared in the synthetic pathway of mineralocorticoids, glucocorticoids, and androgens. Activity of 17α-hydroxylase/17,20 lyase expressed in the zona fasciculata and zona reticularis produces 17-OH-pregnenolone and 17-OH-progesterone necessary to produce androgens and to produce precursors for the glucocorticoid pathway. Cortisol is produced by the activity of 11β-hydroxylase in the zona fasciculata and zona reticularis. Aldosterone is produced by processing deoxycorticosterone (DOC) to corticosterone, and then to aldosterone by the enzyme aldosterone synthase unique to the zona glomerulosa. (Modified with permission from Kronenberg HM, Melmed S, Polonsky KS, Larsen PR. Williams Textbook of Endocrinology. Philadelphia, Saunders Elsevier, 2008). ing. An enzymatic defect of 21-hydroxylase accounts for 95% of the genetic abnormalities in adrenal steroid hormone synthesis (Figure 65–3). The second most frequent abnormality in glucocorticoid synthesis is deficiency of the enzyme 11β-hydroxylase. Deficiencies in these enzymes result in impaired cortisol synthesis, lack of negative feedback inhibition of the release of adrenocorticotropic hormone (ACTH), high ACTH levels, and greater stimulation of cholesterol conversion to pregnenolone. Because of the lack of negative feedback inhibition of ACTH release (due to insufficient cortisol production) and the resulting high ACTH levels and greater stimulation of steroidogenesis (resulting from the higher ACTH-mediated stimulation of the initial steps in steroid hormone synthesis), the intermediate metabolites (before the enzymatic step that is deficient) continue to be synthesized, and their buildup leads to a shunting to the alternate enzymatic pathways. Thus, more pregnenolone is shunted to the DHEA– androstenedione pathway and more intermediate metabolites are converted to androgens, resulting in virilization (presence of masculine traits). One consequence of 21-hydroxylase defi-

ciency is the loss of sodium as a result of mineralocorticoid deficiency. In contrast, patients with 11β-hydroxylase deficiency produce excess 11-deoxycortisol and 11-deoxycorticosterone, which have active mineralocorticoid activity. Because of the resulting excess in mineralocorticoid-like activity, patients with this deficiency retain salt and water and may present with high blood pressure (hypertension).

Glucocorticoid Synthesis and Release The release of cortisol is under direct stimulation by ACTH released from the anterior pituitary. The release of cortisol follows a circadian rhythm that is exquisitely sensitive to light, sleep, stress, and disease (see Figure 60–7). Release of cortisol is greatest during the early waking hours; levels decline as the afternoon progresses and are lowest at around midnight. Cortisol inhibits the biosynthesis and secretion of hypothalamic corticotropin-releasing factor (CRH) and pituitary

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TABLE 65–1 Key enzymes involved in steroid hormone synthesis and metabolism. Enzyme and Relevance

Physiologic Function

Consequence of Deficiency

Converts progesterone to 11-deoxycorticosterone and 17α-hydroxyprogesterone to 11-deoxycortisol

Decreased cortisol and aldosterone. Loss of sodium because of mineralocorticoid deficiency. Virilization because of excess androgen production

Converts 11-deoxycorticosterone to corticosterone; 11-deoxycortisol to cortisol

Excess 11-deoxycortisol and 11-deoxycorticosterone. Excess mineralocorticoid activity. Salt and water retention

Converts cortisol into cortisone that has less affinity for the mineralocorticoid receptor

Decrease in glucocorticoid inactivation in mineralocorticoid-sensitive cells, leading to excess mineralocorticoid activity

21-Hydroxylase Accounts for 95% of genetic abnormalities in adrenal steroid hormone synthesis 11β-Hydroxylase Second most frequent abnormality in adrenal steroid hormone synthesis 11β-Hydroxysteroid dehydrogenase type II Inhibited by glycyrrhetinic acid, a compound in authentic licorice

adrenocorticotropin (ACTH) in a classic example of negative feedback regulation by hormones. This closely regulated circuit is referred to as the hypothalamic–pituitary–adrenal (HPA) axis (Figure 65–4).

glucocorticoid action within the cell, whereas increased 11β-hydroxysteroid dehydrogenase type II activity decreases glucocorticoid action.

Mineralocorticoid Synthesis and Release Metabolism of Glucocorticoids Free cortisol accounts for 5–8% of total cortisol in the circulation. Most (>90%) of cortisol circulates in a conjugated form (e.g., as sulfate or glucuronide derivatives) or bound to proteins (noncovalent, reversible binding). Most of cortisol released into the blood is bound to glucocorticoid-binding α2-globulin (transcortin or cortisol-binding globulin [CBG]), a specific carrier of cortisol. The hepatic synthesis of transcortin is stimulated by estrogen and decreased by liver disease (cirrhosis). The liver and kidney are the two major sites of hormone inactivation and elimination, or catabolism. Inactive hormones are mainly eliminated as urinary (mostly conjugated) metabolites. Inactivation of cortisol to cortisone and to tetrahydrocortisol and tetrahydrocortisone is followed by conjugation and renal excretion. Localized tissue metabolism by the isoforms of the enzyme 11β-hydroxysteroid dehydrogenase contributes to modulation of the physiologic effects of glucocorticoids. Corticosteroid 11β-hydroxysteroid dehydrogenase type I is a low-affinity NADPH-dependent reductase that converts cortisone back to its active form cortisol. This enzyme is expressed in liver, adipose tissue, lung, skeletal muscle, vascular smooth muscle, gonads, and the central nervous system. The conversion of cortisol to cortisone, its less active metabolite, is mediated by the enzyme 11β-hydroxysteroid dehydrogenase type II. This high-affinity NAD-dependent dehydrogenase is expressed primarily in the kidney, where it converts cortisol to the inactive metabolite cortisone. This conversion is critical in preventing excess mineralocorticoid activity resulting from cortisol binding to the mineralocorticoid receptor. Increased expression and activity of 11β-hydroxysteroid dehydrogenase type I amplifies

Aldosterone synthesis and release in the adrenal zona glomerulosa are predominantly regulated by angiotensin II and extracellular K+ and, to a lesser extent, by ACTH (Figure 65–5). Aldosterone is part of the renin–angiotensin–aldosterone system, which is responsible for preserving circulatory homeostasis in response to a loss of salt and water (please review Chapter 45). A decrease in the effective intravascular blood volume leads to decreased renal perfusion pressure, which is sensed by the juxtaglomerular apparatus (baroreceptor) and triggers the release of renin. Renin (pronounced REE-nin) release is also regulated by NaCl concentration in the macula densa, plasma electrolyte concentrations, angiotensin II levels, and sympathetic tone. Renin is an enzyme synthesized in the juxtaglomerular cells of the kidney that cleaves angiotensinogen (a protein produced by the liver) to angiotensin I, which is later converted by angiotensinconverting enzyme to angiotensin II. This renin–angiotensin system is part of an extremely powerful feedback system for longterm control of blood pressure and volume homeostasis. Together, angiotensin II, aldosterone, and antidiuretic hormone (ADH; arginine vasopressin) produce vasoconstriction, and renal retention of Na+ and water. The increase in circulating angiotensin II binds to the angiotensin II receptor in the adrenocortical cells of the zona glomerulosa, stimulating phospholipase C. This results in an increase in intracellular Ca2+, leading to stimulation of aldosterone synthesis and release (Figure 65–5). Potassium is also a major physiologic stimulus for aldosterone production, illustrating a classic example of hormone regulation by the ion it controls (please review Chapter 46). Aldosterone increases potassium excretion in urine, feces, sweat, and saliva, preventing hyperkalemia during periods of high potassium intake or after potassium release from skeletal muscle during strenuous exercise. In turn, increases in circu-

CHAPTER 65 Adrenal Gland

A. 21 Hydroxylase deficiency

659

Cholesterol Pregnenolone

Progesterone

Cortisol

17-Hydroxypregnenolone

17-Hydroxyprogesterone

Aldosterone

Dehydroepiandrosterone

Deoxycortisol

B. 11 β-hydroxylase deficiency

Cholesterol

Pregnenolone

17-Hydroxypregnenolone

Progesterone

Deoxycorticosterone

17-Hydroxyprogesterone

17-Hydroxyprogesterone

11-Deoxycortisol Corticosterone

11-Deoxycortisol

Androstenedione

Cortisol Cortisol

Dehydroepiandrosterone

FIGURE 65–3 Alterations in steroid hormone synthesis in 21-hydroxylase and 11β-hydroxylase enzymatic deficiency. A) 21-Hydroxylase deficiency accounts for 95% of genetic abnormalities in adrenal steroid hormone synthesis. 21-Hydroxylase converts progesterone to deoxycorticosterone and 17-hydroxyprogesterone to 11-deoxycortisol, the precursor metabolites for the synthesis of cortisol and aldosterone. Thus, more pregnenolone is shunted to the DHEA–androstenedione pathway (more androgen synthesis), resulting in virilization (presence of masculine traits). In addition, aldosterone deficiency leads to sodium wasting. B) The second most frequent abnormality in glucocorticoid synthesis is 11β-hydroxylase deficiency, the enzyme that converts 11-deoxycorticosterone to corticosterone and deoxycortisol to cortisol. 11β-Hydroxylase deficiency results in excess deoxycorticosterone and 11-deoxycortisol production. Both metabolites have active mineralocorticoid activity. The resulting excess in mineralocorticoid-like activity leads to salt and water retention and may lead to hypertension. Because of the loss in negative feedback inhibition of ACTH release by cortisol, excess adrenal stimulation leads to increased synthesis of adrenal androgens (androstenedione and dehydroepiandrosterone). (Modified with permission from Molina PE: Endocrine Physiology, 3rd ed. New York: McGraw-Hill Medical, 2010.) lating potassium concentrations stimulate the release of aldosterone from the adrenal cortex. The total amount of aldosterone released and the prevailing plasma concentrations are markedly less than those of glucocorticoids. In addition, binding of aldosterone to plasma proteins is minimal, resulting in a short plasma half-life.

Adrenal Androgen Synthesis and Release The third class of steroid hormones produced by the zona fasciculata and reticularis of the adrenal glands is the adrenal

androgens, including DHEA and DHEAS (Figure 65–2). DHEA is the most abundant circulating hormone in the body and is readily conjugated to its sulfate ester DHEAS. Regulation of DHEA production is not completely understood, but it is, in part, controlled by ACTH. The adrenal androgens are converted into androstenedione and then into potent androgens or estrogens in the peripheral tissues. Dihydrotestosterone and 17β-estradiol, the most potent androgen and estrogen, are synthesized from DHEA. The importance of the adrenal-derived androgens to the overall production of sex steroid hormones is highlighted by the fact that approximately

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Stress

Hypothalamus

CRH

Anterior pituitary gland ACTH Negative feedback Adrenal gland

Cortisol

Bloodstream

FIGURE 65–4 Hypothalamic–pituitary–adrenal axis. Corticotropin-releasing hormone (CRH), produced by the hypothalamus and released in the median eminence, stimulates the synthesis and processing of proopiomelanocortin, with resulting release of proopiomelanocortin peptides that include adrenocorticotropic hormone (ACTH) from the anterior pituitary. ACTH binds to the melanocortin-2 receptor in the adrenal gland and stimulates the cholesterol-derived synthesis of adrenal steroid hormones. Glucocorticoids released into the systemic circulation exert negative feedback inhibition of CRH and ACTH release from the hypothalamus and pituitary, respectively, in a classic example of negative feedback hormone regulation. This closely regulated circuit is referred to as the HPA axis. (Modified with permission from Molina PE: Endocrine Physiology, 3rd ed. New York: McGraw-Hill Medical, 2010.)

50% of total androgens in the prostate of adult men are derived from adrenal steroid precursors. Adrenal secretion of DHEA and DHEAS increases in children at the age of 6–8 years, and values of circulating DHEAS peak between the ages of 20 and 30 years. Thereafter, serum levels of DHEA and DHEAS decrease.

STEROID HORMONE TARGET ORGAN CELLULAR EFFECTS Most of the physiologic effects of glucocorticoid and mineralocorticoid hormones are mediated through binding to intracellular receptors that belong to a superfamily of steroid, thyroid, retinoid, and orphan receptors and that operate as ligand-activated transcription factors to regulate gene expression. Mineralocorticoid and glucocorticoid receptors are closely related, and share similarities in their ligand- and

DNA-binding domain. They are classified into types I and II. Type I receptors are specific for mineralocorticoids but have a high affinity for glucocorticoids. Type II receptors are specific for glucocorticoids and are expressed in virtually all cells. The higher concentration of glucocorticoids, and the high affinity of the mineralocorticoid receptor for glucocorticoids, raises the issue of ligand–receptor specificity and resulting physiologic action. Several factors are in place to enhance the specificity of the mineralocorticoid receptor for aldosterone. First, plasma glucocorticoids bind to CBG and albumin. This plasma protein binding allows only a small amount (< 10%) of the unbound hormone to freely cross cell membranes. Second, aldosterone target cells possess enzymatic activity of 11β-hydroxysteroid dehydrogenase type II, the enzyme that inactivates cortisol to cortisone (Figure 65–6). Third, the mineralocorticoid receptor discriminates between aldosterone and glucocorticoids. Aldosterone dissociates from the mineralocorticoid receptor five times more slowly than do the

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Stimuli to renin Liver

Kidney Angiotensinogen (453 aa) Renin (enzyme)

Angiotensin I (10 aa)

Angiotensin-converting enzyme (endothelium)

Angiotensin I

Angiotensin-converting enzyme (endothelium)

Angiotensin II

Angiotensin II (8 aa)

Cardiovascular system

Adrenal cortex Aldosterone Kidney Salt and H2O retention

Vasoconstriction

Blood pressure

FIGURE 65–5 Regulation of aldosterone release by the renin–angiotensin–aldosterone system. A decrease in the effective circulating blood volume triggers the release of renin from the juxtaglomerular apparatus in the kidney. Renin cleaves angiotensinogen, the hepatic precursor of angiotensin peptides, to form angiotensin I. Angiotensin I is converted to angiotensin II by angiotensin-converting enzyme (ACE), which is bound to the membrane of endothelial cells. Angiotensin II is a potent vasoconstrictor and stimulates the production of aldosterone in the zona glomerulosa of the adrenal cortex. Aldosterone production is also stimulated by potassium and ACTH; aa = amino acids. (Reproduced with permission from Widmaier EP, Raff H, Strang KT [editors]: Vander’s Human Physiology: The Mechanisms of Body Function, 11th ed. McGraw-Hill, 2007.)

glucocorticoids, despite their similar affinity constants. In other words, aldosterone is less easily displaced from the mineralocorticoid receptor than is cortisol. Together, these mechanisms ensure that under normal conditions, mineralocorticoid action is restricted to aldosterone. However, when production and release of glucocorticoids is excessive, or when the conversion of cortisol to its inactive metabolite cortisone is impaired, the higher circulating and tissue cortisol levels may lead to binding and stimulation of mineralocorticoid receptors.

SPECIFIC EFFECTS OF ADRENAL CORTEX HORMONES Glucocorticoids Cortisol binds to the glucocorticoid receptor (type II glucocorticoid receptor) (Figure 65–6). The hormone–receptor complex translocates to the nucleus, where it binds to specific DNA sequences (glucocorticoid response elements) and exerts its

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GC

MC

Cell surface 11β-HSD 2

GC

GC

GR

MR

GRE

MRE

CS

MR

MC MR

MRE

FIGURE 65–6 Steroid hormone receptors and mineralocorticoid specificity. Mineralocorticoids (MC; aldosterone) and glucocorticoid (GC; cortisol) hormones bind to intracellular receptors that share 57% homology in the ligand-binding domain and 94% homology in the DNA-binding domain. Cortisol binds the mineralocorticoid (MR) receptor with high affinity. Because more cortisol is produced than aldosterone, this could complicate the regulation of aldosterone-specific effects. Nonspecificity is prevented by the presence of an enzyme: 11-hydroxysteroid dehydrogenase type 2 (11β-HSD2) in mineralocorticoid target cells. This enzyme converts cortisol into its less active form cortisone (CS) that has less affinity for the mineralocorticoid receptor (MR). Another factor that contributes to ensure that mineralocorticoid effects are kept under regulation is the fact that aldosterone dissociates from the mineralocorticoid receptor more slowly than cortisol despite their similar affinity constants. In other words, aldosterone is less easily displaced from the mineralocorticoid receptor than is cortisol. Thus, glucocorticoids and mineralocorticoids bind to intracellular receptors (GR and MR, respectively), which dimerize prior to binding to glucocorticoid- or mineralocorticoid-responsive elements (GRE and MRE, respectively) in the nucleus, thus modulating (increasing or suppressing) transcription of specific genes. Cortisol, because of its high-affinity binding to the MR, can produce mineralocorticoid-like effects (sodium retention). Conversion to cortisone (CS) decreases the affinity for the receptor shown by the ill-fit of CS with the MR. Decreased activity of the 11β-HSD2 leads to decreased conversion of cortisol to cortisone and increased mineralocorticoid activity. (Modified with permission from Molina, PE: Endocrine Physiology, 3rd ed. New York: McGraw-Hill Medical, 2010) physiologic effects by altering transcription of genes. Because virtually all cells express glucocorticoid receptors, the physiologic effects are multisystemic. Glucocorticoids affect intermediary metabolism, stimulate proteolysis and gluconeogenesis, inhibit muscle protein synthesis, and increase fatty acid mobilization. Their hallmark effect is to increase blood glucose concentrations, hence the name “glucocorticoids.” In the liver, glucocorticoids increase the expression of gluconeogenic enzymes. In muscle, glucocorticoids interfere with GLUT4 translocation to the plasma membrane, causing insulin resistance. In bone and cartilage, glucocorticoids decrease the insulin-like growth factor I, insulin-like growth factor–binding protein 1, and growth hormone expression and action, and affect thyroid hormone interactions. At high circulating levels, glucocorticoids are catabolic and result in loss of lean body mass including bone and skeletal muscle. Glucocorticoids modulate the immune response by increasing anti-inflammatory cytokine synthesis and decreasing proinflammatory cytokine synthesis, exerting an overall anti-inflammatory effect. Their anti-inflammatory effects have been exploited by the use of synthetic analogs of glucocorticoids, such as prednisone, for the treatment of chronic inflammatory diseases. The development of potent inhaled steroids has been a major advance in the treatment of asthma. In the vasculature, glucocorticoids affect reactivity to vasoactive substances, such as angiotensin II and norepinephrine. This interaction becomes evident in patients with gluco-

corticoid deficiency and manifests as hypotension and decreased sensitivity to vasoconstrictor administration. In the central nervous system, glucocorticoids modulate perception and emotion and may produce marked changes in behavior. Some of the main physiologic effects of glucocorticoids are listed in Table 65–2. It is important to note that some of these become evident only at high circulating levels of cortisol.

Mineralocorticoids The principal physiologic function of aldosterone is to regulate renal sodium reabsorption and potassium excretion, hence the name “mineralocorticoid.” Aldosterone binds to the mineralocorticoid receptor in the principal cells of the distal tubule and the collecting duct of the nephron, producing an increase in sodium reabsorption and potassium excretion (Figure 65–7). Aldosterone increases sodium entry at the apical membrane of the cells of the distal nephron through the amiloride-sensitive epithelial Na+ channel (ENaC). The Na+/K+-adenosine triphosphatase (ATPase), located in the basolateral membrane of the cells, maintains the intracellular sodium concentration by extruding the reabsorbed sodium toward the extracellular and blood compartments. The specific effects of aldosterone are to increase the synthesis of Na+ channels in the apical membrane, increase the synthesis and activity of Na+/K+-ATPase in the basolateral

CHAPTER 65 Adrenal Gland

663

TABLE 65–2 Physiologic effects of cortisol*. System

Effects

Metabolism

Degrades muscle protein and increases nitrogen excretion Increases gluconeogenesis and plasma glucose levels Increases hepatic glycogen synthesis Decreases glucose utilization (anti-insulin action) Decreases amino acid utilization Increases fat mobilization Redistributes fat Permissive effects on glucagon and catecholamine effect

Hemodynamic

Maintains vascular integrity and reactivity Maintains responsiveness to catecholamine pressor effects Maintains fluid volume

Immune function

Increases anti-inflammatory cytokine production Decreases proinflammatory cytokine production Decreases inflammation by inhibiting prostaglandin and leukotriene production Inhibits bradykinin and serotonin inflammatory effects Decreases circulating eosinophil, basophil, and lymphocyte counts (redistribution effect) Impairs cell-mediated immunity Increases neutrophil, platelet, and red blood cell counts

Central nervous system

Modulates perception and emotion Decreases CRH and ACTH release

CRH, corticotropin-releasing hormone; ACTH, adrenocorticotropic hormone. *Some of the effects listed (particularly in Immune Function) occur only with very high cortisol levels.

Angiotensin II

Extracellular fluid [K+]

Principal cells

Aldosterone Cortical collectingduct cells K+

Interstitium

Interstitial space

Lumen

Na+ Nucleus

Na+/K+ -ATPase

Apical membrane

3Na+

Na+ K+

Na+

2K+ Na+

K+

ENaC Basolateral membrane

Na+ Na+ Lumen

FIGURE 65–7 Renal physiologic effects of aldosterone. Aldosterone diffuses across the plasma membrane and binds to its cytosolic receptor. The receptor–hormone complex is translocated to the nucleus, where it interacts with the promoter region of target genes, activating or repressing their transcriptional activity and thereby increasing transepithelial Na+ transport. Aldosterone increases Na+ entry at the apical membrane of the cells of the distal nephron through the amiloride-sensitive epithelial Na+ channel (ENaC). Aldosterone promotes potassium excretion through its effects on Na+/K+-ATPase and epithelial Na+ and K+ channels in collecting duct cells. An increase in the extracellular fluid K+ concentration stimulates the secretion of aldosterone, and a decrease in K+ inhibits aldosterone secretion. Angiotensin II has a synergistic effect on the stimulation of aldosterone production induced by hyperkalemia. ATP, adenosine triphosphate. (Reproduced with permission from Gennari JF. Current concepts: Hypokalemia. NEJM. 1998;339:451. Copyright Massachusetts Medical Society. All Rights reserved.)

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membrane (which pulls cytosolic Na+ to the interstitium in exchange for K+ transport into the cell), and increase the expression of H+-ATPase in the apical membrane and the Cl−/ HCO3– exchanger in the basolateral membrane of intercalated cells, described in Chapters 44 and 45. These cells express carbonic anhydrase and contribute to the acidification of urine and alkalinization of plasma. Mineralocorticoids act on fewer cell types than do glucocorticoids. Their receptors are not as widely expressed as those for glucocorticoids. Classic aldosterone-sensitive tissues include epithelia in the distal parts of the nephron, the surface epithelium of the distal colon, and the salivary and sweat gland ducts. Additional effects of aldosterone include increased sodium reabsorption in salivary and sweat glands, and increased K+ excretion from the colon.

Androgens The physiologic effects of DHEA and DHEAS are not completely understood. Current knowledge indicates that low levels of DHEA are associated with cardiovascular disease in men and with an increased risk of premenopausal breast and ovarian cancer in women. In contrast, high levels of DHEA might increase the risk of postmenopausal breast cancer. Exogenous administration of DHEA to the elderly increases several hormone levels, including insulinlike growth factor-1, testosterone, dihydrotestosterone, and estradiol. The specific mechanisms through which DHEA exerts its actions are not completely understood.

DISEASES OF OVERPRODUCTION AND UNDERSECRETION OF GLUCOCORTICOIDS Glucocorticoid Excess Glucocorticoid excess can be due to overproduction by an adrenal tumor, overstimulation of adrenal glucocorticoid synthesis by ACTH produced by a pituitary tumor or an ectopic tumor, or the iatrogenic administration of excess synthetic glucocorticoids. The clinical manifestation of glucocorticoid excess, known as Cushing’s syndrome, can be separated into two categories depending on its etiology. ACTH-independent Cushing’s syndrome is usually due to an adrenal neoplasm autonomously releasing cortisol despite suppressed ACTH (due to cortisol negative feedback). Excess exogenous glucocorticoid therapy is also a form of ACTHindependent Cushing’s syndrome. ACTH-dependent Cushing’s syndrome has two causes: Cushing’s disease is reserved for Cushing’s syndrome caused by excess secretion of ACTH by pituitary corticotroph tumors and is the most common endogenous form of the syndrome. ACTH production may also be ectopic (derived from extrapituitary tissue), most frequently because of small cell lung carcinoma. ACTH-dependent Cushing’s syndrome is characterized by increased glucocorticoid levels due to excess stimulation by ACTH leading to bilateral hyperplasia of the adrenal cortex.

Glucocorticoid Deficiency Glucocorticoid deficiency can result from lack of ACTH stimulation of adrenal glucocorticoid production (secondary deficiency) or from adrenal dysfunction (primary deficiency). Exogenous administration of synthetic analogs of glucocorticoids in the chronic treatment of some diseases will also suppress CRH and ACTH, thereby leading to adrenal atrophy. Therefore, the sudden discontinuation of treatment may be manifested as an acute case of adrenal insufficiency, a medical emergency. Most cases of ACTH deficiency involve deficiencies of other pituitary hormones. Because aldosterone is mainly under the regulation of angiotensin II and K+, individuals may not necessarily manifest with simultaneous mineralocorticoid deficiency when impaired ACTH release is the causative factor. Glucocorticoid deficiency due to primary adrenal insufficiency is also known as Addison’s disease, which can be the result of autoimmune or infectious destruction of the adrenal gland.

DISEASES OF OVERPRODUCTION AND UNDERSECRETION OF MINERALOCORTICOIDS Aldosterone Excess Primary hyperaldosteronism, also known as Conn’s syndrome, is a condition in which autonomous benign tumors of the adrenal glands hypersecrete aldosterone. The excess aldosterone leads to hypertension because of Na+ and H2O retention and hypokalemia because of excess K+ secretion. The release of renin is suppressed. Secondary hyperaldosteronism is a renin-dependent phenomenon. A decrease in the effective arterial blood volume, associated with ascites or heart failure, leads to continuous stimulation of the renin–angiotensin II–aldosterone system.

Aldosterone Deficiency Primary hypoaldosteronism is most often due to primary adrenal insufficiency as described above. Plasma renin levels are elevated, so this condition is also referred to as hyperreninemic hypoaldosteronism. Secondary hypoaldosteronism may be due to inadequate stimulation of aldosterone secretion (hyporeninemic hypoaldosteronism) despite normal adrenal function. This condition is usually associated with renal insufficiency.

DISEASES OF OVERPRODUCTION AND UNDERSECRETION OF ADRENAL ANDROGENS Adrenal Androgen Excess Congenital adrenal hyperplasia is an autosomal recessive disorder due to 21-hydroxylase deficiency in approximately 90% of cases. In this condition, impaired cortisol production leads to a

CHAPTER 65 Adrenal Gland lack of negative glucocorticoid feedback resulting in increased ACTH release. Increased ACTH stimulation of adrenal hormone synthesis leads to a buildup of cortisol precursors that due to the lack of 21-hydroxylase activity get shunted to the androgen synthetic pathway producing an androgen excess. Steroid 21-hydroxylase (a cytochrome P450 enzyme) converts 17-hydroxyprogesterone to 11-deoxycortisol, and progesterone to 11-deoxycorticosterone. Both 11-deoxycortisol and 11-deoxycorticosterone are precursors for cortisol and aldosterone, respectively. Total loss of 21-hydroxylase activity results in cortisol and aldosterone deficiencies. If not detected and treated in time, it can cause death in early infancy owing to shock, hyponatremia, and hyperkalemia. Deficiency of 21-hydroxylase leads to accumulation of steroid hormone precursors, and these can be directed to the androgen hormone synthetic pathway. Increased androgen production can lead to virilization in affected girls and signs of postnatal androgen excess in both sexes, including rapid linear growth and accelerated skeletal maturation.

HORMONES OF THE ADRENAL MEDULLA The adrenal medulla consists of cells that synthesize and secrete the catecholamines epinephrine (in greater amounts) and norepinephrine.

CHEMISTRY AND BIOSYNTHESIS Catecholamines are tyrosine-derived hormones (Figure 65–8). The transporters involved in packaging epinephrine into secretory vesicles are the vesicular monoamine transporters, which are expressed exclusively in neuroendocrine cells. Because of the expression of these transporters in sympathomedullary tissues, their function can be used diagnostically for radioimaging and localization of catecholamine-producing tumors (pheochromocytomas). The synthesis of catecholamines can be regulated by changes in the activity of tyrosine hydroxylase by release from end-product inhibition or by an increase in enzyme synthesis.

CATECHOLAMINE RELEASE, TRANSPORT, AND METABOLISM The release of catecholamines is a direct response to sympathetic nerve stimulation of the adrenal medulla (please review Chapter 19). Acetylcholine released from the preganglionic sympathetic nerve terminals binds to nicotinic cholinergic receptors in the plasma membrane of the chromaffin cells, leading to the exocytosis of secretory granules, which release catecholamines into the interstitial space, from where they are transported in the circulation to their target organs. Catecholamines have a short half-life and for the most part circulate bound to albumin.

665

Catecholamines can undergo reuptake by extraneuronal sites, degradation at target cells by catechol-O-methyltransferase (COMT) or monoamino oxidase (MAO), or direct filtration into the urine. The joint action of MAO and COMT on norepinephrine and epinephrine, especially in the liver, produces the metabolite vanillylmandelic acid (VMA), which is then excreted in the urine; dopamine metabolized through this pathway yields homovanillic acid. Because these metabolites are water soluble and have high levels of urinary excretion, they can play an important role in the clinical detection of tumors that produce excess catecholamines. In humans, VMA is the major end product of norepinephrine and epinephrine metabolism.

TARGET ORGAN CELLULAR EFFECTS The physiologic effects of catecholamines are mediated by binding to G protein–coupled adrenergic receptors distributed widely throughout the body (Table 65–3). Catecholamines released from the adrenal medulla exert their effects almost exclusively in peripheral tissues and not in the brain, because catecholamines do not readily cross the blood–brain barrier.

Alpha-adrenergic Receptors Alpha-adrenergic receptors have greater affinity for epinephrine than for norepinephrine or for isoproterenol, a synthetic agonist. They are subdivided into α1- and α2-receptors. α1-Adrenergic receptors are further subdivided into α1A, α1B, and α1D. α1-Adrenergic receptors play important roles in the regulation of several physiologic processes, including myocardial contractility and chronotropy and hepatic glucose metabolism (Table 65–4). α2-Adrenergic receptors are also subdivided into three groups, including α2A, α2B, and α2C (Table 65–3). Some of the physiologic effects mediated by this subtype of receptor involve actions at two counteracting α2-receptor subtypes. For example, stimulation of α2A-receptors decreases sympathetic outflow and blood pressure, whereas stimulation of α2B-receptors increases blood pressure by direct vasoconstriction. α2-Adrenergic receptors are implicated in diverse physiologic functions, particularly in the cardiovascular system and the central nervous system.

Beta-adrenergic Receptors Beta-adrenergic receptors have been subclassified as β1-, β2-, and β3-receptors. They have greater affinity for isoproterenol than for epinephrine or norepinephrine (Table 65–3). The β1-adrenergic receptor plays an important role in regulating contraction and relaxation of cardiac myocytes (Table 65–4). The β2-adrenergic receptor mediates several physiologic responses, including vasodilatation, bronchial smooth muscle relaxation, and lipolysis, in various tissues. Abnormalities in the function of this adrenergic receptor may lead to hypertension. The β3-adrenergic receptor plays an important role in mediating catecholamine-stimulated thermogenesis and lipolysis.

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HO Tyrosine

COOH NH2 –

Tyrosine hydroxylase HO

HO Dihydroxyphenylalanine (DOPA)

COOH NH2 DOPA decarboxylase HO HO Dopamine Dopamine-β hydroxylase

NH2 HO HO Norepinephrine OH NH2

Phenylethanolamine N-methyltransferase HO HO Epinephrine OH N CH3 H

FIGURE 65–8 Catecholamine synthetic pathway. Catecholamine synthesis from the precursor L-tyrosine involves four enzymatic reactions that take place in the cytosol of chromaffin cells. These are the following: (1) hydroxylation of tyrosine to L-dihydrophenylalanine (L-Dopa) by the enzyme tyrosine hydroxylase. This enzyme is found in the cytosol of catecholamine-producing cells and is the main control point for catecholamine synthesis. The activity of this enzyme is inhibited by norepinephrine, providing feedback control of catecholamine synthesis. (2) Decarboxylation of L-Dopa to dopamine by the enzyme dopa decarboxylase in a reaction that requires pyridoxal phosphate as a cofactor. This end product is packaged into secretory vesicles. (3) Hydroxylation of dopamine to norepinephrine by the enzyme dopamine β-hydroxylase, a membrane-bound enzyme found in synaptic vesicles that uses vitamin C as a cofactor. This reaction occurs inside the secretory vesicles. (4) Methylation of norepinephrine to epinephrine by the enzyme phenylethanolamine N-methyltransferase. The activity of this adrenal medullary enzyme, found in the cytosol of the chromaffin cell, is modulated by adjacent adrenal steroid production, underscoring the importance of radial arterial flow from the cortex to the medulla. The latter enzymatic reaction occurs in the cytoplasm and thus requires that norepinephrine leave the secretory granules by a passive transport mechanism. The epinephrine produced in the cytoplasm must reenter the secretory vesicles through ATP-driven active transport. (Modified with permission from Molina PE: Endocrine Physiology, 3rd ed. New York: McGraw-Hill Medical, 2010.)

CHAPTER 65 Adrenal Gland

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TABLE 65–3 Adrenergic receptors and signaling pathways. Adrenergic Receptor

G Protein

Second Messenger

β-Adrenergic receptors β1, β2, β3

Gαs G protein

Activate adenylate cyclase

α1-Adrenergic receptors α1A, α1B, α1D

Mostly Gαq/11 family of G proteins

Usually activate PLCα (thereby activating PKC via DAG and increasing intracellular Ca2+ via IP3) or PLA2

α2-Adrenergic receptors α2A, α2B, α2C

Mostly varied Gαi and Gα0 proteins

May decrease the activity of adenylate cyclase (opposing the effects of β-adrenergic receptors). Activate K channels. Inhibit Ca2+ channels and activate PLCβ or PLA2 (an effect similar to that of α1-adrenergic receptors)

PL, phospholipase; PKC, protein kinase C; DAG, diacylglycerol; IP3, inositol 1,4,5-trisphosphate.

CATECHOLAMINE PHYSIOLOGIC EFFECTS

REGULATION OF ADRENERGIC RECEPTORS

Catecholamines are released from the adrenal medulla in response to sympathetic stimulation and are central to the stress response to a physical or psychological insult such as severe blood loss, decrease in blood glucose concentration, traumatic injury, surgical intervention, or a fearful experience. Because catecholamines are part of the “fight–or-flight” response, their physiologic effects include arousal, alerting, papillary dilation, piloerection, sweating, bronchial dilation, tachycardia, inhibition of smooth muscle activity in the gastrointestinal tract, constriction of the sphincters, and relaxation of the uterine muscles (Table 65–4). Catecholamines ensure substrate mobilization from the liver, muscle, and fat by stimulating the breakdown of glycogen (glycogenolysis) and fat (lipolysis). Thus, an increase in circulating catecholamines is associated with elevations in plasma glucose and free fatty acid levels. Some of the most important effects of catecholamines are exerted in the cardiovascular system, where they increase heart rate (tachycardia), produce peripheral vasoconstriction, and elevate vascular resistance.

Chronic elevation of catecholamine levels leads to sustained stimulation of adrenergic receptors, which can alter tissue responsiveness. For example, chronic exposure to β-agonists, as in asthmatic patients treated with isoproterenol, promotes receptor desensitization. In contrast, treatment with α-agonists, as found in some nasal decongestants, results in tachyphylaxis. Persistent exposure to an agonist of the adrenergic receptor can also result in an actual loss of receptors because of degradation or receptor desensitization. Adrenergic receptors can also undergo upregulation because of increased transcription of the gene for the receptor. Two hormones are known to produce this effect: glucocorticoids and thyroid hormone. In addition, glucocorticoids and thyroid hormone can regulate the expression of several types of adrenergic receptors through posttranscriptional events.

TABLE 65–4 Catecholamine physiologic effects.

DISEASES OF OVERPRODUCTION OF ADRENAL CATECHOLAMINES Endocrine cells of the sympathoadrenal system are named chromaffin cells, and the tumors arising from these cells are called pheochromocytomas. Pheochromocytomas produce catecholamines, and patients present with signs of excess catecholamine effects, such as sustained or paroxysmal hypertension associated with headache, sweating, or palpitations.

α-Adrenergic Mediated

β-Adrenergic Mediated

Vasoconstriction

Vasodilation

Iris dilation

Cardioacceleration

Intestinal relaxation

Increased myocardial strength

Intestinal sphincter contraction

Intestinal and bladder wall relaxation

CLINICAL CORRELATION

Pilomotor contraction

Uterus relaxation

CASE A

Bladder sphincter contraction

Bronchodilation

Bronchoconstriction

Calorigenesis

Uterine smooth muscle contraction

Glycogenolysis

Cardiac contractility

Lipolysis

Hepatic glucose production

A term newborn infant presents with abnormal-appearing ambiguous genitalia that look more male than female, including an enlarged clitoris. Blood tests reveal hyponatremia, high 17-hydroxyprogesterone, and low cortisol levels. CT scan reveals enlarged adrenal glands. Chromosomal and gonadal sex is assigned as female

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SECTION IX Endocrine and Metabolic Physiology ■

gender. The diagnosis of congenital adrenal hyperplasia is made. Congenital adrenal hyperplasia is most frequently (>90% of cases) the result of steroid 21-hydroxylase deficiency due to a mutation. This is associated with ambiguous external genitalia in females or virilization during the first 2–3 years of life in both girls and boys. Adrenal insufficiency (cortisol deficiency) may present with or without salt wasting (due to decreased aldosterone synthesis). The lack of negative feedback inhibition of ACTH release results in excess ACTH production and stimulation of the early events in adrenal steroid hormone synthesis and adrenal growth (hyperplasia). The partial block in the synthetic pathway of cortisol and aldosterone leads to shunting of pregnenolone to the androgen hormone synthetic pathway, resulting in the excess in progesterone causing increased androgen synthesis. Treatment consists of replacement of glucocorticoids and, if desired or possible, surgical correction of the external genitalia as soon as possible.

CASE B A young adult male patient is admitted to the hospital because of severe headache and hypertension (blood pressure 220/100 mm Hg). The patient’s history includes complaints of episodic mild headaches that resolved spontaneously over the past 3 years. These have progressively increased in severity and frequency and are accompanied by sweating, dizziness, palpitations, and pallor. Measurements of catecholamines and their metabolites in a 24-hour urine specimen were increased, leading to the diagnosis of a pheochromocytoma. An MRI examination of the abdominal revealed a large, unilateral adrenal mass. Surgical resection of the adrenal was performed, revealing a large pheochromocytoma. Pheochromocytomas are rare tumors that produce catecholamines. They usually arise from the adrenal medulla, but about 10% can arise in extra-adrenal chromaffin tissue. The classic clinical presentation is the triad of episodic headache, sweating, and palpitations as a result of the release of stored catecholamines from the tumor. An unrecognized pheochromocytoma may lead to death as the result of a hypertensive crisis, arrhythmia, or myocardial infarction.

CHAPTER SUMMARY ■ ■

Cortisol (adrenal glucocorticoid) production and release is under ACTH regulation. Aldosterone (adrenal mineralocorticoid) release is under angiotensin II and K+ regulation.

■

■ ■ ■ ■

Steroid hormone receptors undergo conformational changes on hormone binding that allow them to bind to DNA and stimulate gene transcription. Specificity of the mineralocorticoid receptor is conferred by conversion of cortisol to cortisone by 11β-hydroxysteroid dehydrogenase. Glucocorticoids facilitate fuel mobilization, decrease glucose utilization, and produce immunosuppression. Aldosterone regulates body sodium balance and stimulates excretion of potassium. Catecholamine release is under sympathetic neural control. The response to stress by the host relies on close interaction between the steroid hormones and catecholamines to ensure adequate fuel mobilization and hemodynamic control.

STUDY QUESTIONS 1. Regulation of steroid hormone production by the adrenals involves which of the following steps? A) ACTH binding to a G protein–coupled receptor, stimulation of cholesterol transfer to inner mitochondrial membrane, and formation of pregnenolone B) ACTH binding to a nuclear receptor, stimulation of pregnenolone transfer to inner mitochondrial membrane, and formation of DHEA C) hydrolysis of cholesterol ester, stimulation of pregnenolone transfer to inner mitochondrial membrane, and formation of androstenedione D) ACTH binding to a G protein–coupled receptor, increased cholesterol ester hydrolysis, and pregnenolone transfer to inner mitochondrial membrane 2. A deficiency in 21-hydroxylase activity would be associated with which of the following? A) central obesity, increased cortisol levels, and decreased androstenedione B) virilization, increased ACTH, and decreased cortisol levels C) decreased ACTH levels and decreased cortisol levels D) hypertension, decreased ACTH, and increased cortisol levels E) virilization, hypertension, increased ACTH, and increased cortisol levels 3. Regarding cortisol production and transport, which of the following statements is true? A) Most cortisol circulates unbound to protein. B) Peak plasma levels occur at noon. C) Most of the plasma cortisol is bound to transcortin. D) More than 90% is excreted intact in the urine. 4. Physiologic effects of cortisol include A) hypoglycemia, increased fatty acid mobilization, and decreased central fat deposition B) increased amino acid–derived gluconeogenesis, increased glucose utilization, and hypoglycemia C) hyperglycemia, decreased fatty acid mobilization, and decreased central fat deposition D) decreased glucose utilization, hyperglycemia, and lipolysis

CHAPTER 65 Adrenal Gland 5. Regarding the production and release of aldosterone from the adrenals, which of the following statements is correct? A) Aldosterone production in the zona glomerulosa is mainly under ACTH control. B) Aldosterone production in the zona glomerulosa is mainly under angiotensin II control. C) Aldosterone production in the adrenal medulla is mainly under angiotensin II control. D) Aldosterone production in the zona glomerulosa is mainly under K+ control.

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6. Which of the following statements is true regarding catecholamine synthesis and release from the adrenals? A) Epinephrine accounts for 20% of total adrenal catecholamine release. B) Norepinephrine is derived from epinephrine through the action of the enzyme phenylethanolamine N-methyltransferase. C) Catecholamine synthesis is regulated by tyrosine hydroxylase. D) 35% of catecholamines released are excreted intact in the urine.

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66 C

Endocrine Pancreas Patricia E. Molina

H A

P

T

E

R

O B J E C T I V E S ■ ■ ■ ■

Identify the principal hormones secreted from the endocrine pancreas, their cells of origin, and their chemical nature. Understand the nutrient, neural, and hormonal mechanisms that regulate pancreatic hormone release. List the principal target organs for insulin and glucagon and their major physiologic effects. Identify the disease states caused by overproduction, underproduction, or decreased sensitivity to insulin, and describe the principal manifestations of each.

The pancreas is a mixed exocrine and endocrine gland that plays a central role in digestion and in the metabolism, utilization, and storage of energy substrates. Normal pancreatic function is essential for the physiologic control of glucose homeostasis, which, in turn involves interaction of several tissues and hormones in the regulated balance between hepatic glucose release (from glycogen breakdown and gluconeogenesis), dietary glucose absorption, and glucose uptake and disposal from skeletal muscle and adipose tissue. The pancreatic hormones insulin and glucagon play central roles in regulating each of these processes; their overall effects are, in part, modified by other hormones such as growth hormone, cortisol, and epinephrine.

FUNCTIONAL ANATOMY The pancreas is a retroperitoneal gland located near the duodenum, composed of exocrine cells that are clustered in acini (see Chapter 51). Embedded within the acini are richly vascularized, small clusters of endocrine cells called the islets of Langerhans, in which two endocrine cell types (β and α) predominate. The β-cells constitute about 73–75% of the total

Ch66_671-682.indd 671

mass of endocrine cells, and their principal secretory product is insulin. The α-cells account for about 18–20% of the endocrine cells and are responsible for glucagon secretion. A small number of δ-cells (4–6%) secrete somatostatin, and an even smaller number of cells (1%) secrete pancreatic polypeptide. The rich vascularization by fenestrated capillaries allows ready access to the circulation for the hormones secreted by the islet cells. Venous blood from the pancreas drains into the hepatic portal vein. Therefore, the liver, a principal target organ for the physiologic effects of pancreatic hormones, is exposed to the highest concentrations of pancreatic hormones. Following first-pass hepatic metabolism, the pancreatic endocrine hormones are distributed to the systemic circulation. Parasympathetic, sympathetic, and sensory nerves richly innervate the pancreatic islets, and the respective neurotransmitters and neuropeptides released from their nerve terminals exert important regulatory effects on pancreatic endocrine hormone release. Acetylcholine, released from the parasympathetic nerve terminals, stimulates the secretion of insulin, glucagon, somatostatin, and pancreatic polypeptide. Norepinephrine released from sympathetic nerve terminals inhibits basal and glucose-stimulated insulin secretion and stimulates glucagon and pancreatic polypeptide secretion.

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SECTION IX Endocrine and Metabolic Physiology

PANCREATIC HORMONES INSULIN Insulin Synthesis Insulin is a polypeptide hormone with a highly conserved amino acid sequence. It is produced from proinsulin cleavage of the connecting C-peptide from the amino-terminal β-chain and the carboxy-terminal α-chain (Figure 66–1A). C-peptide links the α- and β-chains, allowing proper folding of the molecule and the formation of disulfide bonds between the two chains. Removal of the C-peptide exposes the end of the insulin chain that interacts with the insulin receptor. Both insulin and the free C-peptide are packaged into secretory granules of which about 5% are in a readily releasable pool and the rest (>95%) in a reserve pool (Figure 66–1B). Insulin release from granules from different pools leads to a biphasic pattern response to glucose stimulation of the β-cell. Only a small proportion of the cellular stores of insulin is released even under maximal stimulatory conditions. Stimulation of the pancreatic β-cell leads to release of equal amounts of insulin and C-peptide into the portal circulation. Insulin circulates in its free form and has a half-life of 3–8 minutes. It is degraded predominantly by the liver during

A

Proinsulin

its first pass, which extracts about 40–80% of insulin delivered. Additional degradation of insulin occurs in the kidneys as well as at target tissues by insulin proteases following endocytosis of the receptor-bound hormone. C-peptide is not readily degraded in the liver. Thus, the relatively long half-life of C-peptide (35 minutes) allows its release to be used as an index of the secretory capacity of the endocrine pancreas.

Regulation of Insulin Release The release of insulin throughout the day is pulsatile and rhythmic in nature (Figure 66–1C). The pulsatile release of insulin appears to be critical in the suppression of liver glucose production and in insulin-mediated glucose disposal by adipose tissue. Insulin release increases after a meal in response to the increases in plasma levels of glucose and amino acids. An increase in plasma glucose concentration is followed by a transient stimulation of insulin secretion known as first-phase secretion, which consists of a rapid burst of release to a high peak and then a steep decline to a low secretion rate (Figure 66–1B). This is followed by second-phase secretion, which consists of a gradually increasing rate of secretion to a plateau level. This biphasic response to glucose is a major characteristic of glucose-stimulated insulin secretion. The first phase occurs over a period of minutes, the second over an

Insulin

C

S

α-chain

S S

β-chain

S

S

S S

S

S

S

S

S

C-terminal

900 750 450 300 150 0

B

Biphasic insulin release Immature granules

Readily releasable granules

0

Insulin release per beta cell (granules/min)

N-terminal

Pulsatile insulin release

Portal vein INS. conc. (pM)

C peptide

20

40

60

80

100

120

Time (minutes)

glucose 1st phase 15 10

2nd phase 5 0

0

5

10

15

20

t (min)

FIGURE 66–1 Principal feature of insulin synthesis and release. A) Insulin synthesis starts with the translation of insulin mRNA into an inactive protein called preproinsulin. Preproinsulin undergoes posttranslational modification in the endoplasmic reticulum (ER) to form proinsulin. The active form of insulin is produced by modification of proinsulin by cleavage of the C-peptide structure linking the α- and β-chains. Insulin is composed of two amino acid chains. The chains are held together by two disulfide (S–S) bonds. A third disulfide bond is present within the α-chain. Both insulin and the cleaved C-peptide are packaged in secretory granules that accumulate in the β-cell cytosol and are coreleased in response to glucose stimulation. B) Insulin release occurs in a biphasic mode from secretory granules that are immediately available for release (<5%) and from granules that must undergo a series of preparatory reactions including mobilization to the plasma membrane (>95%). These granule preparatory or maturation processes are modulated by intracellular levels of ATP, ADP, and Ca2+. C) Insulin release in response to a meal is characterized by increased frequency and amplitude of pulsatile release. Shown are portal insulin concentrations during basal state (left) and after ingestion of a mixed meal (right) in normal patients. (Modified with permission from Porksen N et al: Human insulin release processes measured by intraportal sampling. Am J Physiol Endocrinol Metab 2002;282(3):E695–E702.)

CHAPTER 66 Endocrine Pancreas

Glucose

673

1

GLUT2 carrier

ATP

Mitochondrion

–

2 K+

Endoplasmic reticulum Ca2+ store

4

Ca2+

ATP-sensitive K+ channel

Depolarization

Ca2+

3

Secretory granules

Voltage-gated Ca2+ channel Ca2+ Exocytosis

β CELL

Insulin

FIGURE 66–2 Regulation of insulin release. Glucose is the principal stimulus for insulin release from the pancreatic β-cell. (1) It enters the β-cell by a specific glucose-transporter protein (GLUT-2) and is immediately phosphorylated by glucokinase (not shown). The increased concentrations of ATP and resulting greater ATP/ADP ratio lead to inhibition and (2) closure of the ATP-sensitive K+ channels (the target of sulfonylurea drugs), resulting in depolarization of the plasma membrane and (3) opening of the voltage-dependent Ca2+ channels. As a result, there is an increased influx of extracellular Ca2+ as well as (4) mobilization of Ca2+ from intracellular stores leading to the fusion of insulin-containing secretory granules with the plasma membrane and the release of insulin (and C-peptide) into the circulation. PLC, phospholipase C; AC, adenylate cyclase; CCK, cholecystokinin; GLP-1, glucagon-like peptide-1. (Reproduced with permission from Kibble J, Halsey CR: The Big Picture, Medical Physiology. New York: McGraw-Hill, 2009.)

hour or more. Secretion is the result of a combination of an increase in the total amount of insulin released in each secretory burst and an increased pulse frequency of a similar magnitude (Figure 66–1C). The pancreatic β-cell functions as a fuel sensor that responds to changes in plasma levels of energy substrates (glucose and amino acids), hormones (glucagon-like peptide 1 [GLP-1] and epinephrine), and neurotransmitters (norepinephrine and acetylcholine) (Figure 66–2). Glucose is the principal stimulus for insulin release from the pancreatic β-cells. The glucose-induced stimulation of insulin release is the result of glucose metabolism by the β-cell and an increase in the adenosine triphosphate (ATP)/ADP ratio in the cytosol. Glucose enters the β-cell through a membrane-bound glucose transporter (GLUT 2) (Figure 66–2). The production of ATP from glucose oxidation results in an increase in intracellular ATP/ADP that inhibits (closes) the ATP-sensitive K+ channels (KATP) in the β-cell, reducing the efflux of K+. This process results in membrane depolarization, activation (opening) of voltage-dependent Ca2+ channels, and increased Ca2+ influx. The increase in intracellular Ca2+ concentrations triggers the exocytosis of insulin secretory granules and the release of insulin into the extracellular space and into the circulation.

Regulation of K+ channels by ATP is mediated by the sulfonylurea receptor, and is the basis for the therapeutic use of sulfonylurea drugs in the treatment of type 2 diabetes mellitus. The β-cell Ca2+ concentrations can also be increased by amino acids through their metabolism and ATP generation, or by direct depolarization of the plasma membrane. Other factors that amplify the glucose-induced release of insulin from the β-cell include acetylcholine, cholecystokinin, gastrointestinal peptide, and GLP-1. Catecholamines and somatostatin inhibit insulin.

Physiologic Effects of Insulin Insulin produces a wide variety of effects that range from immediate (within seconds), such as the modulation of ion (K+) and glucose transport into the cell; early (within minutes), such as the regulation of metabolic enzyme activity; moderate (within minutes to hours), such as the modulation of enzyme synthesis; to delayed (within hours to days), such as the effects on growth and cellular differentiation. Overall, the actions of insulin at target organs are anabolic and promote the synthesis of carbohydrate, fat, and protein, and these effects are mediated through binding to the insulin receptor (Table 66–1).

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TABLE 66–1 Insulin effects on carbohydrate, fat, and protein metabolism. Metabolic Effects

Insulin Stimulates

Insulin Inhibits

Carbohydrate metabolism

Glucose transport in adipose tissue and muscle

Glycogen breakdown in muscle and liver

Rate of glycolysis in muscle and adipose tissue

Gluconeogenesis in the liver

Glycogen synthesis in adipose tissue, muscle, and liver Lipid metabolism

Fatty acid and triacylglycerol synthesis in tissues Uptake of triglycerides from the blood into adipose tissue and muscle

Protein metabolism

Lipolysis in adipose tissue, lowering the plasma fatty acid level Fatty acid oxidation in muscle and liver

Rate of cholesterol synthesis in the liver

Ketogenesis

Amino acid transport into tissues

Protein degradation in muscle

Protein synthesis in muscle, adipose tissue, liver, and other tissues

Urea formation

Insulin Receptor The insulin receptor belongs to the same family of the insulinlike growth factor receptor, and the insulin-related receptor, all of which are involved in cell division, metabolism, and development (Figure 66–3). Insulin binding to the receptor triggers receptor autophosphorylation on tyrosine residues in the cytoplasmic domain (β-chain). The activated receptor phosphorylates tyrosine residues of several proteins known as insulin receptor substrates (IRS-1, -2, -3, -4). These IRS proteins facilitate the interaction of the insulin receptor with intracellular substrates by serving as a scaffold for recruitment of proteins involved in signal transduction to downstream pathways. The result is cou-

Insulin

Insulin receptor

pling of insulin receptor activation to signaling, mainly the phosphatidylinositol 3-kinase (PI 3-kinase) and the mitogen-activated protein kinase (MAPK) pathways (Figure 66–3). Activation of the PI 3-kinase pathway leads to activation of enzymes that catalyze the cellular effects of insulin, particularly the metabolic effects of the hormone, including glucose transport, glycolysis, and glycogen synthesis, and regulation of protein synthesis. Moreover, this pathway is involved in cell growth and transmits a strong antiapoptotic signal, promoting cell survival. The other main signaling pathway that is activated by insulin binding to its receptor is the MAPK pathway, which is involved in mediating the proliferative and differentiation effects elicited by insulin. The number of available insulin receptors is modulated by exercise, diet, insulin, and other hormones. Chronic exposure to high insulin levels, obesity, and excess growth hormone all lead to a downregulation of insulin receptors. In contrast, exercise and starvation upregulate the number of receptors. The affinity of the receptor for insulin is increased following a period of decreased insulin levels.

ATP

Insulin Effects at Target Organs Early effects P

P

IRS-1 P

Other effector systems and secondary mediators

P

Various effects

FIGURE 66–3 Intracellular responses triggered by insulin binding to the insulin receptor. Red balls and balls labeled P represent phosphate groups. IRS-1, insulin receptor substrate-1. (Reproduced with permission from Barrett KE, Barman SM, Boitano S, Brooks H: Ganong’s Review of Medical Physiology, 23rd ed. McGraw-Hill Medical, 2009.)

The effects of insulin on skeletal muscle glucose utilization dominate insulin action. Insulin mediates about 40% of glucose disposal by the body, the great majority of which occurs in skeletal muscle. The movement of glucose into the cell is mediated by a family of carrier proteins, or glucose transporters (GLUT), with their own unique tissue distribution. The main transporters and their predominant tissue distributions are summarized in Table 66–2. Insulin-stimulated glucose transport is mediated through GLUT-4. Approximately 90% of GLUT-4 is sequestered intracellularly in the absence of insulin or other stimuli such as exercise. Insulin binding to its receptor results in recruitment of GLUT-4 from cytosolic vesicular compartments to the plasma membrane.

CHAPTER 66 Endocrine Pancreas

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TABLE 66–2 Main features of glucose transporters. Transporter

Expression

Function

GLUT-1

Ubiquitous, with particularly high levels in human erythrocytes and in the endothelial cells lining the blood vessels of the brain. Expressed in skeletal muscle and fat

Glucose uptake by skeletal muscle and fat under basal conditions

GLUT-2

Low-affinity glucose transporter present in pancreatic β-cells, liver, intestine, and kidney

Functions in the glucose sensor system and ensures that glucose uptake by pancreatic β-cells and hepatocytes occurs only when circulating glucose levels are high

GLUT-3

Primarily in neurons

Together, GLUT-1 and GLUT-3 are crucial in allowing glucose to cross the blood–brain barrier and enter neurons

GLUT-4

Predominantly in striated muscle and adipose tissue. In contrast to the other GLUT isoforms, which are primarily localized on the cell membrane, GLUT-4 transporter proteins are sequestered in specialized storage vesicles that remain within the cell’s interior under basal conditions

The major insulin-responsive transporter

GLUT-5

Spermatozoa and small intestine

Predominantly a fructose transporter

Intermediate effects The intermediate effects of insulin are mediated by modulation of protein phosphorylation of enzymes involved in metabolic processes in muscle, fat, and liver (Table 66–1). In fat, insulin inhibits lipolysis and ketogenesis by triggering the dephosphorylation of hormone-sensitive lipase and stimulates lipogenesis by activating acetyl-CoA carboxylase. In the adipocytes, dephosphorylation of hormone-sensitive lipase inhibits the breakdown of triglycerides to fatty acids and glycerol, the rate-limiting step in the release of free fatty acids mediated by lipolysis. This process thereby reduces the amount of substrate that is available for ketogenesis. Insulin antagonizes catecholamine-induced lipolysis through the phosphorylation and activation of phosphodiesterase, leading to a decrease in intracellular cAMP levels and a concomitant decrease in protein kinase A activity. In the liver, insulin stimulates the gene expression of enzymes involved in glucose utilization (e.g., glucokinase, pyruvate kinase, and lipogenic enzymes) and inhibits the gene expression of enzymes involved in glucose production (e.g., phosphoenolpyruvate carboxykinase and glucose-6phosphatase) (Figure 66–4). Insulin stimulates glycogen synthesis by increasing phosphatase activity, leading to the dephosphorylation of glycogen phosphorylase and glycogen synthase. In addition, insulin-mediated dephosphorylation of inhibitory sites on hepatic acetyl-CoA carboxylase increases the production of malonyl-CoA and simultaneously reduces the rate at which fatty acids can enter hepatic mitochondria for oxidation and ketone body production. In muscle, insulin stimulates glucose uptake and favors protein synthesis though phosphorylation of a serine/threonine protein kinase known as mammalian target of rapamycin (mTOR). In addition, insulin favors lipid storage in muscle as well as in adipose tissue. Insulin deficiency leads to glucose accumulation in blood, a decrease in lipid storage,

and protein loss, resulting in negative nitrogen balance and muscle wasting.

Long-term effects Sustained insulin stimulation enhances the synthesis of lipogenic enzymes and the repression of gluconeogenic enzymes. The growth-promoting and mitogenic effects of insulin are long-term responses mediated through the MAPK pathway.

GLUCAGON Glucagon Synthesis Glucagon is a 29–amino acid polypeptide hormone secreted by the α-cells of the islets of Langerhans, which antagonizes insulin’s action. The primary sequence of glucagon is highly conserved among vertebrates. Glucagon is synthesized as proglucagon and then proteolytically processed to yield glucagon. The prohormone proglucagon is expressed in the pancreas, and also in other tissues, such as enteroendocrine cells in the intestinal tract and the brain. However, the processing of the prohormone differs among tissues. The two main products of proglucagon processing are glucagon in the α-cells of the pancreas and GLP-1 in the intestinal cells. GLP-1 is produced in the intestine in response to a high concentration of glucose in the intestinal lumen. It is known as an incretin, a mediator that amplifies insulin release from the β-cell in response to a glucose load. Glucagon has a short half-life (5–10 minutes) and is degraded mostly in the liver.

Regulation of Glucagon Release Glucagon release is inhibited by hyperglycemia (high blood glucose levels) and stimulated by hypoglycemia (low blood

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Glycogenolysis

Glycolysis

Glycogen

Glucose

G Glycogen I synthase

Glycogen phosphorylase

I G

Glucokinase

G

Glucose-6-phosphate

Glucose-1-P Fructose-6-phosphate ATP

Phosphofructokinase

ADP

G

Gluconeogenesis Fructose-1,6-bisphosphate (2) Pyruvate Dihydroxyacetone phosphate

(2) Oxaloacetate

I

PEP carboxykinase

G

(2) PEP

Glyceraldehyde-3-phosphate

(2) 3-Phosphoglycerate 1,3-Bisphosphoglycerate (2) 1,3-Bisphosphoglycerate 3-Phosphoglycerate

Fructose-1,6-bisphosphate Fructose-1,6-bisphosphate

G 2-Phosphoglycerate

Fructose-6-phosphate

Phosphoenolpyruvate

Glucose-6-phosphate

I

Glucose-6-phosphatase

Glucose

G

I

Pyruvate kinase

G

Pyruvate

FIGURE 66–4 Glucagon and insulin effects on hepatic glucose metabolism. Binding of glucagon and insulin to their respective receptors stimulates a cascade of protein phosphorylation steps that activate (or inhibit) key enzymes involved in the regulation of glycogenolysis, gluconeogenesis, and glycolysis. The principal target enzymes for insulin- and glucagon-mediated effects are presented. The overall result is an increase in hepatic glucose output. G, glucagon; I, insulin; PEP, phosphoenolpyruvate; ATP, adenosine triphosphate; ADP, adenosine diphosphate. (Reproduced with permission from Jiang G, Zhang BB: Glucagon and regulation of glucose metabolism. Am J Physiol Endocrinol Metab 2003;284(4):E671–E678.)

glucose levels). A meal rich in carbohydrates suppresses glucagon release and stimulates insulin release from the β-cells through intestinal release of GLP-1. Somatostatin also inhibits glucagon release. High amino acid levels following an amino acid–rich meal stimulate glucagon release. Epinephrine stimulates release of glucagon through a β2-adrenergic mechanism (while it suppresses insulin release from β-cells through an α2-adrenergic mechanism). Vagal (parasympathetic) stimulation increases glucagon release.

Physiologic Effects of Glucagon Glucagon mediates its effects by binding to the glucagon Gαs protein–coupled receptor (Figure 66–5). The principal target tissue for glucagon is the liver. Glucagon’s main physiologic effect is to increase plasma glucose concentrations by stimulating de novo hepatic glucose production through gluconeogenesis and glycogen breakdown and decreasing glycolysis (Figures

66–4 and 66–5). Glucagon is the principal hormone involved in prevention and counterregulation of hypoglycemia. The key enzymatic steps regulated by glucagon that mediate the stimulation of hepatic glucose output are summarized in Table 66–3. Glucagon can exert effects on adipose tissue as well. However, these are important primarily during periods of prolonged stress or food deprivation, particularly when insulin release is suppressed. In the adipocyte, glucagon activates hormone-sensitive lipase, the enzyme that breaks down triglycerides (stored fat) into diacylglycerol and free fatty acids, releasing them into the circulation. Glycerol released into the circulation can be utilized in the liver for gluconeogenesis or for reesterification. Free fatty acids are used as fuel by most tissues, predominantly skeletal muscle and liver. In the liver, free fatty acids are used for reesterification or they can undergo β-oxidation and conversion into ketone bodies. Thus, ketogenesis is regulated by the balance between the effects of glucagon and insulin at their target organs.

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Glucagon

Phospholipase C

Adenylate cyclase

Gq Receptor

(PiP2)

Gαs

Inositol 1.4.5 triphosphate (IP3)

GDP

β

γ Cytoplasm

GTP

cAMP

Ca2+ PKA

PGC-1 PEPCK G-6-Pase

Glycolysis

Glycogenesis

Phosphorylase Kinase a

Gluconeogenesis

Phosphorylase

b

Glycogenolysis

Glucose

FIGURE 66–5 Glucagon receptor-mediated cellular effects. Glucagon binds to GPCR on target cells. The principal effects of glucagon are mediated in hepatocytes where glucagon, through activation of adenylate cyclase and elevation in cAMP, leads to increased protein kinase A (PKA) activity resulting in phosphorylation of enzymes responsible for control of glucose metabolism. Phosphorylase b is the inactive form of the enzyme; phosphorylase a is the active form. Furthermore, there is a change in phospholipase C activity leading to a change in intracellular Ca2+ release). The ultimate result is an increase in hepatic glucose production through increased gluconeogenesis and glycogenolysis. Additional abbreviations: PGC-1, peroxisome proliferator-activated receptor coactivator-1; PEPCK, phosphoenolpyruvate carboxykinase; G-6-Pase, glucose6-phosphatase; PIP2, phosphatidylinositol 4,5-biphosphate. (Modified with permission from Cooper GM: The Cell: A Molecular Approach, 2nd ed. Sinauer, 2000.)

SOMATOSTATIN

PANCREATIC POLYPEPTIDE

Somatostatin is a 14–amino acid peptide hormone produced by the δ-cells of the pancreas. Its release is stimulated by highfat, high-carbohydrate, and particularly protein-rich meals, and is inhibited by insulin. Somatostatin has a generalized inhibitory effect on virtually all gastrointestinal and pancreatic exocrine and endocrine functions.

Pancreatic polypeptide is a 36–amino acid peptide hormone that belongs to a peptide family including neuropeptide Y and peptide YY. It is produced in the endocrine type F cells located in the periphery of pancreatic islets and is released into the circulation after ingestion of food, exercise, and vagal stimulation. The effects of pancreatic polypeptide include

TABLE 66–3 Effects of glucagon on hepatic glucose metabolism. Effect on Target Enzyme

Metabolic Response

Increased expression of glucose-6-phosphatase

Frees glucose to enter the circulation

Suppression of glucokinase

Decreases glucose entry into the glycolytic cascade

Phosphorylation (activation) of glycogen phosphorylase

Stimulates glycogenolysis

Inhibition of glycogen synthase

Inhibits glycogen synthesis

Stimulation of phosphoenolpyruvate carboxykinase expression

Stimulates gluconeogenesis

Inactivation of phosphofructokinase-2 and activation of fructose-6-phosphatase. PFK-2 is the kinase activity and fructose-2,6-bisphosphatase is the phosphatase activity of the bifunctional regulatory enzyme, phosphofructokinase-2/fructose-2,6bisphosphatase

Inhibits glycolysis

Suppression of activity of the pyruvate kinase

Decreases glycolysis

Stimulates gluconeogenesis

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inhibition of pancreatic exocrine secretion, gallbladder contraction, modulation of gastric acid secretion, and gastrointestinal motility. Pancreatic polypeptide crosses the blood–brain barrier and has been postulated to play a role in regulating feeding behavior.

AMYLIN Amylin, or islet amyloid polypeptide, is a 37–amino acid peptide hormone that belongs to the calcitonin family, which includes calcitonin, calcitonin gene-related peptide, and adrenomedullin. Amylin is synthesized as a small precursor, undergoes posttranslational modification (amidation), is stored in β-cell granules, and is released along with insulin and C-peptide. Plasma amylin concentrations increase after a meal or glucose infusion. Amylin appears to work with insulin to regulate plasma glucose concentrations in the bloodstream, suppressing the postprandial secretion of glucagon and slowing gastric emptying. It is the main component of pancreatic islet amyloid, found in the vast majority of patients with type 2 diabetes mellitus, and is thought to contribute to destruction of the pancreatic β-cell.

DISEASES ASSOCIATED WITH PANCREATIC HORMONES HORMONE-PRODUCING TUMORS Excess pancreatic hormone production and release are usually due to hormone-producing tumors, with insulinoma being the most frequent. Insulinomas produce excessive amounts of insulin, and patients present with episodes of hypoglycemia, confusion, aggressiveness, palpitations, sweating, convulsions, and even unconsciousness. These symptoms are mostly observed before breakfast and following physical exercise. The compensatory or counterregulatory response of the body includes the release of catecholamines, glucagon, cortisol, and growth hormone. Glucagonomas are unusual tumors that may produce symptoms of diabetes. Excessive glucagon production by the tumor may also result in an overall catabolic effect on fat and muscle, leading to severe weight loss and anorexia.

DIABETES MELLITUS The most common disease resulting from impaired pancreatic hormone release or sensitivity is diabetes mellitus. The two forms of diabetes mellitus, type 1 (T1DM) and type 2 (T2DM), are characterized by impaired insulin release, but for different reasons. T1DM is the result of β-cell destruction. It accounts for 2–5% of cases, and it occurs more frequently in younger people, hence its archaic name, juvenile-onset diabetes. T1DM is characterized by the development of ketoacidosis in the

absence of insulin therapy. T2DM results from impaired sensitivity to insulin (insulin resistance) and a subsequent relative loss of normal regulation of insulin secretion and accounts for more than 90% of diabetes cases. It is usually associated with obesity in adults and is characterized by mild hyperglycemia. It rarely leads to ketoacidosis.

Type 1 Diabetes Mellitus The pathophysiology of T1DM involves a complete lack of insulin secretion due to autoimmune destruction of the islet cells. This results in impaired entry of glucose into the cells and accumulation of glucose in the blood. This leads to increased plasma osmolarity and urinary loss of glucose, accompanied by excess loss of water and sodium (polyuria). The resulting dehydration triggers compensatory mechanisms such as thirst (polydipsia). The inability of the cells to utilize glucose resembles a state of cellular starvation, stimulating hunger (polyphagia) and triggering the activation of compensatory responses to increase the release and availability of fuel substrates though activation of lipolysis and proteolysis. Diabetic ketoacidosis is an acute pathologic event characterized by elevated blood glucose levels and ketone bodies and metabolic acidosis, resulting directly from decreased insulin availability and simultaneous elevations of the counterregulatory hormones glucagon, catecholamines, cortisol, and growth hormone. Diabetic ketoacidosis is precipitated by infections, discontinuation of or inadequate insulin use, new-onset (untreated) diabetes, and other events such as the stress associated with surgery. In diabetic ketoacidosis, gluconeogenesis in the liver proceeds unopposed by the physiologic presence of insulin. The excess blood glucose increases osmolarity, which, if severe, can result in diabetic coma. Low insulin levels and the high levels of counterregulatory hormones glucagon, epinephrine, and cortisol combine to increase the activity of hormone-sensitive lipase, increase the release of free fatty acids, and decrease the activity of acetyl-CoA carboxylase, thereby impairing the reesterification of free fatty acids and promoting fatty acid conversion into ketone bodies (Figure 66–6). The steps involved in ketogenesis are β-oxidation of fatty acids to acetyl-CoA, formation of acetoacetyl-CoA, and conversion of acetoacetyl-CoA to 3-hydroxy-3-methylglutarylCoA and then to acetoacetate, which is then reduced to 3-hydroxybutyrate. The enzymes involved in ketogenesis are summarized in Table 66–4. Acetoacetate can be spontaneously decarboxylated to acetone, a highly fat-soluble compound that is excreted slowly by the lungs and is responsible for the fruity odor of the breath of individuals with diabetic ketoacidosis. Ketone bodies released into the blood can freely diffuse across cell membranes and serve as an energy source for extrahepatic tissues including the brain, skeletal muscle, and kidneys. Ketone bodies are filtered and reabsorbed in the kidney. At physiologic pH, ketone bodies, with the exception of

CHAPTER 66 Endocrine Pancreas

Acetyl CoA carboxylase Acetyl CoA Malonyl CoA (FA synthesis)

Adipocyte Tryglycerides +

679

β-oxidation

Acetyl CoA

HSL Acetoacetyl CoA

Free fatty acids HMG CoA

Mitochondria

Acetoacetate +

Hepatocyte

H HO C CH2 CH2 COO-

O=C–CH3 CH2 COOAcetoacetate

3-β -Hydroxybutyrate CH3 O=C CH3 Acetone

FIGURE 66–6 Process of ketogenesis in insulin deficiency. Insulin deficiency and high levels of counterregulatory hormones glucagon, epinephrine, and cortisol combine to increase the activity of hormone-sensitive lipase, increase the release of free fatty acids, and decrease the activity of acetyl-coenzyme A (CoA) carboxylase, thereby impairing the reesterification of free fatty acids and promoting fatty acid conversion into ketone bodies. The excess supply of fatty acetyl-CoA and the deficiency in oxaloacetate increase the oxidation to ketone bodies, with the resulting release of ketone bodies into the blood. Plus signs (+) denote steps that are favored by insulin deficiency. HSL, hormone-sensitive lipase; FA, fatty acid; HMG, 3-hydroxy-3-methylglutaryl. (Reproduced with permission from Molina PE: Endocrine Physiology, 3rd ed. New York: McGraw-Hill Medical, 2010.)

acetone, dissociate completely. The resulting liberation of H+ from ketone body metabolism exceeds the blood’s buffering capacity, leading to metabolic acidosis with an increased anion gap. If severe, this condition can lead to coma.

Type 2 Diabetes Mellitus T2DM is the result of a decreased responsiveness of peripheral tissues to insulin action (insulin resistance) and inadequate responsiveness of the β-cells to glucose, which later is followed by a net reduction in β-cell mass. Patients with type 2 diabetes secrete normal amounts of insulin during fasting, but in response to a meal or glucose load, they secrete less insulin than nondiabetic patients. In addition to a relative reduction in insulin release, the pattern of insulin release is also altered following a meal, with pulses that are significantly smaller, sluggish, and erratic, particularly after dinner. This abnormality results in significantly higher levels of fasting glucose in these patients. Regardless of the etiology (e.g., abnormalities in glucose transport; abnormal insulin synthesis, processing, storage, or secretion), the earliest physiologic indication of β-cell dysfunction is a delay in the acute insulin response to glucose. The defect in the initial response to a glucose load leads to an

excessive rise in plasma glucose, which in turn produces a compensatory and exaggerated second-phase hyperinsulinemic response. This initial period of sustained hyperinsulinemia downregulates the insulin receptors, decreasing the sensitivity of tissues to insulin action and producing a state of insulin resistance. The main pathologic defects in T2DM are excessive hepatic glucose production, defective β-cell secretory function, and peripheral insulin resistance.

INSULIN RESISTANCE Insulin resistance is the inability of peripheral target tissues to respond properly to normal circulating concentrations of insulin. To maintain euglycemia, the pancreas compensates by secreting increased amounts of insulin. In patients with T2DM, insulin resistance precedes the onset of the disease by several years. Compensating for insulin resistance by an increase in insulin release is effective only temporarily. As insulin resistance increases, impaired glucose tolerance develops. Ultimately, failure or exhaustion of the pancreatic β-cell results in a relative decrease in insulin secretion. The combination of insulin resistance and impaired β-cell function characterizes clinical T2DM.

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TABLE 66–4 Three principal enzymes involved in ketogenesis. Enzyme

Tissue

Function

Hormone-sensitive lipase

Adipocytes

Breaks down triglycerides, releasing fatty acids into the circulation

Acetyl-CoA carboxylase

Liver

Catalyzes the conversion of acetyl-CoA to malonyl-CoA, the primary substrate of fatty acid biosynthesis

HMG-CoA synthase

Liver

Involved in the conversion of acetyl-CoA to acetoacetate

tions, including retinopathy, nephropathy, and neuropathy. Treatment aims at the control of blood sugar, and is monitored by prevailing levels of glycosylated hemoglobin. Treatment can include sulfonylureas that increase pancreatic insulin secretion, biguanides that decrease hepatic glucose production, insulin sensitizers (glitazones) that attempt to restore insulin sensitivity, and drugs that can decrease gastrointestinal absorption of glucose. Finally, insulin injections are often used because pharmacological doses of insulin can increase glucose uptake despite the relative insulin resistance. Newly available analogs of GLP-1 can also be used to amplify the insulin response to glucose.

CoA, coenzyme A; HMG, 3-hydroxy-3-methylglutaryl.

Exercise has been demonstrated to increase glucose transport in skeletal muscle and to decrease insulin resistance in patients with T2DM. The increase in glucose transport resulting from exercise is insulin-independent and involves the enzyme AMP-activated protein kinase. AMP-activated protein kinase has been termed a master metabolic switch because it phosphorylates key target proteins that control flux through metabolic pathways. Repeated physical activity improves insulin sensitivity by increasing skeletal muscle expression and/or activity of key signaling proteins involved in the regulation of glucose uptake and metabolism, lipid oxidation and/or turnover, and oxidative capacity.

CHAPTER SUMMARY ■ ■ ■

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■ ■

CLINICAL CORRELATION A middle-aged, overweight Hispanic man is referred for evaluation following detection of an increased fasting plasma glucose of 150 mg/dL by his primary care physician. Attempts of lifestyle modifications including exercise and diet to reduce body weight over the past 7 months have been unsuccessful. In addition, glycosylated hemoglobin, an estimate of blood glucose control over the last month, remains elevated at 7%. The diagnosis of T2DM is established and treatment with oral hypoglycemic drugs is initiated. T2DM is the result of deficient insulin action (insulin resistance) leading to fasting hyperglycemia and the inability to have an adequate insulin-induced increase in glucose uptake from plasma after a glucose load. The incidence of T2DM has increased during the past several decades due to an aging population, increased prevalence of obesity, and decreased physical activity, among other factors that include ethnicity, environmental, and genetic risk factors. Diabetes mellitus is associated increased risk factor for cardiovascular disease and long-term complica-

■

■

Insulin release is under nutrient, neural, and hormonal regulation. The pancreatic β-cell functions as a glucose sensor in the process of insulin release. The PI 3-kinase pathway mediates most of insulin’s metabolic effects, and the MAPK pathway is mostly involved in mediating the proliferative responses. The principal metabolic effects of insulin are to increase glucose utilization in skeletal muscle, suppress hepatic glucose production, and inhibit lipolysis. Glucagon antagonizes insulin’s effects by stimulating hepatic glucose release. T1DM results in hyperglycemia because of β-cell destruction and loss of insulin. T2DM results in hyperglycemia because of tissue resistance to insulin action and an inadequate β-cell response to hyperglycemia. A disruption in the balance of insulin and glucagon can lead to ketogenesis and hyperosmolar coma.

STUDY QUESTIONS 1. In a patient with severe hypoglycemia (38 mg/dL), the differential diagnosis between self-administered insulin overdose and a tumor that produces excess insulin can be made by determining plasma levels of A) insulin B) somatostatin C) C-peptide D) gastrin 2. Physiologic responses to insulin include A) stimulation of glucose transport in skeletal muscle, red blood cells and the brain B) inhibition of triglyceride synthesis in adipose tissue C) stimulation of amino acid uptake by skeletal muscle D) stimulation of glucose reabsorption in the kidney

CHAPTER 66 Endocrine Pancreas 3. A 57-year-old female patient is brought to the emergency room with a history of frequent urination, weight loss, and decreased oral intake. At presentation, the patient is lethargic, dehydrated, hypotensive, and tachycardic. Her caretaker reports that she was recovering from a recent bout of pneumonia. She had been diagnosed with T2DM five years prior to this incident. Which of the following laboratory findings is most likely? A) plasma glucose of 40 mg/dL B) plasma osmolarity of >350 mOsm/L C) low blood pH D) high plasma ketones 4. A 21-year-old male patient with T1DM is brought to the emergency room for abdominal pain, nausea, and vomiting of 16-hour duration. On examination, you notice that his insulin pump has stopped functioning. Which of the following is likely to be associated with his presentation? A) high plasma insulin levels B) increased plasma C-peptide levels C) increased serum ketones D) increased blood pH E) decreased hepatic glycogen breakdown

5. When would plasma insulin levels be expected to be highest? A) following a carbohydrate-rich meal B) after intravenous administration of somatostatin C) during a surgical procedure D) following vigorous exercise

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67 C

Male Reproductive System Patricia E. Molina

H A

P

T

E

R

O B J E C T I V E S ■ ■

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Describe the physiologic functions of the principal components of the male reproductive system. Describe the endocrine regulation of testicular function by gonadotropinreleasing hormone, follicle-stimulating hormone, luteinizing hormone, testosterone, and inhibin. Identify the cell of origin for testosterone, its biosynthesis, and transport within the blood, metabolism, and clearance. List other physiologically produced androgens. List the target organs or cell types, the cellular mechanism of action, and the physiologic effects of testosterone. Describe spermatogenesis and the role of different cell types in this process. Understand the neural, vascular, and endocrine factors involved in the erection and ejaculation response. Compare and contrast the actions of testosterone, dihydrotestosterone, estradiol, and müllerian inhibitory factor in the process of sexual differentiation. Identify the causes and consequences of androgen overproduction and underproduction in prepubertal and postpubescent adult males.

In utero sexual differentiation, maturation, spermatogenesis, and ultimately reproduction are all functions of the male reproductive system. The two principal functions of the testes, the male sex organs, are the production of sperm and the synthesis of testosterone. These processes ensure fertility and maintain male sexual characteristics. Testicular function is regulated by the gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH) as well as paracrine, neural, and other endocrine factors.

FUNCTIONAL ANATOMY The male reproductive organs include the testes (the principal male sex organs), the vas deferens, the ejaculatory ducts, the penis, and the accessory glands, which include the prostate and bulbourethral glands (Figure 67–1). The testes consist of

Ch67_683-694.indd 683

numerous lobules made of convoluted tubes (seminiferous tubules) supported by loose connective tissue. The seminiferous tubules represent approximately 80–85% of the testicular mass. The Leydig cells, embedded in the connective tissue, are the endocrine cells responsible for the production of the most important circulating androgen, testosterone, a steroid hormone. The tubules consist of a basement layer lined with epithelial cells forming the walls of the seminiferous tubules. These walls are lined with germ cells (spermatogonia) and Sertoli cells. Sertoli cells form tight junctions that functionally divide the seminiferous tubules into two compartments or environments for the development of spermatozoa. The basal compartment below the tight junctions has contact with the circulatory system and is the space in which spermatogonia develop to primary spermatocytes. The tight junctions open at specific times and allow progression of spermatocytes to the adluminal compartment, where meiosis is completed. In the adluminal

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Vas Ejaculatory Seminal deferens duct vesicle Urinary Ureter bladder Pubic bone Efferent ductules Epididymis Seminiferous tubule Prostate gland

Penis

Urethra

Epididymis Testis

Bulbourethral gland Rete testis

Vas deferens

FIGURE 67–1 Functional anatomy of the male reproductive system. The male reproductive organs include the testes, the vas deferens, the ejaculatory ducts, the penis, and the accessory glands, which include the prostate and bulbourethral glands. The testes consist of numerous lobules made of tubuli seminiferi supported by loose connective tissue. The tubuli seminiferi are united to form larger ducts called the tubuli recti. These larger tubules form a close anastomosing network of tubes called the rete testis, terminating in the ductuli efferentes. The tubular network carries the seminal fluid from the testis to the epididymis, from where spermatozoa enter the vas deferens and then enter the urethra through the ejaculatory ducts. The penis is composed of two functional compartments: the paired corpora cavernosa and the corpus spongiosum. The corpora cavernosa form the greater part of the substance of the penis and consist of bundles of smooth muscle fibers intertwined to form trabeculae, and containing numerous arteries and nerves. (Modified with permission from Widmaier EP, Raff H, Strang KT [editors]: Vander’s Human Physiology: The Mechanisms of Body Function, 11th ed. McGraw-Hill, 2007.)

compartment, spermatocytes are protected by a blood–testis barrier formed by tight junctions between the Sertoli cells. The principal functions of Sertoli cells are as follows: • provide support for germ cells, forming an environment in which they develop and mature; • provide the signals that initiate spermatogenesis and sustain spermatid development; • modulate pituitary gland function and, in turn, control of spermatogenesis. The seminiferous tubules are united to form larger ducts that form a close anastomosing network of tubes (Figure 67–1). This tubular network carries the seminal fluid containing sperm from the testis to the epididymis; from here, spermatozoa enter the vas deferens and then the ejaculatory ducts. The ejaculatory ducts move semen (sperm-containing fluid) into the urethra. In addition to serving as a route of transport, the tubular network or excretory system and the accessory organs play important roles in the production of sperm-containing semen through absorptive and secretory processes. As summarized in Table 67–1, these absorptive and secretory processes contribute to the final composition of sperm-containing semen. Sperm account for approximately 10% of the volume of the ejaculated semen that is composed of testicular and epididymal fluid together with the secretory products of male accessory glands. Most of the volume of the ejaculate is formed by the seminal vesicles with the remainder consisting of epididymal fluids and secretions from the prostate gland and bulbourethral glands.

TABLE 67–1 Contribution of the genitourinary system and accessory organs to sperm production. Organ

Function

Genitourinary system Efferent ductules, vas deferens, ejaculatory duct, urethra

Movement of spermatozoa Fluid reabsorption

Epididymis

H+ secretion and acidification of luminal fluid Capacitation of spermatozoa; glycoconjugation Reservoir for mature spermatozoa Phagocytosis of aging spermatozoa

Accessory glands Seminal vesicle

Secretion and storage of fructose-rich product (preferred energy substrate for sperm), prostaglandins, ascorbic acid, fibrinogen- and thrombin-like proteins

Prostate

Secretion and storage of fluid rich in acid phosphatase and protease (prostate-specific antigen)

Cowper’s glands

Secretion of mucus into the urethra on arousal

CHAPTER 67 Male Reproductive System The penis is composed of two functional compartments: the paired corpora cavernosa and the corpus spongiosum. The corpora cavernosa form the greater part of the substance of the penis and consist of bundles of smooth muscle fibers intertwined in a collagenous extracellular matrix. Interspersed within this parenchyma is a complex network of endothelial cell–lined sinuses, arteries, and nerve terminals. The penis is innervated by somatic and autonomic (both sympathetic and parasympathetic) nerve fibers. The somatic innervation supplies the penis with sensory fibers and supplies the perineal skeletal muscles with motor fibers. Autonomic nerves mediate vascular dilation leading to penile erection, stimulate prostatic secretions, and control smooth muscle contraction of the vas deferens during ejaculation.

N LH & FSH α GDP

FSH and LH are glycoproteins consisting of a common α-subunit, required for receptor binding, and a unique β-subunit, which confers their biologic specificity. The synthesis and release of the gonadotropins are regulated by the pulsatile release of gonadotropin-releasing hormone (GnRH) from the hypothalamus, as well as by circulating hormones or their metabolites, as illustrated in Figure 67–3. LH stimulates testosterone production by the Leydig cell. Testosterone released into the circulation inhibits LH release in a negative feedback loop. The negative feedback inhibition of FSH release is mediated mainly by inhibin, a Sertoli cell– derived peptide. In addition to the negative feedback inhibition produced by gonadal androgens, inhibin and activin contribute to the reg-

β γ

αi GTP

Adenylate cyclase

GONADOTROPIN REGULATION OF GONADAL FUNCTION

CONTROL OF GONADOTROPIN SYNTHESIS AND RELEASE

β γ

C

cAMP

The primary functions of the Leydig and Sertoli cells are to produce the hormones involved in the regulation of reproductive function and virilization and to produce spermatozoa. These functions are regulated by the pituitary gonadotropins FSH and LH. The gonadotropins produce their physiologic responses by binding to cell membrane G protein–coupled receptors located in the Leydig and Sertoli cells (Figure 67–2). LH is the principal regulator of testosterone production by the Leydig cells. FSH plays an important role in the development of the immature testis, particularly by controlling Sertoli cell proliferation and seminiferous tube growth. Because the tubules account for about 80% of the volume of the testis, FSH is of major importance in determining testicular size. FSH is important in the initiation of spermatogenesis during puberty, and is necessary for the production of androgen-binding protein (ABP) by Sertoli cells and for the development of the blood–testis barrier.

685

Increase in translation of mRNAs for proteins involved in cell growth and differentiation, androgen binding protein synthesis (Sertoli cells), and testosterone synthesis (Leydig cells)

PKA

Protein phosphorylation

P

Gene expression regulation

P

Transcription factors

Nucleus

Leydig & Sertoli Cells

FIGURE 67–2 Receptor-mediated effects of gonadotropins at target tissues. Model of signal transductional pathways of the gonadotropin receptor. On binding of FSH to the FSH receptor, the Gαs subunit dissociates. Together with GTP, this complex directly activates adenylyl cyclase, thereby leading to cAMP synthesis. cAMP activates protein kinase A (PKA), producing the dissociation of the catalytic subunit from the regulatory subunit. The active catalytic site of PKA can activate proteins by phosphorylation, and in the nucleus it can phosphorylate transcription factors and affect gene transcription. As a result, LH and FSH mediate several biologic responses at their target cells. LH is the principal regulator of testosterone production by the Leydig cells. FSH plays an important role in the development of the immature testis, particularly by controlling Sertoli cell proliferation and seminiferous tube growth. (Modified with permission from Molina PE: Endocrine Physiology, 3rd ed. New York: McGraw-Hill Medical, 2010.)

ulation of gonadotropin release. Inhibins are heterodimer glycoproteins consisting of an α- and a β-subunit (βA or βB). Inhibin B is the physiologically important form in males. Inhibin is produced and released from the Sertoli cells in response to FSH stimulation, and its main function is to suppress FSH release in a classic negative feedback loop. Inhibin secretion appears to be dependent on Sertoli cell proliferation, maintenance, and spermatogenesis, all of these functions regulated by FSH. Inhibin B levels correlate with total sperm count and testicular volume and can be used as an

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SECTION IX Endocrine and Metabolic Physiology

Hypothalamus GnRH Pituitary gland LH FSH

LH

FSH Negative feedback Negative feedback

Sertoli cell

Inhibin

FIGURE 67–3 Negative feedback regulation of gonadotropin synthesis and release. Gonadotropin release from the anterior pituitary gland is under control by hypothalamic GnRH release. LH stimulates Leydig cell production and release of testosterone. FSH stimulates inhibin production and release from the Sertoli cells. These two mediators regulate LH and FSH release. The negative feedback inhibition of LH release exerted by testosterone is mediated directly (through androgen receptors) and indirectly (by local aromatase conversion of testosterone to 17β-estradiol). Inhibin produces negative feedback inhibition of FSH release.

Leydig cell

Testosterone

Blood vessels Testes

(Modified with permission from Molina PE: Endocrine Physiology, 3rd ed. New York: McGraw-Hill Medical, 2010.)

index of spermatogenesis. Activins belong to the same family of peptides as the inhibins and are homodimers or heterodimers of the β-subunit of the inhibins. The peptide and their receptor are expressed in a wide variety of tissues. Activin facilitates GnRH-mediated FSH release from the anterior pituitary.

GONADAL FUNCTION The three principal hormones produced by the testis are testosterone, estradiol, and inhibin. Testosterone, a steroid hormone produced by the Leydig cells, is the principal and most important testicular and circulating androgen. Most of the testosterone released into the circulation is bound to plasma proteins, primarily sex hormone–binding globulin (SHBG) and albumin. In the testes, testosterone is bound to androgenbinding protein, a protein with great similarity to SHBG and a product of the same gene. At its target cells, testosterone can

either have a direct androgen receptor–mediated effect or be metabolized to either 17β-estradiol through the action of aromatase or to 5α-dihydrotestosterone (DHT) through the action of 5α-reductase (Figure 67–4). Aromatase is expressed in the Sertoli cells as well as in extragonadal tissues. 17β-Estradiol produced by the testis accounts for approximately 20% of the total circulating estrogens in males. The majority of estradiol in males is produced in adipose tissue through the aromatization of testosterone and, to a smaller extent, of adrenal-derived androstenedione. Although some of the 17β-estradiol produced in peripheral tissues is released into the circulation, not all estrogens produced from testosterone are involved in mediating endocrine responses. Some are involved in intracrine regulation of physiologic responses through estrogen receptor stimulation (Figure 67–4). An example is testosteroneinduced negative feedback regulation of FSH release from the anterior pituitary, which is mostly mediated by aromatization of testosterone to estrogen. Another important exam-

CHAPTER 67 Male Reproductive System

Estradiol

PHYSIOLOGIC EFFECTS OF ANDROGENS AT TARGET ORGANS

Testosterone

DHEAS Aromatase

5αReductase DHT

Sulfatase DHEA

Estradiol AR

3β-OHD

AR

ER

4A

17β-OHD Testosterone AR

Erβ/ERα

687

AR AR

transcription

Testosterone target cells

FIGURE 67–4 Receptor-mediated effects of testosterone at target tissues. Testosterone (a steroid hormone) enters the cell by passive diffusion. It can be converted to dihydrotestosterone (DHT) by 5α-reductase and bind to the androgen receptor (AR), or it can be converted to 17β-estradiol by aromatase. 17β-Estradiol can be released to act on a neighboring cell’s estrogen receptors (ER) (paracrine mechanism); it can enter the circulation (endocrine effects) or it can bind to either the estrogen receptor α or β and subsequently bind to the nucleus and affect transcription. Intracellular testosterone can arise from androstenedione (Δ4A), DHEA, or DHEAS. The desulfated DHEA is converted to androstenedione by 3β-hydroxysteroid dehydrogenase (3β-OHD) and androstenedione transformed into testosterone by 17β-hydroxysteroid dehydrogenase (17β-OHD). Testosterone, DHT, and estradiol all bind to cytosolic steroid receptors. The cytosolic androgen (and estrogen) receptor is complexed to regulatory proteins (heat shock proteins). Hormone binding results in the dissociation of the heat shock protein complex, dimerization of the receptor, nuclear translocation, and DNA binding to regulatory elements. The final result is the activation of gene transcription. (Modified with permission from Molina PE: Endocrine Physiology, 3rd ed. New York: McGraw-Hill Medical, 2010.)

ple is the effect of testosterone on bones, where epiphysial closure is mediated through osteoblast and chondroblast aromatase conversion of testosterone to estradiol. The conversion of testosterone to DHT by 5α-reductase produces the most potent natural androgen (Figure 67–4). Because androgens stimulate the growth of prostate cancer cells and are also involved in benign prostatic hyperplasia, the inhibition of enzymatic conversion of testosterone to DHT has been used effectively as a target for pharmacologic interventions. Finasteride and dutasteride, 5α-reductase inhibitors, are currently used for the treatment of benign prostatic hyperplasia and prostate cancer. Testosterone, dehydroepiandrosterone (DHEA), and androstenedione are degraded primarily by the liver. Biotransformation involves reduction to 17-ketosteroids conjugated (glucuronidation) prior to excretion (Figure 67–5).

Testosterone and DHT affect sexual development, maturation, and function, and contribute to the maintenance of fertility and secondary sexual characteristics in the adult male. In addition, they exert anabolic effects in muscle and bone. Both testosterone and DHT bind to the same androgen (nuclear) receptor, on target cells (see Figure 67–4). DHT is the most potent activator of the androgen receptor. However, distinct physiologic responses can be attributed to each hormone (Table 67–2), in part determined by the local conversion of testosterone to DHT by 5α-reductase.

SEXUAL DEVELOPMENT AND DIFFERENTIATION Sexual differentiation in humans is genetically and hormonally controlled (Figure 67–6). Genes on the Y chromosome signal primordial cells in the embryonic gonad ridge to differentiate into Sertoli cells and stimulate newly migrated germ cells to differentiate as spermatogonia, developing into a testis. The cells of the embryonic testis secrete hormones that lead to the development of male secondary sexual characteristics. The Sertoli cells secrete müllerian inhibitory factor or substance (MIF or MIS) causing regression of the müllerian ducts. The Leydig cells secrete testosterone causing differentiation and growth of the Wolffian duct structures. DHT causes growth of the prostate and penis and fusion of the labioscrotal folds (Figure 67–6). The key events involved in fetal development and sexual differentiation can be summarized as follows.

Sex Determination Mammalian sex determination leading to the development of male or female phenotype involves three sequential processes: • determination of the genetic sex of the embryo when an X- or a Y-bearing sperm fertilizes the oocyte; • determination of the fate of the bipotential or nondifferentiated gonad and thus of gonadal sex; • differentiation of male or female internal and external genitalia, or determination of phenotypic sex. The determination of genetic sex is mediated through the chromosomal set, which in the normal male is 46,XY. The subsequent sexual differentiation is determined by genetic factors. One of the first genes involved in sexual differentiation is on the Y chromosome and is called SRY (sex-regulating region of the Y). The product of the SRY gene is a protein that stimulates the neutral gonadal tissues to differentiate into testes, thereby determining gonadal sex. SRY is necessary and sufficient to initiate the male development cascade. If the SRY gene is mutated or missing on the Y chromosome, the embryo develops into a female.

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SECTION IX Endocrine and Metabolic Physiology

LH Mitochondria

Cholesterol StAR Pregnenolone 3β-Hydroxysteroid dehydrogenase

P450 scc

Progesterone 17α-Hydroxylase • Estrone • Epiandrosterone, Androsterone, Etiocholanolone

Androstenedione 17β-HSD Testosterone

OH

FIGURE 67–5 Key steps in testosterone biosynthesis and metabolism. Diagrammatic representation of the typical biochemical pathway and key enzymes involved in Leydig cell steroidogenesis that facilitate the biosynthesis of testosterone from the precursor cholesterol. Testosterone finally diffuses out of the Leydig cell and reaches the interstitial space and the peripheral circulation. In target cells, testosterone can be converted to the most potent androgen, dihydrotestosterone (DHT), by 5α-reductase or to 17β-estradiol by aromatase. Testosterone, dehydroepiandrosterone (DHEA), androstenedione, and 17β-estradiol are degraded in the liver to 17-ketosteroids or polar metabolites that are excreted in the urine. StAR, steroidogenic acute regulatory protein; scc, side-chain cleavage; HSD, hydroxysteroid dehydrogenase; COMT, catechol-Omethyltransferase. (Modified with permission from Molina PE: Endocrine Physiology, 3rd ed. New York: McGraw-Hill Medical, 2010.)

5α-Reductase

O

OH

Testosterone 3α-Hydroxysteroid dehydrogenase O

3α-Androstenediol (weak androgen)

H

Dihydrotestosterone (DHT)

Aromatase

OH

Estrone OH

Catecholestrogen 17β-Estradiol

Sexual Differentiation Human male gonad differentiation begins in the sixth week of gestation with the development of precursor Sertoli cells. These cells aggregate to form the seminiferous cords, which are then infiltrated by primordial germ cells. By the end of the ninth week, the mesenchyme that separates the seminiferous cords gives rise to the interstitial cells, which differentiate as steroid-secreting Leydig cells. Gonadotropic control of fetal testicular steroidogenesis is mediated initially by placentaderived human chorionic gonadotropin (hCG) and later by fetal LH. The resulting increase in fetal testosterone production stimulates Leydig cell proliferation, increases the expression of steroidogenic enzymes, and increases the expression of the androgen receptor in the target tissues. The postgonadal phase of sexual differentiation or external genitalia differentiation is hormone dependent. Once the

16-OH-estrone

COMT

Estriol

2-Methoxyestrone

gonads have differentiated into testes, the secretion of testicular hormones is sufficient to promote masculinization of the embryo. The production of testosterone and MIF during a critical time in early gestation ensures male development. Initially, both the male (mesonephric or Wolffian) and female (paramesonephric or müllerian) internal genital ducts are present. In females, the mesonephric ducts regress and the paramesonephric ducts develop into the uterine tubes, uterus, and upper vagina. In males, starting at the eighth week of gestation, MIF mediates the regression of the paramesonephric or müllerian ducts. The mesonephric duct system (Wolffian ducts) remains and forms the vas deferens, epididymis, and seminal vesicle. This process is dependent primarily on testosterone. In the female, in the absence of androgens, the Wolffian ducts regress and the müllerian ducts are spared from apoptosis, developing into the uterus, fallopian tubes,

CHAPTER 67 Male Reproductive System

689

TABLE 67–2 Specific actions of testosterone, dihydrotestosterone, and estradiol. Testosterone

DHT (5α-Reductase Activity)

17β-Estradiol (Aromatase Activity)

Embryonic development of Wolffian duct–derived structures

Embryonic development of the prostate

Epiphyseal closure

Postpubertal secretory activity

Descent of the testes

Prevention of osteoporosis

Pubertal growth of larynx and deepening of voice

Phallic growth

Feedback regulation of GnRH secretion

Anabolic effects on muscle and erythropoiesis

Male pattern balding

Inhibition of breast development

Development of pubic and underarm hair

Stimulation of spermatogenesis; libido

Activity of sebaceous glands

Feedback inhibition of GnRH, LH, and FSH release DHT, dihydrotestosterone; GnRH, gonadotropin-releasing hormone. The enzyme activities that metabolize testosterone to DHT or estradiol are in parentheses.

and vagina. Estrogens do not appear to be essential for normal sexual differentiation of either sex, as shown by normal genital development in males with a mutant estrogen receptor gene or with aromatase deficiency. The differentiation of external male genitalia is regulated particularly through the actions of DHT. Following müllerian duct regression and androgendependent virilization of the urogenital system, the testes migrate from their site of origin next to the kidney into the scrotum. This is the critical and final event involved in male

sexual differentiation and is completed during the late gestational period, and is mediated by testosterone and insulin-like peptide 3. In humans, failure of complete testicular descent into the scrotum (cryptorchidism) is one of the most common congenital abnormalities, involving approximately 3% of male births. Testicular descent into the scrotum is important because spermatogenesis requires lower temperatures (as in the scrotum) than those found intra-abdominally. If untreated, cryptorchidism can lead to infertility, and it has been associated with an increased risk of testicular tumors.

Epididymis, seminal vesicles, vas deferens

Wolffian ducts Sex determination SRY

Urogenital ridge

Bipotential gonad

Testis

Leydig cells Sertoli cells

Prostate & penis growth Fusion of labioscrotal folds

Testosterone Insl3

Testicular descent MIF

Uterus, fallopian tubes, cervix, vagina

Mullerian ducts

Sertoli cell Leydig cell activity activity

MIF

Testosterone Testes descent Insl3 External genital Male external genital growth

differentiation Wolffian duct differentiation Mullerian duct regression

Germ cell migration

4

5

6

7

8 9 10 11 12 Gestational period (weeks)

13

14

15

40

FIGURE 67–6 Male sexual differentiation. The bipotential gonad is differentiated into testes by the sex-determining region gene on the Y chromosome (SRY). This period of sex determination is followed by gonad differentiation of the different cell types of the testis. The Sertoli cells of the testis secrete müllerian-inhibiting factor (MIF). The Leydig cells produce testosterone and insulin-like growth factor 3. MIF produces regression of the müllerian ducts. Testosterone stimulates the growth and differentiation of the Wolffian ducts, and growth of the penis and prostate. Insl3 participates in testicular descent, the final step in male sexual development. DHT produced from testosterone also participates in testis descent and development of the prostate. (Modified with permission from Molina PE: Endocrine Physiology, 3rd ed. New York: McGraw-Hill Medical, 2010.)

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SECTION IX Endocrine and Metabolic Physiology

Sexual Maturation and Function Puberty Puberty is the physiologic transition between childhood and adulthood and involves the development of fertility, secondary sexual characteristics and the pubertal growth spurt. The process takes place over a period of about 4 years. Puberty is triggered by increased pulsatile secretion of GnRH by the hypothalamus, leading to increases in serum gonadotropins and, thus, to increases in gonadal secretion of sex steroids. The hypothalamic–pituitary–gonadal system is active during the neonatal period but enters a dormant state in the juvenile, prepubertal period. During the initial phase of puberty, plasma levels of LH increase primarily during sleep. These sleep-associated surges are later present throughout the day and mediate or result in an increase in circulating testosterone levels. Puberty is preceded by adrenarche, a period characterized by increased adrenal production of DHEA and androstenedione at around 6–8 years of age. The peak concentrations of DHEA and androstenedione are reached during late puberty and early adulthood. During this stage, there is some conversion of adrenalderived androgens to testosterone, resulting in a small increase in circulating testosterone levels. The signal that triggers the increase in the synthesis of DHEA and androstenedione is not known. The increase in pulsatile release of GnRH from the hypothalamus into the hypophysial-portal blood is essential for the onset of puberty and is thought to be facilitated by leptin, a hormone secreted from adipose tissue. The increase in the amplitude of GnRH pulses triggers a cascade of events including increases in the amplitude of FSH and LH pulses, followed by marked increases in gonadal sex hormone production. As a result of the increase in testosterone production during puberty, growth hormone release is increased. Together, growth hormone and gonadal steroids are responsible for normal pubertal growth spurt during which the growth velocity increases from 4–6 cm per year to as much as 10–15 cm per year. The physiologic changes associated with puberty are summarized as follows: • Leydig cell maturation and initiation of spermatogenesis; • testis enlargement, and reddening and wrinkling of scrotal skin; • pubic hair growth from base of the penis; • penis enlargement; • prostate, seminal vesicle, and epididymis growth; • facial (mustache and beard) and extremities hair growth, regression of scalp line; • larynx enlargement, thickening of the vocal cords, and deepening of the voice; • enhanced linear growth; • increased muscle mass and hematocrit; • increased libido and sexual potency.

Maturity and senescence Sexual maturity in males is achieved at approximately age 16–18 years. During this stage, sperm production is optimal, plasma gonadotropins are normal, and most sexual anatomic changes have been completed. Beginning at age 40, there is a

gradual decline in circulating testosterone levels, followed at age 50 by a reduction in sperm production. This period of gradual androgen decline is called the andropause and is characterized by diminished sexual desire and erectile capacity, decreased intellectual activity, fatigue, depression, decreased lean body mass, skin alterations, decreased body hair, decreased bone mineral density resulting in osteoporosis, and increased visceral fat and obesity.

FERTILITY AND SECONDARY SEXUAL CHARACTERISTICS Spermatogenesis Spermatogenesis is the process of continuous germ cell differentiation to produce spermatozoa (Figure 67–7). Spermatogenesis is initiated at the time of puberty and is associated with the transition from a relatively hypogonadotropic state in the prepubertal phase of development to the eugonadotropic state in adulthood. It is compartmentalized within the blood–testis barrier. It is under FSH regulation of the Sertoli cell and requires testosterone production from the Leydig cells. Spermatogenesis involves four basic processes: • Proliferation of spermatogonia (stem cells) giving rise to spermatocytes (diploid cells)—Spermatogonia, derived from primordial germ cells, line the seminiferous tubule near the basement membrane. One or two divisions of spermatogonia occur to maintain their population in a stem cell pool, some cells stay in the “resting” pool, whereas others proliferate several times and undergo 1–5 stages of division and differentiation becoming spermatocytes (Figure 67–7). The “resting” or stem cell spermatogonia remain dormant for a time and then join a new proliferation cycle of spermatogonia. These cycles of spermatogonial divisions occur before the previous generation of cells has completed spermatogenesis, so that multiple stages of the process are occurring simultaneously in the seminiferous tubules. This overlap ensures a residual population of spermatogonia that maintain the ability of the testis to continuously produce sperm. • Meiosis of spermatocytes to yield spermatids (haploid cells; 23 chromosomes): The primary spermatocytes undergo two divisions; the first meiotic division produces two secondary spermatocytes. Division of the secondary spermatocytes completes meiosis and produces the spermatids. • Spermiogenesis, or maturation and development of spermatids into spermatozoa (sperm): This phase is characterized by nuclear and cytoplasmic changes that provide spermatozoa with key elements for their function, including formation of the acrosome, as summarized in Table 67–3. • Spermiation: This is the final process of release of mature sperm from the Sertoli cells into the tubule lumen and involves movement of the germ cells from the basal to the adluminal region of the seminiferous tubule into the compartment protected by the blood–testis barrier. The mitotic phase occurs in the basal compartment, whereas the meiotic

CHAPTER 67 Male Reproductive System

691

Head Nucleus Centrioles Mitochondria Acrosome Flaggellum Midpiece

Tail sheath

Mitosis

Spermatogonia

70 days

Primary spermatocyte First meiotic division Second meiotic division

Tail

Secondary spermatocyte

Spermatozoa Lumen of tubule

Spermatids Spermatozoa Residual body

Spermatids Secondary Spermatocyte Primary Spermatocyte

Spermatogonia

FIGURE 67–7 Schematic representation of key events in spermatogenesis. The process of spermatogenesis involves proliferation (mitosis) of spermatogonia, producing primary spermatocytes (diploid cells; 46 chromosomes). Spermatocytes undergo two meiotic divisions to yield spermatids, or haploid cells (23 chromosomes). Spermatids undergo a process of maturation (spermiogenesis) and development into spermatozoa. During this last phase, spermatozoa acquire the key elements for their function (Table 67–3). This continuous process takes about 70 days. At any given time, cells from all steps of spermatogenesis can be identified in the testes. (Modified with permission from Junqueira LC, Carneiro J: Basic Histology: Text & Atlas, 11th ed. McGraw-Hill, 2005.)

and postmeiotic phases occur in the luminal compartment. The overall results of spermatogenesis are the following: cell proliferation and maintenance of a reserve germ cell population, reduction in chromosome number and genetic variation through meiosis, and production of spermatozoa.

The complete maturation of sperm and the development of its capacity to fertilize the ovum are a function of additional processes occurring after sperm is released from the Sertoli cells. These processes are a function of the accessory glands and

Regulation of Spermatogenesis

TABLE 67–3 Key events in spermiogenesis and their

Spermatogenesis is dependent on gonadotropin stimulation and testosterone production. FSH stimulates proliferation and secretory activity of the Sertoli cells, whereas LH stimulates the production of testosterone. Testosterone in turn is a paracrine stimulator of spermatogenesis through receptormediated events in the Sertoli cells. The LH-induced increase in intratesticular testosterone plays an essential role in the initiation and maintenance of spermatogenesis by the Sertoli cells. Androgens produced by the Leydig cells bind to androgen-binding globulin (ABG), a protein produced by the Sertoli cell in response to FSH stimulation and secreted into the lumen of the seminiferous tubules. Testosterone is produced by Leydig cells, which are interstitial cells that reside adjacent to the seminiferous tubules. Sertoli cells require the presence of testosterone for spermatogenesis, underscoring the importance of paracrine mechanisms of hormone action.

functional importance in sperm function. Key Event

Functional Importance

Nuclear chromatin condensation

Haploid chromatin carries either X or Y chromosome

Acrosome development

The acrosome is a large secretory vesicle that overlies the nucleus in the apical region of the sperm head and contains enzymes needed for mucus penetration and fertilization

Repositioning of spermatids; development and growth of flagellum

Microtubular structure provides motility, allowing sperm movement (3 mm/min) through the genital tract

Formation of mitochondrial sheath around flagellum

Provides energy (fructose-derived ATP) for flagellar movement

ATP, adenosine triphosphate.

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SECTION IX Endocrine and Metabolic Physiology

the excretory system, summarized in Table 67–1. The development and function of these organs are androgen dependent.

ANABOLIC AND METABOLIC EFFECTS OF ANDROGENS In bone, the main physiologic effect of testosterone is to reduce bone resorption. This action is mediated both by direct effects of testosterone on the androgen receptor and by localized aromatization of testosterone to estrogen. Testosterone increases osteoblast lifespan and proliferation. Testosterone-derived estrogen is the critical sex hormone in the pubertal growth spurt, skeletal maturation, accrual of peak bone mass, and maintenance of bone mass in the adult. It stimulates chondrogenesis in the epiphysial growth plate, increasing pubertal linear growth. At puberty, estrogen promotes the gradual, progressive closure of the epiphysial growth plate and the termination of chondrogenesis. In the adult, estrogen is important in maintaining the constancy of bone mass through its effects on remodeling and bone turnover. Testosterone decreases osteoblast and osteoclast apoptosis; stimulates osteoblast proliferation, enhancing bone formation; and increases periosteal apposition of bone. It increases protein synthesis and decreases protein breakdown, having an overall anabolic effect in muscle. Testosterone inhibits lipid uptake and lipoprotein lipase activity in adipocytes, stimulates lipolysis by increasing the number of lipolytic β-adrenergic receptors, and inhibits differentiation of adipocyte precursor cells. DHEA stimulates resting metabolic rate and lipid oxidation and enhances glucose disposal by increasing the expression of glucose transporters on the plasma membrane of adipocytes.

NEUROENDOCRINE AND VASCULAR CONTROL OF ERECTION AND EJACULATION The physiologic process of human reproduction involves the fertilization of a mature ovum through the deposition of sperm-containing semen in the vagina of the female. This event involves penile erection and ejaculation of the spermcontaining semen at the time of copulation. Penile erection results from smooth muscle relaxation mediated by a spinal reflex involving central nervous processing and integration of tactile, olfactory, auditory, and mental stimuli. Corporeal vasodilatation and corporeal smooth muscle relaxation allow increased blood flow into the corpus cavernosum. Corporeal vasodilatation is mediated by the parasympathetic nervous system. The concordant contraction of the perineal skeletal muscles leads to a temporary increase in corpus cavernosum blood pressure above mean systolic arterial pressure, helping to increase penile firmness. Parasympathetic fibers directly innervating the corporeal smooth muscle and sinusoidal endothelial cells release acetyl-

choline, stimulating the production of constitutive endothelial nitric oxide. Nitric oxide produced locally in the smooth muscle cell, or reaching it by diffusion from the adjacent endothelial cells, is the major mediator of smooth muscle relaxation through activation of guanylate cyclase and increased production of cyclic guanosine monophosphate (cGMP). The inhibition of cGMP phosphodiesterase (PDE5), the enzyme that degrades cGMP, with drugs such as sildenafil preserves smooth muscle relaxation and prolongs the erection period. This is used commercially to treat erectile dysfunction. The ejaculation phase of the sexual response consists of two sequential processes: emission and ejaculation. Emission is the deposition of seminal fluid into the posterior urethra and is mediated by simultaneous contractions of the ampulla of the vas deferens, the seminal vesicles, and the smooth muscles of the prostate. The second process is ejaculation, which results in expulsion of the seminal fluid from the posterior urethra through the penile meatus. This process is controlled by sympathetic innervation of the genital organs and occurs as a result of a spinal cord reflex arc. Detumescence of the penis following ejaculation, and maintenance of the flaccid penis in the absence of sexual arousal, is produced by sympathetic corporeal vasoconstriction and corporeal smooth muscle contraction by noradrenergic, neuropeptide Y, and endothelin-1 fibers.

DISEASES OF TESTOSTERONE EXCESS OR DEFICIENCY Excess androgen activity in childhood leads to precocious puberty, defined in boys as the appearance of male secondary sex characteristics before age 9 (Table 67–2). Hypothalamic tumors, activating mutations of the LH receptor, congenital adrenal hyperplasia, and androgen-producing tumors are all causes of premature virilization. Decreased testosterone production, or hypogonadism, can be caused by disorders at the hypothalamic/pituitary level (hypogonadotropic or secondary hypogonadism) or by testicular dysfunction (hypergonadotropic or primary hypogonadism). Hypogonadotropic hypogonadism can be due to abnormalities in hypothalamic GnRH secretion or impaired gonadotropin secretion by the anterior pituitary. This condition may result from genetic defects including Kallmann syndrome; abnormalities of the GnRH receptor, LH, or FSH β-subunits; pituitary tumors (including prolactinomas); trauma; or surgery. Abnormal testicular function in the presence of elevated gonadotropin levels (hypergonadotropic or primary hypogonadism) is caused by testicular damage or impaired testicular development, which can be either congenital or acquired following chemotherapy or radiation. Causes include cryptorchidism, gonadal dysgenesis, varicocele, enzyme defects in testosterone biosynthesis, or LH receptor defects. Klinefelter syndrome is a sex chromosome disorder, in which affected males carry an additional X chromosome. This genetic abnormality results in male hypogonadism, androgen deficiency, and impaired sper-

CHAPTER 67 Male Reproductive System matogenesis. Klinefelter’s syndrome is the most common genetic cause of human male infertility. Hyperprolactinemia from any cause results in both reproductive and sexual dysfunction because of prolactin inhibition of GnRH, FSH, and LH release, resulting in hypogonadotropic hypogonadism.

CLINICAL PRESENTATION Excess testosterone in the prepubescent male is associated with the appearance of all the changes of puberty at a very early age. These changes include enlargement of the penis and testicles; appearance of pubic, underarm, and facial hair; spontaneous erections; production of sperm; development of acne; and deepening of the voice. Low levels of testosterone lead to symptoms, which differ according to the time of onset. Androgen deficiency during puberty results in lack of pubertal growth spurt, lack of deepening of the voice, female distribution of secondary hair, anemia, underdeveloped muscles, and genitalia with delayed or absent onset of spermatogenesis and sexual function. Hypogonadism, as well as aromatase deficiency and the inability to synthesize estradiol, result in lack of epiphyseal closure and continued growth. Androgen deficiency in the adult after normal virilization has been completed leads to a decrease in bone mineral density (bone mass), decreased bone marrow activity resulting in anemia, alterations in body composition associated with muscle weakness and atrophy, changes in mood and cognitive function, and regression of sexual function and spermatogenesis. In the adult male, androgen deficiency decreases nocturnal erections and libido.

CLINICAL CORRELATION A 33-year-old father of two healthy children and his wife are referred for evaluation more than a year after failure to conceive despite being sexually active and not taking any contraceptive measures. On physical examination, the husband’s external genitalia are normal, but testes are smaller and softer than normal for his age. He is very muscular and admits to being a body builder. Blood laboratory values show low testosterone levels, low LH and FSH, and normal prolactin levels. Semen analysis shows low sperm count (oligospermia). A diagnosis of anabolic steroid-induced hypogonadotropic hypogonadism is made. Anabolic steroids are androgen hormone analogs that produce negative feedback inhibition of LH and FSH release. This in turn decreases testicular testosterone production and spermatogenesis. Some anabolic steroids that are abused by athletes are not aromatizable so that they are not converted to estrogen and are different enough from native testosterone to not be detected in the standard testosterone assays. Cessation of anabolic hormone utilization restores hypothalamic–gonadal function in most of the cases.

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CHAPTER SUMMARY ■ ■ ■ ■ ■ ■ ■ ■

The Sertoli cells support spermatogenesis and form the blood–testis barrier. Testicular function is under LH and FSH regulation. LH and FSH production and release are under hypothalamic GnRH stimulation and feedback inhibition by gonadal hormones. The main functions of the testes are testosterone production and spermatogenesis. The main hormones produced by the testis are testosterone, estradiol, and inhibin. Testosterone can be metabolized to DHT, a more potent androgen, or to 17β-estradiol, an estrogen. Androgens exert their physiologic effects through modulation of gene transcription. Three essential testis-derived hormones regulate male sexual development: androgens, MIF, and insulin-like peptide 3.

STUDY QUESTIONS 1. A 20-year-old male patient presents to the doctor’s office complaining about continuous growth, lack of facial hair development, and a smaller penis and testicles than his college friends. Laboratory values include low total testosterone and low LH. Thyroid-stimulating hormone and prolactin levels are normal. He has no history of medications, drug use, or disease. Continued growth in this case is due to A) increased estrogen production B) decreased inhibin release C) decreased testosterone production D) decreased sensitivity to LH stimulation 2. In the patient described above, it was observed that in addition to being much taller than young adults his age, his arms were very long. The excessive height and arm length resulting from delayed epiphyseal growth plate closure is due to A) increased DHT formation B) decreased adrenal DHEA production C) decreased estradiol production D) increased estriol production 3. A college football player purchases online natural hormone analogs to increase his muscle mass. After a year of hormone analog injections, his muscle mass increases significantly, and he develops acne. Consultation with the team’s physician leads to a complete physical exam that reveals small testicular size. Being a newlywed, he wants to determine his fertility status and test results show low sperm count. Which of the following is the underlying mechanism for these manifestations? A) increased conversion of DHT to testosterone. B) suppression of LH release from the pituitary C) increased testicular testosterone concentrations D) increasing aromatase activity 4. A 15-year-old male, underweight, high school student is brought to the family physician due to what appears to be a delay in the onset of puberty. The most likely mechanism underlying this defect is A) decreased aromatase activity B) increased DHT production C) decreased leptin production D) increased testosterone production

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68 C

Female Reproductive System Patricia E. Molina

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Describe oogenesis, its relationship to follicular maturation, and the roles of pituitary and ovarian factors in their regulation. Describe the roles of pituitary hormones in regulation of ovarian function including ovulation, formation and decline of the corpus luteum, and estrogen and progesterone biosynthesis and secretion. List the target organs and principal physiologic actions of estrogen and progesterone and how they interact. Identify the transport mechanisms and degradation pathways for estrogen and progesterone. Describe the cellular mechanisms of action for estrogen and progesterone. Describe the endometrial changes (proliferative and secretory phases) that occur throughout the menstrual cycle, and correlate them with the changes in blood levels of pituitary and ovarian hormones. Identify the pathways of sperm and egg transport required for fertilization and for movement of the embryo to the uterus. Describe the endocrine functions of the placenta, particularly the role of placental hormones in rescue of the corpus luteum and maintenance of pregnancy, and the fetal adrenal–placental interactions involved in estrogen production. Understand the roles of oxytocin, relaxin, and prostaglandins in the initiation and maintenance of parturition. Explain the hormonal regulation of mammary gland development during puberty, pregnancy, and lactation, and explain the mechanisms that control milk production and secretion. Explain the physiologic basis for the effects of steroid hormone contraceptive methods. Describe the age-related changes in the female reproductive system, including the mechanisms responsible for these changes, throughout life from fetal development to senescence.

The principal functions of the female reproductive system are to produce the ova for fertilization by sperm, and to provide the appropriate conditions for embryo implantation, fetal growth and development, and birth. Endocrine regulation of the reproductive system is directed by the hypothalamic– pituitary–ovarian axis. The ovarian cycle, which involves changing patterns of hormone production and secretion,

Ch68_695-714.indd 695

regulates the hypothalamic–pituitary–gonadal axis in a classical negative feedback pattern. In addition, the ovarian cycle mediates the maturation and development of the reproductive system throughout life. Throughout the cycle, a selected ovarian follicle is rescued from its apoptotic fate to undergo growth and development, culminating in ovulation. The remnant of the follicle undergoes transformation into the 695

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corpus luteum, a temporary endocrine structure that plays a central role in preparation for, and maintenance of the initial stages of pregnancy. Parallel changes in endometrial morphology and function (the menstrual cycle) occur throughout the ovarian cycle in preparation for implantation of a fertilized ovum. Ovarian and placental hormones maintain pregnancy and prepare the breast for lactation.

under hormonal regulation. The ovaries are the principal female reproductive organs, and their functions are the storage and release of the ovum and the production of the two principal female sex steroid hormones, estrogen and progesterone. The ovaries consist of an outer cortex layer that contains different-sized follicles and their apoptotic remnants embedded in connective tissue and an inner medulla containing vascular connective tissue. The primordial follicle contains a primary oocyte surrounded by epithelial pregranulosa cells separated from the ovarian stroma by a basement membrane. During follicular development, the epithelial cells differentiate into granulosa cells, and a layer of cells from the ovarian stroma is transformed into theca cells. The larger, more mature follicles are filled with a transparent fluid and

FUNCTIONAL ANATOMY The female reproductive organs include the ovaries, the uterus and fallopian tubes, and the breasts or mammary glands (Figure 68–1). Their growth, development, and function are A

Ampulla isthmus

Fallopian tube

Infundibulum

Fundus of uterus

Fimbriae Oviduct

Fimbriae

FIGURE 68–1.

Functional anatomy of the female reproductive tract. A) The female reproductive organs include the ovaries, the uterus and Fallopian tubes, and the breasts or mammary glands. The ovaries consist of an outer cortex layer that contains different-sized follicles and their remains undergoing apoptosis, imbedded in connective tissue. The Fallopian tubes extend from each of the superior angles of the uterus and consist of an isthmus, ampulla, and the infundibulum, which opens into the abdominal cavity and is surrounded by ovarian fimbria and attached to the ovary. The cilia of the epithelial lining of the Fallopian tubes contribute to the orientation of sperm movement, aiding in fertilization as well as facilitating the movement of the zygote (fertilized ovum) to the uterus for implantation and fetal development. B) The ovary contains oocytes at different stages of development. Following ovulation, the follicle is converted to the corpus luteum that contributes to hormone production during the early pregnancy period. C) The breast is organized in lobes made of lobules, connected together by connective tissue, blood vessels, and ducts. The lobules consist of a cluster of rounded alveoli, which open into excretory lactiferous ducts and unite to form larger ducts made of longitudinal and transverse elastic fibers. These ducts converge toward the areola, beneath which they form ampular dilatations, which serve as reservoirs for the milk.

Ovary Ovarian ligament Uterus

Perimetrium Layers of Myometrium uterus Endometrium

B Mesovarium

Cervical canal Vagina Primary follicle

Primordial follicle

Stroma

B. Modified with permission from Curtis O Byer, Louis W Shainberg, Grace Galliano, Louis Shainberg. Dimensions in Human Sexuality. 6th ed. McGraw-Hill; 2001. C. Modified with permission from Gray H. Anatomy of the Human Body. 20th ed; 1918.)

Early antrum formation Atretic follicle Graafian follicle

Blood vessels Corpus albicans

Ovulation Germinal epithelium Mature corpus luteum

C

Ovary Early corpus luteum

Breast

Terminal duct lobular unit

Segmental duct Lactiferous duct Lactiferous sinus Nipple Fat Lobule unraveled

Lactiferous tubule Lobules Ampulla

Ductules or acini Terminal duct Lobule

Adipose tissue

(A. Modified with permission from Molina PE: Endocrine Physiology, 3rd ed. New York: McGraw-Hill Medical, 2010.

Ovary

Broad ligament

Alveoli Fat Duct

CHAPTER 68 Female Reproductive System consist of an external fibrovascular coat, connected with the surrounding stroma of the ovary by a network of blood vessels; and an internal coat, consisting of several layers of nucleated cells (granulosa cells) anchored in the zona pellucida, a glycoprotein-rich eosinophilic material surrounding the oocyte. The zona pellucida forms the corona radiata, which, close to the time of ovulation, is separated from the granulosa cells and expelled with the oocyte. Formation of the follicles begins before birth, and their development and maturation continue uninterrupted from puberty to the end of a woman’s reproductive life, as discussed later. The female genital tract is derived from the müllerian ducts and consists of the uterus, fallopian tubes, and vagina. The fallopian tubes extend from each of the superior angles of the uterus and consist of the isthmus, the ampulla, and the infundibulum, which opens into the abdominal cavity and is surrounded by ovarian fimbriae and attached to the ovary (Figure 68–1). The epithelial lining of the fallopian tubes has secretory and ciliated cells that contribute to sperm movement, aiding in fertilization and facilitating the movement of the zygote (fertilized ovum) to the uterus for implantation and fetal development. These functions are also aided by the rhythmic contraction of the smooth muscle walls. The uterus is composed of a thick muscular coat and a mucous membrane, or endometrium, lined by columnar ciliated secretory epithelium. The endometrium undergoes cycles of regeneration (proliferative phase), differentiation (secretory phase), and shedding (menstrual phase) approximately every 28 days in preparation for embryo implantation. The breast consists of glandular tissue organized in lobes connected by fibrous tissue, with fat deposits interspersed between the lobes (Figure 68–1). The lobules open into excretory lactiferous ducts and unite to form larger ducts that converge toward the areola, beneath which they form ampullar dilatations, which serve as reservoirs for the milk.

GONADOTROPIN REGULATION OF OVARIAN FUNCTION Pulsatile release of gonadotropin-releasing hormone (GnRH) from the hypothalamus stimulates pulsatile pituitary release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Both FSH and LH stimulate ovarian production of estradiol and progesterone through binding to a transmembrane G protein–coupled receptor. Estradiol and progesterone are the two principal ovarian steroid hormones involved in the regulation of ovarian function and control of the reproductive cycle. The variations in pulsatile release of the gonadotropins result in a cyclic response of ovarian function. Each cycle lasts approximately 28 days and can be divided into two phases (follicular and luteal) of approximately 14 days each: • Follicular phase: FSH is responsible for follicular recruitment and growth and for estrogen synthesis during the

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follicular phase of the ovarian cycle. • Luteal phase: The peak in LH immediately precedes ovulation and corpus luteum formation. The rise in LH results in progesterone and estrogen production by the corpus luteum during the early and midluteal phases of the menstrual cycle. Activation of the LH receptors in theca cells stimulates androstenedione production, providing the substrate for the enzymatic conversion to 17β-estradiol that is mediated by the enzyme aromatase in granulosa cells.

OVARIAN HORMONE SYNTHESIS ESTROGEN The production of estrogen involves coordinated enzymatic activities between the theca and granulosa cells of the ovarian follicle (Figure 68–2). During follicle growth, theca cells express the enzymes necessary to convert cholesterol to androgens (mainly androstenedione, a weak androgen) but lack the enzymes necessary to convert androgens to estradiol. Granulosa cells can convert androgens to estradiol and they can produce progesterone, but they are unable to convert pregnenolone or progesterone to androgens. Thus, theca cell–produced androgens diffuse into the granulosa cells where they are aromatized to estradiol (Figure 68–2). More than 95% of circulating estradiol is directly secreted, with a smaller contribution from peripheral conversion of estrone to estradiol in premenopausal women.

ANDROGENS Female androgens are derived from the adrenal glands (dehydroepiandrosterone and androstenedione), the ovaries (androstenedione and testosterone), and peripheral conversion of androstenedione and dehydroepiandrosterone to testosterone. Ovarian androgen secretion parallels that of estrogen throughout the menstrual cycle. Most of the circulating testosterone in females is derived from the peripheral conversion of androstenedione; 30–40% of testosterone is directly secreted. The conversion of testosterone to dihydrotestosterone in peripheral tissues is limited in females because of their higher levels of sex hormone–binding globulin (SHBG) than in males, as well as by the peripheral conversion to estrogen by aromatase, protecting females from virilization by dihydrotestosterone.

PROGESTERONE The preovulatory LH surge results in luteinization of granulosa and theca cells, altering the steroidogenic pathway so that progesterone is the primary steroid hormone produced by each of these cell types after luteinization. The changes leading to the ability to produce progesterone include increased expression of the enzymes involved in the conversion of cholesterol to progesterone (cholesterol side-chain cleavage

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Theca Cell

LH/CG receptor

AC

ATP

Gs

Gq

βγ

PI-4, 5P2

PLCβ

βγ

cAMP

DAG

PKA

PKC

IP3

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Protein P

FIGURE 68–2 Theca and granulosa cells coordinate the production of estrogen. The secretion of estradiol by the dominant follicle requires cooperation between theca cells, which synthesize androstenedione and testosterone; and granulosa cells of mature follicles, which convert androgens to estradiol and estrone. Androgen synthesis in theca cells results from the activity of three enzymes: cholesterol side-chain cleavage (P450scc), 17α-hydroxylaselyase (P450C17), and 3β-hydroxysteroid dehydrogenase (3β-HSD). Luteinizing hormone (LH) stimulates the steroidogenic pathway leading to formation of androstenedione in the theca cells. In granulosa cells, the enzyme 17β-hydroxysteroid dehydrogenase transforms androstenedione into testosterone in follicles from the primary stage. In mature follicles, follicle-stimulating hormone (FSH) stimulates the activity of aromatase, which transforms testosterone into 17β-estradiol. AC, adenylate cyclase; PLCβ, phospholipase Cβ; PI-4,5P2, phosphatidylinositol 4,5-bisphosphate; ATP, adenosine triphosphate; cAMP, cyclic adenosine monophosphate; DAG, diacylglycerol; IP3, inositol 1,4,5-trisphosphate; PKA, protein kinase A; PKC, protein kinase C. (Modified with permission

P

Protein

cAMP/PKA pathway

Protein

DAG/PKA pathway

Cholesterol Progesterone Androstenedione P450scc P450C17α

Systemic circulation

Androstenedione Basal lamina

Androstenedione

17β-Estradiol

Aromatase P

Protein

Protein

PKA

cAMP

ATP

βγ Gαs

AC

Follicular fluid Granulosa Cell

FSH receptor

from Molina PE: Endocrine Physiology, 3rd ed. New York: McGraw-Hill Medical, 2010.)

cytochrome P450 complex and 3β-hydroxysteroid dehydrogenase) and decreased expression of the enzymes that convert progesterone to estrogens (17α-hydroxylase cytochrome P450 and aromatase cytochrome P450).

INHIBINS, ACTIVINS, AND FOLLISTATIN Inhibin production by granulosa cells of mature follicles is regulated by FSH and LH, and by local factors such as growth factors (epidermal, transforming, and insulin-like) and hormones (androstenedione, activin, and follistatin) in an autocrine and paracrine way. Preantral follicles secrete inhibin B exclusively, whereas small antral follicles secrete

both inhibin B and inhibin A. Inhibin B is a good marker of granulosa cell function under the control of FSH, whereas inhibin A is a marker of corpus luteum function under the control of LH. Inhibins contribute to the regulation of LH and FSH release through endocrine feedback regulation at the anterior pituitary. Activin production by the granulosa cells changes during folliculogenesis. Activin promotes granulosa cell proliferation, upregulates FSH receptor expression on granulosa cells, and modulates steroidogenesis in both granulosa and theca cells. Activin is a physiologic antagonist to inhibin and specifically stimulates pituitary FSH synthesis and secretion.

CHAPTER 68 Female Reproductive System

OVARIAN CYCLE During the ovarian cycle, throughout the reproductive life span, a single mature oocyte is usually produced each month. Most of the human oocytes (germ cells) present during prenatal development are destined to undergo atresia through apoptosis, or programmed cell death. Only follicles that are responsive to FSH stimulation (about 350) will enter the final stage of development and progress to ovulation. The ovarian cycle is divided into a follicular and a luteal phase. The follicular phase begins on day 1 of the cycle, the first day of menses, and corresponds to the growth and development of a dominant follicle. At midcycle (day 14), the increasing levels of estrogen stimulate a surge in LH release (positive feedback), which results in ovulation 36 hours later. After ovulation, during the luteal phase, the remnants of the ovulatory follicle form the corpus luteum, a transient endocrine structure that produces estradiol, progesterone, and inhibin A and is under LH regulation. The end of the luteal phase is marked by regression of the corpus luteum and associated decreases in estradiol, inhibin A, and progesterone production. The hormonal changes that occur during the ovarian cycle produce differential regulation of gonadotropin release.

OVARIAN REGULATION OF GONADOTROPIN RELEASE Gonadotropin release is under negative and positive feedback regulation by estradiol, progesterone, and inhibins A and B. The contributions of these ovarian hormones vary according to the stage of the ovarian cycle.

Follicular Phase During this phase, the dominant follicle produces high concentrations of 17β-estradiol and inhibin B. As concentrations of estradiol and inhibin increase, they act on the hypothalamus and pituitary to decrease FSH secretion. The increase in estradiol through positive feedback stimulates LH release during midcycle (Figures 68–3 and 68–4). The midcycle LH surge resulting from positive feedback of estradiol is due to an increased responsiveness of gonadotropic cells to GnRH (following exposure to increasing estradiol), an increase in GnRH receptor number, and a GnRH surge, triggered by the effect on the hypothalamus of increasing estradiol. Progesterone also exerts positive feedback by enhancing pituitary sensitivity to GnRH and increasing GnRH release from the hypothalamus. There is also a smaller pre-ovulatory FSH surge (Figure 68-4). This is because GnRH-stimulated FSH release is restrained by the inhibitory effect of inhibin.

Luteal Phase The surge in LH levels induces ovulation and promotes the survival of the corpus luteum during the luteal phase.

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Following ovulation, as the corpus luteum develops and synthesis and circulating levels of progesterone increase, negative feedback inhibition of LH release is produced. With the decline in LH levels comes the demise of the corpus luteum, unless the corpus luteum is stimulated by human chorionic gonadotropin (hCG), a placental hormone (described later) it regresses.

OOGENESIS AND FORMATION OF THE DOMINANT FOLLICLE The fetal ovary begins germ cell development (oogenesis) early in fetal life. During early intrauterine development (15 weeks), primordial germ cells (oogonia) proliferate and migrate to the genital ridge. On their arrival in the fetal ovary, some of the oogonia continue mitotic proliferation, while others begin to undergo apoptosis (Figure 68–5). Some of these oogonia begin the first meiotic division but arrest at the diplotene stage (end of prophase) at or near birth. The resulting primary oocytes remain arrested in the first meiotic prophase until puberty when they are recruited to grow and mature and undergo meiosis to produce an ovum. Primary oocytes are surrounded by a primordial follicle consisting of a single layer of epithelial granulosa cells and a less organized layer of mesenchymal theca cells. The pool of primordial follicles in the female ovary reaches its maximum number at about 20 weeks of gestational age and then decreases in a logarithmic fashion throughout life until complete depletion occurs during menopause. When reproductive life is initiated, less than 10% of the primordial follicles remain. Folliculogenesis, or formation of the dominant follicle, consists of two stages: the gonadotropin-independent (preantral) period and the gonadotropin-dependent (antral or Graafian) period. Primordial follicular growth up to the antral stage (up to 0.2 mm) occurs during fetal life and infancy and is gonadotropin independent (Figure 68–5). Primary follicles are formed when the flattened epithelial cells become cuboidal and undergo mitosis. During the antral follicle growth phase, there is further proliferation of the granulosa cells, expression of FSH and steroid hormone receptors, and association of the theca cells with the growing follicle and granulosa cells, leading to formation of the secondary follicles. Tertiary follicles are formed following further theca cell hypertrophy and development. Their antrum is filled with estrogen-rich fluid, and the theca interstitial cells start to express FSH and LH receptors. The mechanisms that trigger initiation of follicular growth are thought to involve bidirectional communication between germ and somatic cells through gap junctions and paracrine factors, including cytokines and growth factors (insulin-like growth factor-I [IGF-I], epidermal and fibroblast growth factors, and interleukin-1β). When follicles reach a size of 2–5 mm, approximately 50% are rescued from apoptosis and enter the selection growth phase. This final developmental phase of follicular

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NE NPY Leptin

β -endorphin IL-1 GABA DA

+

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GnRH

LH FSH FSH

FSH

LH

LH

FSH Inhibin A(pg/mL)

Theca cells

200

60

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40

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0

50

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40 30 20

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80

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+Follicular development; ovulation

0

Ovary

FIGURE 68–3

Hypothalamic–pituitary–ovarian axis. Gonadotropin synthesis and release and differential expression are under both positive and negative feedback control by ovarian steroid and peptide hormones. Ovarian hormones can decrease gonadotropin release both by modulating gonadotropin-releasing hormone (GnRH) pulse frequency from the hypothalamus and by affecting the ability of GnRH to stimulate gonadotropin secretion from the pituitary itself. Estradiol enhances luteinizing hormone (LH) and inhibits follicle-stimulating hormone (FSH) release, whereas inhibins A and B (gonadal glycoprotein hormones) reduce FSH secretion. After ovulation, ovarian progesterone production predominates. Progesterone increases hypothalamic opioid activity and slows GnRH pulse secretion, favoring FSH production and decreasing LH release. Inhibin B peaks early in the follicular phase, whereas inhibin A peaks in the midluteal phase. The increasing inhibin B levels in the midfollicular phase act at the pituitary gonadotroph to offset activin signaling and suppress FSH biosynthesis from early follicular phase levels. It also prevents a larger FSH surge in response to estrogen-induced positive feedback on GnRH pulses. The decrease in inhibin A at the end of the luteal phase creates an environment in which FSH levels can again increase. A variety other CNS and peripheral factors can alter GnRH release. NE, norepinephrine; NPY, neuropeptide Y; IL-1, interleukin-1; GABA, γ-aminobutyric acid; DA, dopamine. (Modified with permission from Molina PE: Endocrine Physiology, 3rd ed. New York: McGraw-Hill Medical, 2010.)

growth, in which antral follicles are protected from apoptosis, begins approximately 85 days before ovulation in the luteal phase of the cycle preceding ovulation (Figure 68–5). During this gonadotropin-regulated growth phase, follicles grow exponentially, and FSH stimulates estrogen production from granulosa cells through the induction of the aromatase enzyme that catalyzes androgen conversion into estrogens, with stimulation of follicular fluid formation, cell proliferation, and LH receptor expression in the dominant follicle. The average time between primary follicle development and ovulation is 10–14 days (Figure 68–5). Follicles undergo cyclic recruitment and selection, leading to the emergence of the preovulatory follicle(s). The increase

in circulating FSH stimulates antral follicle growth. One of the leading follicles grows faster than the rest and produces higher levels of estrogens and inhibins. While the reason for why one follicle becomes dominant is unclear, this follicle is likely to be more sensitive to FSH. In turn, the estrogens and inhibins produced by the largest follicle suppress pituitary FSH released during the midfollicular phase. The decrease in FSH then leads to apoptosis of the remaining growing antral follicles. Once a follicle is recruited for growth, the oocyte enters a growth phase that leads to the completion of the first meiotic division. The resumption of meiosis is mediated by the surge in LH. LH acts on mature follicles to terminate the program of gene expression associated with folliculogenesis.

CHAPTER 68 Female Reproductive System

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2

OVARY

4

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16

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20

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Serum hormone concentrations

Progesterone

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Inhibin

UTERUS

PROLIFERATIVE PHASE

SECRETORY PHASE

Spiral artery

MENSTRUAL PHASE Gland

Bleeding

Bleeding

4

Vein

14 Time (days)

Basal artery

28

FIGURE 68–4 Hormonal events during the ovarian and endometrial cycles. Plasma concentrations of FSH, estrogen, LH, and progesterone, during the human menstrual cycle and the corresponding proliferative and secretory changes in the endometrium and ovarian follicular development, ovulation, and corpus luteum formation. (Reproduced with permission from Kibble J, Halsey CR: The Big Picture, Medical Physiology. New York: McGraw-Hill, 2009.) The transcription of genes that control granulosa cell proliferation and those that encode steroidogenic enzymes is rapidly turned off by LH. In addition, LH induces genes involved in ovulation and luteinization. At this stage, mRNA transcription virtually ceases and does not resume until 1–3 days after the egg has been fertilized, when the final phases of meiosis are completed. One preovulatory follicle is selected every

cycle, approximately 350 times during the female reproductive life span.

Ovulation Ovulation involves rupture of the wall of the follicle at the surface of the ovary, releasing the oocyte and corona radiata

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Basal lamina Granulosa precursors Oocyte

25 μ m primordial follicle Birth to 6 months postpartum 60 μm primary follicle

Granulosa cells Basal lamina Theca cells

Puberty to menopause 150 μm primary follicle

Granulosa cells Antral fluid Oocyte Zona pellucida Theca externa Theca interna Granulosa cells

5,000 μm antral (graafian) follicle 2–4 weeks prior to ovulation

Antrum Cumulus oophorus Zona pellucida

FIGURE 68–5

Physiology, 3rd ed. New York: McGraw-Hill Medical, 2010.)

Oocyte

18 16

PREOVULATORY

Follicle size (mm)

14 12

DOMINANT

10 8 6

SELECTED ATR

–

4 ATR

ATR

2

Follicular diameter (mm)

Follicle growth and development. Folliculogenesis, or formation of the dominant follicle, consists of two stages: the gonadotropin-independent (preantral) period and the gonadotropin-dependent (antral or Graafian) period. Primordial follicular growth up to the antral stage occurs during fetal life and infancy and is gonadotropin independent. The final developmental phase of follicular growth, in which antral follicles are protected from apoptosis, begins approximately 85 days before ovulation. One dominant follicle is recruited in the luteal phase of the cycle preceding ovulation. The larger, more mature follicles are filled with a transparent albuminous fluid, consisting of an external fibrovascular coat, connected with the surrounding stroma of the ovary by a network of blood vessels; and an internal coat, consisting of several layers of nucleated cells (granulosa cells) anchored in the zona pellucida, a glycoprotein-rich eosinophilic material surrounding the oocyte. The zona pellucida forms the corona radiata, which close to the time of ovulation is separated from the granulosa cells and expelled with the oocyte during ovulation. Ovulation entails rupture of the wall of the follicle at the surface of the ovary, releasing the oocyte and corona radiata into the peritoneal cavity. ATR, atretic; LH, luteinizing hormone; FSH, folliclestimulating hormone; Ovul, ovulation; M, menstrual phase. (Modified with permission from Molina PE: Endocrine

RECRUITMENT

SELECTION

Late luteal

Early follicular

ATR

EARLY DOMINANCE

ATR

–

ATR

ATR ATR ATR

LATE DOMINANCE FINAL MATURATION

Midfollicular

Late follicular

2-5

Gonadotropin-independent

1-2

0.5-0.9 0.2-0.4

25 days

Early antral 20 days

10 days Gonadotropindependent

15 days

0.15 Preantral Ovul

Ovul M

First cycle

into the peritoneal cavity, close to the opening of the fallopian tubes. The ovum is enclosed by an outer layer of cumulus cells and an inner, thick extracellular glycoprotein coat, the zona pellucida. Ciliary movement on the mucous membrane of the fimbria aids movement of the ovum into the fallopian tubes. Throughout the preovulatory stage, the oocyte, granulosa cells, and theca cells acquire specific functional characteristics. The oocyte becomes competent to undergo meiosis, granulosa cells acquire the ability to produce estrogens and respond to LH via the LH receptor, and theca cells begin to synthesize increasing amounts of androgens that

Ovul M

Second cycle

FSH

LH Ovul

M

Third cycle

serve as substrates for the aromatase enzyme in the granulosa cells. The sequence of temporal events that occurs during ovulation is initiated in the responsive preovulatory follicle by a surge of LH, which starts 34–36 hours before and peaks 12–24 hours before ovulation. This leads to follicular rupture and promotes follicular remodeling to form a corpus luteum. In addition, the surge in LH stimulates resumption of meiosis up to the second meiotic metaphase following extrusion of the first polar body (remnants of one X chromosome) before ovulation. Meiosis is again arrested and then completed with the release of the second polar body following fertilization.

CHAPTER 68 Female Reproductive System

Formation of the Corpus Luteum The surge in LH release produces reorganization of the follicle and formation of the corpus luteum, composed of small (theca lutein) and large (granulosa-lutein) cells, fibroblasts, endothelial cells, and immune cells. On rupture of the follicle (following ovulation), small amounts of bleeding into the antral cavity lead to the formation of the corpus hemorrhagicum and the invasion by macrophages and mesenchymal cells, leading to revascularization of the corpus luteum. The granulosa-lutein cells transform into the corpus luteum, a temporary endocrine gland. The corpus luteum continues to autonomously produce and secrete progesterone and estradiol, playing a key role in regulating the length of the ovarian cycle, maintaining gestation in its early stages, and suppressing LH and FSH release through the inhibition of GnRH release. During the initial gestational period, placental production of hCG prevents the regression of the corpus luteum, transforming the corpus luteum of the ovarian cycle into the corpus luteum of pregnancy. hCG stimulates the granulosa-lutein cells to produce progesterone, 17-hydroxyprogesterone, estrogen, inhibin A, and relaxin, a polypeptide hormone from the insulin/IGF hormone family. Relaxin regulates the synthesis and release of metalloproteinases, mediators of tissue (uterus, mammary gland, fetal membranes, birth canal) growth and remodeling, in preparation for birth and lactation.

Luteolysis Luteolysis is a two-phase process of lysis or regression of the corpus luteum and marks the end of the female reproductive cycle. The process involves an initial decline in progesterone secretion (functional luteolysis), followed by programmed luteal cell apoptosis leading to gradual corpus luteum involution (structural or morphologic luteolysis) to form a small scar of connective tissue known as the corpus albicans. This sequence of events takes place if fertilization does not occur within 1–2 days of ovulation. If fertilization occurs, the corpus luteum continues to grow and function for the first 2–3 months of pregnancy. Thereafter, it slowly regresses as the placenta assumes the role of hormone biosynthesis for the maintenance of pregnancy.

ENDOMETRIAL CYCLE The ovarian cycle is accompanied by cyclic growth and shedding of the endometrium controlled by estrogen and progesterone (Figure 68–4). Three distinct phases can be identified in the endometrium throughout the menstrual cycle.

PROLIFERATIVE PHASE The proliferative phase corresponds to the ovarian follicular phase (Figure 68–4). It is characterized by estrogen-induced endometrial epithelial cell proliferation and upregulation of estradiol and progesterone receptor expression to reach a peak by the time of ovulation. This is the initial phase of endome-

703

trial maturation in preparation for implantation of the embryo. The preovulatory endometrial proliferation leads to relative hypertrophy of the uterine mucosa.

SECRETORY PHASE This phase corresponds to the ovarian luteal phase and is characterized by progesterone-induced differentiation of the endometrial epithelial cells into secretory cells. During the secretory phase, there is a short, well-defined period of uterine receptivity for embryo implantation. Toward the end of the secretory phase, glandular expression of estrogen receptors is markedly decreased, reflecting the suppressive effect of increasing progesterone levels.

MENSTRUAL PHASE The menstrual period is characterized by shedding of the endometrium, resulting from proteolysis and ischemia in its superficial layer. Proteolytic enzymes accumulate in membrane-bound lysosomes during the first half of the postovulatory period. The integrity of the lysosomal membrane is lost with the decline in estrogen and progesterone on day 25, resulting in lysis of the glandular and stromal cells and the vascular endothelium. Ischemia due to vasoconstriction of endometrial vessels during the early part of the menstrual period results in rupture of the capillaries, leading to bleeding. In addition, a significant increase in prostaglandin F2α in the late secretory endometrium contributes by releasing acid hydrolases from lysosomes and enhancing myometrial contractions, aiding in the expulsion of degenerated endometrium.

FERTILIZATION Fertilization is the union of the two germ cells, the ovum and the sperm, restoring chromosome number to 46 and initiating the development of a new individual. The final steps of mammalian oogenesis (and of spermatogenesis) prepare eggs (and sperm) for fertilization. In preparation for ovulation, fully grown oocytes undergo “meiotic maturation,” preparing them to interact with sperm. A very low proportion of the sperm deposited into the vagina migrates up the female reproductive tract to the site of fertilization in the ampullary– isthmic junction of the fallopian tubes (Figure 68–6). During this journey, sperm undergo activation (capacitation), a series of changes in the sperm plasma membrane that increase its affinity for the zona pellucida, enabling the sperm to bind to the ovum and undergo the acrosome reaction. In the fallopian tubes, sperm bind to the zona pellucida, leading to fusion of the ovum and sperm plasma membranes to form a single “activated” cell, the zygote (Figure 68–6). This simple process requires several events: • Sperm acrosome reaction and penetration of the ovum’s zona pellucida: Sperm binding to the zona pellucida primes the sperm cell to initiate the acrosome reaction. The

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1

2

Sperm

Perivitelline space

3

Zona pellucida Cortical granules

Ovum

Zona pellucida Ovum 4

FIGURE 68–6 Fertilization and embryo migration. Sperm binds to the zona pellucida and undergoes the acrosome reaction, releasing its enzymatic contents, which are necessary for penetration of the zona pellucida. In addition, cortical granules in the ovum release their contents, preventing multiple sperm from fertilizing one ovum. Once the sperm penetrates the zona pellucida and begins entry into the perivitelline space, the sperm repositions itself from its original orientation with binding at the tip of the head to binding in an equatorial or sideways position, leading to fusion with the egg plasma membrane and formation of the zygote. This leads to completion of the meiotic division and initiation of mitotic divisions while the zygote is being propelled through the fallopian tubes through both ciliary movements by the epithelium and rhythmic contractions of the smooth muscle walls. The embryo enters the uterine cavity (where implantation occurs) as a blastocyst on day 4 following fertilization.

5

Inner cell mass of blastocyst Day 3

Day 2 Day 1

Day 4

Blastocyst

Day 7

2 cells Zygote Fertilization 4 cells

Morula

Day 0

Embryo

Acrosomal reaction

(Modified with permission from Molina PE: Endocrine Physiology, 3rd ed. New York: McGraw-Hill Medical, 2010.)

acrosome reaction involves fusion of the acrosome with the sperm plasma membrane and exocytosis of its enzymatic contents (proteases and glycosidases) and is required for sperm penetration. During or after the acrosome reaction, the fertilizing sperm detaches from the zona pellucida. It penetrates through the zona pellucida and fuses with the ovum plasma membrane. • Cortical and zona reaction: Fusion of the sperm and the ovum triggers the second meiotic division of the ovum, leading to the formation of the mature oocyte and the second polar body. In addition, this fusion triggers mechanisms that prevent fertilization of the ovum by multiple sperm, such as exocytosis of cortical granules (cortical reaction) from the oocyte, resulting in proteolysis of zona pellucida glycoproteins, as well as cross-linking of proteins forming the perivitelline barrier. The fusion of the

Blastocyst implanting

Muscle layer Endometrium

Ovulated egg Uterine wall

sperm and ovum pronuclei reconstitutes a diploid cell, called the zygote. During migration of the zygote through the fallopian tubes toward the site of implantation in the uterine cavity, mitosis yields a morula and then a blastocyst. The outer cells of the blastocyst are the trophoblast cells, which participate in the implantation process and form the fetal components of the placenta. If fertilization does not take place, both the ovum and sperm degenerate relatively rapidly in the female reproductive tract.

IMPLANTATION The human embryo (blastocyst) enters the uterus three days before implantation. The window of implantation corresponds

CHAPTER 68 Female Reproductive System to the short period of endometrial receptivity for the embryo, between days 20 and 24 of the menstrual cycle. Outside of this period, implantation fails. Many of the physiologic events crucial to successful implantation are due to cyclic changes in ovarian hormone levels, leading to morphologic and functional maturation of the endometrium.

In premenopausal women, 17β-estradiol produced by the ovaries is the chief circulating estrogen. Serum estradiol concentrations are low in preadolescent girls and increase at menarche, defined as the time of the first menstrual bleed. Estradiol production varies cyclically throughout the menstrual cycle. The highest rates of production and serum concentrations are in the preovulatory phase and the lowest during the premenstrual phase (Figure 68–4). Estradiol levels increase during pregnancy. After menopause, serum estradiol concentrations decrease to values similar to or lower than those in men of a similar age. Most of the estradiol released into the blood circulates bound to SHBG and to albumin, with only 2–3% circulating in the free form. Estradiol (as well as androstenedione) is converted to estrone (a weak estrogen) in peripheral tissues (Figure 68–7).

PHYSIOLOGIC EFFECTS OF OVARIAN HORMONES ESTROGEN Estrogen Synthesis, Transport, and Metabolism

Estrogen Receptor–Mediated (Genomic) Effects

The primary source of estradiol in women is the granulosa cell of the ovaries. However, both granulosa and theca cells and both gonadotropins (FSH and LH) are required for the production of estrogen. The theca cells secrete androgens that diffuse to the granulosa cells to be aromatized to estrogens (Figure 68–2).

CH3 C

The estrogen receptors are members of the superfamily of steroid hormone receptors (see Figure 60–6). Two subtypes of estrogen receptors have been identified that differ in

CH3 O

C

HO

O Progesterone

CH3 O

H

HO

H

705

C

OH

H

Pregnenolone

Pregnandiol

H O

HO Estradiol

O

HO Estrone H O

O

OH

HO HO

HO 2-Hydroxyestrone

Estriol O CH2O HO

FIGURE 68–7 Metabolic fate of progesterone and estrogen. Progesterone and estrogen are degraded primarily in the liver. Estradiol and androstenedione are converted to estrone (a weak estrogen) in peripheral tissues. Estrone is converted to estriol, primarily in the liver. Estrogens are metabolized by sulfation or glucuronidation, and the conjugates are excreted into the urine. Estrogen can also be metabolized through hydroxylation and subsequent methylation to form catecholestrogens and methoxyestrogens (not shown). (Modified with permission from Molina PE: Endocrine Physiology,

2-Methoxyestrone

3rd ed. New York: McGraw-Hill Medical, 2010.)

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structure and tissue distribution and are encoded by different genes. Estrogen receptor alpha (α) is considered the classic estrogen receptor. It is found predominantly in endometrium, breast cancer cells, and ovarian stroma. Estrogen receptor beta (β) is found predominantly in granulosa cells and developing spermatids, as well as in several nonreproductive target tissues, including the kidney, intestinal mucosa, lung parenchyma, bone marrow, bone, brain, endothelial cells, and prostate gland. Estrogen receptors are mostly nuclear, but are also found in the cytoplasm. Similar to other steroid hormones, free estrogen diffuses into the cell and binds to the ligand-binding domain of the receptor, which dissociates from its cytoplasmic chaperone proteins. The estrogen receptor complex then translocates into the cell nucleus, where it binds as homodimers or heterodimers to specific sequences of DNA called estrogen response elements, regulating gene transcription. The physiologic effects of estrogens that are mediated through transcriptional activation take minutes or hours to occur.

Nongenomic Effects of Estrogen Some rapid effects of estrogen cannot be explained by a transcriptional mechanism (nongenomic) and are the result of direct estrogenic action on cell membranes mediated by cell

membrane forms of estrogen receptor. Although these receptors remain largely uncharacterized, they are thought to resemble their intracellular counterparts.

Physiologic Actions of Estrogen at Target Organs Reproductive system Estrogen exerts multiple effects in reproductive organs (Figure 68–8): • Uterus: Estrogen promotes proliferation of the endometrium by stimulating mitosis and angiogenesis. It sensitizes uterine smooth muscle to the effects of oxytocin by increasing the expression of oxytocin receptors and contractile proteins. Estrogen increases watery cervical mucus production. • Ovary: Estrogen exerts potent mitotic effects on granulosa cells and augments the FSH-mediated differentiation process (an autocrine action). • Breast: Estrogen stimulates growth and differentiation of the ductal epithelium, induces mitotic activity of ductal cylindrical cells, and stimulates the growth of connective tissue (Figure 68–9). The density of estrogen receptors in breast tissue is highest in the follicular phase of the menstrual cycle and decreases after ovulation. Estrogen can also

Neuroprotection Influence on mood Reduction of intraocular pressure

Slowing of skin aging

FIGURE 68–8 Systemic effects of estrogen. In addition to its reproductive organ effects, estrogen has neuroprotective effects and reduces perimenopausal mood fluctuations in women. Estrogen is cardioprotective and may protect against colon cancer, and it has vasodilatory effects. In the liver, estrogen stimulates the uptake of serum lipoproteins and the production of coagulation factors. Estrogen protects against bone loss. In the skin, it increases skin turgor and collagen production and reduces the depth of wrinkles. (Reproduced with permission from

Arterial vasodilation Maintenance of bone density Cardioprotection

Increased production of liver proteins such as coagulation factors and hepatic lipoprotein receptors

Growth and proliferation of breast tissue: risk factor for breast cancer

Putative reduction in risk of colon cancer

Gruber CJ et al. Mechanisms of Disease: production and actions of estrogens. NEJM. 2002;346:340. Copyright Massachusetts Medical Society. All rights reserved.

Growth and differentiation of, and water retention in primary sex organs: risk factor for endometrial cancer

CHAPTER 68 Female Reproductive System

707

Atrophic ducts Estrogen GH, IGF-I EGF

Ductal growth

Lactogenesis

Pregnancy & post-partum lactation

Prolactin IGF-I, hPL, Cortisol, Insulin Oxytocin

Puberty

Progesterone, Sexual Estrogen, Cortisol, maturation & Prolactin, Thyroid pregnancy hormone

FIGURE 68–9 Hormonal regulation of breast development and lactogenesis. Mammary gland development is initiated at puberty through the actions of estradiol and growth factors and is further regulated during pregnancy through the effects of prolactin and human placental lactogen (hPL). Throughout pregnancy, progesterone inhibits lactogenesis. This inhibitory effect is removed following parturition, when prolactin levels act unopposed to stimulate lactogenesis. Through neuroendocrine reflexes, suckling stimulates the release of oxytocin from the posterior pituitary, producing the milk “let-down” reflex. GH, growth hormone; IGF-I, insulin-like growth factor I; EGF, epidermal growth factor. (Modified with permission from Molina PE: Endocrine Physiology, 3rd ed. New York: McGraw-Hill

Lobuloalveolar growth

indirectly affect mammary gland development by increasing prolactin and progesterone levels and inducing progesterone receptors in mammary epithelium. The growthpromoting effects of estrogen have been implicated in breast and endometrial cancer. • Other body systems: a) Liver: Estrogen affects the expression of apoprotein genes and increases lipoprotein receptor expression, resulting in a decrease in serum concentrations of total cholesterol and low-density lipoprotein (LDL) cholesterol, increases in serum high-density lipoprotein cholesterol and triglyceride concentrations, and decreases in serum lipoprotein A concentrations. It regulates the hepatic expression of genes involved in coagulation and fibrinolysis. Estrogen decreases plasma concentrations of fibrinogen, antithrombin III and protein S, and plasminogen activator inhibitor type 1. Elevated plasma estrogen levels are associated with an overall increase in the potential for fibrinolysis. Estrogen stimulates the synthesis of transport proteins (thyroxine-binding globulin and transcortin). b) Central nervous system: Estrogen has neuroprotective actions, and its age-associated decline is associated with a decline in cognitive function. c) Bone: Overall, the effects of estrogen are antiresorptive. Estrogen promotes bone maturation and closure of epiphysial plates in long bones at the end of puberty. It conserves bone mass by suppressing bone turnover and maintaining balanced rates of bone formation and bone resorption. Estrogen affects the generation, life span, and functional activity of both osteoclasts and osteoblasts. It decreases osteoclast formation and activity and increases osteoclast apoptosis.

Medical, 2010.)

PROGESTERONE Progesterone is produced by both theca and granulosa cells and is the predominant ovarian hormone produced in the luteal phase, a period during which plasma concentrations increase 10-fold. Production of progesterone by the corpus luteum is mainly under LH stimulation. The majority (80%) of progesterone secreted circulates bound to albumin. The principal targets of progesterone are the reproductive tract and the hypothalamic–pituitary axis. The degradation of progesterone is similar to that of androgens and estrogens and occurs primarily in the liver.

Progesterone Receptor–Mediated Effects Progesterone appears to exert most of its effects by directly regulating transcription of genes through two specific progesterone receptor proteins, termed A and B. These progesterone receptor proteins arise from a single gene and act as ligand-inducible transcription factors, regulating the expression of genes by binding specific progesterone responsive elements on the DNA. The expression of progesterone receptors is upregulated by estrogen and downregulated by progesterone in most target tissues. Previous exposure to estrogen induces the production of receptors for progesterone and is required for progesterone to act on the reproductive tract. Progesterone receptor expression in the uterus is increased during the first half of the menstrual cycle. During the second half, as serum progesterone levels increase, total progesterone receptor levels in the uterus decrease. In the mid and late luteal phases, the density of progesterone receptors in the luminal and glandular epithelium declines markedly to

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undetectable levels; on the other hand, stromal and myometrial cells continue to express high levels of progesterone receptor despite high circulating progesterone and absent estrogen receptor. In general, progesterone acts on the reproductive tract to prepare it for initiation and maintenance of pregnancy. The major physiologic roles of progesterone are mediated in the uterus and ovary, where it stimulates the release of mature oocytes, facilitates implantation, and maintains pregnancy through stimulation of uterine growth and differentiation and suppression of myometrial contractility. In the brain, progesterone modulates sexual behavior. Increased progesterone levels during the luteal phase increase both core and skin temperatures. This results in a biphasic pattern of body core temperature throughout the menstrual cycle, with a higher temperature in the luteal phase of the cycle.

Physiologic Actions of Progesterone at Target Organs • Effects on the uterus during early pregnancy: Progesterone induces stromal differentiation; stimulates glandular secretions, changing the pattern of proteins secreted by endometrial cells; and modulates cyclic proliferation during the menstrual cycle. Progesterone induces uterine cell proliferation and differentiation in early pregnancy through regulation of localized growth factor synthesis and cell type–specific expression of their receptors, thereby regulating cellular sensitivity to the autocrine or paracrine effects of growth factors and producing an environment that supports early embryonic development. • Promotion and maintenance of implantation: Progesterone plays a major role in preparing the endometrium for implantation of a fertilized ovum. It facilitates implantation by stimulating the synthesis of enzymes responsible for lysis of the zona pellucida. Finally, it promotes and maintains implantation through effects on both the maternal uterus and the developing blastocyst. • Effects on uterine contractility: Progesterone induces quiescence of the myometrium by increasing resting membrane potential and preventing electrical coupling between myometrial cells. It also prevents uterine contractions by blocking the ability of estradiol to induce membrane expression of α-adrenergic receptors (α-adrenergic activation causes contractions). Progesterone decreases prostaglandin synthesis and increases the rate of prostaglandin inactivation through the stimulation of prostaglandin 15-dehydrogenase and opposes the stimulatory effects of estrogen on endometrial prostaglandin F2α expression in the luteal phase of the menstrual cycle. Progesterone maintains the levels of relaxin, inhibiting spontaneous or prostaglandin-induced myometrial contraction, and contributes to the maintenance of implanta-

tion and early pregnancy by increasing the collagen framework and distensibility of the uterus. At the end of pregnancy, the decrease in progesterone levels is associated with increased prostaglandin synthase activity and prostaglandin F2α production, enhancing uterine contractility. The antiprogestin mifepristone antagonizes the actions of progesterone on prostaglandin synthesis and catabolism and stimulates prostaglandin production, thereby producing its abortive effects. • Effects on lactation: In the mammary gland, progesterone stimulates lobular–alveolar development in preparation for milk secretion but suppresses milk protein synthesis before parturition. Progesterone antagonizes prolactin’s effects in mid to late pregnancy, preventing the synthesis of milk proteins. The sudden decrease in circulating progesterone that occurs with parturition is associated with a concurrent increase in prolactin secretion and the onset of lactation. • Antiestrogen actions: Progesterone antagonizes estrogen induction of many of the known hormone-responsive genes. This effect is mediated by downregulation of estrogen receptor protein concentrations, decreasing the active estrogen concentration (and antagonizing the action of estrogen receptor at the molecular level), particularly in the uterus.

THE PLACENTA Structure and Physiologic Function The placenta is derived from two major cell types, which are the source of the principal placental hormones. The outer cell mass of the blastocyst, the precursor to the trophoblast, is in contact with the endometrium and undergoes proliferation and tissue penetration during implantation. The trophoblast has two cell populations: an inner cytotrophoblast and an outer invasive syncytiotrophoblast. The maternal side of the placenta contains fetal chorionic villi that provide an extensive surface area for nutrient and gas exchange between the fetal and maternal circulation. The villi are covered with multinucleated syncytiotrophoblast and trophoblast stem cells, stromal cells, and blood vessels. The villous cytotrophoblast cells are entirely secluded from maternal elements, with the exception of any molecules that might be transported across the placenta by the syncytiotrophoblast. By contrast, the extravillous trophoblast cells are continuously exposed to maternal tissues. The middle layer of the placenta consists of densely packed cytotrophoblast cell columns and serves as structural support for the underlying villi. The physiologic functions of the placenta can be classified as follows: • supportive, transporting nutrients and oxygen necessary for fetal growth; removing of waste products; • immune, suppressing the local immune system to prevent immunologic rejection of the fetus by the mother; • endocrine, including hormone synthesis, transport, and metabolism to promote fetal growth and survival.

CHAPTER 68 Female Reproductive System Inability of the placental unit to perform these functions leads to multiple complications of human pregnancy, including abortion, miscarriage, impaired fetal growth, and preeclampsia.

Endocrine Function of the Placenta The placenta produces cytokines, hormones, and growth factors that are essential for regulation of the fetomaternal unit. In addition, the placenta expresses enzymes involved in hormone metabolism, playing an important role in protection of the fetus from maternal adrenal-derived androgens through aromatase activity and from glucocorticoids through the activity of 11β-hydroxysteroid dehydrogenase type II. The principal placental hormones are as follows: • hCG: hCG is a heterodimeric glycoprotein from the same hormone family as LH, FSH, and TSH. It is produced by the syncytiotrophoblast and released into the fetal and maternal circulation. It is known as the hormone of pregnancy and is the basis for the pregnancy test. hCG is detected in serum at days 6–8 after implantation, and its levels peak at 60–90 days of gestation, declining thereafter. hCG has structural and functional similarity to LH, has a much longer half-life, and exerts its physiologic effects primarily through binding to the LH receptors. The main function of hCG is to maintain the corpus luteum to ensure the production of progesterone until placental production takes over. Maternal hCG levels are a useful index of functional status of the trophoblast (placental health). • Human placental lactogen and growth hormone: hPL is produced by the syncytiotrophoblast and is secreted into both the maternal and fetal circulations after the sixth week of pregnancy. In the fetus, hPL modulates embryonic development, contributes to regulation of intermediary metabolism, and stimulates the production of IGFs, insulin, adrenocortical hormones, and pulmonary surfactant. During pregnancy, hGH-V, a GH variant expressed by the placenta, becomes the predominant GH in the mother. This hormone has structural and functional similarity to pituitary GH and is not released into the fetus. Starting from the 15th to the 20th week of gestation up to term of pregnancy, placental GH gradually replaces maternal pituitary GH, which becomes undetectable. hGH-V stimulates IGF-I production and modulates maternal intermediary metabolism, increasing the availability of glucose and amino acids to the fetus. Placental GH is not detectable in the fetal circulation, and thus it does not appear to have a direct effect on fetal growth. • Progesterone: The major source of progesterone during the initial phase of pregnancy is the corpus luteum under hCG regulation. Starting from about week 8 of gestation, the placenta (syncytiotrophoblast) becomes the principal source of progesterone, leading to increasing levels of maternal progesterone throughout pregnancy. Because the placenta is unable to produce cholesterol from acetate, cholesterol for placental progesterone synthesis is derived from circulating

709

LDL. As discussed earlier, progesterone plays an important role in maintaining uterine quiescence during pregnancy, inhibiting prostaglandin synthesis, and modulating the immune response to preserve pregnancy. • Estrogen: The main source of estrogen during the initial phase of pregnancy is the corpus luteum, being replaced later by placental production. The production of estrogen by the placenta requires coordinated interaction between fetal and maternal adrenal gland steroid hormone production (fetoplacental unit of steroid biosynthesis). The placenta lacks 17α-hydroxylase activity and is thus unable to convert progesterone to estrogen or to produce androgens. This lack of placental androgen production protects the female fetus from masculinization; protection is also aided by the strong aromatase activity that converts maternal and fetal adrenalderived androgens to estrogens. Therefore, maternal and fetal adrenal-derived androgens (dehydroepiandrosterone sulfate [DHEAS]) are required for placental 17β-estradiol and estriol production. Estriol is synthesized through the aromatization of 16α-hydroxyandrostenedione derived from 16α-hydroxyepiandrosterone sulfate produced by the fetal liver and desulfated in the placenta (Figure 68–10); 16α-hydroxyepiandrosterone sulfate is derived from DHEAS produced in the fetal adrenal gland. The enzymes involved are placental sulfatase (DHEAS deconjugation), 3β-hydroxysteroid dehydrogenase (pregnenolone to progesterone conversion), and aromatase. The principal physiologic effects of estrogen during pregnancy include stimulation of uterine growth, prostaglandin synthesis, thickening of the vaginal epithelium, sensitization to oxytocin effects, growth and development of the mammary epithelium, and inhibition of milk production. • Corticotropin-releasing hormone (CRH): CRH is produced by the syncytiotrophoblast and trophoblast cells of the placenta. Its structure and function are similar to those of hypothalamus-derived CRH. The CRH concentration increases throughout pregnancy and peaks during labor. Placental production of CRH has been linked to the length of gestation in humans. CRH is secreted into the maternal circulation in large amounts during the third trimester of pregnancy and may play an important role in the onset of labor.

PREGNANCY AND LACTATION Hormonal Control of Parturition Uterine contractility during pregnancy and parturition can be divided into at least four distinct phases: • Phase 0: During pregnancy, the uterus is maintained in a relatively quiescent state, mainly through the effects of progesterone. Additional factors involved in modulation of uterine activity during this period are prostacyclin, relaxin, parathyroid hormone-related peptide, and CRH. The initiation of parturition results from the transition from the quiescent phase (phase 0) to a phase of activation (phase 1).

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Mother

Acetate

Placenta

Cholesterol

Estriol glucosiduronate

LDL cholesterol

Fetus

Pregnenolone sulfate

Pregnenolone DHEA

Progesterone

16α -OHDEA Urinary excretion 16α -OHDEAS Estriol

FIGURE 68–10 Fetoplacental unit hormone synthesis. The production of estrogen by the placenta requires the coordinated interaction between fetal and maternal adrenal gland steroid hormone production. The placenta lacks 17α-hydroxylase and is thus unable to convert progesterone to estrogen or to produce androgens. Maternal and fetal adrenal-derived androgens (dehydroepiandrosterone sulfate, DHEAS) are required for 17β-estradiol and estrone production. Estriol is synthesized through the aromatization of 16α-hydroxyandrostenedione derived from 16α-hydroxyepiandrosterone sulfate (16α-OHDEAS) produced by the fetal liver and desulfated in the placenta; 16α-hydroxyepiandrosterone sulfate in turn is derived from DHEAS produced in the fetal adrenal gland. LDL, low-density lipoprotein; 16α-OHDEA, 16α-hydroxyepiandrosterone. (Modified with permission from Molina PE: Endocrine Physiology, 3rd ed. New York: McGraw-Hill Medical, 2010.)

• Phase 1: This phase of parturition is associated with activation of uterine function and is characterized by release from the inhibitory mechanisms maintaining uterine quiescence throughout pregnancy and activation of factors promoting uterine activity. These factors include uterine stretch and tension caused by the fully grown fetus, activation of the fetal hypothalamic–pituitary–adrenal axis, and increased prostaglandin synthesis. Mechanical stretch or hormonal priming leads to upregulation of gene expression of proteins that facilitate smooth muscle contraction, including connexins (key components of gap junctions), prostaglandin and oxytocin receptors, and ion channel proteins. • Phase 2: This phase of parturition is a period of active uterine contraction and is stimulated by prostaglandins, oxytocin, and CRH. Prostaglandins, particularly those produced in the intrauterine tissues, play a central role in the initiation and progression of labor. They induce myometrial contractility and help produce the changes associated with cervical softening at the onset of labor.

• Phase 3: This postpartum phase involves uterine involution after delivery of the fetus and placenta and is mainly due to the effects of oxytocin.

Mammary Gland Development Mammary gland development involves cell proliferation, differentiation, and morphogenesis. Most mammary gland development occurs postnatally and involves branching and extension of ductal growth points and secretory lobules into a fatty stroma. This process is regulated by the associated alterations in hormones and growth factors during the various reproductive states (puberty and pregnancy) (Figure 68–9). Ductal elongation is mediated by estrogen, GH, IGF-I, and epidermal growth factor. Ductal branching and alveolar budding are regulated by progesterone, prolactin, and thyroid hormone. Progesterone stimulates ductal side branching and alveolar development. Prolactin acts directly on mammary epithelium to induce alveolar development. Both progesterone

CHAPTER 68 Female Reproductive System and prolactin synergize to stimulate proliferation of ductal epithelium. During pregnancy, prolactin, progesterone, and hPL act on duct lobular units to promote expansion and differentiation of their secretory function. This stage of mammary differentiation into a secretory function is called stage I lactogenesis. The elevated levels of progesterone prevent milk production during this period. The second stage (stage II lactogenesis) is initiated after termination of pregnancy. The sudden decrease in circulating progesterone that accompanies parturition in association with the concurrent increase in prolactin secretion marks the onset of lactation. The decrease in progesterone levels results in removal of the inhibition of synthesis of α-lactalbumin and β-casein. In the presence of prolactin, insulin, and glucocorticoids, the synthesis of milk proteins is established. Continuous milk production is maintained by prolactin secretion from the anterior pituitary throughout the period of lactation. The high prolactin levels are in part due to increased lactotroph synthesis resulting from the high estrogen levels during pregnancy. Prolactin is the main regulator of milk protein synthesis through its effects on the prolactin receptor located on mammary epithelial cells. Prolactin release is under negative control by dopamine; thus, pharmacologic analogs of dopamine such as bromocriptine inhibit lactogenesis. Weaning, or cessation of the lactation period, is followed by involution of the terminal duct lobular units mediated by alveolar cell apoptosis and gland remodeling, returning the breast to its mature quiescent state.

Hormonal Control of Milk Secretion and Ejection The onset of adequate milk production during the postpartum period requires developed mammary epithelium, persistent elevation in plasma prolactin, and a decrease in circulating levels of progesterone. Milk secretion from the mammary glands is triggered by stimulation of tactile receptors in the nipples by suckling. Sensory impulses are transmitted to the secretory oxytocinergic neurons in the hypothalamus, which in response release oxytocin into the systemic circulation. Oxytocin produces contraction of the myoepithelial cells of the lactiferous ducts, sinuses, and breast tissue alveoli.

AGE-RELATED CHANGES IN THE FEMALE REPRODUCTIVE SYSTEM PUBERTY Female puberty is initiated by low-amplitude nocturnal pulses of gonadotropin release. The increased synthesis and secretion of estrogen by the ovary cause the progressive skeletal maturation that eventually leads to epiphysial fusion and the termination of linear growth. The onset of puberty causes a rapid increase in bone mass that correlates with bone age. The initial

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stage of puberty (at age 8–13) in girls involves breast development, accompanied by ovarian and follicular growth. This is followed by androgen- plus estrogen-induced pubic and axillary hair growth and the onset of menses (approximately at age 13), indicating sufficient estrogen production to stimulate endometrial proliferation. The first cycles are usually anovulatory, becoming fully ovulatory after 2–3 years. In girls, serum leptin concentrations increase as pubertal development progresses, and this increase in leptin levels parallels the increase in body fat mass.

MENOPAUSE Menopause is the permanent cessation of menstruation resulting from loss of ovarian follicular activity. It is preceded by a perimenopausal period, starting when the first features of impending menopause begin (i.e., irregular menstrual bleeding and cycle frequency) and lasting until at least 1 year after the final menstrual period. During the menopausal transition, gonadotropins, estradiol, and inhibin show a marked degree of variability in their circulating levels. Within 1–2 years after the final menstrual period or the onset of menopause, FSH levels are markedly increased, LH levels are moderately high, and estradiol and inhibin levels are low or undetectable. Postmenopausally, adrenal androstenedione is the major source of estrogen, and serum testosterone levels fall moderately. Starting from the mid-thirties, ovarian follicular apoptosis accelerates, leading to a steady decline in ovarian estradiol production (Figure 68–11). This loss of ovarian function results in a 90% loss of circulating estradiol. However, extragonadal estrogen synthesis increases as a function of age and body weight, and most of the estradiol is formed by extragonadal conversion of testosterone. The predominant estrogen in menopausal women is the weak estrogen estrone, produced through aromatase conversion of androstenedione. The decline in ovarian function associated with the perimenopausal period is also responsible for an early decline in the release of inhibin B leading to an increase in follicular phase FSH. The decrease in serum inhibin B is believed to reflect the age-related decrease in ovarian follicle reserve, which is the primary source of serum inhibin B. The later rise in serum LH during the menopausal transition is due to the cessation of ovarian follicle development. Despite a 30% decrease in GnRH pulse frequency with aging, there is an increase in the overall amount of GnRH secreted. FSH levels gradually increase with age in women who continue to cycle regularly. The consequences of loss of ovarian function during reproductive life may be severe. Symptoms include hot flushes, night sweats, vaginal dryness and dyspareunia (painful intercourse), loss of libido, loss of bone mass with subsequent osteoporosis, and abnormalities of cardiovascular function, including a substantial increase in the risk of ischemic heart disease. As already mentioned, estrogens (like androgens) have general metabolic roles that are not directly involved in reproductive processes. These include actions on vascular function,

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Hormonal changes in menopause Ovarian estradiol Adrenal estrone Androgen: estrogen ratio Progesterone levels

FIGURE 68–11

Changes in gonadotropin and ovarian hormone production associated with aging. Lower levels of inhibin B and estradiol result in impaired negative feedback regulation of gonadotropin release, increasing FSH and LH. Production of androstenedione and testosterone during early menopause continues, with some conversion to estradiol by aromatase activity in adipose tissue. Adrenal-derived androstenedione is converted to estrone, principally in adipose tissue. (Reproduced with

GnRH

Negative feedback

LH and FSH

Aromatase

Testosterone Androstenedione Inhibin B Estradiol

Ovary

Estradiol Estrone Adipose tissue

Androstenedione DHEA Progesterone

permission from Gruber CJ et al. Production and actions of estrogens. NEJM.

Adrenals

2002;346:340.)

lipid and carbohydrate metabolism, and bone mineralization and epiphysial closure at sites such as breast, bone, vasculature, and brain. Within these sites, aromatase action can generate high levels of estradiol locally without significantly affecting circulating levels. Circulating C19 steroid precursors are essential substrates for extragonadal estrogen synthesis. The levels of these androgenic precursors decline markedly with advancing age in women, possibly from the mid to late reproductive years. This is thought to contribute to the greater risk of bone mineral loss and fracture, and possibly the decline in cognitive function, in women as compared with men.

CONTRACEPTION AND THE FEMALE REPRODUCTIVE TRACT The multiple steps involved in the regulation of ovarian hormone production, the consequent modifications of the endometrium, and the regulation of uterine motility are all under tight control, ensuring ovulation, fertilization, implantation, and maintenance of pregnancy. Multiple approaches have been implemented for contraception. Some of the principal interventions are summarized in Table 68–1.

TABLE 68–1 Principal contraceptive methods. Method

Mechanism Involved

Steroid contraceptives

Suppression of LH surge preventing ovulation

Intrauterine devices

Prevent blastocyst implantation by altering the endometrial lining Some release progesterone, modifying the endometrial lining

Barrier methods: condoms, foam, and diaphragms

Prevent fertilization by either interfering with the access of sperm to the uterine cavity or destroying sperm in the vaginal cavity

Sterilization

Surgically disrupts the continuity of the fallopian tubes, impairing access of the fertilized ovum to the uterine cavity and implantation

Abortive

Antiprogestin mifepristone produces an increase in prostaglandin F2α synthesis, leading to expulsion of the embryo

Rhythm

Relies on changes in mucus thickness and body temperature throughout the menstrual cycle, indicating a “safe” period for intercourse

CHAPTER 68 Female Reproductive System

DISEASES OF OVERPRODUCTION AND UNDERSECRETION OF OVARIAN HORMONES Alterations in female reproductive endocrine function are of multiple etiologies and produce manifestations that range from precocious puberty to infertility, depending on the age at presentation. The most frequent are abnormalities in the menstrual cycle, consisting of either absent menstruation (amenorrhea) or excess bleeding (metrorrhagia), and infertility. Abnormalities of ovarian development and function are usually caused by defective development of the gonads and rarely by defects in the synthesis of ovarian steroids. In general, increased ovarian hormone production can be due to increased gonadotropin release (hypergonadotropic hypergonadism) related to tumors, brain inflammatory diseases, and head injury, among other causes, or it can result from excess hormone production by ovarian tumors. Decreased ovarian hormone production can be genetic (e.g., FSH and LH receptor gene mutations, mutation of the β-subunit of FSH, enzymatic deficiencies) or acquired (e.g., radiation) despite adequate gonadotropin release (hypergonadotropic hypogonadism). Decreased ovarian hormone production due to impaired gonadotropin release (hypogonadotropic hypogonadism) is rare and may result from GnRH receptor gene mutations, lesions in the hypothalamic area, and other causes.

for her age and according to height of her parents. Body mass index is 19%. Physical examination does not reveal abnormalities in her clitoris or vagina. No physical problems are identified. Laboratory values are negative for elevations in prolactin. The diagnosis of “exercise”-induced amenorrhea is made. A frequent cause of amenorrhea in adolescents is hypothalamic amenorrhea. Energy deficit results in suppression of hypothalamic secretion of GnRH in anorexia nervosa, exercise-induced amenorrhea, and amenorrhea associated with chronic illness. This is in part mediated by leptin deficiency due to decreased adipose tissue. Leptin is a hormone secreted by adipose tissue and signals energy availability. Young athletes, particularly ballet dancers, who start training at a young age, may present with primary amenorrhea, and this is frequently associated with low BMI and body weight. Additional factors that can contribute to lack of menses are the decreased androgen aromatization to estrogen resulting from low fat mass.

CHAPTER SUMMARY ■ ■

■

CLINICAL CORRELATION

■

CASE A

■

A postmenopausal woman presents with a history of acute low back pain. She had menopause at 20 years prior to consultation and has never received hormone replacement therapy. She reports a history of a wrist fracture four years before this visit. Lumbar spine films reveal a new vertebral fracture. Dual-energy x-ray absorptiometry of the hip shows a low bone mineral density. The diagnosis of osteoporosis is made. Postmenopausal osteoporosis is a common disease with a spectrum ranging from asymptomatic bone loss to disabling hip fracture. Osteoporosis is a disease of increased skeletal fragility accompanied by low bone mineral density measured by dual-energy x-ray absorptiometry. Fractures occur because of microarchitectural deterioration resulting from deterioration in the trabecular and cortical skeleton. Risk factors for osteoporosis include low calcium and vitamin D intakes, sedentary life, smoking, alcohol use, and low estrogen.

CASE B A 19-year-old female ballet dancer is brought to the clinic because she has never started menstruating. Height is normal

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■

■ ■

Gonadotropin release is under negative and positive feedback regulation by ovarian steroid and peptide hormones. Estrogen synthesis requires LH and FSH regulation of coordinated metabolism by granulosa and theca cells of the ovarian follicle. LH and FSH rescue selected ovarian follicles from apoptosis and stimulate their growth and maturation. The corpus luteum is a temporary endocrine organ that plays a central role during the initial stages of pregnancy. The ovarian cycle produces cyclic changes in steroid hormone production, which in parallel produce marked morphologic and functional changes in the endometrium, preparing it for embryo implantation. Estrogen has important systemic effects affecting the risk of cardiovascular disease, osteoporosis, and endometrial and breast cancer. Progesterone ensures uterine quiescence and prevents lactogenesis during pregnancy. Mammary gland morphologic development occurs during puberty and is functionally modified during pregnancy by prolactin and hPL, ensuring lactogenesis.

STUDY QUESTIONS 1. A 30-year-old female patient arrives at your office because of missed menstrual periods for 2 months. Her history indicates regular menstrual periods in the past. During physical examination, you suspect that she may be pregnant. Which of the following laboratory values would be compatible with your diagnosis? A) low plasma progesterone and high LH B) high prolactin, low LH, and low progesterone C) high urinary estradiol and low progesterone D) high urinary hCG and increased plasma progesterone

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2. A 5-month pregnant woman is referred to your office with newly diagnosed hypertension. You are concerned that the fetus and placenta may be compromised. To assess fetal and placental health, which of the following hormone measurements would be most informative? A) urinary estriol and serum hCG B) serum progesterone and prolactin C) serum LH and hPL D) urinary estriol and serum progesterone 3. Increased fasting plasma glucose levels in pregnant women with no history of diabetes may be related to A) increased estrogen production B) decreased progesterone clearance C) increased hPL/GH-V production D) increased insulin degradation

4. The effects of progesterone on the myometrium during pregnancy include A) preventing electrical coupling between myometrial cells. B) increased estradiol-induced α-adrenergic receptor expression C) decreased prostaglandin inactivation D) increased prostaglandin synthase activity 5. Systemic and hepatic effects of estrogen include A) increased serum concentrations of total cholesterol and LDL B) increased lipoprotein receptor expression C) increased plasma concentrations of fibrinogen and antithrombin III D) decreased synthesis of thyroxine-binding globulin and transcortin

Endocrine Integration of Energy and Electrolyte Balance Patricia E. Molina

69 C

H A

P

T

E

R

O B J E C T I V E S ■ ■

■ ■ ■

■

Identify the normal range of plasma glucose concentrations and the hormonal regulation of its metabolism, storage, and mobilization. Identify the specific roles of insulin, glucagon, glucocorticoids, catecholamines, growth hormone, and thyroid hormone in the regulation of energy substrate utilization, storage, and mobilization. Describe the hormonal regulation of energy substrate metabolism during the fed and fasted states and understand the consequences of its dysregulation. Identify the mechanisms involved in the maintenance of long-term energy balance. Identify the normal range of dietary sodium intake, its body distribution, and routes of excretion. Explain the roles of antidiuretic hormone, aldosterone, angiotensin, and atrial natriuretic hormone in the regulation of sodium balance. Identify the normal range of dietary potassium intake, its body distribution, and routes of excretion. Explain the hormonal regulation of plasma potassium concentration, distribution, and balance in the acute and chronic settings.

NEUROENDOCRINE REGULATION OF ENERGY STORAGE, MOBILIZATION, AND UTILIZATION Two distinct phases directly related to the ingestion of a meal alternate throughout the day in the regulation of energy metabolism. The fed state reflects overall anabolic metabolism, during which energy is stored in the form of energy-rich compounds (adenosine triphosphate [ATP], phosphocreatinine), glycogen, fat, and proteins. The fasted or catabolic phase is the period during which endogenous energy sources are utilized. The anabolic and catabolic phases alternate to preserve adequate glucose supply to the brain as well as sufficient energy to maintain body functions, such as thermoregulation (maintaining a constant core temperature), food digestion, and physical activity. The two hormones at the core of maintaining this balance are insulin and glucagon; in particular, their ratio plays a critical role in the dynamic regulation of substrate metabolism (summarized in Table 69–1). However, several other established and newly discovered hormones participate in the regulation of

Ch69_715-728.indd 715

energy metabolism to different extents, according to age, sex, nutritional state, and metabolic demands of the individual. Because the autonomic nervous system also interacts with the endocrine system in the modulation of glucose and fat metabolism, the system is involved in neuroendocrine regulation. The autonomic nervous system exerts its effects both directly and indirectly. For example, activation of the sympathetic nervous system through norepinephrine release from nerve terminals and epinephrine release from the adrenal medulla stimulates skeletal muscle glycogenolysis, glucagon release, and hepatic glucose output while inhibiting the release of insulin (Figure 69–1).

NEUROENDOCRINE REGULATION OF ENERGY METABOLISM DURING THE FED STATE Glucose Blood glucose regulation occurs through interactions among hormonal, neural, and hepatic autoregulatory mechanisms. Following a meal (postprandial state), in response to the increase 715

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TABLE 69–1 Regulation of metabolic processes by insulin/glucagon ratios. Anabolic (↑ I:G)

Metabolic Process

Catabolic (↓ I:G)

↑

Glycogen synthesis (liver and muscle)

↓

↓

Glycogen breakdown

↑

↓

Gluconeogenesis

↑

↑

Fatty acid synthesis and triglycerides (hepatocytes and adipose tissue)

↓

↑

Muscle protein synthesis

↓

↑

Lipogenesis and triglyceride formation

↓

↓

Lipolysis

↑

↓

Free fatty acid oxidation

↑

↓

Ketone body formation

↑

↓

Muscle proteolysis

↑

I, insulin; G, glucagon.

in pancreatic insulin release, glucose uptake is increased in muscle, fat, and the liver; hepatic glucose output is suppressed; and glycogen synthesis is increased. Glucose disposal by insulin-sensitive tissues is regulated initially by an increase in glucose transport and enzyme phosphorylation leading to the activation of glycogen synthase, phosphofructokinase, and pyruvate dehydrogenase (see Figure 66–5). The majority of insulin-stimulated glucose taken up is stored as glycogen.

Fat Most of the body’s energy reserve is stored in adipose tissue in the form of triacylglycerol in the adipocytes. The principal hormone involved in lipogenesis is insulin, through activation of lipogenic enzymes. Opposing the effects of insulin are growth hormone and leptin (described later), which inhibit lipogenesis. The balance between lipogenesis and lipolysis followed by fatty acid oxidation determines the overall accumulation of body fat. Both processes are under hormonal and cytokine regulation.

Protein The balance between protein synthesis and degradation is regulated by interactions among hormonal, nutritional, neural, and inflammatory mediators. Hormonally, regulation of protein metabolism is predominantly under the influence of insulin, hGH, and insulin-like growth factor-I (IGF-I). During the fed state, insulin acts primarily to inhibit proteolysis, and GH stimulates protein synthesis. IGF-I has antiproteolytic effects during the postabsorptive state that progress to stimulation of protein synthesis in the fed state or when amino

acids are provided. GH and testosterone are of particular importance during growth and development, as well as during adulthood and senescence.

NEUROENDOCRINE REGULATION OF ENERGY METABOLISM DURING THE FASTED STATE During the fasted postabsorptive state, catabolism of stored energy sources provides the energy required for bodily functions. The amount of energy expended by an awake, resting individual, measured 12–14 hours following the last meal, and at normal (or thermoneutral) body temperature is called the basal metabolic rate (BMR). The BMR is the amount of energy required to maintain breathing, brain activity, enzymatic activity, and other functions without any physical movement of the individual. Any deviation from the basal condition, such as changes in body temperature (fever or hypothermia), the level of activity of the individual (exercise or sleeping), or time from the last meal (fed or fasted), will affect the metabolic rate. In addition, BMR can be directly affected by hormone action, particularly thyroid hormones, which increase Na+/K+-ATPase activity and body temperature, resulting in an increase in the BMR.

Glucose In the resting postabsorptive state, release of glucose from the liver through glycogenolysis and gluconeogenesis is the key regulated process. During fasting, hepatic glucose production is increased and peripheral glucose utilization is inhibited. Initially, hepatic glucose output is derived from breakdown of hepatic glycogen stores through glycogenolysis. Following an overnight fast, glycogenolysis provides approximately 50% of the overall hepatic glucose output. As hepatic glycogen stores are depleted during a period of prolonged fasting (approximately 60 hours), the contribution of glycogenolysis to hepatic glucose output becomes negligible, with hepatic gluconeogenesis predominating. Glycogenolysis depends on the relative activities of glycogen synthase and phosphorylase (see Figure 66–4). Gluconeogenesis is regulated by the activities of fructose-1,6-diphosphatase, phosphoenolpyruvate carboxykinase, pyruvate kinase, and pyruvate dehydrogenase, and by the availability of the principal gluconeogenic precursors, lactate, glycerol, glutamine, and alanine. A smaller, yet significant amount (approximately 25%) of systemic glucose production in the postabsorptive state is derived from renal gluconeogenesis. Usually, the kidney is not a net producer of glucose. The proximal tubule cells produce glucose at a rate similar to that of glucose utilization by the renal medulla.

Fat After an overnight fast, most of the resting energy requirement is provided by oxidation of fatty acids derived from adipose tissue. Lipolysis in adipose tissue is mostly dependent on the concentrations of hormones (epinephrine stimulates lipolysis, and insulin inhibits lipolysis). During a period of acute energy deprivation

CHAPTER 69 Endocrine Integration of Energy and Electrolyte Balance

717

A

Pancreas

Glucagon Insulin Paraventricular nucleus CRH, ADH

glucose

Pituitary Cortisol Glycogenolysis Gluconeogenesis

Gluconeogenic substrates

GH

Locus ceruleus (noradrenergic system) Norepinephrine

ACTH

Cortisol FFA

Lipolysis

Epinephrine Norepinephrine

FFA

Glycogenolysis FA oxidation Protein synthesis

B

Sympathetic ganglion

Norepinephrine Neuropeptides Heart rate Blood pressure Peripheral vasoconstriction

Protein

Neuropeptides

Glycogen Glucose

Amino acids ATP

Dorsal-root ganglion

Fat Glycerol

Fatty acids

Glycolysis

NH2 Pyruvate CO2

Urea

Acetyl coenzyme A Krebs cycle

CO2 ATP

O2

Oxidative phosphorylation

H2O

FIGURE 69–1 Neuroendocrine response to exercise. A. The principal pathways activated by stress are the hypothalamic–pituitary–adrenal axis and the sympathetic nervous system, resulting in the release of corticotropin-releasing hormone (CRH), antidiuretic hormone (ADH), catecholamines, and growth hormone (GH). In the periphery, increased production and release of cortisol, glucagon, and catecholamines and suppressed release of insulin favor an overall catabolic response. Stimulation of hepatic glycogenolysis and gluconeogenesis, muscle glycogenolysis, and adipose tissue lipolysis ensures the production and mobilization of energy stores to meet the enhanced metabolic demands of the individual. Reproductive and growth functions are inhibited, conserving energy to sustain fundamental processes that ensure survival. B. Stimulation of hepatic glycogenolysis and gluconeogenesis, muscle glycogenolysis and adipose tissue lipolysis ensure the production and mobilization of energy stores to sustain the enhanced metabolic demands of the individual as shown in the metabolic pathway. ATP, adenosine triphosphate; FFA, free fatty acid; FA, fatty acid. (Modified with permission from Molina PE: Endocrine Physiology, 3rd ed.

ATP

or prolonged starvation, lipolysis mobilizes triglycerides, providing nonesterified fatty acids as energy substrates for tissues such as muscle, heart, and liver; and substrates for glucose (glycerol) and lipoprotein (free fatty acids) synthesis to the liver. Unlike most other tissues, the brain cannot utilize fatty acids for energy when blood glucose levels become compromised. In this case, ketone bodies provide the brain with an alternative source of energy, providing close to two thirds of the brain’s energy needs during periods of prolonged fasting and starvation. The release of glycerol and free fatty acids from adipose tissue is inhibited by insulin and stimulated primarily by catecholamines. During fasting, or more frequently during periods

New York: McGraw-Hill Medical, 2010.)

of acute glucose deficiency (insulin-induced hypoglycemia) or increased energy demand (as with strenuous exercise), catecholamines play an important role in the stimulation of lipolysis (Figure 69–1). The amount of energy stored as triglycerides in adipose tissue is substantial. For example, an adult with 15 kg of body fat has enough energy to support the whole body energy requirements (8.37 MJ; 2,000 kcal) for about 2 months.

Protein Unlike excess fat and glucose, which are stored as fat and glycogen in adipose tissue, liver, and muscle, there is no storage

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pool for body protein. Therefore, under catabolic conditions, essential proteins are catabolized. Cortisol, epinephrine, and glucagon together favor muscle protein breakdown and hepatic amino acid uptake, some of which can be utilized for gluconeogenesis.

COUNTERREGULATION TO ACUTE STRESS During acute decreases in plasma glucose (hypoglycemia) or in response to acute stress, the role of the counterregulatory hormones glucagon, epinephrine, growth hormone, and cortisol becomes evident. Glucagon’s primary role is to stimulate hepatic gluconeogenesis and glycogenolysis, resulting in an overall increase in hepatic glucose output. GH and cortisol facilitate glucose production and limit glucose utilization. Their effects are not immediate; thus, they are mostly involved in defense against prolonged hypoglycemia. Cortisol exerts permissive effects on the lipolytic action of catecholamines and GH in adipose tissue and on the glycogenolytic action of catecholamines in skeletal muscle. In addition, cortisol induces hepatic enzymatic gene expression required for enhanced gluconeogenic rates and exerts permissive effects on the stimulation of gluconeogenesis in the liver by glucagon and epinephrine. Epinephrine stimulates hepatic glycogenolysis and hepatic and renal gluconeogenesis, largely by mobilizing gluconeogenic precursors including lactate, alanine, glutamine, and glycerol. It also limits glucose utilization by insulin-sensitive tissues. The role of epinephrine is critical when glucagon release is deficient. Together, glucagon and epinephrine act within minutes to raise plasma glucose concentrations. The contribution of the activation of the autonomic nervous system is more easily understood when described in the context of acute and severe hypoglycemia. The decrease in plasma glucose concentrations (hypoglycemia) within and below the physiologic postabsorptive concentration range of about 70–110 mg/ dL (3.9–6.1 mmol/L) triggers the activation of a counterregulatory neuroendocrine response. The release of counterregulatory hormones glucagon, epinephrine, GH, and cortisol contributes to the increase in hepatic glucose output and the suppression of tissue glucose uptake, partly through an increase in tissue fatty acid oxidation. As plasma glucose levels are restored, peripheral glucose sensors in the portal vein, small intestine, and liver decrease firing. This afferent signal is transmitted to the hypothalamus and to the nucleus solitarius in the medulla through the vagus nerve, conveying information on the prevailing peripheral glucose levels. In the hypothalamus, glucose sensors contribute to the central nervous system integration of these signals. This initiates an appropriate response through the inhibition of hepatic and adrenal nerve activity, with consequently decreased release of adrenomedullary catecholamines. The decreased sympathetic activation allows hyperglycemia to induce pancreatic insulin secretion. Thus, glucose acts as a feedback signal contributing to integration of the neuroendocrine mechanisms that regulate its homeostasis.

MAINTENANCE OF LONG-TERM ENERGY BALANCE AND FAT STORAGE The balanced transition from fed to fasted and the consumption of adequate energy commensurate with the level of physical activity ensure that adequate energy reserves are available for short-term increases in metabolic demands, such as those described for exercise. An imbalance in either energy intake or expenditure leads to one of the following two extremes: loss of lean body mass or wasting syndrome and obesity. In the absence of chronic physical or psychiatric illness, development of a wasting syndrome is infrequent. Obesity is an important health problem that increases the risk of several diseases. Because of the rising incidence of obesity in our society, a brief discussion follows on the endocrine physiologic responses implicated in the development of this condition.

Obesity Obesity is defined as a significant increase above the ideal weight. The increase in body mass index (BMI), an indicator of the adiposity or fatness that accompanies obesity, has become an important worldwide health problem. Life expectancy is reduced when BMI is significantly increased. Obesity is associated with an increased risk of type 2 diabetes mellitus, dyslipidemia, hypertension, heart disease, and cancer. Approximately 30% of the US population is considered obese, according to the definition of the World Health Organization. Body weight and the excess weight gain leading to obesity are determined by interactions among genetic, environmental, and psychosocial factors that affect the physiologic mediators of energy intake and expenditure, several of which pertain to the endocrine system. Energy expended by the individual can be in the form of work (physical activity) or heat production (thermogenesis), which can be affected by environmental temperature, diet, and the neuroendocrine system (catecholamines and thyroid hormone). The uncoupling of ATP production from mitochondrial respiration dissipates heat and affects the efficiency with which the body utilizes energy substrates. The expression of proteins involved in this process (uncoupling protein-1 expressed in brown adipose tissue and uncoupling protein-3 in skeletal muscle) is modulated by catecholamines, thyroid hormones, and leptin. The role of genetics in the predisposition to obesity has been demonstrated convincingly. Susceptibility genes have been identified that increase the risk of developing obesity, and their relevance has been shown in studies in which pairs of twins were exposed to periods of positive and negative energy balance. The differences in the rate of weight gain, the proportion of weight gained, and the sites of fat deposition showed greater similarity within pairs than between pairs, indicating a close genetic relationship. Although a clear correlation between energy expenditure and weight gain has not been demonstrated, increasing physical activity, which represents 20–50% of total energy expenditure, has been actively promoted as an approach to prevent obesity and improve insulin

CHAPTER 69 Endocrine Integration of Energy and Electrolyte Balance responsiveness. Environmental factors are also thought to unmask genetic tendencies toward obesity. The responsiveness to hormones that regulate lipolysis varies according to the distribution of fat depots. The lipolytic response to norepinephrine is greater in abdominal than in gluteal or femoral adipose tissue in both men and women. The exaggerated release of free fatty acids from abdominal adipocytes directly into the portal system, an increased hepatic gluconeogenesis, and hepatic glucose release, and hyperinsulinemia are hallmarks of patients with upper-body obesity. The endocrine properties of the different fat depots may be more important than the anatomic location. The severity of medical complications is more closely related to body fat distribution, being greater in individuals with abdominal (visceral) obesity than those with an excess total body fat. Differential fat deposition leading to upper-body or abdominal obesity is reflected in a high waist–hip ratio, an index used for predicting risks associated with fat accumulation. The presence of visceral obesity, insulin resistance, dyslipidemia, and hypertension is collectively termed the metabolic syndrome. Excess energy intake in relation to the energy expended by the organism leads to the accumulation of fat. The fat mass itself is determined by the balance between breakdown (lipolysis) and synthesis (lipogenesis). The sympathetic nervous system is the principal stimulator of lipolysis, particularly when the energy demands of the individual are increased. When intake exceeds energy utilization, lipogenesis occurs in liver and adipose tissue. Lipogenesis is influenced by diet (increased by carbohydrate-rich diets) and hormones (principally GH, insulin, and leptin) through modification of transcription factors (e.g., peroxisome proliferator-activated receptor-γ [PPAR-γ]). The transcription factor PPAR, the target for the insulin sensitizer thiazolidinedione drugs, affects gene transcription of several enzymes involved in glucose and fat metabolism and is involved in preadipocyte differentiation into mature fat cells. The main hormones involved in fat storage are insulin (which stimulates lipogenesis), and GH and leptin (which reduce lipogenesis). Other hormones involved in the regulation of body fat stores include testosterone, dehydroepiandrosterone, and thyroid hormone.

Regulation of Energy Intake Regulation of energy intake is mediated by several factors. Central integration of peripheral signals, including those mediated by mechanoreceptors and chemoreceptors, signals the presence and energy density of food in the gastrointestinal tract. Hypothalamic glucose sensors monitor fluctuations in circulating glucose concentrations. Hormones signal the central release of peptides that regulate appetite and satiety. Two hormones that have been identified as crucial in the long-term regulation of energy balance are insulin and leptin, the product of the ob gene (discussed later). Both hormones are released in proportion to body fat (Figure 69–2). In the brain,

719

they modulate the expression of hypothalamic neuropeptides known to regulate feeding behavior and body weight, resulting in inhibition of food intake and increase in energy expenditure. While insulin release is directly correlated to meals, that of leptin does not correlate with food intake but reflects body fat mass (Figure 69–2).

Hypothalamic Integration The hypothalamus receives innervation from several areas, notably the nucleus tractus solitarius and area postrema in the brainstem. These areas relay many neural and hormonal signals from the gastrointestinal tract. Mechanical stretch receptors sense stretch of the stomach and other areas of the intestine. Gastrointestinal hormones such as cholecystokinin (CCK), released following a meal in response to the presence of lipids or protein in the intestinal lumen, are involved in afferent signaling to the brain regarding the intestinal nutritional content. The nucleus tractus solitarius also relays taste information to the hypothalamus and other centers. Other signals regarding smell, sight, memory of food, and the social context under which it is ingested are also integrated and may also influence energy intake by modulating output from the hypothalamus. Integration of these signals results in the activation of gene expression of mediators implicated in the regulation of satiety and development of obesity. These genes control thermogenesis (uncoupling proteins), hormone synthesis (ghrelin, leptin, and CCK and adiponectin), and neurotransmitter (neuropeptide Y) availability, as summarized in Table 69–2. The relative contributions of these mediators to the regulation of caloric intake, energy expenditure, body weight, and fat mass are not completely understood. However, important new discoveries, such as the secretory function of adipose tissue, have provided new insight into potential factors contributing to obesity. Adipose tissue is an endocrine tissue participating in a complex network regulating energy homeostasis, glucose and lipid metabolism, vascular homeostasis, immune response, and even reproduction. Among the hormones identified that are produced by adipose tissue are leptin, cytokines (TNF-α, interleukin-6), adipsin and acylation-stimulating protein, angiotensinogen, plasminogen activator inhibitor-1, adiponectin, resistin, and steroid hormones (Table 69–2). Secretion of almost all of these hormones and cytokines is dysregulated as a consequence of both excess and deficiency in the mass of adipose tissue, suggesting that they are involved in the pathophysiology of both obesity and cachexia. Of particular interest are the contributions of the proinflammatory cytokines, such as TNF-α, to the development of insulin resistance in obese individuals and the potential role of leptin as a regulator of fat mass.

Leptin Leptin is a peptide hormone (146 amino acids) thought to serve as an indicator of energy stores, as well as a modulator of

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Arcuate nucleus

Nucleus of the solitary tract

Hypothalamus Vagus nerves Spinal nerves

Neurons in other hypothalamic areas

PVN

Orexigenic

Ghrelin Leptin

Anorexigenic

NPY/ AgRP

ARC

POMC/ CART

Insulin CCK

PYY

NPY-Y1R NPY-Y2R NPY-Y4R

MC3 R MC4 R GLP-1R

Ghrelin R Leptin R Insulin R

Hunger Meal size Meal duration Intake

Thermogenic response Energy stores Substrate metabolism Expenditure

Stretch Chemoreceptors Nutrients

– – PYY3-36

Ghrelin +

Stomach (or duodenum)

+

Leptin

Adipose tissue

– + Insulin

Pancreas

FIGURE 69–2 The brain integrates multiple peripheral and neural signals to control the regulation of energy homeostasis, maintaining a balance between food intake and energy expenditure. The hypothalamus receives innervation from several areas, notably the nucleus tractus solitarius and area postrema in the brainstem, that relay many neural and hormonal signals from the gastrointestinal tract, such as mechanical signals indicating stretch of the stomach and other areas of the intestine; and hormonal signals indicating the presence of food in the gut, such as CCK. Additional signals regarding smell, sight, memory of food, and the social context under which it is ingested are also integrated and may also influence energy intake by modulating output from the hypothalamus. Collectively, these signals act on two subsets of neurons that control food intake in the arcuate nucleus of the hypothalamus (ARC), which stimulate and inhibit energy intake. Orexigenic (appetite-stimulating) neurotransmitters are agouti-related peptide (AgRP) and neuropeptide Y (NPY). Anorexigenic (appetite-suppressant) neurotransmitters are cocaine- and amphetamine-regulated transcript (CART) and proopiomelanocortin (POMC) neurotransmitters. Both neuronal populations innervate the paraventricular nucleus (PVN), which, in turn, sends signals to other areas of the brain. These include hypothalamic areas such as the ventromedial nucleus, dorsomedial nucleus, and the lateral hypothalamic area, which modulate this control system. Brain circuits integrate information from the NTS and multiple hypothalamic nuclei to regulate overall body homeostasis. Leptin and insulin decrease appetite by inhibiting the production of neuropeptide Y (NPY) and AgRP, while stimulating melanocortin-producing neurons in the arcuate nucleus region of the hypothalamus. NPY and AgRP stimulate eating, and melanocortins inhibit eating. Ghrelin stimulates appetite by activating the NPY/AgRP-expressing neurons. PYY3-36, released from the colon, inhibits these neurons and transiently decreases appetite. Integration of these signals results in regulation of energy intake, satiety, control of thermogenesis, and energy expenditure.

energy balance. The specific effects of leptin on fat metabolism are as follows: • decrease in fat storage; • increase in sympathetic-mediated energy expenditure; • increase in expression of uncoupling proteins;

• decrease in triglyceride content by increasing fatty acid oxidation; • decrease in activity and expression of esterification and lipogenic enzymes; • decrease in lipogenic activity of insulin, favoring lipolysis.

CHAPTER 69 Endocrine Integration of Energy and Electrolyte Balance

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TABLE 69–2 Mediators implicated in regulation of energy intake. Mediator

Regulation and Target Effect

Gastrointestinal tract Cholecystokinin

Released in the duodenum during a meal. Stimulates the vagus nerve projecting to the NTS and signals within the hypothalamus to induce satiety

Ghrelin

Released from the GI tract before meals. Plasma levels are low in obese patients. Stimulates growth hormone release, decreases fat oxidation, increases food intake and adiposity. Overall has antileptin action

PYY3-36

Member of the neuropeptide Y family, released in the distal small intestine and colon in response to food. Blood levels remain elevated between meals. Decreases food intake at the arcuate nucleus in the hypothalamus

Adipose tissue Adiponectin (adipocyte complement-related protein of 30 kDa, AdipoQ)

Produced by adipose tissue (decreased in obese patients; plasma levels correlate negatively with triglycerides). Increases insulin sensitivity and tissue fat oxidation, resulting in reduced circulating fatty acid levels and reduced intramyocellular and liver triglyceride content

Acylation-stimulating protein

Produced by adipose tissue. Paracrine signal increases efficiency of triacylglycerol synthesis in adipocytes, resulting in more rapid postprandial lipid clearance

Leptin

Produced in adipose tissue. Acts on neuropeptide Y, AgRP-containing neurons, and α-MSH neurons in the arcuate nucleus of the hypothalamus to decrease food intake

Resistin

Peptide hormone induced during adipogenesis. It antagonizes insulin action

Hypothalamus Neuropeptide Y (NPY)

Produced by hypothalamic neurons that express AgRP. Release is under leptin, insulin, and cortisol regulation. Stimulates food intake via the NPY5 receptor

α-MSH

Product of POMC in hypothalamic neuronal subset under leptin regulation. Decreases food intake through melanocortin-4 receptors in the hypothalamus

Cocaine- and amphetamine-regulated transcript (CART)

Leptin and amphetamines stimulate production of this peptide by hypothalamic POMC-expressing neurons. Reduces food intake

Agouti-related peptide (AgRP)

Released from hypothalamic NPY-expressing neurons. Inhibits neuronal melanocortin-4 receptors and increases food intake

Orexins (A and B)

Produced by neurons in the lateral hypothalamus perifornical area. Regulated by glucose, leptin, neuropeptide Y, and POMC neurons. They stimulate food intake

NTS, nucleus tractus solitarius; GI, gastrointestinal; PYY, polypeptide YY; AgRP, agouti-related peptide; MSH, melanocyte-stimulating hormone; POMC, proopiomelanocortin.

Leptin produced by white adipose tissue functions as a signal that provides information about the level of energy stores (adipose tissue mass). The signal is integrated by hypothalamic neurons, and an effector response, most likely involving modulation of appetite centers and sympathetic nervous system activity, regulates the two main determinants of energy balance: intake and expenditure. Leptin secretion exhibits a circadian rhythm, with a nocturnal rise over daytime secretion. These changes in leptin plasma concentrations are not influenced by meal ingestion and meal-induced increases in the circulating insulin concentration. The effects of leptin are mediated through the leptin receptor, a member of the gp130 family of cytokine receptors, which activates a gene transcription factor on two populations of hypothalamic neurons. This process results in reduced expression of two orexigenic (feeding-inducing) neuropeptides, neuropeptide Y and agouti-related peptide (AgRP); and enhanced expression of two anorexigenic peptides, α-melanocyte-stimulating hormone (α-MSH) and cocaine-

and amphetamine-regulated transcript (CART). Thus, leptin-induced inhibition of food intake results from both the suppression of orexigenic and the induction of anorexigenic neuropeptides (Figure 69–2). The feedback regulatory loop for leptin’s effects has been well established in rodents; however, many unsolved questions remain about its applicability to body weight regulation in humans. The role of leptin in humans appears to be mostly one of the adaptations to low energy intake rather than a brake on overconsumption and obesity. Leptin concentrations decrease during fasting and energy-restricted diets, independent of body fat changes, stimulating an increase in food intake before body energy stores become depleted. Because leptin levels do not increase in response to individual meals, it is not thought to serve as a meal-related satiety signal. Finally, it is notable that obese individuals have high plasma leptin concentrations that do not result in the expected reduction in food intake and increase in energy expenditure, suggesting that obesity is related to leptin resistance.

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Ghrelin Ghrelin is a hormone produced by the enteroendocrine cells of the stomach, and to a lesser extent by the pituitary, and hypothalamus. Circulating levels of ghrelin decrease during meals and are highest in the fasted state. Ghrelin levels are decreased in obese individuals and increased in individuals consuming low calorie diets, chronic strenuous exercise, cancer anorexia, and anorexia nervosa. In humans, ghrelin has been shown to be a potent growth hormone secretagogue and appetite stimulant.

ELECTROLYTE BALANCE REGULATION OF SODIUM BALANCE Sodium is the primary electrolyte that regulates extracellular fluid (ECF) levels and osmolarity in the body. Regulation of extracellular Na+ concentration controls the distribution of water between the ECF and intracellular fluid (ICF) and maintains cell volume, ensuring normal physiologic function. Sodium is maintained in the ECF by the action of Na+/K+ATPase, whereas water crosses cell membranes through ubiquitously expressed aquaporins (maintaining ICF and ECF isotonicity). The overall mass of Na+ is under aldosterone regulation, whereas the Na+ concentration in plasma is under antidiuretic hormone (ADH) regulation. Thus, low Na+ concentrations do not necessarily mean that total Na+ mass is low. In chronic heart failure, osmolarity can be low, yet Na+ mass can be high because of excess water and Na+ in the ECF, with greater increases in total body water than in Na+ mass.

Hormonal Regulation of Sodium and Water Balance The system that controls total body water is a negative feedback homeostatic mechanism, of which thirst and ADH are the major effectors. Two stimuli regulate the system: tonicity of the ECF through osmoreceptors and intravascular volume through stretch or baroreceptors. The system works primarily to maintain intravascular volume and to a lesser extent to maintain tonicity. Thirst is stimulated by an increase in tonicity (1–2% changes are sufficient to elicit thirst) and by reductions in the ECF volume. Water intake is inhibited by hypotonicity and ECF volume expansion. Sudden decreases in blood volume are sensed by mechanoreceptors in the left ventricle, carotid sinus, aortic arch, and renal afferent arterioles (Figure 69–3). These mechanoreceptors respond to decreased stretch resulting from decreases in systemic arterial pressure, stroke volume, renal perfusion, or peripheral vascular resistance by triggering an increase in sympathetic outflow from the central nervous system, activation of the renin–angiotensin–aldosterone system, and nonosmotic release of antidiuretic hormone, as well as stimulation of thirst. Low blood pressure results in decreased renal perfusion pressure and lower glomerular filtration rates, which

stimulate the release of renin from juxtaglomerular cells in the afferent and efferent arterioles.

Antidiuretic hormone ADH directly controls water excretion by the kidneys. ADH secretion and compensatory thirst are stimulated by hypothalamic osmoreceptors and by decreased stimulation of aortic and carotid stretch receptors. Release of ADH is inhibited by increased stretch of mechanoreceptors (stretch receptors) in the atria of the heart. ADH stimulates insertion of aquaporins into the cell membrane, increases water reabsorption in the collecting ducts, and concentrates excreted urine.

Angiotensin II Angiotensin II increases blood pressure by several mechanisms, including direct vasoconstriction, potentiation of the activity of the sympathetic nervous system at both the central and peripheral levels, stimulation of aldosterone synthesis and release with consequent sodium reabsorption by the kidney, stimulation of ADH release and increased water retention, and intrarenal efferent arteriolar constriction.

Aldosterone Aldosterone increases sodium reabsorption and potassium excretion in the distal tubule and the collecting duct of the nephron, playing a central role in determining total body Na+ mass, and thus long-term blood pressure regulation. Aldosterone release from the adrenals is stimulated by angiotensin II. Atrial natriuretic factor Atrial natriuretic factor is a peptide hormone produced in atrial myocardial cells and released in response to increased stretch, usually resulting from increased intravascular volume. It increases renal Na+ excretion and water loss through an increase in glomerular filtration rate and a decrease in Na+ reabsorption in the medullary collecting duct.

Abnormalities in Sodium and Water Balance Abnormalities in sodium and water balance can be classified into four categories. Excess Na+ is characterized by expansion of the ECF volume and frequently by low effective circulating blood volume (i.e., heart failure, hypoalbuminemia, renal insufficiency). Deficit in Na+ is characterized by reduced ECF volume. Excess water is due to either excess intake or enhanced ADH release and is manifested by hyponatremia and hypoosmolarity. Water deficit is due to lack of intake or excess loss (renal and nonrenal) and is manifested by hypernatremia and hyperosmolarity.

REGULATION OF POTASSIUM BALANCE Potassium is the most abundant cation in the body and the main intracellular electrolyte. Most (98%) of the potassium in the body is sequestered within cells. The ratio of extracellular to intracellular potassium (1:10) is maintained by a sodium–

CHAPTER 69 Endocrine Integration of Energy and Electrolyte Balance

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Cardioregulatory center

Glossopharyngeal & vagal afferents from baroreceptors

Sympathetic trunk

Sympathetic ganglia AVP Sympathetic nerves Aldosterone

Renin Angiotensin II production

Peripheral vasoconstriction

Water reabsorption Na reabsorption K+ excretion

potassium pump and is the major determinant of resting membrane potential. Small losses (1%, or 35 mmol) of total body potassium content can seriously disturb the delicate balance between intracellular and extracellular potassium and can result in profound physiologic changes. The tissues most severely affected by potassium imbalance are muscle and renal tubular cells. Manifestations of hypokalemia include generalized muscle weakness, paralytic ileus, and cardiac arrhythmias.

Intake, Distribution, and Excretion of Potassium The daily intake of potassium in the Western diet is about 80–120 mmol, and this exceeds the minimum daily require-

FIGURE 69–3 Neuroendocrine control of blood volume. Sudden decreases in blood volume are sensed by mechanoreceptors in the left ventricle, carotid sinus, aortic arch, and renal afferent arterioles, triggering an increase in sympathetic outflow from the central nervous system, activation of the renin–angiotensin– aldosterone system, nonosmotic release of arginine vasopressin (AVP), and stimulation of thirst. The decreases in renal perfusion pressure and glomerular filtration rates stimulate the release of renin, the enzyme responsible for the conversion of angiotensinogen to angiotensin I (later converted by angiotensinconverting enzyme to angiotensin II). Angiotensin II, aldosterone, and ADH produce vasoconstriction, venoconstriction, and renal retention of Na+ and water. (Modified with permission from Molina PE: Endocrine Physiology, 3rd ed. New York: McGraw-Hill Medical, 2010.)

ment. Only a small fraction (10%) of potassium is excreted through the gastrointestinal tract and the majority is excreted by the kidney. Thus, the kidney is responsible for long-term potassium homeostasis, as well as for regulating the serum potassium concentration. On a short-term basis, serum potassium is also regulated by the shift of potassium between the ICF and ECF. This short-term regulation of serum potassium is principally controlled by insulin and catecholamines through regulation of the transcellular distribution of potassium. Dietary potassium, which is rapidly absorbed by the gut, increases serum potassium transiently. The release of insulin and catecholamines during a meal quickly shifts the potassium into the cells. The principal site for the regulation of K+ excretion is the distal tubule, where secretion is indirectly but tightly coupled

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SECTION IX Endocrine and Metabolic Physiology

to sodium reabsorption via the amiloride-sensitive sodium channel, and under regulation by aldosterone. Because the kidney is the major regulator of potassium homeostasis, renal dysfunction results in abnormal levels of serum potassium. Potassium contributes to regulation of its balance by stimulating aldosterone secretion by the zona glomerulosa cells of the adrenal cortex. Aldosterone enhances renal and colonic K+ secretion, promoting the loss of K+ in the urine and stool (Figure 69–4). Sustained hyperkalemia does not occur in individuals with normal renal function despite marked increases in potassium intake because of an adaptive change in distal tubular K+ secretion, such that intake is matched by rapid and equivalent increases in K+ excretion. The mechanisms involved in the chronic adaptation to increased levels of K+ include changes in apical K+ and Na+ conductance and in basolateral Na+/K+-ATPase pump activity, an increase in apical Na+ delivery and reabsorption, and an increase in K+ excretion per nephron to match K+ intake.

Hormonal Regulation of Potassium Balance Total body stores of potassium and its cellular distribution in the body are closely regulated by key hormones.

Aldosterone Aldosterone increases the synthesis and activity of Na+/K+-ATPase in the basolateral membrane of the distal tubule, promoting the exchange of cytosolic Na+ for K+. The overall

result is an increase in Na+ reabsorption and an increase in K+ excretion.

Insulin Insulin stimulates entry of K+ into the cell through activation of the electroneutral Na+/H+ antiporter, leading to Na influx. The increase in intracellular Na+ produced by insulin triggers the activation of the electrogenic Na+/K+-ATPase, which extrudes Na+ from the cell in exchange for K+. The treatment of patients with diabetic ketoacidosis with high insulin doses produces a significant influx of K+ into the cells that may result in hypokalemia, manifested by changes in the electrocardiogram.

Catecholamines Catecholamines (β-adrenergic receptor stimulation) increase cellular potassium uptake by stimulating cell membrane Na+/K+-ATPase. Indirectly, catecholamines stimulate glycogenolysis, resulting in a rise in plasma glucose concentrations, release of insulin from the pancreas, and insulin-mediated effects on K+ redistribution. Stimulation of the α-adrenergic receptor shifts K+ out of the cell and can also affect K+ distribution through inhibition of pancreatic insulin release. Insulin and catecholamines are both stimulated by the ingestion of glucose- and potassium-rich foods, thereby maintaining K+ homeostasis despite large dietary intake. These hormones are essential in moving potassium primarily into the intracellular compartment of the liver and striated muscle cells.

β-Adrenergic catecholamines

Potassium concentration in extracellular fluid

Insulin

Cortical collectingduct cells

Na+ K+

Aldosterone K+

Na+

H+

Na+/K+ -ATPase

Na+

Na+ Na+/K+ -ATPase

Na+ K+

K+ Na+ Na+ Na+

Muscle cell

A

K+

Lumen B

FIGURE 69–4 Key hormones involved in normal potassium homeostasis. A) Insulin stimulates entry of K+ into the cell through the activation of the electroneutral Na+/H+ antiporter. The increase in intracellular Na+ produced by insulin triggers the activation of the electrogenic Na+/K+-ATPase, which extrudes Na+ from the cell in exchange for K+. Catecholamines (β-adrenergic receptor stimulation) increase cellular potassium uptake by stimulating cell membrane Na+/K+-ATPase. Stimulation of the α-adrenergic receptor shifts K+ out of the cell. B) Aldosterone promotes potassium excretion through its effects on the Na+/K+-adenosine triphosphatase (ATPase) and epithelial sodium and potassium channels in collecting duct cells. Angiotensin II has a synergistic effect on the stimulation of aldosterone production induced by hyperkalemia. (Reproduced with permission from Gennari F. Current concepts: Hypokalemia. NEJM. 1998;339:451. Copyright Massachusetts Medical Society. All Rights reserved.)

CHAPTER 69 Endocrine Integration of Energy and Electrolyte Balance

Acid–Base and Osmolar Regulation of Potassium Distribution Intracellular potassium homeostasis is also affected by changes in acid–base balance and osmolarity. Sudden changes in plasma osmolarity redistribute water between the ICF and ECF. This movement of water out of a cell creates a solvent drag phenomenon, pulling K+ out of the cell and therefore increasing serum potassium. Similarly, metabolic acidosis caused by a loss of bicarbonate or a gain in hydrogen ion concentration [H+] leads to a shift of K+ across cell membranes and hyperkalemia. However, integrity of renal function and stimulation of aldosterone release rapidly correct this imbalance. In diabetic ketoacidosis, there is a net loss of K+ from the body because of osmotic diuresis, despite elevations in ECF K+ concentrations (hyperkalemia), because of insulin deficiency. Following aggressive insulin treatment, hypokalemia becomes apparent. Opposite effects are observed during alkalosis. In metabolic alkalosis, the excess bicarbonate causes H+ in the ECF to fall, leading to entry of Na+ into the cell in exchange for H+. Na+ is pumped out of the cell by the Na+/K+-ATPase in exchange for K+ movement into the cell, creating a shift of K+ into the cells. Hypokalemia is a common electrolyte abnormality encountered in clinical practice. It is almost always the result of potassium depletion induced by abnormal fluid losses (i.e., vomiting, colonic diarrhea, profuse sweating, diuretic use, or nasogastric suction). Patients present with muscle weakness and changes in the electrocardiogram. More rarely, hypokalemia occurs because of an abrupt shift of potassium from the ECF into cells, frequently as an effect of prescription drugs. Hyperkalemia, also a common electrolyte disorder, is caused by renal dysfunction, decreased aldosterone production by the adrenal gland, potassium shifting from the intracellular to the extracellular compartment, and some drugs. Patients can present asymptomatic or have altered electrocardiogram.

NEUROENDOCRINE REGULATION OF THE STRESS RESPONSE Alterations in the environment or in the host that require adaptation involve the synchronized interaction of virtually all aspects of neuroendocrine function that have been described (Figure 69–5). The adaptation to a biologic, psychosocial, or environmental insult to the host is referred to as the stress response; in the acute setting, it is also termed the fight-orflight response. It is now clear that this stress response can be chronic, with a significant cost to the health of the individual (Figure 69–5). Chronic activation of the mechanisms that restore homeostasis results in excessive and, in some cases, inadequate responses that ultimately alter the function of virtually all organ systems (e.g., hypertension, autoimmune disorders, metabolic syndrome) (Figure 69–5). Many of the effects of this

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dysregulated state are mediated by chronic activation of the hypothalamic–pituitary–adrenal (HPA) axis and the sympathetic nervous system, producing marked alterations in endocrine function, such as the following: • Inhibition of reproduction function: Enhanced release of corticotropin-releasing hormone (CRH) and β-endorphin suppresses GnRH release directly and indirectly through the release of glucocorticoids. Glucocorticoids decrease the release of luteinizing hormone and produce gonadotropin resistance at the gonads. This suppression in gonadal function is evident in patients with anorexia nervosa, athletes, and ballet dancers. • Inhibition of the GH–IGF-I axis: Chronic activation of the HPA axis suppresses GH release and inhibits the effects of IGF-I at target tissues. • Suppression of thyroid function: CRH and cortisol suppress the production of thyroid-stimulating hormone and inhibit the activity of peripheral 5ʹ-deiodinase, leading to the euthyroid sick syndrome. • Dysregulation of energy substrate metabolism: An increase in catecholamines stimulates lipolysis and decreases triglyceride synthesis in white adipose tissue. In the liver, increased epinephrine levels stimulate hepatic glycogenolysis and, together with high cortisol levels, increase hepatic glucose output. High cortisol levels resulting from activation of the HPA increase gluconeogenesis, produce insulin resistance in peripheral tissues, inhibit the lipolytic action of GH, and inhibit bone osteoblastic activation (remodeling) by sex steroids. This leads to increases in visceral adiposity and loss of BMD and lean body mass. This aspect of the stress response may be of particular importance in the treatment of diabetic patients during stressful periods such as surgery or infection. • Alterations in the Immune Response: The significant increase in circulating cortisol levels affects virtually all aspects of the immune response, including cytokine production, leukocyte trafficking and recruitment, and production of chemokines. Overall, glucocorticoids exert an anti-inflammatory response. Activation of the autonomic nervous system also affects the immune response through effects on neutrophil demargination and cytokine production. Short-term activation of these stress response mechanisms ensures that energy substrates are available to meet the increased metabolic demands of the individual. However, prolonged duration and increased magnitude of these activities lead to erosion of lean body mass and tissue injury. Nevertheless, impaired activation or lack of responsiveness of the HPA and autonomic nervous system can also be deleterious, as in the case of the critically ill patient. Thus, the overall regulation of the neuroendocrine responses that mediate the physiologic functions involved in maintaining and restoring homeostasis is critically important in situations such as illness, trauma, surgery, or fasting.

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SECTION IX Endocrine and Metabolic Physiology

Stress Developmental history Nutrition Genetic variation Aging

CRH ADH

Stress system

LC NE Systemic sympathetic adrenomedullary systems

HPA axis Cortisol

NE, E Target tissues

GH and/or IGF-I LH, T, E2 TSH, T3

Metabolic syndrome (insulin resistance, visceral obesity, sarcopenia)

Polycystic ovary syndrome

TG LDL HDL

APR Cytokines

ABP Coagulopathy

Sleep apnea

Osteopenia or osteoporosis

Endothelial dysfunction and inflammation

Atherosclerosis Cardiovascular and neurovascular disease

FIGURE 69–5 Neuroendocrine responses to chronic or severe stress. Chronic activation of the neuroendocrine response to restore homeostasis influences virtually all organ systems. The short-term activation of these stress response mechanisms ensures that energy substrates are available to meet the increased metabolic demands of the individual. However, prolonged duration and increased magnitude of these activities lead to erosion of lean body mass and tissue injury. ABP, arterial blood pressure; ACTH, adrenocorticotropic hormone; APR, acute-phase reactants; ADH, antidiuretic hormone; CRH, corticotropin-releasing hormone; iCRH, immune CRH; E, epinephrine; E2, estradiol; GH, growth hormone; HPA, hypothalamic–pituitary–adrenal; IGF-I, insulinlike growth factor I; IL-6, interleukin 6; LC, locus ceruleus; LH, luteinizing hormone; NE, norepinephrine; T, testosterone; TG, triglycerides. (Adapted with permission from Chrousos G. Stress and disorders of the stress system. Nat Rev Endocrinol. 2009;5(7):347–381, 2009.)

CLINICAL CORRELATION A woman with type 1 diabetes mellitus on an insulin pump is brought to the emergency room after she fainted during her daily exercise class. First responders administered intravenous glucose solutions after obtaining a blood sample for analysis. On examination, she is tachycardic and agitated, and has sweaty palms. Laboratory values showed high insulin and low plasma glucose levels. A diagnosis of insulin-induced hypoglycemia is made. Diabetic patients treated with insulin are at risk for developing insulin-induced hypoglycemia. These episodes are sometimes asymptomatic and occur during

night time, over time diminishing the autonomic responses to hypoglycemic episodes. Hypoglycemia deprives the brain of its preferred substrate, glucose, leading to rapid activation of neuroendocrine responses aimed at restoring glycemia including increased release of glucagon, epinephrine, and growth hormone. Together, these counterregulatory hormones increase hepatic glucose output (from gluconeogenesis and glycogenolysis) and peripheral glycogenolysis and lipolysis. The activation of the sympathetic nervous system leads to increased heart rate. Insulin-induced hypoglycemic episodes are more frequent in patients treated with insulin than in those treated with oral hypoglycemics.

CHAPTER 69 Endocrine Integration of Energy and Electrolyte Balance

CHAPTER SUMMARY ■ ■ ■ ■ ■ ■

Energy substrate mobilization, utilization, and storage are under neuroendocrine regulation. Hepatic glycogen and adipose tissue triglycerides are the principal sites of energy storage. The central nervous system integrates the counterregulatory response to acute decreases in energy substrate availability. Regulation of sodium balance determines blood volume and blood pressure control. The kidney is responsible for long-term potassium homeostasis and serum potassium concentration. Insulin and catecholamines regulate the cellular distribution of potassium.

STUDY QUESTIONS 1. Which of the following neuroendocrine responses contributes to meeting the enhanced energy demands during exercise? A) glucagon stimulation of hepatic glycogen synthesis B) epinephrine stimulation of hepatic glycogenolysis C) norepinephrine-induced stimulation of insulin release D) cortisol inhibition of gluconeogenesis

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2. Which of the following processes takes place immediately after a balanced meal? A) suppression of pancreatic insulin release B) increased muscle and fat glucose uptake C) increased hepatic glycogenolysis D) suppressed lipogenesis 3. Activation of the renin–angiotensin–aldosterone system during loss of effective intravascular volume results in all of the following except A) increased renal sodium and fluid retention B) potentiation of the activity of the sympathetic nervous system C) peripheral venodilatation D) enhanced ADH release 4. Regulation of body potassium content and distribution can be affected by all of the following except A) aldosterone-induced increase in K+ excretion B) insulin stimulation of intracellular K+ efflux C) β-adrenergic stimulation of cell membrane Na+/K+-ATPase D) sudden changes in plasma osmolarity

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SECTION X INTEGRATIVE PHYSIOLOGY

70 C

Control of Body Temperature Hershel Raff and Michael Levitzky

H A

P

T

E

R

O B J E C T I V E S ■ ■ ■ ■

■ ■

Understand the mass balance characteristics of the control of internal body temperature. List and define the four mechanisms of heat transfer from the skin to the environment. Explain the feedback control of internal body temperature. Understand the short-term response to cold (to increase heat production and minimize heat loss) and heat (to decrease heat production and maximize heat loss). Describe the adaptations to cold and warm environments. Understand the mechanisms of fever.

Like all mammals, humans are endotherms, meaning they generate their own internal heat. Humans are also homeotherms— they maintain body temperature within a narrow range despite large swings in environmental temperature. The maintenance of internal body temperature within a narrow range is therefore one of the most important regulated variables in humans. This is because enzymatic reactions, and optimal cell and organ function, occur in a fairly small range of temperatures. Despite wide swings in environmental temperature, the core body temperature—the internal temperature in the organs such as the liver (often estimated by rectal or tympanic membrane temperature)—is usually maintained within ±0.6°C (±1.0°F). The core temperature averages about 37°C (98.6°F) for humans, although it varies from person to person. The maintenance of a stable body temperature involves a negative feedback control system with a very high gain since the perturbation to the sys-

Ch70_729-734.indd 729

tem (changes in environmental temperature) can be very large compared with the maintenance of a stable internal body temperature. In fact, the gain of the body temperature control system is 25–30—compare this with the gain of only 4 for the blood pressure restoration in response to moderate hemorrhage shown in Figure 1–5. Furthermore, there is usually a daily (circadian) rhythm in body temperature with a low point in the early morning and a high point in the early evening. Body temperature also varies depending on the level of muscular activity and with the menstrual cycle in women. The core body temperature is the central compartment of a mass balance system (see Figure 1–4) composed of heat gained from the environment and produced in the body by cellular metabolism, and the heat lost to the environment. Since body temperature is usually quite stable in the steady state, heat production is approximately equal to heat loss.

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MECHANISMS OF HEAT LOSS OR GAIN

EFFECTOR MECHANISMS REGULATING TEMPERATURE

Most of the gain or loss of heat between the body and the environment is through the skin. Heat is mainly transferred to the skin from the internal environment by the circulatory system. There are four general mechanisms of heat transfer between the body and the environment. Radiation is the emission of heat to and from the skin by electromagnetic waves—the rate of the temperature transfer by radiation is proportional to the temperature difference between the body surface and the environment. Conduction is intermolecular thermal heat transfer and usually occurs between the skin and air. One loses heat more rapidly when immersed in water because conduction between the skin and water is faster than that between skin and air. Convection is the loss or gain of heat by the movement of air or water over the body. Because heat rises, air carries heat away from the body by convection. This is one reason why having a fan circulating air in a room helps one to keep cool on a hot day. Finally, evaporation of water from the skin and the respiratory tract can carry a large amount of heat generated by the body because of the amount of heat required to transform water from the liquid to the gas phase. Air circulation also improves the rate of evaporation of sweat from the skin.

Body temperature can be increased when the body is cold by decreasing heat loss and/or by increasing heat production. Decreasing heat loss is accomplished primarily by vasoconstriction of the arterioles of the skin, minimizing heat transfer to the environment. Another mechanism of heat conservation is the reduction of body surface area by, for example, curling up, and behavioral responses such as putting on warm clothes or moving to a warmer environment. As mentioned above, the shortterm increase in heat production is accomplished primarily by an increase in voluntary movement and by shivering. Body temperature can be decreased when the body is hot by increasing heat loss and/or by decreasing heat production. Increasing heat loss is accomplished primarily by vasodilation of arterioles in the skin, thereby increasing heat transfer from the blood to the skin and then to the environment, and by sweating to lose heat by increased evaporation. Sweat production is increased by increasing activity of autonomic nerves innervating sweat glands in the skin. The principal mechanism to decrease heat production is a decrease in voluntary movement. Now let us return to Figure 70–1 to summarize the control of body temperature. When first exposed to a cold environment, the thermal sensors in the skin signal the brain to decrease blood flow to and sweat production from the skin, thus minimizing heat loss. If the core temperature decreases, shivering and increases in adrenal medullary epinephrine can increase to increase heat production, although the latter is a minor pathway in humans. When one is exposed to a hot environment, thermal sensors in the skin can increase blood flow to the skin and sweat production, thus increasing heat loss. If core temperature increases, sweat production can increase profusely to greatly increase heat loss by evaporation. However, if evaporation cannot occur or is difficult because the air is already saturated or nearly saturated with water vapor, sweating is not a very effective means of heat loss.

FEEDBACK MECHANISMS REGULATING BODY TEMPERATURE As mentioned above, the control of the internal body temperature is a classic example of negative feedback control. If you recall from Chapter 1, feedback control systems involve sensors that detect the regulated variable (in this case, body temperature) with afferent input to the controller, a controller (in this case, in the brain), and efferent input to the effectors that can alter the rate of heat gain or loss. Figure 70–1 summarizes the regulation of body temperature. The sensors are located in the skin (peripheral thermoreceptors) and the brain (central thermoreceptors), primarily in the hypothalamus. It is the central thermoreceptors that sense core temperature and provide input to control body temperature, whereas the peripheral thermoreceptors provide the brain with information about changes in environmental temperature. The main temperature control center is also located in the hypothalamus. The most important effectors are the sympathetic nerves to sweat glands, arterioles of the skin, and the adrenal medulla, as well as motor neurons to skeletal muscles. Heat production in humans is usually by metabolism. The basal metabolic rate can be altered by circulating thyroid hormone (see Chapter 63), and by shivering thermogenesis, driven by innervation of skeletal muscle. Shivering is the rhythmic, involuntary contraction and relaxation of skeletal muscles that generates heat due to increased metabolic rate. Of course, one can voluntarily increase heat production from skeletal muscle with movement.

ADAPTATION TO A HOT OR COLD ENVIRONMENT Humans can adapt to a variety of environments. You will learn in the next chapter that humans can adapt when chronically exposed to low oxygen (hypoxia) at altitude. Humans also have the ability to adapt to changes in environmental temperature. Adaptation to a hot environment is much better understood than adaptation to a cold environment. Most people have difficulty when first exposed to a very hot environment and have difficulty exercising. The core temperature can increase and a feeling of malaise and weakness can ensue. Heat stroke can occur if core temperature increases above 41°C and body functions begin to fail. After days to weeks of exposure to a hot environment, people do better—this process of acclimatization allows us to improve performance

CHAPTER 70 Control of Body Temperature

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Voluntary motor responses Begin

Begin

Cerebral cortex Skin temperature

Core temperature

Peripheral thermoreceptors

Central thermoreceptors

Hypothalamus Involuntary motor responses

Via sympathetic nerves

Adrenal medulla

Via motor nerves

Sweat glands

Skin arterioles

Skeletal muscles

Epinephrine

FIGURE 70–1 Summary of temperature-regulating mechanisms beginning with peripheral and central thermoreceptors. The dashed arrow from the adrenal medulla indicates that this pathway is of minor importance in humans. (Reproduced with permission from Widmaier EP, Raff H, Strang KT: Vander’s Human Physiology, 11th ed. McGraw-Hill, 2008.)

during hot weather. When the environment is warmer than skin temperature, the only efficient way to lose heat is by increased evaporation from sweating. Over a few months in a hot environment, the ability to sweat increases dramatically (up to a 4-fold increase). Since sweat contains electrolytes, and specifically sodium, an increase in blood aldosterone occurs, which not only increases sodium reabsorption in the kidney (see Chapter 44), but also increases sodium and chloride reabsorption from sweat in the sweat glands. The increase in aldosterone can lead to hypokalemia due to increased renal potassium excretion and loss of potassium in sweat, however, so increased dietary potassium intake is important during acclimatization to a hot environment. This is particularly true when working or exercising. You have probably observed marathon runners lose the ability to function when performing heroic exercise in a hot environment, particularly when they have not had time to acclimatize to hot weather. The adaptation to a cold environment is not as well understood particularly since modern humans have the ability to wear highly efficient warm clothing and to heat their environments. It is known that constriction of the blood vessels in the skin and the inhibition of sweat production does minimize heat lost to a cold environment. There may be the ability to increase basal metabolic rate, although the role of changes in hormones such as catecholamines and thyroid hormone in this response is controversial. Probably the most common cause of lethal hypothermia is immersion in cold water for an extended period of time. Wearing a wetsuit is one way to avoid this.

FEVER Fever is an increase in body temperature that occurs usually due to a pathophysiological process such as infection. It is due to an increase in the hypothalamic set point for temperature so that body temperature increases to a new plateau at which body temperature is then regulated. Although infection is the most common cause of fever, there are other etiologies including a form of severe hyperthyroidism called thyroid storm (see Chapter 63). Figure 70–2 summarizes the development of fever due to infection. Pyrogens are circulating factors that cause fever. Although some bacteria release exogenous pyrogens such as lipopolysaccharides (endotoxins), the unifying cause of fever during infection is the release of small proteins called endogenous pyrogens from macrophages and other immune cells. Macrophages activated during infection are an integral part of the immune response. Examples of endogenous pyrogens are cytokines such as the interleukins and tumor necrosis factor. These endogenous pyrogens can activate vagal afferents to the hypothalamus, and can also circulate to the brain to directly alter the hypothalamic set point for temperature. Since these pyrogens are peptides, they must be able to signal the hypothalamus despite the existence of the blood–brain barrier. One theory to explain this is that the areas in the brain that can sense cytokines, such as the circumventricular organs near the hypothalamus, have a “leaky” blood–brain barrier (see Chapter 27). Endogenous pyrogens can be sensed and the

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SECTION X Integrative Physiology

Infection

Liver Macrophages

Multiple organs Macrophages

Secrete endogenous pyrogens (IL–1, IL–6, ? others)

Secrete endogenous pyrogens (IL–1, IL–6, ? others)

Firing of neural receptors

Plasma IL–1, IL–6, ? others

Vagus nerve

Systemic circulation

Hypothalamus Temperature setpoint

Skeletal muscles Curl up, put on clothes Shivering and blankets

Heat production

Skin arterioles Vasoconstriction

to curling up increase body temperature in the same way as exposure to cold. Although it is not known exactly why an increase in body temperature is beneficial during infection, it is thought that some of the cells of the immune system operate more efficiently at higher body temperature. When a fever “breaks” and the set point of the hypothalamus returns to normal, the body must dissipate heat to return body temperature to normal. Therefore, profuse sweating can occur as one recovers from the acute phase of an infection. There are a variety of drugs that can be used to lower temperature during a fever. Aspirin inhibits prostaglandin synthesis throughout the body. In addition to the action of prostaglandins in the resetting of the hypothalamic set point for temperature, local production of prostaglandins is thought to be involved in the muscle and joint aches that occur with fever, which is why aspirin is effective in treating those symptoms. Acetaminophen is a potent inhibitor of prostaglandin synthesis within the brain, so it also is effective in treating fever. Glucocorticoid therapy with drugs such as prednisone can also inhibit fever due to their inhibition of the immune response (see Table 65–2), as well as their inhibition of prostaglandin synthesis. If fever is long-lasting and excessive (>40°C [>104°F]), tissue damage and organ failure can ensue, so heroic measures may be instituted to lower body temperature. An example of this is immersion in cold water to decrease body temperature. Finally, high fever can be much more dangerous in the elderly.

Heat loss

CLINICAL CORRELATION Heat production greater than heat loss

Heat retention

Body temperature

FIGURE 70–2 Pathways by which infection causes fever. IL-1, interleukin 1; IL-6, interleukin 6. (Reproduced with permission from Widmaier EP, Raff H, Strang KT: Vander’s Human Physiology, 11th ed. McGraw-Hill, 2008.)

appropriate change in hypothalamic set point occurs, possibly due to release of prostaglandins in or near the hypothalamic controller that results in an alteration in the set point for body temperature. Once the hypothalamic set point is increased, the body temperature is lower than the set point, so the hypothalamus “thinks” that the body is too cold. The brain then activates all of the mechanisms previously described to increase body temperature when cold. This is why one can feel cold just before and during the onset of fever despite the fact that body temperature is normal or even increasing. The increase in heat production due to shivering and the decrease in heat loss due

A 32-year-old woman is brought into an emergency room by her husband. She is confused, and complaining of palpitations, (rapid, strong heart beats) shortness of breath, and excessive sweating. Her blood pressure and heart rate are markedly increased and her body temperature is dangerously high at 40.3°C. The woman is placed on a cooling bed to try to lower her body temperature. The emergency room doctor suspects an infection and orders the appropriate blood testing. However, a medical student notices that the woman’s eyes are bulging out and immediately suspects that the woman may have severe thyrotoxicosis (a pathological increase in thyroid hormone secretion). When the student interviews the patient and her husband, it is discovered that the woman always feels warm in a cold room and often has palpitations. Blood tests are immediately ordered and show a suppressed serum thyroid-stimulating hormone (TSH) and an increased serum thyroxine level indicating primary hyperthyroidism. Hyperthyroidism is a very common disease, particularly in women. By far the most common cause is primary hyperthyroidism defined as an increase in thyroid gland function independent of TSH, the anterior pituitary hormone that controls most aspects of thyroid hormone synthesis and gland function. The most common cause of

CHAPTER 70 Control of Body Temperature

primary hyperthyroidism is Graves disease (see Chapter 63). It is caused by an autoimmune phenomenon in which antibodies that activate the TSH receptor on the thyroid follicular cell are produced and stimulate thyroid hormone synthesis and secretion just as TSH normally would. The increase in thyroid hormone in the blood then suppresses pituitary TSH release due to negative feedback. The immune dysfunction can also result in a lymphocytic infiltration of the muscles and fat behind the eyes. The resultant swelling pushes the eyes forward (away from the eye socket) resulting in the eyes bulging out—this is called proptosis or exophthalmos. To confirm the cause of thyrotoxicosis is Graves disease, a radioactive iodine uptake test is performed by having the patient ingest a small amount of radioactive iodine to measure the amount and distribution of iodine that accumulates in the thyroid gland. Iodine is required for the synthesis of thyroid hormone and its uptake is stimulated by activation of the TSH receptor (see Table 63–1 and Figure 63–3). The iodine uptake is uniformly increased in Graves disease and in our patient. The combination of the blood tests and uniformly increased thyroid uptake, plus other tests and physical findings such as proptosis, strongly suggests that the patient has Graves disease. In fact, her increase in body temperature, her mental confusion, and other symptoms define her as the most extreme form of thyrotoxicosis called thyroid storm. The short-term goal in treating this patient is decreasing her body temperature and heart rate. This is accomplished by giving drugs that decrease thyroid hormone synthesis, beta-adrenergic blocking drugs to lower her heart rate, stroke volume, and blood pressure, and glucocorticoid therapy that is immunosuppressive and also decreases the conversion of thyroxine to triiodothyronine the more potent endogenous thyroid hormone. The long-term goal is normalizing the thyroid function. This is usually accomplished by giving radioactive iodine to destroy the thyroid. Alternative therapies are drugs that inhibit thyroid hormone synthesis or, in an extreme case, a surgical thyroidectomy. Why was this woman’s body temperature so elevated? Thyroid hormone causes an increase in metabolic rate in virtually all organs of the body. This results in an increase in heat production. When severe enough, the ability to lose heat to the environment by sweating cannot keep up with the increase in heat produced by increased metabolism, and the body temperature increases. This can be extremely dangerous, and urgent treatment is usually required.

CHAPTER SUMMARY ■ ■

Internal body temperature is the central compartment of a mass balance system—heat loss usually equals heat gain. Heat transfer between the skin and environment occurs by radiation, conduction, convection, and evaporation.

■

■ ■

733

Feedback control of body temperature involves sensors (thermoreceptors) in the skin and hypothalamus, a central controller in the hypothalamus, and effectors consisting of autonomic (sympathetic) control of blood flow to the skin and sweat production. Adaptation to hot weather involves increasing the capacity to sweat to lose heat by evaporation. Fever due to infection results from pyrogens released from bacteria and from macrophages—these pyrogens increase the set point of the hypothalamic controller such that heat production and body temperature increase.

STUDY QUESTIONS 1. Which of the following will increase body temperature? A) an increase in heat loss from the skin to the environment B) a decrease in basal metabolic rate C) a decrease in circulating thyroid hormone D) shivering 2. All of the following are mechanisms to increase heat transfer from the skin to the environment except A) vasoconstriction B) radiation C) conduction D) convection 3. Which of the following is false? A) Sweating increases due to an increase in sympathetic nerve input. B) Skin arterioles vasoconstrict primarily due to input from motor nerves. C) The hypothalamus is the location of the central controller of body temperature. D) The hypothalamus is the location of the central thermoreceptors. 4. All of the following will reduce fever except A) aspirin-induced decrease in hypothalamic prostaglandin synthesis B) acetaminophen-induced decrease in hypothalamic prostaglandin synthesis C) an increase in endotoxin in the blood D) cortisol-induced suppression of immune function

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71 C

Hypoxia and Hyperbaria Michael Levitzky and Hershel Raff

H A

P

T

E

R

O B J E C T I V E S ■ ■ ■ ■ ■ ■

Discuss the physiologic responses to hypoxia and hyperbaria. Identify the physiologic stresses involved in the ascent to altitude. Predict the initial responses of the central nervous, cardiovascular, and respiratory systems to the ascent to altitude. Describe the acclimatization of the cardiovascular, respiratory, and renal systems to residence at high altitudes. Identify the physiologic stresses involved in diving. Predict the responses of the respiratory, cardiovascular, and renal systems to various types of diving.

HYPOXIA Hypoxia means low oxygen. As was discussed in Chapter 37, tissue hypoxia has many causes that can be classified into four main types (see Table 37–7). One of these is low arterial partial pressure of oxygen (“hypoxic hypoxia”) that may result from a low alveolar partial pressure of oxygen. Other causes of hypoxic hypoxia are described in Chapter 37. The most common reason for decreased inspired oxygen in a healthy individual is ascent to altitude.

ALTITUDE AND ACCLIMATIZATION The barometric pressure decreases at greater altitudes because the total pressure at any altitude is proportional to the weight of the air above it. There is a greater change in barometric pressure per change in altitude closer to the earth’s surface than at very great altitudes because air, which is attracted to the earth’s surface by gravity, is compressible. The fractional concentration of oxygen in the atmosphere does not change appreciably with altitude; it is therefore 21% of the total pressure of dry ambient air at any altitude. As

Ch71_735-744.indd 735

inspired air passes through the airways, it is warmed to body temperature and completely humidified. Therefore, the partial pressure exerted by the water vapor in the air entering the alveoli is 47 mm Hg. The alveolar Po2 can therefore be calculated by using the alveolar air equation discussed in Chapter 33: P

A Pao2 = Pio2 – ____ + [F] R co2

(1)

The inspired Po2 is equal to 0.21 times the total barometric pressure (if ambient air is breathed) after the subtraction of the water vapor pressure of 47 mm Hg: Pio2 = 0.21 × (PB – 47mm Hg)

(2)

The alveolar Pco2 decreases at greater altitudes because hypoxic stimulation of the arterial chemoreceptors increases alveolar ventilation (hyperventilation). As shown in Figure 71–1, the decrease in alveolar Pco2 brings the alveolar Po2 closer to the inspired Po2, as calculated by equation (1). For example, at an altitude of 15,000 ft, the total barometric pressure is about 429 mm Hg. The inspired Po2 is therefore 0.21 × (429 – 47) mm Hg, or 80.2 mm Hg. The alveolar Pco2 is likely to be decreased to about 32 mm Hg, resulting in a Pao2 of about 45 mm Hg. At 18,000 ft, the total barometric pressure is about 380 mm Hg; at 20,000 ft, it is 349 mm Hg.

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SECTION X Integrative Physiology

18

30 140 120

Inspired gas PO2

14 12

Alveolar gas PO2

10

100 80 Everest

Partial pressure (kPa)

16

CARDIOVASCULAR SYSTEM 25

8 6

60

Alveolar gas PCO2

40

Partial pressure (mm Hg)

5 Denver

20

0

Altitude (1000 feet) 10 15 20 Mt. Blanc Highest permanent habitation Silver hut

736

4 20

2 0

0

1

2

3

4 5 6 Altitude (km)

7

8

9

0

FIGURE 71–1 Calculated inspired and alveolar partial pressures of oxygen and carbon dioxide at rest plotted versus increasing altitude. Note that as increasing arterial chemoreceptor drive decreases alveolar PCO2, alveolar PO2 is closer to inspired PO2. (Adapted with permission from Lumb AB: Nunn’s Applied Respiratory Physiology, 5th ed. Oxford: Butterworth-Heinemann, 2000 [Figure 16.1, p. 359].)

ACUTE EFFECTS OF ALTITUDE Ascent to altitude causes significant alterations in the central nervous system, the cardiovascular system, the respiratory system, and the regulation of body fluids by the renal system. Because low temperatures are commonly encountered at altitude, the temperature regulatory mechanisms discussed in Chapter 70 are also usually involved. If a healthy person were to ascend rapidly to altitudes greater than 3,000–4,500 m (approximately 10,000–15,000 ft) above sea level, he or she would suffer a deterioration of nervous system function. Similar problems could occur if cabin pressure is lost in an airplane. The symptoms are mainly due to hypoxia; they may include sleepiness, laziness, a false sense of well-being, impaired judgment, blunted pain perception, increasing errors on simple tasks, decreased visual acuity, clumsiness, and tremors. Severe hypoxia may result in a loss of consciousness or even death. If an unacclimatized person (a person who has not adapted to being at altitude) ascends to altitudes greater than 3,000–4,500 m above sea level, he or she may suffer from a group of symptoms known collectively as acute mountain sickness. The symptoms include headache, dizziness, breathlessness at rest, weakness, malaise, nausea, anorexia, sweating, palpitations, impaired vision, partial deafness, sleeplessness, fluid retention, and dyspnea on exertion. These symptoms are a result of hypoxia and hypocapnia, and alkalosis or cerebral edema, or both.

There is an increase in cardiac output, heart rate, and systemic blood pressure at altitude. These effects are probably a result of increased sympathetic stimulation of the cardiovascular system secondary to arterial chemoreceptor stimulation. There may also be a direct stimulatory effect of hypoxia on the myocardium. Alveolar hypoxia results in hypoxic pulmonary vasoconstriction (see Chapter 34). The increased cardiac output, along with hypoxic pulmonary vasoconstriction and sympathetic stimulation of larger pulmonary vessels, results in an increase in mean pulmonary artery pressure and tends to abolish any preexisting zone 1 (see Figure 34–7) by recruiting previously unperfused capillaries. Undesirable consequences of these effects include vascular distention and engorgement of the lung secondary to the pulmonary hypertension, which may lead to highaltitude pulmonary edema and a greatly increased right ventricular workload. People who are more susceptible to high-altitude pulmonary edema also seem to have greater hypoxic pulmonary vasoconstriction responses than less susceptible individuals. Analysis of high-altitude pulmonary edema fluid shows that it contains large-molecular-weight proteins, which indicates that the edema is caused by increased capillary permeability as well as increased capillary hydrostatic pressure. The increased capillary permeability may result from capillary stress failure caused by high pulmonary artery pressure and blood flow and by altered release of cytokines or other mediators. The effects of ascent to high altitude on the cerebral circulation are complex. Hypoxic stimulation of the arterial chemoreceptors causes hypocapnia and respiratory alkalosis, as already discussed. Cerebral arterial hypocapnia not only could cause constriction of the cerebral blood vessels, but would also cause alkalosis of the cerebrospinal fluid. Most of the central nervous system symptoms of acute mountain sickness could be attributed to cerebral hypoperfusion, alkalosis, or both. However, it now appears that in most cases the symptoms of acute mountain sickness result from cerebral hyperperfusion and edema. This hyperperfusion is mainly a result of vasodilation, which is the direct effect of hypoxia on the cerebral blood vessels. As the cerebral arterioles dilate, the hydrostatic pressure in the cerebral capillaries increases, increasing the tendency of fluid to leave the cerebral capillaries and cause cerebral edema. The hyperperfusion and cerebral edema increase intracranial pressure, compressing and distorting intracranial structures. This may lead to a general increase in sympathetic activity in the body, increasing the possibility of pulmonary edema and promoting renal salt and water retention.

RESPIRATORY SYSTEM The decreased arterial partial pressures of oxygen that occur at altitude stimulate the arterial chemoreceptors and increase

CHAPTER 71 Hypoxia and Hyperbaria alveolar ventilation; the central chemoreceptors are not responsive to hypoxia, as was discussed in Chapter 38. Although the arterial chemoreceptors are not very sensitive to changes in arterial Po2 above approximately 60 mm Hg (see Figure 38–8), at an arterial Po2 of 45 mm Hg, minute ventilation is approximately doubled. Because carbon dioxide production is initially normal (it does increase with the increased work of breathing caused by greater alveolar ventilation), alveolar and arterial Pco2 decrease to approximately 20 mm Hg, causing respiratory alkalosis. Arterial hypocapnia also results in “diffusion” of carbon dioxide from the cerebrospinal fluid into the blood (see Figure 38–6), causing an increase in the pH of the cerebrospinal fluid. Therefore, not only are the central chemoreceptors unresponsive to the hypoxia of altitude, but their activity is also depressed by the secondary hypocapnia and the alkalosis of the cerebrospinal fluid. Increased tidal volumes and respiratory rates increase the elastic work of breathing. High ventilatory rates may be accompanied by active expiration, resulting in dynamic compression of airways. This airway compression, coupled with arterial chemoreceptor-mediated reflex parasympathetic bronchoconstriction in response to the arterial hypoxemia, results in increased resistance work of breathing. More turbulent airflow, which is likely to be encountered at higher ventilatory rates, may also contribute to increased resistance work. Maximum airflow rates may increase because of decreased gas density at altitude. The deeper inspirations and expirations would likely result in a more uniform regional distribution of alveolar ventilation; previously collapsed or poorly ventilated alveoli would be better ventilated. The increased pulmonary blood flow seen acutely at high altitude, coupled with the more uniform alveolar ventilation, would be expected to improve regional ventilation–perfusion matching. Surprisingly, studies have not shown striking differences in VA/Qc relationships at high altitude, although they do appear to improve. At high altitude, the partial pressure gradient for oxygen diffusion is decreased because the alveolar Po2 is decreased more than the mixed venous Po2. This decrease in the partial pressure gradient is partly offset by effects of increases in cardiac output and increased pulmonary artery pressure, which increase the surface area available for diffusion by recruitment of unperfused capillaries and decrease the time erythrocytes spend in pulmonary capillaries. Oxygen loading in the lung may be compromised at alveolar partial pressures of oxygen low enough to be below the flat part of the oxyhemoglobin dissociation curve (see Figure 36–1), causing a low arterial oxygen content. Hypocapnia may aid somewhat in oxygen loading in the lung but will interfere with oxygen unloading at the tissues (see Figure 36–2). The main short-term compensatory mechanism for maintenance of oxygen delivery is the increased cardiac output. The hemoglobin concentration may also increase slightly within the first 2 days. This is a result of hemoconcentration secondary to fluid shifting into the extravascular space, not an increase in erythrocyte production.

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Prevention and Treatment of Acute Mountain Sickness Acetazolamide, a carbonic anhydrase inhibitor, taken for a few days before ascending to altitude can prevent the symptoms of acute mountain sickness in many people. The mechanism by which it does this is unclear because acetazolamide has several actions that may help prevent acute mountain sickness. It decreases reabsorption of bicarbonate by the proximal tubule of the kidney. This may lead to a moderate metabolic acidosis that may partly offset the respiratory alkalosis and therefore also help stimulate ventilation. Acetazolamide is also a diuretic, so it may help prevent fluid retention and edema. It is likely that both proposed mechanisms are involved. Acetazolamide may also inhibit hypoxic pulmonary vasoconstriction. By far the most important treatment of acute mountain sickness is increasing alveolar Po2. This can be performed at altitude by breathing increased concentrations of oxygen from a gas cylinder. Descent to lower altitudes is most effective in treating acute mountain sickness.

Acclimatization to Altitude Longer-term compensation to high altitude begins to occur after several hours of ascent and continues for days or even weeks. The immediate responses to the ascent and the early and late adaptive responses are summarized in Table 71–1. Renal compensation for respiratory alkalosis begins within a day: renal excretion of base is increased, and hydrogen ions are conserved. A second major compensatory mechanism is erythropoiesis. Within 3–5 days, new red blood cells are produced, increasing the hematocrit and the oxygen-carrying capacity. Much of this response is due to an increase in the secretion of the hormone erythropoietin from the kidney due to local renal hypoxia; erythropoietin then stimulates red cell production in bone marrow (see function 5 in Chapter 39). (Commonly known as “Epo,” this protein is available for injection and has been used for “blood doping” in athletes.) Thus, although the arterial Po2 is not improved, the arterial oxygen content increases because of the increased blood hemoglobin concentration. This is at the cost of a higher blood viscosity and ventricular workload. Increased concentrations of 2,3-BPG (DPG) may help release oxygen at the tissues (Figure 36–2). Hypoxic stimulation of the arterial chemoreceptors persists and may be augmented during the acclimatization. A more immediate finding is that the ventilatory response curve to carbon dioxide shifts to the left (Figure 38–4). That is, for any given alveolar or arterial Pco2, the ventilatory response is greater after several days at high altitude. The current theory for the increase in ventilation that occurs during acclimatization is that carotid body chemoreceptor sensitivity to hypoxia increases through cellular mechanisms that are not well established. The increase in alveolar ventilation results in an increase in alveolar, and hence arterial, Po2. It is this adaptive response that allows people to live at altitude for long periods of time. The central nervous system symptoms usually abate at the same time as the resolution of

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TABLE 71–1 Physiologic responses to high altitude relative to sea-level control values.a Immediate

Early Adaptive (72 Hours)

Late Adaptive (2–6 Weeks)

↑

↑

↑

Variable

Variable

Variable

Tidal volume

↑

↑

↑

Arterial PO2

↓

↓

↓

Arterial PCO2

↓

↓

↓

Arterial pH

↑

↑↔

↑↔

Arterial HCO3−

↔

↓

↓

Vital capacity

↔

↔

↔

Maximum airflow rates

↑

↑

↑

Functional residual capacity

↔

↔

↔

Ventilatory response to inhaled CO2

↔

↑

↑

Ventilatory response to hypoxia

↔

↔

↔

Pulmonary vascular resistance

↑

↑

↑

Hemoglobin

↔

↑

↑

Erythropoietin

↑

↔

↔

P50

↓

↑

↑

2,3-BPG

↔

↑

↑

Cardiac output

↑

↔

↔↓

Headaches, nausea, insomnia

↑

↔

↔

Perception, judgment

↓

↔

↔

Cerebral edema

↑

↔

↔

Minute ventilation Respiratory rate

Evaluation of lung function

Oxygen transport

Central nervous system

a

These values apply to native sea-level inhabitants. ↑, increased; ↓, decreased; ↔, no change.

Adapted with permission from Guenter CA. Pulmonary Medicine, 2nd ed. Philadelphia, PA: Lippincott; 1982.

the cerebral edema and higher intracranial pressure. This is likely due to increased reabsorption of cerebrospinal fluid, autoregulation of cerebral blood flow, and a sympathetically mediated vasoconstriction that for some reason takes several days to develop. It is also possible that the cerebral vessels produce less nitric oxide, which may mediate the cerebral vasodilatation in response to hypoxia (see Chapter 27). The increased cardiac output, heart rate, and systemic blood pressure return to normal levels after a few days at high altitude. This probably reflects a decrease in sympathetic activity or downregulation of adrenergic receptors. Nevertheless, hypoxic pulmonary vasoconstriction and pulmonary hypertension persist (along with increased blood viscosity due to higher hematocrit), leading to right ventricular hypertrophy and frequently chronic cor pulmonale (right ventricular failure secondary to pulmonary hypertension).

HYPERBARIA Hyperbaria means increased ambient pressure. Healthy people can experience hyperbaric conditions during underwater diving. Hyperbaric chambers are used clinically to increase ambient gas pressures as treatment for decompression illness (discussed below) or to enhance wound healing (hyperbaric oxygen therapy or HBOT).

DIVING The major physiologic stresses involved in diving include increased ambient pressure, decreased effects of gravity because of buoyancy, altered respiration, hypothermia, and sensory impairment. The severity of the stress depends on the

CHAPTER 71 Hypoxia and Hyperbaria depth attained, the length of the dive, and whether the breath is held or breathing apparatus is used. The physiologic stresses of elevated ambient pressure, decreased effects of gravity, and altered respiration are the focus of this discussion.

PHYSICAL PRINCIPLES The pressure at the bottom of a column of liquid is proportional to the height of the column (h), the density of the liquid (ρ), and the acceleration of gravity (g): Pressure = h × p × g

(3)

For example, for each 10 m (33 ft) of seawater, ambient pressure increases by 1 atm. Thus, at a depth of 10 m of seawater, total ambient pressure is equal to 1,520 mm Hg or twice the barometric pressure at sea level. The tissues of the body are composed mainly of water and are therefore incompressible, but gases are compressible and follow Boyle’s law. Thus, in a breath-hold dive, the volume of gas in the lungs is inversely proportional to the depth attained. At 10 m of depth (2 atm), lung volume is cut in half; at 20 m (3 atm), it is one third the original lung volume. As a gas is compressed, its density increases. As the total pressure increases, the partial pressures of the constituent gases also increase, according to Dalton’s law (see Chapter 33). The biologic effects of gases are generally dependent on their partial pressures rather than on their fractional concentrations. Also, as the partial pressures of a gas increases, the amount dissolved in the tissues of the body increases, according to Henry’s law (see Chapter 35).

EFFECTS OF IMMERSION UP TO THE NECK Merely immersing oneself up to the neck in water causes profound alterations in the cardiovascular and pulmonary systems. These effects are mainly a result of an increase in pressure outside the thorax, abdomen, and limbs.

Cardiovascular and Renal Effects During immersion up to the neck, increased pressure outside the limbs and abdomen results in less pooling of systemic venous blood in gravity-dependent regions of the body (see Chapter 30). If the water temperature is below body temperature, a sympathetically mediated venoconstriction occurs, also augmenting venous return (see Chapter 70). The increased venous return increases the central blood volume by approximately 500 mL. Right atrial pressure increases from about –2 to +16 mm Hg. As a result of this increase in preload, the cardiac output and stroke volume increase by about 30%. The increases in pulmonary blood flow and pulmonary blood volume result in increased mean pulmonary artery pressure, capillary recruitment, an increase in the diffusing capacity, and a somewhat improved matching of ventilation and perfusion.

739

An additional effect of neck-deep immersion is immersion diuresis. Within a few minutes of immersion, urine flow increases 4–5-fold. These findings are consistent with stimulation of stretch receptors in the cardiac atria and elsewhere in thoracic vessels by the increased thoracic blood volume. This, in turn, is believed to decrease the secretion of antidiuretic hormone (ADH) by the posterior pituitary gland or to cause the release of natriuretic hormones from the cardiac atria (see Chapter 45).

Respiratory Effects The pressure outside the chest wall of a person standing or seated in neck-deep water is greater than atmospheric, averaging about 20 cm H2O (14.7 mm Hg). This positive pressure outside the chest opposes the normal outward elastic recoil of the chest wall and decreases the functional residual capacity by about 50%. This occurs at the expense of the expiratory reserve volume, which may be decreased by as much as 70%. The intrapleural pressure is less negative at the functional residual capacity because of decreased outward elastic recoil of the chest wall. The work that must be done to bring air into the lungs is greatly increased because extra inspiratory work is necessary to overcome the positive pressure outside the chest. Immersion up to the neck in water results in an increase in the work of breathing by about 60%. The hydrostatic pressure effects of water outside the chest prevent a submerged person, who is trying to breathe through a tube that is communicating with the air above the surface of the water, from descending more than about 3 ft. This is true even if the increased airway resistance offered by the tube were negligible and if the person avoided increasing the effective dead space by occluding the mouth end of the tube and exhaling directly into the water (or by using a one-way valve). The reason is that the maximal inspiratory pressure that normal individuals can generate is about 80–100 cm H2O (i.e., intrapleural pressures of –80 to –100 cm H2O). Because 100 cm is 1 m (39.37 in), the maximum depth a person can attain while breathing through a tube in this manner is a little more than 1 m (3 ft).

BREATH-HOLD DIVING During a breath-hold dive, the total pressure of gases within the lungs is approximately equal to the increased ambient pressure. Therefore, the volume within the thorax must decrease proportionately and partial pressures of gases must increase.

The Diving Reflex Many subjects demonstrate a profound vagally mediated bradycardia (decreased heart rate) and increased systemic vascular resistance with face immersion (especially into cold water), as well as apnea. This “diving reflex” is initiated by sensors in the face or nose with afferents to the brain via the trigeminal nerves. A similar response is seen when

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SECTION X Integrative Physiology

Face immersion

FIGURE 71–2

The author’s (MGL) electrocardiographic response to face immersion in ice water (the diving reflex). The experiment was performed in the prone position, and face immersion was performed without changing the position of the head to avoid the effects of changes in baroreceptor activity. The heart rate decreased from about 75 to about 43 beats/min. (Time between the vertical ticks above or below the ECG = 3sec.) (Reproduced with permission from Levitzky MG: Pulmonary Physiology, 7th ed. New York: McGraw-Hill Medical, 2007.)

aquatic mammals such as whales and seals dive. The reflex decreases the workload of the heart and severely limits perfusion to all systemic vascular beds except for the strongest autoregulators—namely, the heart and brain. The cardiovascular effects of the diving reflex are similar to those produced by stimulation of the arterial chemoreceptors when no increase in ventilation can occur, except that the diving reflex also appears to cause the spleen to slowly contract, which releases erythrocytes stored in the spleen into the venous blood. This increases the oxygen-carrying capacity of the blood and therefore the oxygen content of the blood at the same arterial Po2. The bradycardic component of the diving reflex is demonstrated in Figure 71–2.

Gas Exchange Breath-hold divers usually hyperventilate before a dive so that the typical alveolar Po2 and Pco2 might be 120 and 30 mm Hg, respectively. Indeed, breath-hold divers must take care not to hyperventilate so much that their Pco2 gets so low that they do not reach their “breakpoint” until after they lose consciousness from arterial hypoxemia. (The breakpoint is the point at which an individual can no longer voluntarily hold his or her breath, which is mainly determined by Paco2.) During a breath-hold dive to a depth of 10 m (33 ft), lung volume decreases and gases are compressed. Total gas pressure approximately doubles: thus, after 20 seconds at 10 m, the alveolar Po2 may be 160–180 mm Hg; even after 1 minute at 10 m, the alveolar Po2 is well above 100 mm Hg. The alveolar Pco2 (that would be less than 40 mm Hg at the surface because of hyperventilation before the dive) also increases to above 40 mm Hg during descent, reversing the gradient for CO2 transfer. Carbon dioxide therefore diffuses from the alveoli into the pulmonary capillary blood. The alveolar Pco2 therefore does not increase as much as would be predicted by the compression of gases caused by the increased pressure as CO2 diffuses into the blood. This is believed to result from the much greater solubility of CO2 than O2 in the blood. Thus, the transfer of oxygen from alveolus to blood is undisturbed until ascent; however, the normal transfer of carbon dioxide from blood

to alveolus is reversed during descent and results in significant retention of carbon dioxide in the blood. During ascent, the ambient pressure decreases rapidly, lung volume increases, and alveolar gas partial pressures decrease accordingly. Alveolar Pco2 decreases, allowing CO2 to diffuse from pulmonary capillary blood into the alveoli. However, the rapid decrease in alveolar Po2 during ascent may result in a decrease in arterial Po2 sufficient to cause the breath-hold diver to lose consciousness. This loss of consciousness can occur rapidly and without warning and usually occurs as divers ascend to a depth of approximately 5 m or less. It is therefore known as “shallow water blackout.”

THE USE OF UNDERWATER BREATHING APPARATUS Self-contained underwater breathing apparatus, or scuba gear, mainly consists of a tank of compressed gas that can be delivered by a demand regulator to the diver when the diver’s mouth pressure decreases during inspiration to slightly less than the ambient pressure. Expired gas is simply released into the water as bubbles. Therefore, during a dive with scuba gear, gas pressure within the lungs remains close to the ambient pressure at any particular depth. As a result, the physiologic stresses on the respiratory system during scuba diving are mainly a consequence of elevated gas densities and partial pressures. During scuba diving, the inspiratory work of breathing is not a great problem at moderate depths because gas is delivered at ambient pressures. At very great depths, however, increased gas density becomes a problem because it increases the airway resistance work of breathing during turbulent flow. For example, in long-term experiments performed with subjects simulating dives of over 600 m (2,000 ft) inside hyperbaric chambers, all subjects reported that they could breathe only through their mouths; the work of breathing through the nose was too great. This is one reason for replacing nitrogen with helium for deep dives. Helium is only about one seventh as dense as nitrogen. The respiratory control system’s sensitivity to carbon dioxide is decreased at great depths because of increased gas

CHAPTER 71 Hypoxia and Hyperbaria densities and high arterial Po2 and because divers learn to suppress carbon dioxide stimuli to conserve compressed gas.

CLINICAL PROBLEMS ASSOCIATED WITH DIVING Clinical problems that may be encountered in diving, particularly to great depths, include barotrauma, decompression illness, nitrogen narcosis, oxygen toxicity, and high-pressure nervous syndrome (HPNS). Barotrauma occurs when ambient pressure increases or decreases, but the pressure in a closed unventilated area of the body that cannot equilibrate with ambient pressure does not. The barotrauma of descent is called “squeeze.” It can affect the middle ear, if the Eustachian tube is clogged or edematous, so that a person cannot equilibrate pressure in the middle ear; the sinuses; the lungs, resulting in pulmonary congestion, edema, or hemorrhage; and even cavities in the teeth. The barotrauma of ascent can occur if gases are trapped in areas of the body and begin to expand as the diver ascends. If a diver does not exhale while ascending, expanding pulmonary gas may overdistend and rupture the lung (“burst lung”). This may result in hemorrhage, pneumothorax, or air embolism. Gases trapped in the gastrointestinal tract may cause abdominal discomfort and eructation (belching) or flatus as they expand. Barotrauma of the ears, sinuses, and teeth may also occur on rapid ascent from great depths. Decompression illness occurs when gas bubbles form in the blood and body tissues as the ambient pressure decreases. The term “decompression illness” encompasses two different problems, both of which involve gas bubbles. Arterial gas embolism is gas bubbles in the arterial blood. Because bubbles do not seem to form in the arterial blood itself, arterial gas embolism usually occurs when airway obstruction prevents expanding gas from being exhaled. As expanding alveoli rupture, gas bubbles may enter pulmonary capillaries and be carried into the arterial blood. Arterial gas embolism is a likely consequence of an ascending diver neglecting to exhale on rapid ascent. Bubbles resulting from arterial gas embolism may be carried to cerebral blood vessels where they may cause a stroke. The second component of decompression illness, decompression sickness, occurs when bubbles form in tissues of the body. During a dive, the increasing ambient pressure causes an elevation of the partial pressure of nitrogen in the body. The high partial pressure of nitrogen causes this normally poorly soluble gas to dissolve in the body tissues and fluids according to Henry’s law (discussed in Chapter 35). This is especially the case in body fat, which has a relatively high nitrogen solubility. At great depths, body tissues become supersaturated with nitrogen. During a fast ascent, ambient pressure decreases rapidly and nitrogen comes out of solution, forming bubbles in body tissues and fluids. The effect is the same as opening a bottle of a carbonated beverage. During the production of a carbonated beverage, it is exposed to higher-than-atmospheric pressures

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of gases, mainly carbon dioxide, and then capped. The total pressure in the gas layer above the liquid remains greater than atmospheric pressure. The partial pressures of gases dissolved in the liquid phase are in equilibrium with the partial pressures in the gas phase. Gases dissolve in the liquid phase according to Henry’s law. When the bottle is uncapped, the pressure in the gas phase suddenly decreases and the gas dissolved in the liquid phase comes out of solution, forming bubbles. The bubbles formed in decompression sickness may enter the venous blood or affect the joints of the extremities. Bubbles that enter the venous blood are usually trapped in the pulmonary circulation and rarely cause symptoms. The symptoms that do occasionally occur, which are known as “the chokes” by divers, include substernal chest pain, dyspnea, and cough and may be accompanied by pulmonary hypertension, pulmonary edema, and hypoxemia. This is obviously an extremely dangerous form of decompression illness. Even more dangerous, of course, are bubbles in the circulation of the central nervous system, which may result in brain damage and paralysis. They may result from alveolar rupture and arterial gas embolism, as discussed previously, or be carried from the venous blood to the arterial side through a patent foramen ovale (see Chapter 30) or an intrapulmonary shunt. Bubbles that form in the joints of the limbs cause pain (“the bends”). Osteonecrosis of joints may also be caused by inadequate decompression. The treatment for decompression illness is immediate recompression in a hyperbaric chamber that forces the gas in bubbles back into solution, followed by slow decompression. Decompression illness may be prevented by slow ascents from great depths (using decompression tables) and by substituting helium for nitrogen in inspired gas mixtures. Helium is only about half as soluble as nitrogen in body tissues. Gas bubbles, although they are sterile, are perceived by the body as foreign. They elicit inflammatory and other responses, including platelet activation, blood clotting, the release of cytokines and other mediators, leukocyte aggregation, free radical production, and endothelial damage. These responses are not reversed by recompression and may continue unless additional treatment is initiated. Divers who ascend from submersion with no immediate effects of decompression may subsequently suffer decompression illness if they ride in an airplane within a few hours of the dive. Commercial airplanes normally maintain cabin pressures well below 760 mm Hg, with cabin pressures similar to those at altitudes 5,000–8,000 ft above sea level. This is why people with pulmonary impairment may need to use supplemental oxygen during an airplane flight. Very high partial pressures of nitrogen directly affect the central nervous system, causing euphoria, loss of memory, clumsiness, and irrational behavior. This nitrogen narcosis or “rapture of the deep” occurs at depths of 30 m (100 ft) or more and at greater depths may result in numbness of the limbs, disorientation, motor impairment, and ultimately unconsciousness. The mechanism of nitrogen narcosis is unknown.

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Oxygen toxicity can be caused by inhalation of 100% oxygen at 760 mm Hg, or of lower oxygen concentrations at higher ambient pressures. It can cause central nervous system, visual system, and alveolar damage, although pulmonary manifestations are rare among divers. The mechanism of oxygen toxicity is controversial but probably involves the formation of superoxide anions or other free radicals. Exposure to very high ambient pressures, such as those encountered at very great depths (greater than 75 m), is associated with tremors, decreased mental ability, nausea, vomiting, dizziness, and decreased manual dexterity. This high-pressure nervous syndrome (HPNS) usually occurs when nitrogen has been replaced by helium to decrease gas density, prevent nitrogen narcosis, and help avoid decompression sickness. Small amounts of nitrogen added to the inspired gas mixture help counteract the problem. One hypothesis explaining HPNS is that the syndrome may result from alterations in cerebral neurotransmission. A person inside an intact submarine is not at risk for any of the clinical problems associated with diving discussed above. The rigid walls of a submarine allow its inhabitants to reside at an ambient pressure similar to that at the surface.

always lived at sea level because the increased pulmonary artery pressure and increased blood viscosity have greatly increased his right ventricular afterload. This has resulted in right ventricular hypertrophy, which explains his right axis deviation. This has resulted in right ventricular failure. As the right ventricle failed, it could no longer keep up with venous return, leading to increased venous pressure, which explains his distended jugular veins, and increased capillary hydrostatic pressure, particularly in lower parts of the body. This caused his peripheral edema. His headache, sleep difficulties, and problems with his memory are a result of insufficient oxygen delivery to his brain. The most effective treatment for chronic mountain sickness is to have the patient move to a lower altitude, but this may not be possible for psychosocial reasons. Other treatments may include repetitive removal of red blood cells, and possibly acetazolamide.

CHAPTER SUMMARY ■

CLINICAL CORRELATION Physicians on a medical mission in the mountains of South America treat a 65-year-old man who has lived at altitudes above 3,600 m (about 12,000 ft) since he was born. He has a chronic headache, feels dizzy and tired, has trouble remembering things, and does not sleep well. He is cyanotic (his skin and mucosa appear to be blue; see Chapter 36), and has peripheral edema. His jugular veins are distended even though he is sitting upright. An electrocardiogram indicates right axis deviation (a frontal plane mean electrical axis greater than +105°). The patient has chronic mountain sickness (also known as Monge’s disease) with chronic cor pulmonale. Chronic cor pulmonale is right ventricular failure secondary to pulmonary hypertension, in this case exacerbated by polycythemia (increased hematocrit resulting from increased production of red blood cells). His pulmonary hypertension is mainly a result of the effects of chronic hypoxic pulmonary vasoconstriction, which not only causes constriction of pulmonary arterioles, but also causes structural changes in the affected blood vessels over time. He has polycythemia because of chronic hypoxemia leading to erythropoiesis. The increase in hematocrit resulted in higher blood viscosity. His low arterial Po2 combined with his increased hematocrit (see Chapter 36) explains his cyanosis. The workload of his right ventricle is much greater than that of a healthy individual who has

■

The main physiologic stresses of altitude are hypoxia and secondary hypocapnia and respiratory alkalosis; acclimatization occurs mainly by renal compensation for the respiratory alkalosis, erythropoiesis, elevated 2,3-BPG concentrations, and resolution of cerebral edema. The main physiologic stresses of diving are caused by increased ambient pressures causing gas compression, leading to increased partial pressures and densities and viscosities of gases.

STUDY QUESTIONS 1. Three hours after climbing from sea level to an altitude of 3,500 m, a healthy person breathing ambient air would likely have a lower-than-normal A) pulmonary artery pressure B) alveolar ventilation C) arterial pH D) arterial Pco 2 E) work of breathing 2. Which of the following would be lower-than-normal sea-level values in a healthy person breathing ambient air after 5 days at an altitude of 15,000 ft? A) plasma bicarbonate concentration B) hematocrit C) pulmonary vascular resistance D) 2,3-BPG (2,3-DPG) E) alveolar ventilation 3. Immersion in cold water up to the neck decreases A) the inspiratory work of breathing B) venous return C) the functional residual capacity D) the inspiratory reserve volume E) right atrial pressure

CHAPTER 71 Hypoxia and Hyperbaria 4. During the descent phase of a 1-minute breath-hold dive to a depth of 10 m A) lung volume is increasing B) alveolar pressure is increasing C) the partial pressure gradient for diffusion of oxygen from the alveoli into the pulmonary capillary blood is decreasing D) the partial pressure gradient for carbon dioxide diffusion from the pulmonary capillary blood into the alveoli is increasing

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5. When a healthy person immerses his or her face in cold water A) vagal tone to the cardiac pacemakers decreases B) sympathetic stimulation of most of the systemic vascular beds, except for the coronary and cerebral beds, increases C) heart rate increases D) systemic vascular resistance decreases

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72 C

Exercise Michael Levitzky and Kathleen H. McDonough

H A

P

T

E

R

O B J E C T I V E S ■ ■ ■

Identify the physiologic demands of exercise. Predict the physiologic responses to acute exercise. Describe the effects of long-term exercise programs (training) on the physiologic response to exercise.

Exercise increases the metabolism of the working muscles. Physical activity increases the requirement for oxygen and the production of carbon dioxide. Moderate to severe levels of exercise also cause increased lactic acid production. The respiratory and cardiovascular systems must increase the amount of oxygen supplied to the exercising tissues and increase the removal of carbon dioxide and hydrogen ions from the body. Although the muscular and cardiopulmonary systems are the primary responders to exercise, there are also adjustments in intermediary metabolism and fluid and electrolyte balance that allow the individual to maintain an increase in physical activity.

molecule of glucose (2 molecules when glucose is the substrate and 3 when the glucose-6-phosphate produced by hydrolysis of glycogen is the substrate), as opposed to the 32 molecules of ATP produced per molecule of glucose by oxidative phosphorylation. Therefore, anaerobic metabolism cannot be sustained for long periods of time. During strenuous exercise, glycolysis can maintain ATP production for muscular activity at least for a short time and, on completion of the exercise session, the oxygen debt is then repaid by the increased oxygen consumption that continues in spite of the cessation of the higher rate of skeletal muscle contraction. Lactate produced during the anaerobic phase can be converted to glucose by the liver and glycogen and triacylglycerol stores are subsequently restored.

MUSCLE METABOLISM During exercise, increases in cardiac output (CO) and the supply of substrates for energy are coordinated primarily by the sympathetic nervous system. Epinephrine increases glucose output from the liver and fatty acid output from adipose tissue, providing more substrate for oxidative metabolism by the exercising muscle. Muscle also has an intracellular supply of glycogen that provides glucose-6-phosphate for energy. Oxidative phosphorylation of glucose supports the initial few minutes of exercise and, during the intermediate phase, both glucose and fatty acids are used in approximately equal proportions. More prolonged exercise is mainly supported by fatty acid oxidation. With strenuous and prolonged exercise, oxygen delivery may be limiting and glycolysis and lactic acid formation become more important sources of energy. Anaerobic metabolism provides only 2–3 molecules of ATP per

Ch72_745-752.indd 745

ACUTE EFFECTS OF INCREASES IN PHYSICAL ACTIVITY The response to exercise in an untrained person is mainly a function of increased CO and alveolar ventilation to meet the demand for increased oxygen delivery and carbon dioxide and hydrogen ion removal.

CARDIOVASCULAR SYSTEM The CO increases during exercise to provide more blood flow to the exercising muscles. In most situations, blood flow to the skin increases in order to help dissipate the heat generated by muscle metabolism. CO increases nearly linearly with work

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Cardiac output (L/min)

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SECTION X Integrative Physiology

25

Trained

20

Untrained

5

Heart rate (beats/min)

Work rate 200

Untrained

Trained

70

Stroke volume (ml)

Work rate

Trained

125

Untrained 70

O2 consumption

FIGURE 72–1 Changes in cardiac output, heart rate, and stroke volume with increasing workload in untrained and trained individuals. (Reproduced with permission from Widmaier EP, Raff H, Strang KT: Vander’s Human Physiology, 11th ed. McGraw-Hill, 2008.)

rate up to 4–5-fold in a healthy untrained person during maximal exercise (Figure 72–1); it may increase even more in a trained athlete. The CO increases immediately with the onset of exercise or even in anticipation of exercise. The cerebral cortex initiates the command to exercise, resulting in increased skeletal muscle activity and metabolism (Figure 72–2). At the same time, the cerebral cortex exerts a “central command” on the medullary cardiovascular centers from corticohypothalamic pathways that decreases parasympathetic activity to the heart and increases sympathetic activity to the heart and blood vessels. The set point of the arterial baroreceptor reflex is increased, which allows arterial pressure to be regulated to a higher-than-resting level. It is also possible that chemoreceptor and mechanoreceptor afferents from active skeletal muscles influence the medullary cardiovascular centers. Such inputs would also contribute to the increases in sympathetic activity and mean arterial pressure that accompany exercise and may also contribute to increasing the baroreceptor reflex set point. Heart rate and stroke volume increase to support the increase in CO. Heart rate increases linearly with increasing work rate up to about three times that at rest; stroke volume does not increase linearly with workload, but plateaus at an increase of approximately 50%. The increase in heart rate is mediated by reduced parasympathetic and augmented sympathetic activity to the SA node; the increased stroke volume occurs primarily by a sympathetically mediated increase in myocardial contractility and ejection fraction, with the Frank–Starling mechanism (see Figure 24–4) playing a lesser role. The distribution of the left ventricular output changes during exercise to support increased local oxygen consumption (Figure 72–3). Blood flow to the exercising skeletal muscle

Begin

FIGURE 72–2

Control of the cardiovascular system during exercise. “Exercise centers” in the brain (mainly in the cerebral cortex and hypothalamus) adjust autonomic control to the heart and blood vessels and increase the baroreceptor reflex set point via the medullary cardiovascular center. Afferent input from mechanoreceptors and chemoreceptors in the exercising muscles also influences the medullary cardiovascular center. (Reproduced with permission from Widmaier EP, Raff H, Strang KT: Vander’s Human Physiology, 11th ed. McGraw-Hill, 2008.)

Brain “Exercise centers”

Arterial baroreceptors Reset upward

Exercising skeletal muscles Contractions

Medullary cardiovascular center

Afferent input

Afferent input Parasympathetic output to heart Sympathetic output to heart, veins, and arterioles in abdominal organs and kidneys

Cardiac output Vasoconstriction in abdominal organs and kidneys

Stimulate Local chemical mechanoreceptors changes in the muscles

Stimulate chemoreceptors in the muscles

Dilate arterioles in the muscle

Muscle blood flow

CHAPTER 72 Exercise

Flow at rest (ml/min) Brain

650 (13%)

Heart

215 (4%)

750 (4%) 750 (4%)

12,500 (73%)

Rest Minute ventilation (L/min)

Flow during strenuous exercise (ml/min)

Exercise

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Recovery

(2)

(1)

Skeletal muscle 1030 (20%) Skin

430 (9%)

Kidneys

950 (20%)

Time

FIGURE 72–4 Changes in ventilation during exercise. Note the instantaneous increase at the onset of exercise (1) and the instantaneous decrease at the end of exercise (2). (Reproduced with permission from Widmaier EP, Raff H, Strang KT. Van der’s Human Physiology. 11th ed. McGraw-Hill; 2008.)

Abdominal organs

1200 (24%)

Other

525 (10%)

Total

5000

1900 (11%)

600 (3%)

vascular resistance (SVR) caused by dilation of blood vessels supplying the exercising muscle:

600 (3%)

MABP – RAP = CO × SVR

400 (2%) 17,500

Right atrial pressure (RAP) does not usually change significantly during exercise; it may increase slightly during strenuous exercise because of the large increase in venous return (preload). The increased MABP is characterized by an increase in pulse pressure without a significant change in diastolic pressure. The pulse pressure mainly increases because of the greater stroke volumes noted above and because of more rapid aortic pressure development (increased dP/dt) caused by increased ventricular contractility. Furthermore, the set point for the baroreceptor reflex increases to allow the increased systemic blood pressure (see Figure 72–2).

FIGURE 72–3 Distribution of the left ventricular output at rest and during strenuous exercise. Flows at rest are typical for a 70-kg individual. The numbers in parentheses represent the percent of the total for each organ. (Reproduced with permission from Widmaier EP, Raff H, Strang KT. Van der’s Human Physiology. 11th ed. McGraw-Hill; 2008.)

(including the respiratory muscles), heart, and skin increases significantly, while blood flow to the kidneys, gastrointestinal tract, and other abdominal organs decreases significantly. Blood flow to the brain is not significantly altered. The increase in blood flow to the exercising muscles occurs primarily by local metabolic regulation; the increased blood flow to the skin occurs primarily by withdrawal of sympathetic tone. The decreased blood flow to the kidneys and other abdominal organs occurs by sympathetically mediated vasoconstriction. Venous return must increase in order for the CO to increase. Three mechanisms combine to increase venous return: increased activity in the exercising skeletal muscle compressing veins and squeezing blood through one-way valves toward the heart (the skeletal muscle pump), increased tidal volume and breathing frequency increasing the abdominal–thoracic pressure difference so that intrapleural pressure is more negative and abdominal pressure more positive during inspiration (the thoracoabdominal pump), and a sympathetically mediated increase in venous tone, which decreases venous capacitance. The dilation of skeletal muscle arterioles also lowers resistance to blood flow from the arterial to the venous vessels. Mean arterial blood pressure (MABP) increases moderately with increasing exercise, indicating that the increase in CO must be slightly greater than the decrease in systemic

(1)

RESPIRATORY SYSTEM Minute ventilation increases (hyperpnea) linearly with both oxygen consumption and carbon dioxide production up to a level of about 60% of the maximal work capacity. Above that, minute ventilation increases faster than oxygen consumption but continues to rise proportionally to the increase in carbon dioxide production. This increase in ventilation above oxygen consumption at high work levels is caused in part by the increased lactic acid production that occurs as a result of anaerobic metabolism. The hydrogen ions liberated in this process directly stimulate the arterial chemoreceptors. In addition, the buffering of hydrogen ions by bicarbonate ions results in production of carbon dioxide in addition to that derived from aerobic metabolism. The ventilatory response to constant work rate exercise consists of three phases (Figure 72–4). At the beginning of exercise, there is an immediate increase in ventilation, which may even occur in anticipation of physical activity. This is followed by a phase of slowly increasing ventilation, ultimately increasing to a final steady-state phase if the exercise is not too strenuous. The

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initial immediate increase in ventilation may constitute as much as 50% of the total steady-state response. The increase in minute ventilation is usually a result of increases in both tidal volume and breathing frequency. The mechanisms by which exercise increases minute ventilation are summarized in Table 72–1. No single factor can fully account for the ventilatory response to exercise, and much of the response remains unexplained. The immediate increase in ventilation occurs too quickly to be due to changes in metabolism or blood gases. This “neural component” consists in part of collateral fibers to the respiratory muscles from the motor cortex neurons that primarily innervate the exercising skeletal muscles. It may also be partly accounted for by a conditioned reflex; that is, a learned response to exercise. Input to the respiratory centers from proprioceptors located in the joints and muscles of the exercising limbs may play a role. The ventilatory and cardiovascular responses to exercise may be coordinated (and in part initiated) in an “exercise center” in the hypothalamus. The arterial chemoreceptors do not appear to play a role in the initial ventilatory response to exercise. In mild or moderate exercise, average arterial Pco2 and Po2 are not altered significantly (see Figure 72–5), even during the increasing ventilation phase (the “humoral component”). It is possible that the arterial chemoreceptors are responding to greater oscillations in the blood gases during exercise. Other potential afferent stimuli to ventilation during moderate exercise are summarized in Table 72–1. The work of breathing is increased during exercise. Larger tidal volumes result in increased work necessary to overcome the elastic recoil of the lungs and chest wall during inspiration because the lungs are less compliant at higher lung volumes and because the elastic recoil of the chest wall is inward at high thoracic volumes. The high airflow rates generated during exercise result in a much greater airway resistance component of the work of breathing because of greater turbulence and dynamic compression of airways secondary to active expiration. . In normal adults, the resting minute ventilation (VE ) of 5–6 L/min can be increased to as much as 150 L/min during short periods of maximal exercise. Maximal increases in CO during exercise are only in the range of four to five times the resting level in healthy adults compared with this 25-fold potential increase in minute ventilation. Therefore, it is the cardiovascular system rather than the respiratory system that is the limiting factor in exercise by healthy people. However, significant decreases in respiratory function that can occur with a variety of pulmonary diseases often limits exercise capacity. The breathing frequency may increase to 40–50 breaths/min in healthy adults (and as high as 70 breaths/min in children) with strenuous exercise. Arterial Pco2 is stable until anaerobic metabolism results in appreciable lactic acid generation (Figure 72–5). The hydrogen ions liberated directly stimulate alveolar ventilation via the arterial chemoreceptors and may cause arterial Pco2 to fall below the resting arterial Pco2. As CO increases, mean pulmonary arterial and mean left atrial pressures increase, but the increase is not as great as the

TABLE 72–1 Ventilatory response to exercise. Immediate response—“neural component” Central command Learned or conditioned reflex Direct connections from motor cortex—collaterals from motor neurons to muscles Coordination in hypothalamus Proprioceptors or mechanoreceptors in limbs—probably not muscle spindles or Golgi tendon organs Subsequent increase During moderate exercise Arterial chemoreceptors PO2—usually no change in mean PCO2—usually no change in mean [H+]—usually no change unless cross anaerobic threshold [K+]—released from exercising muscle cells could stimulate arterial chemoreceptors—minor role Oscillations in arterial PO2 and PCO2 Metaboreceptors Nociceptors—H+, K+, bradykinin, arachidonic acid released during exercise could stimulate pain receptors Cardiac receptors Venous chemoreceptors Temperature receptors During exercise severe enough to exceed anaerobic threshold Lactic acid buffered by HCO3− produces CO2 Arterial chemoreceptors ↑ PCO2 ↑ [H+] Central chemoreceptors ↑ PCO2 → ↑ H+ Potentiation of chemoreceptor responses during exercise Reproduced with permission from Levitzky MG: Pulmonary Physiology, 7th ed. New York: McGraw-Hill Medical, 2007.

increase in pulmonary blood flow. This indicates a decrease in pulmonary vascular resistance that occurs passively by recruitment and distention of pulmonary vessels. It results in more uniform distribution of pulmonary blood flow and more uniform matching of ventilation and perfusion throughout the lung. Because ventilation increases more than perfusion in moderate to strenuous . . exercise, the whole lung ventilation– perfusion ratio (VA /QC ) increases to a range of 2.0–4.0. Thus, the location of the perfusion is better matched to the location of the ventilation during exercise, but the ventilation–perfusion ratios increase in most alveolar–capillary units. The diffusing capacities for oxygen and carbon dioxide normally increase substantially during exercise. The increase in diffusing capacity during exercise is largely a result of the increase in pulmonary blood flow. Recruitment of capillaries, especially in upper regions of the lungs, increases the surface area available for diffusion. Increased linear velocity of blood flow through pulmonary capillaries reduces the time that red

CHAPTER 72 Exercise

the arterial chemoreceptors (especially the carotid bodies) and cause a further compensatory increase in alveolar ventilation, maintaining arterial pH near the normal level.

Minute ventilation (L/min)

100 80 60 40

FLUID AND ELECTROLYTE BALANCE

20

Arterial PCO2 (mmHg)

Arterial PO2 (mmHg)

0

Arterial [H+] (nmol/L)

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110 100 90 40

30

60 48 36

O2 consumption (ml/min) Rest

Maximal exercise

FIGURE 72–5 Effect of exercise on minute ventilation, arterial oxygen and carbon dioxide partial pressures, and arterial hydrogen ion concentration with increasing exercise workloads. Note that the average arterial carbon dioxide levels are not altered significantly until exercise is sufficiently strenuous to produce increased levels of lactic acid. As the additional hydrogen ions stimulate the arterial chemoreceptors, arterial carbon dioxide levels decrease; the individual is therefore hyperventilating. (Reproduced with permission from Widmaier EP, Raff H, Strang KT: Vander’s Human Physiology, 11th ed. McGraw-Hill, 2008.)

blood cells spend in contact with the alveolar air, decreasing the perfusion limitation of gas transfer. The alveolar–arterial oxygen difference usually increases during exercise. . .This is probably because of a number of factors, including VA /QC mismatch, diffusion limitation of gas transfer, a decreased mixed venous Po2 , an increased alveolar Po2 , and alterations in the oxyhemoglobin dissociation curve. The loading of carbon dioxide into the blood and the unloading of oxygen from the blood are enhanced in exercising muscles. Oxygen unloading is improved because the tissue Po2 in the exercising muscle is decreased, resulting in an increased diffusion gradient for oxygen. Oxygen unloading is also enhanced by the rightward shift of the oxyhemoglobin dissociation curve caused by the increased local Pco2 (the Bohr effect), hydrogen ion concentrations, and temperatures found in exercising muscle. Low capillary Po2 also leads to improved carbon dioxide loading because lower oxyhemoglobin levels shift the carbon dioxide dissociation curve to the left (the Haldane effect). Exercise strenuous enough to cause a significant degree of anaerobic metabolism results in metabolic acidosis secondary to the increased lactic acid production. As discussed previously, the hydrogen ions generated by this process stimulate

Exercise causes a decrease in plasma volume, particularly if the exercise is performed in a warm environment. The increased metabolism generates heat. As was discussed in Chapter 70, evaporation of water in perspiration produced by sweat glands is a primary mechanism of heat loss by the body. A 70-kg person can lose more than 2 L/h of water via perspiration. A second cause of decreased plasma volume during exercise is increased filtration of plasma fluid from capillaries into the interstitial space. Capillary hydrostatic pressure increases in exercising muscles because of arteriolar vasodilation and to a lesser extent because MABP increases. Also, the circulating blood volume decreases because as body temperature increases, compliance of the veins of skin increases to help dissipate heat, resulting in a greater amount of blood in the skin. Perspiration is hypotonic to plasma, so relatively more water is lost than ions. The composition of sweat is variable from person to person and is also dependent on the rate of sweat production. At higher flows, sweat contains increased concentrations of sodium and chloride, and less potassium although it remains hypotonic to plasma. Training (see the next section) and heat acclimatization lead to production of more dilute sweat, which helps conserve sodium and chloride and increase exercise tolerance; this effect is probably mediated by aldosterone release in response to sodium ion loss. Ingesting sodium chloride with water improves recovery from exercise and/or heat stress dehydration. Drinking water without salt decreases extracellular fluid osmolality and decreases thirst, delaying rehydration. This is the basis of sports drinks that contain sodium chloride and potassium; some also contain carbohydrates for energy. However, overhydration causing dangerous hyponatremia during exercise is a significant problem particularly in those new to strenuous, sustained exercise.

TRAINING EFFECTS The ability to perform physical exercise increases with training. Most of the changes that occur as a result of physical training are a function of alterations in the cardiovascular system and in muscle metabolism (Figure 72–1). The maximal oxygen uptake increases with physical training mainly as a result of a higher maximal CO. As stated earlier, the maximal CO is probably the limiting factor in exercise. Physical training decreases the resting heart rate and increases the resting stroke volume; an elite cross-country skier can have a resting heart rate as low as 40 beats/min. The maximal heart rate does not appear to be affected by physical training, but the heart rate of a trained person is lower than that of an untrained person at most levels of physical activity. Stroke volume is increased.

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The arterial hemoglobin concentration and the hematocrit do not appear to change with physical training at sea level, but the arteriovenous oxygen content difference can increase with physical training. This is probably a function of the greater effects of local pH, Pco2 , and temperature in the exercising muscles, as well as an increased ability of the muscles to use oxygen. Blood volume is usually higher after an exercise– training program. Physical training augments the oxidative capacity of skeletal muscle by inducing mitochondrial proliferation and increasing the concentration of oxidative enzymes and the synthesis of glycogen and triglyceride. These alterations result in lower concentrations of blood lactate in trained subjects than those found in untrained people, reflecting increased aerobic energy production. Nevertheless, blood lactate levels during maximal exercise may be higher in trained athletes than in untrained people. Maximal ventilation and resting ventilation do not appear to be affected by physical training, but ventilation at submaximal loads is decreased, probably because of the lower lactic acid levels of the trained person during submaximal exercise. The strength and endurance of the respiratory muscles appear to improve with training. Total lung capacity is not affected by training; vital capacity may be normal or elevated. Pulmonary diffusing capacity is often elevated in athletes, probably as a result of their increased blood volumes and maximal COs. There are many changes in other physiologic systems that can occur with training. One of the most important is the female athlete triad that, by definition, occurs in women. The triad is amenorrhea (lack of menstrual cycles), osteoporosis (significant decreases in bone mineral density), and disordered eating. This triad is found primarily in elite female athletes with low body energy stores. The amenorrhea (or oligomenorrhea—irregular menses) is caused primarily by a decrease in luteinizing hormone (LH) release from the anterior pituitary. Although the precise signal for this is not known, a decrease in the hormone leptin, released by adipose tissue, resulting in a reduction of gonadotropin-releasing hormone (GnRH) pulsatility has been implicated. Exercise by itself does not cause amenorrhea—it contributes to the negative caloric balance due to decreased caloric intake. The loss of bone mass is primarily due to low estrogen levels because of decreased LH (see Chapter 68). This greatly increases the risk of stress fractures in female athletes. Unfortunately, some of this loss of bone mass is not reversible even if normal menses and estrogen secretion occur with treatment. It is generally appreciated that eating disorders are more common in athletes. In women, these are primarily anorexia nervosa (refusal to maintain caloric input to maintain body weight) and bulimia nervosa (characterized by self-induced vomiting, as well as laxative and diuretic abuse). Although these extreme eating disorders are not a requisite for the triad, caloric intake is usually significantly lower than the increased energy expenditure in athletes. The treatment of the female athlete triad generally includes alterations in training type and intensity, increased caloric intake, and even administration of birth control pills or estrogen to try to restore bone mass.

CLINICAL CORRELATION A 58-year-old man, complaining of chest pain on exertion, was referred to a cardiologist for a graded exercise stress test. The patient’s electrocardiogram, blood pressure, heart rate, tidal volume, respiratory rate, and arterial oxygen saturation by pulse oximetry were monitored during the test, which used a treadmill to provide an incremental workload. At the stage of the test when the workload had doubled, the patient complained of chest pain and the stress test was stopped. During the test, his heart rate increased from 75 to 135/min, and his blood pressure increased from 150/90 to 180/95 mm Hg. His electrocardiogram was normal at rest, but showed significant ST segment depression at the highest exercise level (see Chapter 25). His oxygen consumption increased from 300 mL/min to 1.5 L/min during the test. Pulse oximetry did not show significant oxygen desaturation. Exercise stress tests are used to help diagnose cardiovascular and pulmonary disease, as well as to determine the severity of the disease and the efficacy of treatment. Patients may be asymptomatic at rest because of the physiologic reserves of the cardiovascular and respiratory systems; these reserves are often decreased in cardiopulmonary disease. The data obtained during the increased workload of an exercise stress test can be useful in differentiating whether the problem is cardiovascular, respiratory, or both. In this case, the problem was cardiovascular, with coronary artery disease the most likely diagnosis. The respiratory system was able to meet the increased demand for alveolar ventilation in order to supply more oxygen and remove more carbon dioxide. However, the increased cardiac work led to ST segment depression, indicating an inability of the coronary arteries to dilate sufficiently to provide additional blood flow to meet the higher myocardial oxygen demand. The cardiac workload, particularly the left ventricular workload, is increased during exercise because of the increases in contractility and heart rate and stroke volume to increase the cardiac output, and because the increase in blood pressure increases the afterload. Furthermore, left ventricular coronary perfusion mainly occurs during diastole, which is much shorter at higher heart rates. Treatment of coronary artery disease is dependent on the severity of the disease and may include low doses of aspirin to prevent blood clotting, drugs to decrease blood pressure and blood cholesterol, or interventions such as angioplasty (to open clogged arteries) with or without stents (to keep them opened), or coronary artery bypass surgery.

CHAPTER SUMMARY ■

The main physiologic stresses of exercise are increased oxygen demand and removal of carbon dioxide and hydrogen ions, and dissipation of heat produced by muscle metabolism.

CHAPTER 72 Exercise ■ ■ ■ ■ ■

The response to exercise is mainly an increase in cardiac output and alveolar ventilation. In a healthy young person, exercise is limited by the cardiovascular system, not the respiratory system. Prolonged exercise decreases plasma volume, particularly in a warm environment. Training improves exercise performance mainly by improving the cardiovascular response. The female athlete triad is the combination of menstrual disorders and low estrogen, decreases in bone mass, and decreased caloric intake despite increased energy expenditure leading to a low body fat mass.

STUDY QUESTIONS 1. Which of the following would be expected to decrease as an untrained person transitions from rest to moderate exercise? A) pulmonary vascular resistance B) pulmonary blood flow C) alveolar ventilation D) tidal volume E) diffusing capacity

2. Which of the following would be expected to have the largest percent increase as a healthy person transitions from rest to moderate exercise? A) heart rate B) stroke volume C) cardiac output D) mean arterial blood pressure E) diastolic arterial blood pressure 3. Which of the following would be expected to decrease as a healthy untrained person undergoes an exercise–training program? A) resting stroke volume B) resting cardiac output C) resting heart rate D) maximal oxygen uptake E) maximal alveolar ventilation

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73 C

Aging Hershel Raff

H A

P

T

E

R

O B J E C T I V E S ■ ■

Understand the changes in the nervous, muscular, cardiovascular, respiratory, renal, gastrointestinal, and endocrine function that occur with aging. Appreciate the pathophysiology of Alzheimer disease.

The life expectancy in most areas of the world has increased over the past few centuries. Much of this is due to the development of vaccines against infectious diseases as well as the development of antibiotics and antiviral therapy resulting in decreased infant mortality. Furthermore, improvements in the treatment of other chronic conditions such as cancer and cardiovascular disorders, as well as improved sanitation, have increased life expectancy. Along with this increase of lifespan, there are many chronic diseases associated with aging such as type 2 diabetes mellitus and osteoporosis that have increased in frequency. Successful or healthy aging promotes the concept that aging is not an illness, but a natural phenomenon that can be influenced by lifestyle, genetics, and environmental factors. In general, functional reserves such as exercise capacity decrease with age and, eventually, function itself declines and the susceptibility to disease increases. It is also important to note that the effects of aging are quite variable between males and females, ethnic groups, and populations. Table 73–1 summarizes some aging-related changes in the organ systems you have learned about in this book.

One of the important pathological causes of neurological decline associated with aging is dementia that is defined as a significant loss of memory recall and other cognitive functions. Although there are many types of dementia, Alzheimer disease, a pathological deterioration of cognitive and behavioral function associated with aging, is the most common type. This condition is associated with the development of amyloid plaques and neurofibrillary tangles in the central nervous system that leads to inflammation and neurotoxicity.

NEURAL SYSTEM

CARDIOVASCULAR SYSTEMS

It is generally accepted that healthy individuals lose some cognitive abilities with age. However, this is different from the development of neurological diseases and syndromes associated with aging. Reflexes can slow, resulting in an increased response time. Normal aging can often include a decline in visual, auditory, gustatory, and olfactory acuity, as well as deterioration in gait and balance. This is why fall prevention is so critical in the elderly.

One of the hallmarks of healthy aging is an increase in systolic blood pressure with either no change or a decline in diastolic blood pressure (Figure 73–1). This increase in pulse pressure indicates a loss of vascular compliance. Calcification of blood vessels increases with age. When extreme, this “stiffening” of the vascular bed is defined as arteriosclerosis. Table 73–2 lists other common cardiovascular changes with aging.

Ch73_753-756.indd 753

MUSCULAR SYSTEM There is an overall loss of skeletal muscle mass (sarcopenia) with normal aging—this results in a decrease in lean body mass. In addition, there is a loss of mitochondria, tendon strength, and elasticity. There is also loss of blood vessel density and cellular respiratory enzyme activity, leading to a decrease in the ability to extract oxygen during exercise and decreased force production.

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TABLE 73–1 Aging-related changes. Organ System Nervous system

TABLE 73–2 Cardiovascular changes with aging. Heart

Aging-related Changes Degenerative changes in neurons Loss of dendrites and synaptic connections

Decrease in left ventricular compliance

Decreases in sensation, memory recall, and communication

Increase in valve calcifications

Diminished visual, gustatory, auditory, and olfactory senses Muscular

Decrease in number of skeletal muscle fibers and decrease in strength

Cardiovascular

See Table 73–2

Respiratory

Decrease in maximal heart rate during exercise Decrease in maximal cardiac output during exercise

Increase in calcification of coronary arteries Vascular

Increase in total peripheral resistance Increase in “stiffness”, decrease in aortic compliance and capillary density (rarefaction)

CV control

Blunted baroreceptor reflex Decrease in response to beta-adrenergic stimulation

Loss of elasticity of lungs (increase in compliance) Decrease in the number of alveoli and surface area for gas exchange Reduced vital capacity and increased dead space

Blood

Decrease in total body water and blood volume

CV hormones

Decrease in plasma renin activity, angiotensin, and aldosterone

Reduced ability to clear airways by coughing Renal/urinary

Decrease in number of functional nephrons Decrease in glomerular filtration rate Decrease in tubular secretion and reabsorption Increased risk of dehydration Increase in the frequency of incontinence

Gastrointestinal

Decreased capacity to secrete pancreatic enzymes Decreased vitamin D and calcium absorption (contributes to loss of bone mineral density) Decrease in motility (contributes to constipation)

Endocrine

Decrease in some hormones in the blood (e.g., GH, androgens, DHEA) Menopause and associated phenomena (e.g., loss of bone mineral density)

Data from Shier D, Butler J, Lewis R. Hole’s Human Anatomy & Physiology 11th Edition. McGraw Hill Higher Education. Boston, 2007 and Kane RL, Ouslander JG, Abrass IB, Resnick B. Essentials of Clinical Geriatrics 6th Edition. McGraw Hill Medical, New York, 2009.

200

Pressure (mmHg)

150

Systolic pressure Mean pressure

100

Diastolic pressure

0

20

40

60

80

Age (years)

FIGURE 73–1 Changes in arterial pressure with age in the US population. (Adapted with permission from National Institutes of Health Publication #04-5230, August 2004.)

Important changes in the structure and function of the pulmonary system include loss of alveolar elastic recoil resulting in increased lung compliance, decreased respiratory muscle strength, changes in the rib cage and spinal column resulting in decreased chest wall compliance, and loss of alveolar surface area and pulmonary capillary volume. The decreases in lung elastic recoil can lead to an increase in functional residual and closing capacities. One of the hallmarks of aging is an increase in the difference between the partial pressure of alveolar oxygen (PAo2), which is calculated using the alveolar air equation and does not change significantly with age, and arterial oxygen (Pao2). This increase in the so-called A–a oxygen gradient reflects a nearly linear decrease in Pao2 with age. This is primarily due to an increase in ventilation–perfusion mismatching resulting from changes in pulmonary blood flow and volume, increases in pulmonary compliance leading to airway and alveolar collapse, and a decrease in diffusing capacity due to a decreased surface area for gas exchange. When evaluating blood gases in an elderly patient, it is important to realize that a lower Pao2 may be a result of normal aging rather than due to a specific disease that requires treatment.

RENAL/URINARY SYSTEM

50

0

PULMONARY SYSTEM

After the age of about 30 years, the number of functional glomeruli declines and, by age 80, may have decreased from a peak of about 2.2 to about 1.2 million. In addition, there is a decrease in renal plasma flow due to changes in the small renal arteries and the afferent arterioles. As a result, creatinine clearance, an index of glomerular filtration rate, decreases by approximately 30%. There is also a decrease in urinary

CHAPTER 73 Aging diluting and concentrating capacity. Despite this, basal water and electrolyte balance are usually not significantly altered during healthy aging. The decrease in total body water is more due to a loss of lean body mass rather than renal function. The risk of dehydration is increased during healthy aging. This is due to a decrease in the ability to maximally concentrate the urine due to a decline in tubular function. Thirst is also compromised with aging. Furthermore, the antidiuretic hormone (arginine vasopressin) response to an increase in plasma osmolality can be altered, and the ability to defend total body water and blood volume during dehydration is compromised. Incontinence is involuntary urination with many causes, and is a significant health and hygiene problem in the elderly. In men, the development of benign prostatic hyperplasia can lead to difficulty in voiding. In women after menopause, estrogen deficiency is known to be associated with structural changes in the vagina, urethra, and bladder, all of which increase the risk of incontinence.

GASTROINTESTINAL SYSTEM The changes in the gastrointestinal tract with aging are subtler than the other systems described in this chapter. A loss of swallowing coordination, combined with increased gastroesophageal reflux, can lead to an increased risk of aspiration pneumonia. The colon tends to thicken, resulting in increased contraction strength that may increase the risk of diverticuli, which are pouches that can form from the wall of the colon that can become infected and even burst, releasing luminal contents into the peritoneal cavity. The decline in vitamin D absorption and tendency to get less sunlight leads to vitamin D insufficiency and a subsequent decrease in calcium absorption. This can exacerbate the decline in bone mineral density that occurs with age. The subtle decline in liver function can alter drug metabolism sufficiently to increase the risk of drug toxicity. Although decreases in motility of the intestine are not dramatic, there is an increase in the risk of constipation. Finally, the maximal function of the exocrine pancreas can result in a decrease in enzyme secretion into the small intestine—this is usually not sufficient to alter the digestion and absorption of proteins and fats.

ENDOCRINE SYSTEM There are many hormonal changes that occur with aging. The most dramatic is the cessation of ovarian function in women that results in menopause described in detail in Chapter 68. Briefly, loss of estrogen synthesis from the ovaries results in a large increase in gonadotropin secretion from the anterior pituitary due to loss of negative feedback. Low estrogen levels result in many physiological changes, probably the most dramatic being loss of bone mineral density (osteopenia) that can become severe enough to increase the risk of bone fractures (osteoporosis). The low estrogen levels can lead to physiologi-

755

cal changes in autonomic function and behavior, as well as systemic consequences. There appears to be a higher incidence of cardiovascular dysfunction after menopause. The decline in male reproductive function (the andropause) is much more subtle. Although there can be a decrease in plasma free and total testosterone levels and sperm production, it is well known that many men can remain fertile well into their 80s. There is a subtle decline in insulin sensitivity such that fasting blood glucose tends to increase, as does the risk of the development of type 2 diabetes mellitus. Finally, growth hormone and insulin-like growth factor I (IGF-1) concentrations decline with aging. It has been hypothesized that these contribute to the loss of muscle mass described earlier, and some have advocated growth hormone replacement therapy in the elderly with established growth hormone deficiency.

CLINICAL CORRELATION (Adapted from Toy E et al: CASE FILES; Pathology. McGrawHill, 2006): An elderly man is found wandering around your campus looking for his way home. You notice a wristband that says he is 88 years old and a resident of a local nursing home. He is not bleeding, has no obvious bruises, and is not limping. In addition to being lost and disoriented, his sentences do not make sense and his conversation is not coherent. He is alert and cooperative, but confused. You call the nursing home and they immediately call for an ambulance that arrives in 10 minutes and takes the man to the emergency room of the local hospital. The emergency room physician makes a provisional diagnosis of dementia and examines the patient. He has no obvious injuries nor does he have neurological signs that would suggest a brain tumor or stroke. A representative of the nursing home arrives at the emergency room with the patient’s medical records that indicate the man has Alzheimer disease. Alzheimer disease is the most common cause of dementia in the elderly. It usually starts with a slow loss of advanced mental functions such as the ability to do mathematical problems (e.g., pay bills, manage the check book or household finances) and word recall. There is often a change in mood and behavior early in the disease. As the disease progresses, higher brain functions involving the cerebral cortex are lost, leading to disorientation (demonstrated in our patient) and memory loss. In late stages, patients often do not speak or move. Although there is a familial form of Alzheimer disease, most cases in the elderly occur without a strong family history. When the brain is examined post mortem, atrophy of the cerebral cortex is a common finding. The most common abnormalities found during histological examination of the brain are neurofibrillary tangles and amyloid plaque deposition. Neurofibrillary tangles are bundles of filaments composed primarily of phosphorylated tau protein found

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in the neuronal cytoplasm around the nucleus. Amyloid plaque deposits are extracellular, and contain several abnormal proteins. All of these abnormal proteins interfere with normal neurological function. Alzheimer disease usually progresses slowly for 10–20 years. As in our patient, forgetfulness and difficulty with sentence formation (aphasia) are common signs. As the disease progresses, the loss of motor function ensues. Patients develop difficulty with balance and walking, and are prone to fall. The cause of death is usually another primary disease, such as pneumonia, the susceptibility to which increases dramatically due to the loss of motor functions such as the ability to chew and swallow properly.

CHAPTER SUMMARY ■ ■ ■ ■

■ ■

It is normal for some memory and sensory functions to decrease with age. There is typically a loss of muscle mass with aging. An increase in arterial systolic and pulse pressure is typical with aging. Decreased lung elasticity increases the functional residual capacity and decreased Pao2 increases the alveolar–arterial gradient for oxygen with aging. A decrease in renal glomerular number and creatinine clearance occurs with aging. In women, ovarian function invariably ceases, causing menopause characterized by a decrease in estrogen in the blood and loss of bone mass. A decrease in vitamin D and calcium absorption further contributes to the loss of bone mass.

STUDY QUESTIONS 1. Which of the following is true? A) Both arterial and pulmonary compliance increase with aging. B) Arterial compliance decreases and pulmonary compliance increases with aging. C) Arterial compliance increases and pulmonary compliance decreases with aging. D) Both arterial and pulmonary compliance decrease with aging. 2. All of the following decrease with aging except A) number of glomeruli in the kidney B) creatinine clearance C) renal plasma flow D) risk of dehydration 3. The decrease in bone mineral density in elderly women is due at least in part to A) decrease in vitamin D absorption B) increase in calcium absorption C) increase in estrogen secretion D) decrease in cortisol 4. Which plasma hormone increases with aging? A) renin B) pituitary gonadotropins in women C) growth hormone D) free testosterone in men

Answers to Study Questions

Chapter 1 1. B 2. D

3. C

Chapter 12 4. B

1. B

2. E

3. B

Chapter 2

Chapter 13

1. C

1. C

2. E

Chapter 3 1. C

2. E

3. D

2. D

3. C

3. A

4. E

5. C

6. D

1. C

2. E

3. C

4. B

1. D

2. D

3. B

Chapter 16

1. A

1. E

3. A

Chapter 6 1. C

2. B

2. D

3. E 4. C 5. A

3. B

2. B

3. A

2. B

3. C

6. D

1. D

2. C

5. C 6. C 7. D

1. C

2. E

3. E

1. D

2. B

3. D

1. B 2. C 3. B

1. C

Chapter 10

Chapter 21

3. A

4. A

Chapter 11 1. A

2. C

Answers_757-760.indd 757

3. B

7. D

4. E

5. D 6. D

7. E

4. D

5. C

6. D

4. D

5. C

Chapter 19 4. C

Chapter 20

2. D

5. D 6. B

3. D

Chapter 9

1. D

4. E

Chapter 18 4. B

Chapter 8 1. D

4. E

Chapter 17

Chapter 7 1. A

5. D

Chapter 15

Chapter 5 2. D

4. D

Chapter 14

Chapter 4 1. A

2. D

4. D 5. E

1. A

2. D

2. C

3. C

3. D

4. D

4. D

5. A

6. C

4. B

5. D

6. D

4. B

5. B

Chapter 22 4. C

1. E

2. D

3. E

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Answers to Study Questions

Chapter 23 1. B 2. E

3. C

Chapter 37 4. B

5. A

4. A

5. A

4. C

5. C

Chapter 24 1. B 2. A

3. C

3. A

2. E

3. D

3. A

4. C

5. A

2. B

3. A

4. C

5. C

2. B

3. E

4. D

5. E

2. B

3. C

3. D

1. B.

2. C

3. C

1. D

2. B

3. B

1. D

2. A

3. C

1. C

2. D

3. B

4. A

5. A

1. C

2. D

3. A

4. E

5. E

1. B

2. B

3. D

Chapter 45

1. F

1. D

2. E

Chapter 32 2. D

3. A

2. D

3. C

5. B 6. D

4. C

5. A

2. E

3. B

2. A

3. B

4. B

2. D

3. E

5. C

4. B

5. C

4. D

5. A

4. C

5. A

6. B

4. A 5. B

6. C

2. A

3. A

4. C

5. A

1. D

2. C

3. B

4. B

5. D

1. B

2. A 3. D

4. C

5. C

6. B

5. E

1. C

2. B

3. A

4. A

5. D

6. D

4. B

5. E

4. D

5. B

Chapter 49 4. A

Chapter 36 1. E

4. C

Chapter 48

Chapter 35 1. E

6. B

Chapter 47

Chapter 34 1. C

5. D

Chapter 46 4. C

Chapter 33 1. F

4. C

Chapter 44

Chapter 31

1. C

4. B

Chapter 43

Chapter 30 1. E

2. D

Chapter 42

Chapter 29 1. A

1. B

Chapter 41

Chapter 28 1. E

4. A

Chapter 40

Chapter 27 1. B 2. C

3. B

Chapter 39

Chapter 26 1. E

2. D

Chapter 38

Chapter 25 1. B 2. D

1. C

1. A

2. D

3. A

Chapter 50 4. A

1. A

2. E

3. E

6. A

Answers to Study Questions

Chapter 51 1. A

2. E 3. C

Chapter 63 4. C

5. D

1. C

Chapter 52 1. A

2. A

3. D

4. E 5. A

1. B

2. E 3. A

2. C

3. D

5. C

2. E 3. A

4. C

5. B

2. E

3. B

4. E

5. D

1. A

2. B

4. B

5. A

2. D

3. E 4. E

3. D

5. B

3. D

4. D

5. E

2. D

3. B

4. C

3. C

6. E

1. C

2. C

3. B

4. C

5. A

1. C

2. C

3. B

4. C

1. D

2. A

3. C

4. A

1. B

2. B

3. C

5. B

4. B

1. D

2. A

3. B

4. C

1. D

2. A

3. C

4. B

1. A

2. C

3. C

Chapter 73 4. C

Chapter 62 1. B 2. A

5. B

Chapter 72

Chapter 61 1. A

4. D

Chapter 71

Chapter 60 1. B 2. E

3. C

Chapter 70

Chapter 59 1. E

2. B

Chapter 69

Chapter 58 1. C

5. C

Chapter 68

Chapter 57 1. C

4. C

Chapter 67

Chapter 56 1. A

3. A

Chapter 66 4. B

Chapter 55 1. E

2. D

Chapter 65 4. E 5. D

Chapter 54 1. A

3. A 4. C

Chapter 64

Chapter 53 1. B 2. C 3. C

2. C

4. B

5. D

1. B

2. D

3. A

4. B

5. B

6. C

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INDEX

Index Page numbers followed by f or t indicate figures or tables, respectively. A A–a oxygen gradient, 754 ABC transporters, 24 ABC5 transporter, 568 ABC8 transporter, 568 Abducens nerves, 143 Absence seizures, 185 Absolute refractory state, 212 Absorption process, 491 Accessory muscles of inspiration, 315, 316 Acclimatization process, 730 Accommodation, 136 ACE inhibitors, 453, 461 Acetaminophen, 732 Acetazolamide, 737 Acetylcholine (ACh), 56, 60–61, 85, 86, 178, 188, 206, 216, 268, 346, 510, 519, 529, 544, 671 receptors, 57, 60, 62f synapse, 62f Acetylcholinesterase (AChE), 61, 85f, 86, 103 Acetyl-CoA carboxylase, 675 ACh. See Acetylcholine (ACh) ACh-activated K channel (KACh), 57 ACh receptor channels (AChRs), 20 muscarinic AChRs, 20 nicotinic AChRs, 20 ACh receptors (AChRs), 60 Muscarinic AChRs, 60 nicotinic AChRs, 60 Acid–base balance, 306, 375–382, 471–472 acid–base chemistry, 375–377 acid–base paths in vivo, 378f aldosterone, influence of, 482–483 chloride depletion, influence of, 482 extracellular volume contraction, influence of, 482 fundamentals, 472–473 and osmolar regulation of potassium distribution, 725 regulation, 398, 471 renal excretion, 476–478 hydrogen ion excretion on ammonium, 478–480 phosphate and organic acids as urinary buffers, 477–478 quantification, 480 titratable acidity, 480 urinary buffers, hydrogen ion excretion, 477 renal handling, 474–476 regulation, renal glutamine control, metabolism and, 480–481 sources carbohydrate and fat, anaerobic metabolism, 474 dietary protein, metabolism, 473 dietary weak acids, metabolism, 473 GI secretions, 473–474 intravenous solutions, lactated Ringer’s, 474 Acid–base disorders, 377, 481 acid–base disturbances, 381t metabolic acidosis, 377, 379, 382, 392, 481, 679, 725, 737, 749 metabolic alkalosis, 379, 481, 482, 483f

metabolic acidosis, renal response to, 482 metabolic alkalosis, factors, 482 respiratory acidosis, 378, 481 respiratory alkalosis, 378–379, 394, 481, 736 respiratory acidosis and alkalosis, renal response to, 481–482 Acidemia, 375, 380, 464, 469, 470 Acidosis, 375, 377, 647 Acid-sensing ion channels (ASICs), 45 Acini, 308, 492 Acromegaly, 630, 631 ACTH-independent Cushing’s syndrome, 664 Actin, 80, 83 Actin filament, 80, 83 Action potential, 10, 47 cardiac muscle, 54–55 SA and AV node, 55–56 compound, 54 depolarization, 48 externally recorded, 53f positive feedback cycle, 48f propagated, 10 refractory periods, 47, 51 absolute and relative, 52f regenerated, 39 threshold, 51 Activation gate, 213 Activation of microglia, 112 Active expiration, 317 Active hyperemia, 265 Active membrane transport pathways, characteristics, 528t Active spread of action potentials, 39 Active transport, 4 Activin, 686 Acute cholecystitis, 572 Acute mountain sickness, 736, 737, 742 prevention and treatment, 737 Acute respiratory distress syndrome, 321 Adaptation, 118 Addison’s disease, 664 Adenohypophysis, 623 Adenoids, 308 Adenoma, 470 Adenosine, 102, 232, 264, 457 Adenosine triphosphate (ATP), 11, 45, 79, 607 production, 745 Adenylyl cyclase (AC), 21, 25, 607 Adequate stimulus, 43, 117 ADH. See Antidiuretic hormone (ADH) Adjuvant, 538 ADP/ATP ratio, 18 Adrenal androgens, 664. See also Androgens Adrenal cortex, 268, 405, 452f, 454, 455, 457, 467, 602, 626 Adrenal cortex hormones androgens, 664 glucocorticoids, 661–662 deficiency, 664 excess, 664 mineralocorticoids, 662–664 Adrenal gland, 178, 656f

761

adrenal medulla, hormones adrenal catecholamines, overproduction diseases, 667 adrenergic receptors, regulation, 667 catecholamine physiologic effects, 667, 667t catecholamine release, transport, and metabolism, 665 chemistry and biosynthesis, 665 target organ cellular effects, 665–667 functional anatomy and zonation, 655 adrenal androgens diseases, 664–665 adrenal cortex hormones, 656–664 glucocorticoids diseases, 664 mineralocorticoids diseases, 664 steroid hormone, target organ cellular effects, 660–661 Adrenal insufficiency, 664 Adrenal medulla, 56, 63, 72f, 178f, 179, 182, 268, 405, 464, 715 Adrenergic receptors, 63 α-Agonists, 667 β-Agonists, 667 β-Adrenergic blockers, 222, 273 β1-Adrenergic receptor blockers, 231 β1-Adrenergic receptor–protein kinase A-dependent process, 451–452 alpha-adrenergic receptors, 64, 267, 708 α1−Adrenergic receptors, 267, 665 α2−Adrenergic receptors, 665 isoproterenol, 665 beta-adrenergic receptors, 64, 638, 692 β1−Adrenergic receptors, 665 β2−Adrenergic receptors, 268, 665 β3−Adrenergic receptors, 665 and signaling pathways, 667t Adrenergic sympathetic nerves, 323 Adrenocorticotropic hormone (ACTH), 623 Adult respiratory distress syndrome, 321 Afferent arterioles, 409 Afferent fibers, 127 Afterload, 87, 88, 95 aortic pressure, 95 cardiac, 232, 301 and isotonic contraction, 219–220 muscle, 96 result in less shortening, 95 ventricular, 227 effect of changes, 228–229 Ageusia, 162 Aging, 712 cardiovascular changes, 754t cardiovascular systems, 753–754 changes in arterial pressure with age, 754f clinical correlation, 755–756 endocrine system, 755 gastrointestinal system, 755 hormone production associated with, 712f muscular system, 753 neural system, 753 pulmonary system, 754

762

INDEX

Aging (continued) related changes, 754t renal/urinary system, 754–755 successful/healthy, 753 Agouti-related peptide (AgRP), 721 Air conduction, 153 Airway resistance, 322 Akinesia, 171 Albumin, 208, 404, 412, 426, 431, 569, 576, 578, 637, 647, 660, 665, 705 Aldosterone, 268, 405, 454, 467, 480, 531, 626, 656, 724, 731. See also Mineralocorticoids action mechanism, 456f deficiency, 664 excess, 664 renal physiologic effects, 663f Alerting reaction, 289 Alerting response, 290 Alkalemia, 375, 376, 381, 464, 469, 470, 484 Alkaline phosphatase, 647 Alkaline tide, 513 Alkalosis, 375, 376, 377, 379, 647. See also Metabolic alkalosis; Respiratory alkalosis Allodynia, 116 Alpha-adrenergic receptors, 64, 102, 323 Altitude, 735 acclimatization to, 737–738 acute effects of, 736 acute mountain sickness, 736 adaptive response, 737 physiologic responses to, 738t symptoms, 736 Alveolar air equation, 338, 355, 735 Alveolar–arterial PO2 difference, 355, 383 Alveolar–capillary diffusion, 382 Alveolar–capillary unit, 309 Alveolar dead space, 347, 354, 361 Alveolar ducts, 308 Alveolar edema, 382 Alveolar gas, 337 Alveolar hypercapnia, 348 Alveolar hypoxia, 348 Alveolar macrophage, 310 Alveolar PO2, 735 Alveolar pressure, 314, 735 Alveolar sacs, 308 Alveolar septa, 308 Alveolar ventilation, 331, 334, 353, 481 anatomic dead space and, 334–335 and carbon dioxide, 337 measurement of, 335 and oxygen, 338 physiologic dead space, 335–336 Bohr equation, 335 regional distribution, 338–339 closing volume, 339 Alveolar vessels, 343 Alzheimer’s disease, 63, 193–195, 753, 755 familial form, 755 Ambiguous genitalia, 667 Amenorrhea, 631, 750 Amiloride, 163, 470 Amiloride-sensitive epithelial Na+ channel (ENaC), 163, 662 Amino acids, 61 essential, 583, 587–588 naturally occurring, 588f nonessential, 560 transporters, 430, 531, 590 γ-Aminobutyrate (GABA), 106, 159 synapse, 63f

Aminoglycoside antibiotics gentamicin, 154 streptomycin, 154 α-Amino-3-hydroxyl-5-methyl-4-isoxazolepropionate (AMPA), 194 channel, 74 receptors, 194 Amiodarone, 639 Ammonia (NH3), 477, 578 homeostasis, 579f metabolism, principles extraintestinal production, 579 intestinal production, 578–579 role and significance, 578 urea cycle, 579 urea disposition, 579–580 production, sources, 578f Ammoniagenesis, 477, 479f and excretion, 479f Ammonium ion (NH4+), 478 AMP-activated protein kinase, 680 Amphipathic, 565 character of bile acids, 567, 596 lipids, 16 term defined, 565 Ampulla, 150 Amygdala, 159, 161f, 173f, 192f, 194–196 Amylin, 678 Amyloid plaques, 753, 755 Amyloid precursor protein (APP), 194 Amylolytic enzymes, 517 Amylopectin, 584 structure, 585f Amylose, 584 structure, 585f Amyotrophic lateral sclerosis (ALS), 63, 86, 130, 176 Anabolic metabolism, 715 Anaerobic metabolism, 745 Anal canal, anatomy, 553f Anandamide, 75 Anaphylactic shock, 301 Anaphylaxis, 307, 541 Anatomic dead space, 308, 334, 335 Anatomic shunts, 355 Androgen-binding protein (ABP), 685 Androgens, 664, 687 anabolic and metabolic effects of, 692 physiologic effects, 687 sex determination, 687 sexual development, 687 sexual differentiation, 688–689 sexual maturation, 690 Andropause, 755 Anemia, 406, 693 Anemic hypoxia, 383 Anergy, 538 Angina pectoris, 231, 248, 272 Angioplasty, 750 Angiotensin angiotensin I, 451, 658 angiotensin II, 268, 302, 451, 454–456, 658 Angiotensin converting enzyme (ACE), 451, 658 inhibitor, 282, 293, 309, 461 Angiotensin II receptor blockers (ARBs), 293, 453, 470 Angiotensinogen, 451, 658 Angle-closure glaucoma, 133 Anion exchanger (AE), 24 Anion gap, 381–382, 679

Anomic aphasia, 196 Anorexia nervosa, 722, 750 Anosmia, 161, 165 ANS. See Autonomic nervous system (ANS) Antagonists, 20 Anterior insula, 162 Anterior pituitary cell type, 625t Anterior pituitary gland, 613 diseases of hormone-producing pituitary adenoma, 630 hypopituitarism, 630–631 function, evaluation of, 613 functional anatomy, 623 hypothalamic control of, 623–624 Anterior pituitary hormones, 615, 623–630, 625f deficiency of, 630 glycoproteins, 625–626 growth hormone, 626–629 measurements, 631 prolactin family, 629–630 proopiomelanocortin (POMC), 626 target organs, and physiologic effects, 624f Anterior wall myocardial infarctions, 222 Anterograde conduction, 110 Anterograde amnesia, 196 Anticholinergics, 384 Anticholinesterases, 61, 70 Anticoagulants, 209, 361 Antidiuresis, renal water handling, 446f Antidiuretic hormone (ADH), 27, 64, 268, 404–406, 443, 444, 446, 448, 458–461, 615, 739, 755 cellular mechanism of, 618f magnocellular neurons, 614, 617 osmoreceptor control, 459 physiologic effects of, 618–619 production, disorders of, 620 release, control of, 619–620 secretion, inappropriate syndrome of, 620 signals, integration of, 619f synthesis and processing of, 616f Antigen–antibody complexes, 416 Antileukotriene, 384 Antrum, 508, 548 Aortic arterial chemoreceptors, 386 Aortic baroreceptors, 287 Aortic insufficiency, 247 Aortic regurgitation, 247 Aortic stenosis, 245–247 Aortic valve obstruction, 229 Aortic valve stenosis, 247, 282 Aphasias, 196, 756 Apical epithelial cell membrane. See Luminal epithelial cell membrane Apical membrane, 29, 424 Apical sodium-dependent bile salt transporter (asbt), 569 Apnea, 388, 739 Apneustic center, 387 Apoproteins, 597 Apoptosis, 493 Aptotagmin, 66 Aquaporins (AQPs), 21, 27, 426, 442, 458 key features of, 619t phosphorylation of, 618 Arachidonic acid metabolites, 455 Arcuate arteries, 409 Area postrema, chemoreceptor trigger zone, 551

INDEX

A receptors, 21 Areflexia, 168 Arginase, 579 Arginine, 579 Arginine succinate, 579 Arginine vasopressin (AVP), 444, 458, 615, 617, 755. See also Antidiuretic hormone (ADH) Aromatase, 686 Arterial–alveolar CO2 difference, 336, 355 Arterial baroreceptors, 287, 390 pathway, 286f reflex, 286, 286f, 746 Arterial blood gases, 380 clinical interpretation, 380–381 anion gap, 381–382, 679 base excess, 381 Arterial blood pressure, 203, 210, 252, 290, 300, 372, 444, 458, 460. See also Arterial pressure regulation, 267, 288, 291, 398 Arterial chemoreceptors, 289, 323, 351, 372, 390, 392, 394, 473, 736, 747 carotid bodies, 749 Arterial–end-tidal CO2 difference, 355 Arterial gas embolism, 741 Arterial hypocapnia, 737 Arterial oxygen, 754 Arterial pressure auscultation technique, 260 changes with age, 754f determinants, 260 arterial compliance, 261 arterial pulse pressure, 260–261 mean arterial pressure, 260 Korotkoff sounds, 260 long-term regulation, 290 fluid balance & arterial pressure, 291 on urinary output rate, 291–292 measurement, 259–260 regulation of, 285–286 short-term regulation, 286 arterial baroreceptor reflex, 286–288 central command, 290 chemoreceptor reflexes, 289 reflexes from receptors in heart & lungs, 289 reflex responses to pain, 290 responses associated with emotion, 289 Arterial pulse pressure, 260 Arteriolar tone, 264 control of, 264 basal tone, 264 flow responses caused by, 265–267 hormonal influences, 268 angiotensin II, 268 circulating catecholamines, 268 vasopressin, 268 local influences on, 264, 266t local metabolic influences, 264–265 local nonmetabolic influences, 265 transmural pressure, 265 neural influences, 267 sympathetic vasoconstrictor nerves, 267 organ blood flow responses caused by, 267f Arteriosclerosis, 261, 753 Asbestosis, 329, 360 Ascending reticular system, 111f Ascites, 284, 563, 664 Ascorbic acid, 590 Aspartate, 430, 579 Aspiration, 329

Aspirin, 117, 282, 732, 750 Associative learning, 76 Astereognosis, 195 Asthma, 309, 326 Astigmatism, 136 Astrocytes, 105, 106, 110, 176 Astrocytic proliferation, 112 Ataxia, 175, 183 Atelectasis, 319, 348, 360, 388 Atherosclerosis, 248, 261, 272, 462 Athetosis, 171 ATPase activity, 91 ATP-binding cassette (ABC), 24 ATP-sensitive channels, 21 ATP-sensitive K+ channels (KATP), 673 Atrial fibrillation, 242, 420 Atrial flutter, 241 Atrioventricular (AV) nodes, 54, 212, 236 Atrophic gastritis, 538 Atropine, 60, 61, 72, 179, 432 Auditory agnosia, 121 Auditory cortex, 153 Auditory meatus, external, 147 Auditory ossicles, 147 incus, 147 malleus, 147 stapes, 147 Auditory receptors, 149, 150, 152 electrical responses, 150 genesis of action potentials in, 150, 152 sound transmission, 152 Auditory (Eustachian) tube, 147, 153f Auscultation, 226, 235, 260f Autoimmune disease, 86, 112, 634 Autoimmunity, 538 Autonomic activity reflex and central control, 183 Autonomic nerve activity, 181 responses of some effector organs to, 181–182t Autonomic nervous system (ANS), 71, 80, 94, 177, 286, 523 craniosacral division, 178 efferent fibers and motoneurons, 72f intermediolateral column (IML), 177 parasympathetic, 177 oculomotor, facial, glossopharyngeal nerves, 178 vagus nerves, 178 peripheral organization and transmitters released by, 178 preganglionic and postganglionic neurons, 177 sympathetic, 177 Autoregulation, 266, 415 Autotransfusion, 302 AVP. See Arginine vasopressin (AVP) Axis deviations, ventricular, 240f Axon, 9, 10f, 106 conduction velocity, 107 degeneration, 111–112 of first-order neurons, 119f initial segment, 106 reaction, 66 regeneration, 111–112 of second-order neurons, 162 sprouting, 111 of sympathetic preganglionic neurons, 177 unmyelinated, 106, 615 Axonal conduction velocity, 107 Axonal sprouting, 111 Axon collaterals, 130 Axon hillock, 72, 106

763

Axoplasmic transport, 60, 66 orthograde/retrograde., 66 Azotemia, 461 B Babinski sign, 169 Bacteremias, 379 Bacterial metabolism, 577 Bacteroides, 538 β2-Adrenergic agonist, 384 β-Adrenergic blockers, 222, 273, 293 β1-Adrenergic receptor blockers, 231 β1-Adrenergic receptor–protein kinase A-dependent process, 451–452 β1-Adrenergic receptors, 217 β2-Adrenergic receptors, 268 Balance concept. See Electrolyte balance concept; Water, balance concept Ballism, 171 β-Amyloid peptides (Αβ), 194 Barbiturates, 63, 74 Baroreceptors, 222, 297, 372, 450, 450f intrarenal, 451 Barotrauma, 741 Basal electrical rhythm (BER), 549, 549f Basal ganglia, 167, 171, 172f, 173f, 183 caudate nucleus, 171 globus pallidus, 171 hyperkinetic diseases, 171 tremor, chorea, athetosis, ballism, 171 hypokinetic diseases, 171 akinesia and bradykinesia, 171 putamen, 171 substantia nigra, 171 pars compacta and pars reticulata, 171 subthalamic nucleus, 171 Basal metabolic rate (BMR), 716 Basal stem cells, 159 Basal tone, 264 Base deficit, 381 Base excess, 381 Basement membrane, 494 circular muscle, 494 lamina propria, 494 mucosa, 494 muscularis mucosae, 494 submucous (submucosal) plexus, 494 Basilar membrane, 149 Basket cells, 109, 174 Basolateral membrane, 29, 424 B cells, 536 Bell’s palsy, 162 Benign prostatic hyperplasia, 755 Benzocaine, 53 Benzodiazepines diazepam (Valium) 63, 74 Beta-adrenergic receptor blockers, 282 Beta-adrenergic receptors, 94 Beta2 (β2) receptors, 323 Bezoars, 551 Bicarbonate reabsorption, predominant proximal tubule mechanism, 475f secretion generic model, 474f renal contribution, 480t Biguanides, 680 Bile composition canalicular bile, 567–568

764

INDEX

Bile (continued) changes in, 571f ductular bile, 568 hepatic bile, 569 concentration mechanism, 572f ducts, 562 excretion and secretion, principles role and significance, 565 relationship to cholesterol, 570f solute entry pathways, 568f Bile acids, 530, 561, 565 circulation, quantitative aspects, 566 conjugated bile acids, 566, 567f enterohepatic circulation, schematic, 561f conjugation, 566–567 enterohepatic circulation hepatocyte transport mechanisms, 569 intestinal uptake mechanisms, 569 synthesis and transport, regulation, 569–570 metabolism from cholesterol, 565–566 physical forms, 567f physicochemical properties, 567 primary, 566 structures, 566f secondary, 566 structures, 566f Bile ducts, 562 Bile salt export pump (BSEP), 569 Biliary colic, 572 Biliary ductules, 562 Biliary system, 559, 561 functional anatomy, 562f motor functions contraction, 571 sphincter of Oddi function, 571–572 Bilirubin, 539 conversion of heme, 576f cycling, 577f handling by hepatocytes, 577f homeostasis bacterial metabolism, 577 hyperbilirubinemia, 578 urinary elimination, 577–578 metabolism, principles hepatic transport mechanisms, 576 hepatocyte conjugation, 576–577 role and significance, 575 pigment stones, 572 Bilirubin diglucuronide, 576 Biliverdin reductase, 575 Binding proteins. See Carrier proteins fatty acid binding protein (hepatic) FABP, 597 Bioactive substances, excretion, 398 Biogenic amines, 63 Biological cell membrane associated proteins in, 2f Biphasic action, 53 Birth, 300 Birth control pills, 261 2,3-Bisphosphoglycerate (2,3-BPG), 364 Bisphosphonates, 652 Bitemporal hemianopia, 144 BK potassium channels, 466 activity, 467f Black (or brown) widow spider venom (BWSV), 61 Bladder, 399 Blebs, 330 Blind spot, 134 Blobs, 141 Blood

acidify/alkalinize process, 481t cells, 207–208, 208t flow, basic physics of, 202–203 hemostasis, 208–209 macrophages, 559 plasma, 4, 208 of adult, normal constituents, 209t pressure, 398–399, 411f Blood–brain barrier, 106, 272, 392, 394, 575, 675, 731 Blood gas analysis, 483 Blood glucose regulation, 715 postprandial state, 715 Blood oxygen content, 363 Blood plasma, 4 Blood–testis barrier, 684, 685, 690 Blood urea nitrogen (BUN), 434 Body fluid compartments, 200, 437–438 Body plethysmography, 325, 333, 334 Body temperature control, 729–734 clinical correlation, 732–733 effector mechanisms, 730 feedback mechanisms, 730 fever, 731–732 infection pathway, 732f heat loss/gain mechanisms, 730 hot/cold environment, adaptation, 730–731 Bohr effect, 366, 371, 376, 749 Bohr equation, 335, 355 Bone, 487 fractures (See Osteoporosis) marrow, 575 mineral density (See Osteopenia and Osteoporosis) Bone conduction, 153 Bone density, 652 T score, 652 Z score, 652 Bone metabolism factors involved in regulation of, 650t hormonal regulation, 651 childhood–adult, 651 menopause, 652–653 pregnancy and lactation, 651 Bone remodeling, 643, 646, 648f, 651 Bone resorption, 644 Bony labyrinth, 149 Borborygmi, 540 Botulinum toxin (Botox), 61 Botulism, 70 Bowman glands, 161 Bowman’s capsule, 400, 402, 440 hydraulic pressure in, 412 oncotic pressure of fluid, 412 Bowman’s space, 423, 464 Boyle’s law, 313, 334, 739 Bradycardia, 221, 232, 241, 242, 289, 299, 739 Bradykinesia, 171–173 Bradykinin, 116, 265, 307 Brain, 105 endorphins in, 120 Brain areas, concerned with somatic sensation, 119f Brain injury, 80 Brain natriuretic peptide (BNP), 457 Brain rhythms in wakefulness and sleep, 186 distribution of sleep stages, 187 sleep stages, 186–187 Brain stem pathways

reticulospinal, 167 rubrospinal, 167 tectospinal, 167 vestibulospinal tracts, 167 Breast milk lipase. See Cholesterol esterase Breathing work, 748 elastic work, 737 resistance work, 737 Broca’s area, 195 Brodmann’s area , 118, 141, 153, 169 Bronchial blood flow, 341 Bronchial circulation, 341 Bronchioles, 307, 308 Bronchitis, 326 chronic, 481 Bronchoconstriction, 737 Brown-Séquard syndrome, 131 Bruits, 258 Brush border, 29 hydrolysis, 585 membrane, 584, 586f, 596, 598 Buffer, 5, 375 Buffer systems, 4–5, 472 calcium-buffering system, 487 and pH, 4–5 phosphate and albumin, 472 Bulbourethral glands, 683 Bulimia nervosa, 750 Bundle branch blocks, 242 α-Bungarotoxin, 70 Burst lung, 741 C Ca-activated K channels, 19, 75 Ca-ATPase, 486 Cable properties, 39 Cadherins, 26, 74 Caffeine, 21, 156 Ca2+ influx, 194 Ca2+ ion channels, 194 Calbindins, 486 Calcarine fissure, 141 Calcinosis, 650 Calcitonin, 487, 633, 652 Calcitonin gene–related peptide (CGRP), 64, 117, 512, 555 Calcium, 79, 80, 643 channels, 11, 55, 80, 86, 94, 102, 214, 607 blockers, 233, 273 L-type, 94 factors involved in regulation of, 650t homeostasis, 647 clinical evaluation of abnormalities in, 652t hormonal regulation of, 649 interaction of bone, kidney, and intestine in maintaining, 648–649 role of calcitonin in, 650 role of vitamin D in, 649–650 malabsorption, 651 reabsorption, 644 Calcium ATPase activity, 94 Calcium balance, 485–486 effector sites bone, 487 GI tract, 486 hormonal control, 487–489 kidneys, 486 reabsorption, mechanism, 487f regulation, 485 transcellular transport, generic method, 486f

INDEX

Calcium-binding proteins, 80, 486 Calcium channel blockers, 222, 273, 293 Calcium channels, 86 Calcium reabsorption, 644 Calcium-sensing receptor, 643 Calmodulin, 79, 80, 99, 102, 193f, 607 Calsequestrin, 86 Calyces, 399 cAMP response element-binding protein (CREB), 607 Canalicular bile, 567 composition, 568 Canaliculi, 509, 512, 561 Canal of Schlemm, 133 Canals of Hering, 568 Cannabinoid receptors (CB1), 75 Capacitance, 34 Capacitance vessels, 207 Capillary filtration coefficient, 349 Capillary hydrostatic pressure, 349 Capsaicin receptor, 45 Ca pumps, 23 Carbamoyl phosphate, 579 Carbohydrates assimilation, basic principles barriers to water-soluble macromolecules, 584 luminal digestion, 584–585 monosaccharide uptake pathways, 587 oligosaccharides/disaccharides, brush border digestion, 585–586 regulation, 587 role and significance, 583 sources in diet, 584 digestion and absorption, 583 Carbon dioxide production, 336, 747 Carbon dioxide inspired and alveolar partial pressures, 736 Carbon dioxide transport, by blood, 368, 371f bicarbonate, 370 carbamino compounds, 369–370 dissociation curve, 370–371 chloride shift, 372 Haldane effect, 370 isohydric shift, 370 physically dissolved, 368–369 Carbonic acid, 472 Carbonic anhydrase, 472 carbonic anhydrase II, 512 inhibitor (See Acetazolamide) Carbon monoxide, 364 diffusing capacity, 360 for metabolic acidosis, 379t partial pressures of, 358f, 359 poisoning, 383 Carboxyhemoglobin (COHb), 368 Carboxypeptidases, 588 carboxypeptidase A, 588 carboxypeptidase B, 588 Carcinoma, 489, 653, 664 Cardia, 495, 548 Cardiac action potentials, 54 cell-to-cell conduction, 215f conduction, 214–216 velocity, 215 Cardiac afterload, 232 Cardiac arrhythmias, 52, 240–244, 650, 723 Cardiac cell membrane potentials, 212–214 Cardiac contractility, estimations, 245 echocardiography, 245

ejection fraction (EF), 245 end-systolic pressure–volume relationship, 245 Cardiac cycle, 224 diastolic pressure, 225 end-diastolic volume, 225 heart sounds, 226 atrial gallop rhythm, 226 isovolumetric contraction phase, 225 left heart pump, 224 mitral valve, 225 peak systolic pressure, 225 phases, 224 pressure–volume & length–tension relationships, 226–227 ventricular afterload, 227 ventricular preload, 226 pulse pressure, 225 QRS complex, 225 right heart pump, 225–226 c wave, 226 jugular venous pulse, 226 v wave, 226 a wave, 226 ventricular diastole, 224 ventricular systole, 225 Cardiac dipoles and electrocardiographic records, 237–238 Cardiac excitation, abnormal, 240 Cardiac function sympathetic neural influences on, 231 techniques for assessment, 235 Cardiac function curve, 230, 231, 282 Cardiac glycoside, 22, 218 Cardiac index, 244 Cardiac muscle, 79–81, 93–97 contraction—force–velocity, 95–96 contraction—length–tension, 94–95 excitation–contraction coupling, 93–94 increases in strength of contraction in, 96–97 involuntary, 80 isometric contractions, 94–95 isotonic contractions, 95–96 Cardiac muscle cells, 212 contractility, 220–221 lusitropic effect, 221 excitation–contraction coupling, 217 mechanics, 218 relating to ventricular function, 221 relaxation, 217–218 Cardiac output (CO), 227, 253, 341, 745 determinants of, 227–228, 230 cardiac function curves, 230–231 sinoatrial (SA) node, 228 measurement of, 244 cardiac index, 244 Fick principle, 244 Cardiac pacemaker, 93, 205, 212, 216, 222 Cardiac valve function, abnormal, 245–246 Cardiogenic shock, 301 Cardiomyopathy, 222, 282 Cardiopulmonary baroreceptors, 289, 297 Cardiopulmonary resuscitation (CPR), 244 Cardiovascular adaptations, normal, 298 cardiovascular changes, with normal aging, 300 fetal circulation & changes at birth, 299–300 gender-dependent differences, 300–301 pediatric cardiovascular characteristics, 300 during pregnancy, 299 respiratory activity, responses to, 298–299 Cardiovascular adjustments, to hemorrhage, 281f Cardiovascular system

765

arterial blood, 201 blood flow, basic physics, 202–203 cardiac output, 201 distribution of, 201f effects of ascent to high altitude on, 736 during exercise, 745–747 hemorrhage, 6f, 301–302 homeostatic role, 200–202 myocardium, 201 pulmonary circulation, 201, 341–352 systemic circulation, 201, 199–304 Cardiovascular transport endothelial cells, 254 Fick principle, 252 lymphatic system, 255 transcapillary fluid movement, 254–255 factors influencing, 255f transcapillary solute diffusion, 253–254 Cardioversion, 244 Carotid bodies, 749 Carotid chemoreceptors, 386 Carotid massage, 232 Carotid sinus baroreceptors, 287 Carpal tunnel syndrome, 122 Carrier proteins, 603 β-Casein, 711 Cataplexy, 187 Catecholamines, 63–64, 231, 346, 665, 724, 731 physiologic effects, 667t synthetic pathway, 666f Catechol-O-methyltransferase (COMT), 63, 665 C cells, 633 CCK. See Cholecystokinin (CCK) CCK-A receptors, 549 CCK-releasing peptide (CCK-RP), 519 CD4 and CD8 molecules, 25, 536 Celiac disease, 538 Cell adhesion molecules, 26 Cell body soma, 106 Cell–cell interactions, 6 Cell membrane, 1, 15 receptors, 605–607 G protein–coupled receptors, 605f, 607 intracellular receptors, 606f receptor kinase, 606f receptor-linked kinase receptors, 606f α-Cells, 671 β-Cells, 671, 678 δ-Cells, 671 Cellular processes, 9 of hypothetical three-celled organism, 10f messenger to control, 19 phosphorylation of molecules, regulatory roles, 231 Cellular respiration enzyme activity, 753 waste product of, 4 Central chemoreceptors, 289, 392, 394, 737 Central command, 290 Central delay, 127 Central nervous system (CNS), 9, 105, 115, 125, 494 modulatory neurotransmitters, 74–75 synapses, 72, 74f axon hillock, 72 cell body (soma), 72 convergence and divergence, 72, 73f Central sleep apnea, 187, 391 Central swallowing center, 544 Central tendon, 315

766

INDEX

Central thermoreceptors, 730 Central venous compartment, 275 Central venous pool, 258 Central venous pressure, 258, 277, 289 abnormal, clinical implications of, 281–282 and cardiac output and venous return, 279–281 influence on venous return, 277–278 Central venous volume, 258 Centrosomes, 3 Cephalic, 511, 519 Cerebellar ataxia, 183 Cerebellar cortex basket cells, 174 Golgi cells, 174 granule cells, 174 Purkinje cells, 174 stellate cells, 174 Cerebellar disease, 175 Cerebellum, 167, 173–174 cellular organization, 174–175 functional divisions of, 174f inferior peduncles, 174 neural connections in, 175f neuronal types in cerebellar cortex, 174f superior, middle, 174 vestibulocerebellum, 174f Cerebral circulation, 232, 736 Cerebral cortex, 107–110, 110f, 169f, 385 Cerebral edema, 30, 736, 738 Cerebral hyperperfusion, 736 Cerebral ischemic response, 289 Cerebral palsy, 340 Cerebral vascular accidents, 299 Cerebrocerebellum, 174f, 175 Cerebrospinal fluid (CSF), 4, 106, 183, 272, 289, 393f, 736 Cerumen, 154 CFTR. See Cystic fibrosis transmembrane regulator (CFTR) Chandelier cells, 109 Channels, 11, 16–18 cell–cell, 21–22 chemosensitive, 20–21 involved in synaptic release, 65 mechanosensitive, 18–19 voltage-sensitive, 19 water, 21 Charges. See also Anion gap separation of, 34–35 Chemical synapses, 60, 68, 73 Chemoreceptors, 115, 159, 289, 311, 380, 390, 392, 473, 737, 746 peripheral, 392, 394 reflexes, 289 Chemoreceptor trigger zone, 551 Chemosensitive channels, 11, 17, 20, 24, 44, 73 Chenodeoxycholic acid, 566 Chest wall, 305 Chest wall compliance, 754 Chief cells, 494, 508–513, 588, 643 Chloride reabsorption, 439, 731 transport pathways for, 440f, 442f, 443f secretion, regulation, 533f shift, 372 Chloride–iodide transporting protein, 635. See also Iodide channel Chloride reabsorption, 731 Chloride shift, 372 Cholangiocytes, 562, 568 Cholecalciferol, 650

Cholecystectomy, 572 Cholecystitis acute/chronic, 572 Cholecystokinin (CCK), 64, 499, 501, 519, 571, 594, 719 CCK-A receptors, 549 CCK releasing peptide (CCK-RP), 519 cholecystokinin (CCK)-B receptors, 510 effects of, 519f role, factors causing CCK release, 519 Cholera, 25, 529, 533 Cholesterol, 16, 566, 570 intestinal handling, 597f Cholesterol 7a-hydroxylase, 566 Cholesterol esterase, 595 Cholesterol stones, 572 Cholic acid, 566, 569 Choline acetyl transferase (CAT), 60 Cholinergic neurons, 178 Cholinergic parasympathetic nerve fibers, 206 Cholinergic parasympathetic postganglionic nerves, 323 Cholinesterase inhibitors, 71, 91 Chondrogenesis, 692 Chorda tympani branch of the facial nerve, 162 Chorea, 171 Chorionic somatomammotropin, 626 Choroid plexus, 272 Chromaffin cells, 665 Chromatin, 3 Chromatolysis, 66, 111 Chronic bronchitis, 309, 333, 360 Chronic cholecystitis, 572 Chronic congestive heart failure (CHF), 282 Chronic cor pulmonale, 742 Chronic hypertension, 292 Chronic obstructive pulmonary disease (COPD), 360, 392 Chronic renal failure, 653 Chronic thyroiditis, 640 Chronotropic, 220, 638 Chronotropic effect on heart rate, positive and negative, 217, 220 Chvostek’s sign, 647 Chylomicrons, 496, 597 lipid-bearing, 598 secretion of, 597f triglyceride-rich, 629 Chymotrypsin, 588 Cilia, 134, 159 Ciliary muscle, 136 Circadian rhythms, 185, 187–188, 610, 615, 623 Circular muscle, 494 Circulatory shock, 301, 301t, 372 Circumventricular organs, 731 Cirrhosis, 580, 658 Cisternae, 86, 94 Citrulline, 579 Clara cells, 307, 308 Clasp-knife effect, 130 Class 1 cytokine receptor superfamily, 628 Classic sensory pathways specific/nonspecific, 110 Clathrin-coated pit, 66 Clearance, renal derivation of, 418f measuring GFR, practical method creatinine clearance, 419 plasma creatinine and urea concentrations, 419–420

quantification of, 418–419 units, 417–418 Cl–HCO3— antiporters, 475 Cl/HCO3— exchanger, 24 Climbing fibers, 175 Clonus, 130 Closing capacity, 339 Closing volume, 325, 339 Clostridium botulinum, 70 Clostridium difficile, 534, 539 Clotting function, 272 CNS postsynaptic receptors gammaaminobutyric acid (GABAAR), 20 for glycine (glyR), 20 serotonin (5HT3R), 20 CNS synapse, 74 α-γ Coactivation, 129 Cobalamin, 507. See Vitamin B12 CO2-bicarbonate system, 474 buffer system, 472 Cocaine, 64 Cocaine-and amphetamine-regulated transcript (CART), 721 Cochlea, 147 Cockcroft–Gault formula, 420, 421 Cogwheel rigidity, 173 Colipase, 517, 595 role of, 595f Colitis, 538 Collecting duct system, 438, 443–444, 464 Colloid, 633 Colloid osmotic (oncotic) pressure, 29, 254, 412, 349 Colon, 496 chloride secretion, 532f colonocytes, 496 defecation, 496 electrogenic sodium absorption, 531 electroneutral NaCl absorption, 532f epithelial layers, morphology of, 493f functions, 553 haustrations, 496 ion transport mechanisms, 528t Color agnosia, 121 Color blindness, 143 Colors hue, intensity, and saturation, 142 Color vision, 134, 142–143 Commensal, 538 Commensal bacteria, 492 Common bile duct, 562 Communication, 12 Comparator, 12 Compensation, 372, 380, 481 acid–base disorders and, 481–482 short-term cardiovascular, 297 Complementary color, 142 Complex cells, 142 Compliance, 5, 259, 318 Compound action potential, 54 Conditioned reflex, 748 Conducting airways, 305 Conducting zone, 308 Conduction, 51, 52, 54, 107, 153, 204, 214–216, 236, 241, 242, 730 Conduit vessels, 207 Congenital adrenal hyperplasia, 664, 668, 692 Congestive heart failure, 281–283, 482, 620 Connecting tubule, 406 Connexins, 21, 214 topology of, 21f

INDEX

Connexons, 21 Conn’s syndrome, 664 Constant field equation, 39 Continuous positive airway pressure (CPAP), 190 Contraception, 712 principal methods for, 712t Contractile element (CE), 87 Contractility, 93 Convection, 730 Convective transport, 252 Convergence, 72 Convergence movements, 144 Coordinated movement, 167 Core body temperature, 729 Coronary angioplasty, 273 Coronary arteries, 269, 270, 272, 273 disease, 248, 272, 750 stent, 292 Coronary artery bypass surgery, 750 Coronary artery disease, 282, 750 Coronary artery stent, 292 Corpora cavernosa, 685 Cor pulmonale, 738 Corpus, 548 Corpus hemorrhagicum, 703 Corpus luteum, 696, 703 Correction, 6 Cortical collecting tubule, 406 Cortical radial arteries, 409 Corticobulbar tract, 168 Corticohypothalamic pathway, 289 Corticosteroids, 384 Corticostriate pathway, 171 Corticotropin-releasing hormone (CRH) or factor (CRF), 626, 657, 725 Cortisol, 405, 456, 602, 604, 609, 626, 631, 657, 659, 662, 668, 718, 725, 726f conversion to cortisone, 658 negative feedback, 664 physiologic effects, 663t precursors, 665 Cortisol-binding globulin (CBG), 658 Cough, 390 Coulomb (C), 34 Countercurrent exchange, 445 Cranial nerves, 107, 125, 143, 155f, 164f, 177, 619f functions of, 109t Creatine phosphate (CP), 80 Creatinine clearance, 419, 420, 754 Cretinism, 638 Cribriform plate, 159 Cricopharyngeal muscle, 545 Crista ampullaris, 150 Critical micellar concentration (CMC), 567, 571, 596 Critical opening pressure, 345 Crohn’s disease, 534, 538, 598 Cross-bridge cycling, 83 Crossed extensor response, 130 Crura, 315 Crypt, 493 Cryptorchidism, 689, 692 CSF. See Cerebrospinal fluid (CSF) Cuneate nuclei, 118 Cupula, 150 Curare, 60 Cushing reflex, 289 Cushing’s disease, 664 Cushing’s syndrome, 630, 631, 664

Cutaneous pain, 290 Cu/Zn superoxide dismutase (SOD-1), 176 Cyanide, 383 Cyanosis, 368, 383, 742 Cyberneticists, 10 Cyclic 3′, 5′-adenosine monophosphate (cAMP), 11, 607, 618 Cyclic guanosine monophosphate (cGMP), 11, 692 Cyclic nucleotide-gated channels, 11, 19, 44, 44f Cyclic nucleotide–gated (CNG) nonspecific cation channel, 44 Cystic duct, 562, 562f, 570, 572 Cystic fibrosis, 24, 524, 584 Cystic fibrosis transmembrane regulator (CFTR), 24, 25, 521, 522, 524, 525, 532, 533, 568, 572 Cytochrome P450 sidechain cleavage (SCC) enzyme, 656 Cytokine receptor superfamily, class 1, 628 Cytokines, 311, 384, 499t, 500, 536, 538, 731 Cytoplasm, 2 Cytoplasmic/nuclear inclusions, 183 Cytoplasmic organelles, 3 Cytosolic proteolysis, 590 D Dalton’s law, 336, 739 D cells, 509, 510 Dead space, 739 Deafness, 154 conductive, 154 partial, 736 sensorineural, 154 Decerebrate deficits in humans, 172f Decerebrate rigidity, 171 Decerebration, 171, 172 Declarative memory, 75, 191, 196 Decomposition of movement, 175 Decompression illness, 738, 741 Decompression sickness, 741 Decorticate deficits in humans, 172f Decorticate rigidity, 171 Decortication, 171, 172f Deep cerebellar nuclei, 175 Deep pain, 290 Deep tendon reflex, 126 Deep vein thrombosis (DVT), 262, 360 Defecation, 299, 496, 553, 554, 556 Defensins, 538 Defibrillation, 244 Deglutition, 544, 545 Dehydroepiandrosterone (DHEA), 686, 687 Deiodinases, 637 Dementia, 194, 195, 580, 753, 755. See also Aging Alzheimer disease, 753 Demyelinating diseases, 53 Dendrites, 9, 106 Dendritic cells, 536 Dendritic spines, 106 Denervation supersensitivity, 111 Deoxycholic acid, 566 Dephosphorylation, 99 Depolarize membrane, 38 Depression, 70 Derecruitment of pulmonary capillaries, 345 Desensitization, 69–70, 118, 608 of acetylcholine receptors, 70f Desmopressin, 620 Desmosomes, 214 Diabetes insipidus, 448, 620 Diabetes mellitus, 120, 442

767

type I, 394, 587, 678–679, 726 type II, 292, 406, 679, 718, 753 Diabetic coma, 678 Diabetic ketoacidosis, 376, 379, 394, 678, 724 Diabetic neuropathy, 116 Diacylglycerol (DAG), 25, 101, 605f, 607, 676, 698f Diads, 93 Diaminopyridine, 70 Diaphragm, 305, 315, 386 Diarrhea, 379, 533 Diastole, 55, 56, 94, 95, 204, 225, 227, 247, 259, 276, 300 ventricular, 204, 224 Diastolic failure, 228 Diastolic murmur, 247 Diastolic pressure, 225 Diazepam (Valium), 63, 74 Diencephalon, 107, 189, 193, 613 Dietary fiber, 532, 539, 584 Dietary lipids, 565 Dietary polymers, 584 Dietary potassium, 468, 723, 731 Dietary salt restriction, 293 Diffusing capacity, 350, 360, 748, 750, 754 Diffusion, 4 facilitated, 4, 26, 27, 531, 596 simple, 4, 26, 27, 424 Digestion process, 491 gastrointestinal motility, 491 Digitalis, 22, 37, 218 Digoxin, 420 Dihydropyridines (DHP), 55 receptors, 80, 86, 94, 102f Dihydrotestosterone, 659, 664, 687, 688f, 689t, 697 Dihydroxyphenylalanine (DOPA), 63, 64, 666 1,25-Dihydroxyvitamin D, 398, 531 Diiodinated tyrosine (DIT), 636 Diluting segment, 443 Dipalmitoyl phosphatidylcholine, 321 Disordered eating, 750 Distal nephron delivery of sodium, 467 flow rate, 468 Distal stump, 111 Distal tubule, 406 Distensibility, 5 Diuresis, 430 Diuretics, 57, 293, 442, 443, 468, 469f, 737 effects of, 468–469 heavy use of, 482 promoting calcium reabsorption, 487f Diuretic therapy, 293 Divergence, 72 Diverticula, 556, 755 Diving breath-hold diving, 739–740 clinical problems, 741–742 immersion up effects to neck, 739 physical principles, 739 reflex, 739–740 electrocardiographic response, 740f underwater breathing apparatus, use, 740–741 DNA-binding transcription factors, 638 Dominant hemisphere, 195 l-DOPA (levodopa), 173, 666 DOPA decarboxylase, 63 Dopamine, 63, 629 Dopamine agonists, 631

768

INDEX

Dopamine beta-hydroxylase (DBH), 63 Dorsal cochlear nuclei, 153 Dorsal column–medial lemniscus pathway, 115 Dorsal column system, 118 Dorsal respiratory groups (DRG), 386 Dorsal root ganglia, 125 Dorsal vagal complex, 509, 545 Driving force, 35 on ions crossing through membrane, 36f Dry atmospheric air, 337 D-Tubocurare, 70, 179 Dual-energy x-ray absorptiometry (DEXA), 652 Dubin–Johnson syndrome, 576 Duchenne muscular dystrophy, 85 Duct of Santorini, 518 Ductus arteriosus, 300 Duodenal cluster unit, 495, 519 Duodenal I cells cholecystokinin (CCK) release, 520f Duodenum, 495 bicarbonate secretion, 533f Dutasteride, 687 DVT. See Deep vein thrombosis (DVT) Dwarfism, 631 Dynamic cell processes, 9 Dynamic compliance, 319 Dynamic compression, 324 Dynamic equilibrium, 604 Dynamic response, 126 Dyneins, 66 Dynorphin, 64 Dysdiadochokinesia, 175 Dysgeusia, 163 Dyslexia, 195 Dyslipidemia, 718, 719 Dysmetria, 175 Dyspareunia, 711 Dysphagia, 176, 556 Dyspnea, 247, 283, 316, 329, 339, 350, 383, 390, 470 Dystonia, 61 Dystrophin, 85 E Ear anatomy, 147 cochlea, 149–150, 150f external ear, 147 middle ear, 147, 148f inner ear, 149–150 cochlea, 147 saccule, 147 semicircular canals, 147 utricle, 147 vestibular system, 154 Ear dust, 150 Ebner gland, 162 ECF. See Extracellular fluid (ECF) Echocardiogram, 282 Echocardiography, 245 Ectopeptidases, 588 Edema, 29, 207, 255, 261, 297, 736, 738. See also Pulmonary edema Edinger–Westphal nucleus, 143 Edrophonium chloride (Tensilon), 71, 77 Effective renal plasma flow, 419 Effector, 12 Efferent arterioles, 400, 402, 409, 411f, 722, 753 Efferent control, 45, 108 Einthoven’s triangle, 236, 238, 240 Elastance, 5

Elastase, 588 Elasticity, 318 Elastic recoil, 314, 332, 748 at functional residual capacity, 754 closing capacities, 754 Elastic work of breathing, 329, 737 Elastin, 207 Electrical dipoles, 237 Electrical synapses, 73f Electrocardiogram, 216, 224, 235–236, 750 basic conventions, 236–237 Einthoven’s conventions, 237f P, QRS, and T waves, 236 PR segment, 236 QT interval, 236 Electrocardiography, 216, 235 Electrochemical equilibrium potential, 36 Electrochemical forces, 486 Electrochemical gradients, 16, 35 Electroencephalogram (EEG), 185 Electrolytes, 2, 208, 731 balance concept, regulation, 397–398 exercise, effect on, 749 regulation of potassium balance, 722–725 of sodium balance, 722 transport pathways, 527 Electromotive force, 34 Embolectomy, 361 Emboli, 262, 272 Emesis, 552 Emmetropic eye, 137 Emphysema, 319, 325, 326, 329, 332, 333, 339, 360 End-capillary oxygen content, 355 End-diastolic volume (EDV), 245 Endocardial (inner) surface, 55 Endocrine physiology, 601–728 endocrine function, assessment of hormone measurements, interpretation, 610–611 hormone cellular effects, 605 hormone chemistry, and mechanisms of action amino acid–derived hormones, 603 hormone effects, 603 hormone transport, 603–604, 604f protein/peptide hormones, 602 steroid hormones, 602 hormone receptors, and signal transduction cell membrane receptors, 605–607 hormone–receptor regulation, 608 intracellular receptors, 607–608 hormone release control hormonal control, 608–609 neural control, 608 nutrient/ion regulation, 609–610 principles, 601 Endocrine system, 601–602, 602f disorders, 610 endocrine glands, 601 hormones, 601–602 physiologic functions and components, 601–602 target organ, 602 Endocytosis, 30 Endogenous opioid peptide, 626 Endogenous pyrogens, 731 Endolymph, 149 Endometrial cycle. See also Ovarian hormones fertilization, 703–704 implantation, 704–705 menstrual phase, 703

proliferative phase, 703 secretory phase, 703 Endopeptidases, 64, 65, 70, 588 Endoperoxides, 307 Endoplasmic reticulum, 2, 15, 60, 66, 597, 603f, 607, 616, 672, 673f Endorphin, 64 β-Endorphin, 626 Endothelial cells, 103, 206, 253, 254, 265, 401, 416, 451, 562, 597, 626, 692, 703, 706 Endothelin, 346 endothelin-1, 102 receptors, 102 Endotherms, 729 Endotoxins, 731 Endplate, 10f, 11, 68, 128f End plate potential, 86 Endplate potential (EPP), 11, 68 recording, 68–69 End-stage renal disease (ESRD), 406 End-systolic pressure–volume relationship, 245 End-tidal CO2, 336 Energy intake, regulation of, 719 mediators implicated in regulation, 721t Enkephalin, 64 En passant synapses, 72 ENS. See Enteric nervous system (ENS) Enteric bacteria metabolic effects, 539t populations, 538t Enteric flora, 538. See Microbiota Enteric nervous system (ENS), 494, 497, 510, 529, 549, 554 enteric nerves, classification, 503t enteric neurotransmitters, 503 little brain model, 502–503 neurokinin A, 554 pelvic nerves, 554 plexuses of, 497f pudendal nerves, 554 schematic diagram, 502f Enterochromaffin-like (ECL) cells, 503, 509, 529 Enteroendocrine cells, 464, 494, 502, 503, 509, 530 Enteroglucagon, 502 Enterohepatic circulation, 561 Enterokinase, 588, 589f Eosinophil chemotactic factors, 307 Epicardial (outer) surface, 55 Epididymis, 684, 688, 689 Epilepsy, 52, 63, 185 Epimerization, 566 Epinephrine (EPI), 56, 63, 268, 346, 405, 464, 665, 666f, 676, 717f, 725, 731f Epithelial cells, 619 polarization, 425 Epithelial salt and water, reabsorption, 425 Epithelial sodium channel (ENaC), 21, 44, 443, 531 EPSPs. See Excitatory postsynaptic potentials (EPSPs) Equal pressure point, 325 Erectile dysfunction, 692 Ergocalciferol, 650 Error, 6 Eructation, 741 Erythropoiesis, 737 Erythropoietin, 398, 406, 450, 602, 737 Esophageal varices, 563 Esophageal motility, features of LES relaxation, 547 peristalsis, 545–547

INDEX

swallowing, 545 Esophageal motility, principles role and significance, 543–544 Esophagus, 493, 543 functional anatomy and innervation, 544f lower esophageal sphincter (LES), 544 upper esophageal sphincter, 544 Estradiol, 611, 686, 687f, 693, 697–699, 705, 707f, 711, 712f, 726f 17β−Estradiol, 659 Estrogen, 261, 755 deficiency, 652 estrogen receptor–mediated (genomic) effects, 705–706 metabolic fate of, 705f nongenomic effects, 706 physiologic actions, 706–707 replacement therapy, 652 synthesis, 755 transport, and metabolism, 705 theca and granulosa cells coordination forproduction of, 698f Estrogen receptor beta (β), 706 Ethmoid bone, 165 Eubacteria, 538 Eukaryotic cell, 1, 2f Eupnea, 315 Eustachian tube, 147 Euthyroid, 638 Evaporation, 439, 730, 731 Excitability, 6, 9, 33, 52, 68, 131, 212, 243, 463, 485, 647 Excitation–contraction coupling, 86, 93–94 Excitatory amino acid transporter (EAAT), 62 Excitatory postsynaptic potentials (EPSPs), 11, 20, 67, 86, 125 Excitatory spinal pathways, 287 Exercise, 265, 745–752 capacity, 753 cardiovascular system, control, 746f changes in cardiac output, 746f heart rate, 746f stroke volume, 746f ventilation, 747f effect on minute ventilation, 749f muscle metabolism, 745 neuroendocrine response to, 717f physical activity, acute effects cardiovascular system, 745–747 fluid and electrolyte balance, 749 respiratory system, 747–749 stress tests, 750 training effects, 749–750 ventilatory response to, 748 Exercise capacity, 753 Exercise stress tests, 750 Exocrine pancreas, 517 amylolytic enzymes, 517 colipase/trypsin inhibitors, 517 lipases, 517 nucleases, 517 proteases, 517 Exocytosis, 30 Exogenous pyrogens, 731 Exophthalmos, 639, 733 Expiratory neurons, 386 Expiratory reserve volume (ERV), 332, 333f, 334f, 739 Expired air, 337 Explicit memory, 75

External anal sphincter, 494, 554 External auditory meatus, 147 External intercostal muscles, 315 Extra-alveolar vessels, 343 Extracellular fluid (ECF), 4, 437 total body water, distribution, 438f volume, 450, 453–454 Extrafusal fibers, 126 Eye accommodation, 137–138, 138f anatomy, 133–134, 134f aqueous humor, 133 canal of Schlemm, 133 choroid, 133 ciliary body, 133 cornea, 133 crystalline lens, 133 eyeball sclera, 133 image-forming mechanism, 135–136 common defects, 136–137 iris, 133 lens suspensary ligament (zonule), 133 movements, 143–144 convergence, 144 extraocular muscles, 143f saccades, 143 smooth pursuit, 144 vestibular, 144 pupil, 133 retina, 133 vitreous humor, 133 F Facial nerves, 162, 163f, 178, 648, 653 Facilitated diffusion, 4, 26, 27 Facilitation, 70 Familial dysautonomia, 162 Familial Hyper KPP, 57 Fanconi syndrome, 427 Farad (F), 34 Faraday’s constant, 34, 36, 39 Fasciculations, 168, 176 Fat-soluble vitamins, 565, 593, 594, 596, 597 absorption of, 598 Fatty acid, 597 oxidation, 93, 745 Feature detectors, 142 Feedback control mechanism, 604. See also Hormones, regulation negative feedback, 6, 608, 610 positive feedback, 12, 610 Feedback control systems, 6f, 730 feedback device, 128 feed-forward inhibition, 175 Female athlete triad, 750 Female genital tract, 697 Female reproductive organs, 696 age-related changes, 711 menopause, 711–712 puberty, 711 functional anatomy, 696f Feminization, 580 Fenestrae, 411, 562 Fermentation, 539 Fertility, 683 Fertilization, 695 and embryo migration, 704f Fetal development, 299 Fetal hemoglobin (HbF), 364 Fever, 731–732

769

infection pathway, 732f Fiber, 85, 584 dietary, 539 types, 90–91 Fibrillation, 272 Fibrosis, 319, 322, 326, 580 Fibrous astrocytes, 105 Fick principle, 244, 252 Fick’s first law, 26 of diffusion, 253, 357 Fight–or-flight response, 667 Filtered load, 414–415, 430 Filtration, 253 Filtration fraction, 414 Filtration of inspired air, 308 Final common pathway, 131, 167 Finasteride, 687 Fixed/nonvolatile acids, 376 Fixed obstructions, 326 Flaccid, 129 Flaccid paralysis, 168 Flippase, 16 Flow, 5 Flow-induced distribution of blood volume and pressure, 277 Flow–volume curves, 326–327, 329. See also Respiratory system effort-dependent, 326 effort-independent, 326 inspiratory and expiratory, 328f maximal expiratory, 328f of varying intensities, 327f Fluid balance model, 290 Fluoxetine hydrochloride (Prozac), 24, 64 Follicle-stimulating hormone (FSH), 64, 614f, 615, 623, 625f, 683, 685, 691, 697, 698f, 700f, 711, 713 Follicular cell, 633, 733 Foot plate, 147 Foot processes, 411 Foramen ovale, 299 Force, 86 Forced expiratory volume, 325 Forced vital capacity (FVC), 325 maneuver using rolling seal spirometer, 326f Fovea centralis, 134 Fractionate, 130 Frank–Starling mechanism, 746 Frontal operculum, 162 Fructose, 586 Fruit juice paradox, 473 FSH. See Follicle-stimulating hormone (FSH) F-type H pump, 23 Functional magnetic resonance imaging (fMRI), 191 Functional residual capacity (FRC), 321–322, 332, 739 Fundus, 508, 548 G GABAA receptors, 63 Gain, 6 Galactorrhea, 630, 631 Gallbladder, 562, 570 function, principles role and significance, 570 functional anatomy epithelium, 570 musculature, 570–571

770

INDEX

Gallbladder (continued) motor functions contraction, 571 sphincter of Oddi function, 571–572 neurohumoral control, 570f storage of bile bile concentration, mechanism, 571 effects on composition, 571 Gallstone disease, 571, 572 Gamma-aminobutyric acid (GABA), 63, 74 GABAA receptors, 20, 63, 74 GABAB receptors, 63, 74 Gamma-glutamyl transpeptidase (GGT), 568 Gamma loop, 171 Ganglionic synapse, 71 Gap junctions, 6, 21, 93, 101, 134, 214 Gases, diffusion of, 357 diffusing capacity, measurement of, 360 diffusion limitation, 358–359 diffusion of carbon dioxide, 359–360 diffusion of oxygen, 359 Fick’s law, 357–358 perfusion limitation, 359 Gαs protein–coupled receptor, 676 Gαs signaling pathway, 25 Gastric acid secretion, regulation, 511f cephalic phase, 511 gastric phase, 512 intestinal phase, 512 Gastric glands, 495, 508 chief cells, 588 pepsinogens, 588 pepsins, 588 structure, 508f Gastric inhibitory peptide (GIP), 499 Gastric motility, features of basal electrical rhythm, 549 during fasting, 551 gastric emptying, 550–551 mixing and grinding, 549–550 pylorus, role, 550–551 receptive relaxation, 549 vomiting, 551–552 Gastric motility, principles patterns, 550 role and significance, 547–548 Gastric musculature, functional anatomy innervation, 548–549 muscle layers, 548 Gastric pacemaker, 548f, 549f, 550 Gastric peristalsis, 594 Gastric phase, 512 Gastric pits, 508 Gastric secretion anatomical considerations gastric cell types, 508–509 innervation, 509 stomach, functional regions, 508 basic principles gastric secretory products, 507–508 role and significance, 507 cellular basis of acid secretion, 512–513 other products, 513–514 neural regulation, 510f products, 508t regulation, 509 in interdigestive phase, 510–511 postprandial secretion, 511–512 regulatory strata, 510

Gastrin, 64, 499, 501, 508, 547 biologically active forms, 501 Gastrin-releasing peptide (GRP), 504, 510, 519 Gastrocolic reflex, 549 Gastroesophageal reflux disease (GERD), 309, 495, 556, 755 Gastrointestinal hormones, 499 candidate, 502 enteroglucagon, 502 glucagon like peptide-1, 502 ileal brake, 502 pancreatic polypeptide, 502 peptide YY (tyrosine-tyrosine), 502 factors influencing release, 501t sites of production, 500f Gastrointestinal immune system, 492 Gastrointestinal system, 492f, 491–600 anatomy of, 494f communication, specific modes endocrine communication, 498–499 immune communication, 500 neurocrine regulation, 499–500 paracrine communication, 500 endocrine regulation, principles candidate GI hormones, 502 gastrin/CCK family, 501 GI hormones, 500 motilin, 501 engineering considerations cellular specialization, 492–494 hollow organs, design, 492 intestine division into functional segments, 494 functions digestion and absorption, 491–492 excretion, 492 host defense, 492 physiologic neurohumoral regulators, 499t regulation, 498 gastrointestinal tract chemical signals, characteristics, 498 crypt and villus structures, 493 epithelium, 493 esophagus, 493 lumen, 492 neurohumoral regulation, features, 498 paracrine and immune mediators, 503t stratified squamous epithelium, 493 immune system, 492 neural control, 498f neurocrine regulation, principles enteric nervous system, little brain model, 502–503 enteric neurotransmitters, 503 organs and systems colon, 496 duodenal cluster unit, 495–496 neuromuscular system, 497 oral cavity and esophagus, 495 small intestine, 496 splanchnic circulation and lymphatics, 496–497 stomach, 495 paracrine and immune regulation important mediators, 503–504 mechanisms of activation, 504 regulatory systems, integration, 504 Gastrointestinal (GI) tract, 4, 5, 491–600 absorption, 5 chemical signals, characteristics, 498 crypt and villus structures, 493

epithelium, 493 esophagus, 493 liquids and absorption, 4 lumen, 492 neurohumoral regulation, features, 498 paracrine and immune mediators, 503t stratified squamous epithelium, 493 Gate-control hypothesis, 120 Gating current, 49 G cells, 509 Gender-dependent differences in the cardiovascular system, 300 General anesthetics, 74 chloroform, 74 ether, 74 halothane, 74 Generalized seizures, 185 Generator potential, 125 Geniculocalcarine tract, 141 Genomic effects, 637–638 GFR. See Glomerular filtration rate (GFR) GH. See Growth hormone (GH) GH–IGF-I axis, 725 GH insensitivity syndrome, 631 GH receptor antagonists, 631 Ghrelin, 501, 627, 722 Gibbs–Donnan equilibrium, 29 Gigantism, 630 GIP (glucose-dependent insulinotropic peptide), 499–502, 512 Glands, 508, 523 Glial cells, 105 microglia/macroglia, 105 principal types, in nervous system, 106f Glia-like supporting (sustentacular) cells, 159 Glitazones, 680 Globulins, 208, 404, 603 Glomerular capillary hydraulic pressure, 412 Glomerular capillary plasma pressure in, 413 Glomerular filtration fenestrae, 411 filtered load, 414–415 forces involved, 413f formation, 411–412 GFR, direct determinants, 412–414 summary of, 414t Glomerular filtration rate (GFR), 404, 412, 414, 415, 418–420, 430, 449, 453, 456, 457, 462, 486, 754 autoregulation, 415f filtration coefficient, 412 oncotic/colloid osmotic pressures, 412 resistance, changes effect, 415f Starling forces, 412 Glomeruli, 159, 161, 400, 410, 412, 413, 416, 456, 754 Glomerulonephritis, 416 Glomerulus, 159, 161, 400, 401f, 403, 405, 409, 426, 453f, 579 Glossopharyngeal nerves, 162, 163f, 178, 386, 390, 545 Glucagon, 676, 715 effects on hepatic glucose metabolism, 676f, 677 physiologic effects, 676 receptor-mediated cellular effects, 677f regulation of release, 675–676 synthesis, 675 Glucagon-like peptide 1 (GLP-1), 502, 673, 675, 676, 680

INDEX

Glucagonomas, 678 Glucoamylase, 585f Glucocorticoids, 608, 626, 651, 732 diseases, 664 metabolism, 658 synthesis and release, 657–658 Glucocorticoid therapy, 732 Gluconeogenesis, 398, 405, 559, 676f, 716, 717f, 718, 726 Glucose, 430 glucose-6-phosphate, 745 liver synthesis of, 5 oligomers, 585–586 polymers, types, 584 tolerance test, 631 Glucose buffer function, 559 Glucose-dependent insulinotropic peptide, 499 Glucose tolerance test, 631 Glucose transporter (GLUT), 23, 430, 675t GLUT1, 27 GLUT2, 531, 587 GLUT3, 27 GLUT4, 27, 662 GLUT5, 586, 587 Na-GLUT, 27 Glutamate, 61–63, 74, 106, 159 synapse, 62f Glutamate decarboxylase (GAD), 63 Glutamate receptors (gluRs), 20 metabotropic gluRs (mgluRs), 61 NMDA gluRs, 61 NMDA-type, 61, 74 non-NMDA-type, 61, 74 umami taste, 44 Glutamine, 62, 405, 434, 478, 479f, 480 Glutarate, 579 Glycerophospholipids, 15, 16f Glycine, 74 Glycine receptors, 20, 63 Glycogen phosphorylase, 675 Glycogen synthase, 675 Glycolipids, 1 Glycoproteins, 1, 624 gonadotropins, 626 thyroid-stimulating hormone, 625–626 Glycosphingolipids, 16 Goblet cells, 307–309, 494 Goiter, 639–640 Goldman–Hodgkin–Katz (GHK) equation, 39 Golgi apparatus, 2, 16, 17, 597, 603f Golgi cells, 175 Golgi tendon organs, 117, 129 Gonadal dysgenesis, 692 Gonadal function, 686–687 Gonadotropin-releasing hormone (GnRH), 626, 685, 697, 700, 750 Gonadotropins, 623, 626, 685, 755 receptor-mediated effects of, 685f regulation, of ovarian function, 697 release, ovarian regulation of, 699 follicular phase, 699 luteal phase, 699 synthesis and release control of, 685–686 negative feedback regulation, 686f Gout, 432 G protein–activated inward rectifier GIRK channel, 56

G protein-coupled receptors (GPCRs), 18, 44, 62f, 64, 71, 74, 75, 163, 521, 605f, 607, 618, 677f, 685, 697 adrenergic receptors, 665 G proteins, 25, 44, 45, 71, 161, 164f, 533, 605, 607, 618, 625, 645, 665, 685 Gq/11 protein–coupled oxytocin receptors, 617 Gracilis nucleus, 118 Gradient-limited systems, 426, 427 Granular cells, 403, 451–454 Granule cells, 159, 174 Graves’ disease, 634, 638–640, 733 Gray rami communicans, 178 Growth hormone (GH), 615, 623, 624, 709, 755 deficiency, 755 effects at target organs, 629 insensitivity syndrome, 631 physiologic effects of, 628 receptor, 628–629 receptor antagonists, 631 regulation of, 627 release and effects, 628f stimulation of, 628t Growth hormone-releasing hormone (GHRH), 627 Gs protein–cAMP–protein kinase A, 220 Guanosine diphosphate (GDP), 25, 605, 607, 677f, 685f Guanosine triphosphate (GTP), 25, 139, 605f, 607, 677f, 685f Guanylate cyclase, 692 Guanylin, 529, 530, 533, 534 Gustation, 161 Gustducin, 163 H Hair cells, 147, 150. See also Auditory receptors inner hair cells, 149 outer hair cells, 149 role of tip link, 151f structure, 151f supporting (sustentacular) cells, 150 tectorial membrane, 149 Haldane effect, 370, 749 Halothane, 350 Haptocorrin, 291 Hashimoto’s thyroiditis, 638 H-ATPase, 475, 476 Haustra, 496f, 553, 555 Haustrations, 496 hCG. See Human chorionic gonadotropin (hCG) Hearing action potentials in, 153 bone and air conduction, 152–153 central pathway, 153 loss (see Deafness) sound transmission, 152 sound waves, 152 traveling waves, 153 Heart, 203 autonomic neural influences, 205–206 block, 242 conduction velocity, 215 control of cardiac output, 205–206 diastolic filling, 205 effective operation, requirements for, 205 electrical activity of, 215f electrocardiograms, 216 excitation, 204–205 failure, 664

771

pumping action, 203–204 Purkinje fibers, 216 rate, 232 control of, 216–217 sounds, 226 ventricular gallop rhythm, 226 Heart failure, 228, 620, 664 Heart rate, 232 Heat stroke, 730 Helicobacter pylori, 514 Helicotrema, 149 Helium-dilution technique, 333 Hematocrit, 207, 372, 737 Hematuria, 416 Heme-containing proteins, 575 Heme oxygenase, 575 Hemianopia, 142 Hemiblocks, 242 Hemichannels, 21 Hemochromatosis, 531 Hemoglobin, 363, 377, 472 chemical reaction of oxygen and, 364 hemoglobin M, 368 hemoglobin S, 364 structure, 363–364 Hemophilia, 209 Hemorrhage, 6, 171, 230, 280, 336, 348, 454 Hemorrhagic shock, 618 Hemorrhagic hypovolemic shock, 301 Hemostasis, 208–209, 563 activity of vitamin K, 209 anticoagulants, 209 blood clotting, 209 calcium chelators, 209 citrate, 209 EDTA, 209 endogenous tissue plasminogen activator (tPA), 209 formation of thrombin, 209 heparin, 209 intrinsic pathway, 209 local vasoconstriction, 209 oxalate, 209 platelet aggregation, 208–209 thrombolytic agents, 209 Henderson–Hasselbalch equation, 377, 380, 472 Henle’s loop, 400, 402, 405, 406, 434, 435, 438, 440, 442–444, 458, 464, 465, 468, 469, 475, 476, 486 aquaporins, 442 diluting segment, 443 loop diuretics, 442 bumetanide, 442 furosemide (Lasix), 442 Na–K–2Cl symporter, 442 Henry’s law, 357, 739 Heparin, 262, 307 Hepatic artery, 497, 560, 561f, 562 Hepatic bile, 569 Hepatic ducts, 562, 562f, 569 Hepatic encephalopathy, 130, 580 Hepatic endothelial cells, 598 fenestrae, 598 Hepatic stellate cells, 562, 563, 580 Hepatic triad, 560 Hepatitis, 580 Hepatitis C virus, 563 Hepatocytes, 496, 561, 565 transporters, 568t Hering–Breuer deflation reflex, 388 Hering–Breuer inflation reflex, 388

772

INDEX

Herpes simplex, 66 Heteronymous hemianopia, 142, 144 Heterotrimeric guanine-binding (G) proteins, 161, 607 Hexamethonium, 71, 179 H/glutamate antiporter, 24, 27 High altitude pulmonary edema, 736 High-amplitude propagating contractions, 555 High-pressure nervous syndrome (HPNS), 741, 742 Hippocampus, 76, 108f, 191, 192f, 193–196 Histamine, 63, 64, 116, 188, 255, 307, 323, 346, 510, 529 H2 receptors, 510 antagonists, 510 Histotoxic hypoxia, 383 H–K antiporters, 465 H+,K+-ATPase, 475, 512. See also Proton pump H/K pump, 23 Holter monitor, 210 Homeostasis, 1, 11 energy, brain’s signals to control regulation, 720f and feedback control, 12 Homeotherms, 729 Homovanillic acid, 665 Homunculus, 118 Hooke’s law, 5 Hormone-producing tumors, 678 Hormone–receptor agonists/antagonists, 605 Hormone–receptor complex, 604, 605, 607, 608, 628, 661 Hormones, 498. See also Endocrine physiology; Endocrine system; Gastrointestinal hormones; Ovarian hormones; Steroid hormones affinity, 605 of anterior pituitary, 624–630 autocrine, 603 biologic effect, 603 endocrine, 603 events, during ovarian and endometrial cycles, 701f free/unbound hormone, 603 half-life, 603 interpretation of measurements, 610–611, 611t intracrine, 603 neural control, 610f paracrine, 603 precursor, 604 product, 625 receptor function, 611 release patterns, 609f regulation of, 615–616 sensitivity, 611f specificity, 605 Hormone-sensitive lipase (HSL), 638, 675 hPL. See Human placental lactogen (hPL) H2 receptor antagonists, 510 5HT1 receptors, 551 5HT3 receptors, 64, 551 Human body, 3f Human chorionic gonadotropin (hCG), 602, 625, 688, 699, 703, 709 Human language, 195 Human placental lactogen (hPL), 626, 707f, 709, 711 Human taste modalities bitter, 163

salt, 163 sour, 163 sweet, 163 umami, 163 Humoral hypercalcemia of malignancy, 489 Huntington’s disease, 63 Hydraulic pressure in Bowman’s capsule, 412 Hydrogen ions excretion of, 477f, 478 secretion generic model, 474f tubular segments, contributions, 475t Hydrophobic groups, 16 Hydrostatic forces, 5 Hydrostatic pressure, 5, 28, 254, 258, 348, 349, 412, 413 of interstitial fluid, 254 of intracapillary fluid, 254 Hydroxyapatite, 377, 487, 646 deposition of, 488 resorption of, 488 11β-Hydroxylase, 657 enzymatic deficiency, 659f 21-Hydroxylase, 657 enzymatic deficiency, 659f 11β-Hydroxysteroid dehydrogenase, 658 type I, 658 type II, 658 5-Hydroxytryptamine (5-HT), (also see serotonin) 64, 503, 529, 550 Hyperaldosteronism primary, 470, 664 Hyperalgesia, 116 Hyperbaria, 738 Hyperbaric chambers, 738 Hyperbaric oxygen therapy (HBOT), 738 Hyperbilirubinemia, 577, 578 Hypercalcemia, 653 Hypercalcemia of malignancy, 645 Hypercalciuria, 653 Hypercapnia, 346 Hypercoagulable, 262 Hyperemia, 265 Hyperglycemia, 406. See also Diabetes mellitus Hypergonadotropic hypergonadism, 713 Hyperkalemia,38, 222, 463, 658, 665, 725 Hyperkalemic periodic paralysis (HyperKPP), 52 Hypernatremia, 620 Hyperopia, 136 Hyperosmolarity, 722 Hyperparathyroidism primary, 488, 489 (see also Thyroid gland) secondary, 489, 651 Hyperphosphatemia, 489, 653 Hyperpnea, 388, 747 Hyperpolarization, 38 Hyperpolarization-activated current, 55 Hyperprolactinemia, 640, 693 Hyperreninemic hypoaldosteronism, 664 Hyperresonant, 329 Hypersensitivity, 111 Hypersomnolence, 187 Hypertension, 229, 282, 290, 292, 470, 640, 657, 664, 718 Hyperthyroidism, 634, 638, 731, 732 Graves’ disease, 639 primary, 732 TSH-secreting adenomas, 639 Hypertonia, 169 Hypertonic (spastic) muscle, 129 Hypertonic solutions, 28

Hypertrophy, 292 Hyperventilation, 361, 378, 735, 740 syndrome, 378 Hyperventilation syndrome, 378 Hypesthesia, 161 Hypoaldosteronism, 664 Hypocalcemia, 52, 57, 68, 484, 487, 644, 647, 653 Hypocalcemic tetany, 653 Hypocapnia, 372, 384, 736, 737 Hypogeusia, 162, 165 Hypoglycemia, 626, 627, 676, 717, 718, 726 Hypogonadism, 580, 630, 692, 693 Hypogonadotropic hypogonadism, 692, 693, 713 Hypokalemia, 463, 620, 664, 724, 725, 731 Hypomagnesemia, 644 Hyponatremia, 30, 620, 665, 749 Hyponatremic encephalopathy, 30 Hypoparathyroidism, 652t, 653 Hypoperfusion hypoxia, 383 Hypophosphatemia, 651 Hypophysiotropic hormones, 613, 615 key aspects of, 615t Hypophysis, 623 Hypopituitarism, 630, 639 Hyporeflexia, 168, 176 Hyporeninemic hypoaldosteronism, 664 Hyposmia, 161 Hypothalamic integration, 719 Hypothalamic neurons, 613 Hypothalamic neuropeptides, 615 Hypothalamic nuclei, 613–615 Hypothalamic peptides, 625 Hypothalamic–pituitary–adrenal axis, 660f Hypothalamic–pituitary–ovarian axis, 695, 700f Hypothalamic–pituitary–thyroid axis, 634, 634f Hypothalamic tumors, 692 Hypothalamohypophysial tract, 613, 615 Hypothalamo-pituitary hormone-mediated effects cellular signaling pathways, 625f Hypothalamus, 161f, 183, 188, 189f, 287, 385, 450f, 501, 509, 602, 613, 614f, 626, 630 anatomic and functional relationship, 614f endocrine functions of, 615 supraoptic/paraventricular nuclei, 459 Hypothermia, 716, 731 Hypothyroidism, 638 primary hypothyroidism, 638–639 secondary hypothyroidism, 639 Hypotonia, 168, 175, 176 Hypotonic encephalopathy, 30 Hypotonic muscle, 129 Hypotonic solutions, 28 Hypoventilation, 366, 377, 382, 480 Hypovolemia, 484 Hypovolemic shock, 301 Hypoxemia, 321, 379, 384 Hypoxia, 321, 346, 382, 391, 394, 730, 735 altitude and acclimatization altitude, acute effects, 736 cardiovascular system, 736 respiratory system, 736–738 anemic hypoxia, 383 classification of causes, 382t effects of, 383 histotoxic hypoxia, 383 hypoperfusion hypoxia, 383 hypoxic hypoxia, 382–383, 735 Hypoxic hypoxia, 382, 735 diffusion impairment, 382–383

INDEX

low alveolar PO2, 382 shunts, 383 Hypoxic pulmonary vasoconstriction, 384, 736 chronic, 742 Hysteresis, 319, 320 I IgA system, 537. See also Mucosal immune system physiological functions, 537 secretion of IgA across, 535, 537f, 568, 569 structural aspects of IgA, 536–537 IGF receptor, 629 Ileal brake, 502 Ileal-fatty acid binding protein (I-FABP), 597 Ileocecal valve, 494, 554 Ileum, 496 Immune communication, 500 Immune responses, alterations in, 725 Impaired glucose tolerance, 631 Implicit memory, 76 Implicit/nondeclarative memory, 191 Impotence, 631 Inactivation gate, 213 Incontinence, 183, 754t, 755 Incretin, 501, 675 Infant respiratory distress syndrome, 321 Inferior colliculi, 153 Inferior olivary nuclei, 175 Inflammation, 112 Inflammatory bowel diseases, 534, 538 Crohn’s disease, 534, 538 ulcerative colitis, 534, 538 Inhibin B, 685 Inhibitory G proteins, 216 Inhibitory postsynaptic potentials (IPSPs), 11, 67, 125 Inhibitory spinal pathways, 287 Innocent murmurs, 300 Inositol triphosphate (IP3) receptor (IP3R), 21 Inositol trisphosphate (IP3), 607 Inotropic, 220, 638 Input–process–output structural framework, 10 Inspiratory capacity (IC), 332 Inspiratory neurons, 386 Inspiratory reserve volume (IRV), 332 Insulin, 394, 464, 587, 671, 715, 724 effects at target organs, 674 early effects, 674 intermediate effects, 675 long-term effects, 675 effects on carbohydrate, fat, and protein metabolism, 674 effects on hepatic glucose metabolism, 676f glucose-induced stimulation of, 673 physiologic effects of, 673 receptor, 25, 674 substrates, 674 regulation of release, 672, 673f resistance, 662, 678–680 sensitivity, 755 synthesis, 672 Insulin/glucagon ratios, 716 Insulin-like growth factor-1 (IGF-1), 627–629, 755 Insulin-like growth factor binding proteins (IGFBPs), 629 Insulinoma, 678 Insulin resistance, 662 Integrins, 26 Intensity, 118 Intention tremor, 175 Intercalated cells, 403, 466 type A, 475, 476f

type B, 476, 476f Intercalated disks, 214 Intercalated ducts, 523 Intercellular adhesion molecules (ICAMs), 26 Intercostal muscles, 305 Interdependence of alveolar units, 315 Interferon therapy, 563 Interleukins, 629, 646, 699, 700f, 719, 726f, 731, 732f Intermediolateral column (IML), 177 Internal anal sphincter, 554 Interstitial/alveolar edema, 382 Interstitial cells of Cajal, 549 Interstitial fibrosis, 382 Interstitial fluid, 4, 28 Interstitial hydrostatic pressure, 349 Interstitium, 399, 477f, 479f, 487, 499, 603f, 663f, 664 Intestinal calcium absorption, 644 Intestinal flatus, composition, 540f Intestinal fluid transport anatomical considerations innervation and regulatory cells, 528–529 intestinal surface area, amplification of, 528 cellular basis absorptive mechanisms, 531–532 secretory mechanisms, 532–533 endogenous regulators, 529t integration of influences, 530f principles electrolytes involved, 527–528 role and significance, 527 water and electrolyte transport, regulation acute regulation, 530 chronic adaptation, 531 regulatory strata, 529–530 Intestinal lipolysis, mediators, 595t Intestinal microecology gas generation in intestine, 540 intestinal microbiota, development, 538–539 microbiota, physiological functions, 539–540 Intestinal motility basic principles role and significance in colon, 553 role and significance in small intestine, 552–553 esophageal musculature, functional anatomy innervation, 544 muscle layers, 544 features of colonic motility, 555 defecation, 556 fed versus fasted patterns, 554–555 mixing and segmentation, 555 peristalsis, 555 functional anatomy enteric nervous system, 554 muscle layers, 553 sphincters, 554 Intestinal pathogens, pathophysiological mechanisms, 540t Intestinal phase, 519 Intestine organization, 493f Intracellular fluid (ICF), 437 Intracellular receptors, 606f Intraepithelial, 536 Intraepithelial lymphocytes, 536 Intrafusal fibers, 126 Intralaminar nuclei, 108 Intralobular ducts, 523

773

Intrapleural pressure, 309, 314, 739 Intrapulmonary shunts, 355, 366 Intrarenal chemical messengers, 405 Intrinsic factor, 507, 513 Intrinsic factor-cobalamin receptor (IFCR), 591 Intrinsic proteins, 16 Intubated patient, 309 Inulin, 418 renal handling, 419f Invasion of immune cell, 112 Inverse stretch reflex, 129 Inward-going pacemaker current, 216 Inward rectifier, 17, 18 Inward rectifier K channel (Kir), 17, 18f, 55 Iodide channel, 635 Iodine, uptake and organification, 634 Ion movements factors controlling, 35–36 receptors channels allowing, 102 Ionotropic ligand receptors, 20 Ions of importance, across muscle cell membrane, 35t Ion transport pathways, 522f, 525f IP3 receptors, 101, 102f, 677f, 698 IPSPs. See Inhibitory postsynaptic potentials (IPSPs) Ischemia, 22, 63, 117, 248, 289, 302, 360, 372, 630, 703 Ischemic heart disease, 711 Ischemic stroke, 63 Islets of Langerhans, 518 Isohydric principle, 376 Isohydric shift, 370 Isomaltase, 585, 586 Isometric contraction, 85, 86 Iso-osmotic process, 423 Isopotential, 40 Isoproterenol, 346, 350 Isosmotic solution, 28 Isotonic contraction, 85, 86 Isotonic solution, 28 Ito cells, 562 J Jaundice, 575 differential diagnosis, 578f J chain, 536 Jejunum, 496, 499, 500, 552, 554 J receptors, 390 Juxtaglomerular (JG) apparatus, 403, 451 baroreceptor, 658 components, 403f extraglomerular mesangial cells, 403 glomerular filtration rate (GFR), 403 granular cells, 403 juxtamedullary nephron, 403 macula densa cells, 403 renin, 403 Juxtaglomerular cells, 401f, 403, 451 K KAch channels, 216 Kainate channels, 74 Kallmann syndrome, 692 K channels, 18, 37, 55, 74, 102, 214, 673f Kernicterus, 575 Ketoacidosis, 376, 379, 382, 394 Ketogenesis, 674–676, 680 enzymes involved in, 680t in insulin deficiency, 679f Ketone bodies, 93, 394, 474, 676, 678, 679, 717

774

INDEX

Kidney, 397–490 anatomy, 399 calyces, 399 cortex, 399 functions, 397 glucose handling by, 430f Henle’s loop, 486 hilum, 399 influence of, 450f medulla, 399 pyramids, 399 stone, 435 structural components, 399f urea handling, 434f Kinesins, 66 Kinocilium, 150 Klinefelter syndrome, 692 Knee-jerk reflex, 12, 126 Kölliker-Fuse nucleus, 387 Korotkoff sounds, 260 Krebs–Henseleit cycle, 578 Kupffer cells, 559, 561, 562, 575 Kyphoscoliosis, 319, 340, 382 Kyphosis, 340 L Labyrinth. See Inner ear Labyrinth righting reflexes, 156 Lacrimal duct, 134 Lacrimal gland, 134 Lactase, 585, 586 Lactated Ringer’s solution, 474 Lactation, 617, 630, 651, 696, 703, 707f, 708, 709, 711 Lactic acid, 91, 474 production, 745 Lactic acidosis, 382, 474 Lactic acid production, 745 Lactoferrin, 523 Lactose, 584, 586 bush border digestion ad assimilation, 586f in dairy products, 591 Lactose intolerance, 591, 592 Lactotrophs, 629 Lactulose, 580 Lambert–Eaton syndrome, 70 Lamina propria, 528 Laminar flow, 257, 322 Language disorders, 196 hemisphere concerned with, 195f physiology of, 195 hemisphere concerned with, 195f path taken by impulses, 196f and speech, 195 Laplace’s law, 320 Large intestine anatomy, 496f L-arginine, 265 Laron syndrome, 631 Latch state, 100, 101 Latent pacemaker, 214 Lateral corticospinal tracts, 167 Lateral geniculate bodies, 108, 139 Lateral inhibition, 117, 139, 161 Lateral olfactory stria, 159 Lateral sacs, 86 Law of Laplace, 221, 232 L-DOPA (levodopa), 173, 666 Lead pipe rigidity, 173 Lean body mass, 755 Learning, 191

synaptic plasticity and, 192–193 habituation, 192 sensitization, 192 Left heart failure, 283 Left ventricular failure, 226, 349, 390 Left ventricular hypertrophy, 247, 282 Length constant (λ), 40 Length–tension relationship, 81, 88, 95, 95f Lenticular nucleus, 171 Leptin, 501, 719–721, 750 Leptin receptor, 721 Leukotrienes, 307, 323 Levator ani muscles, 556 Leydig cells, 683 LH. See Luteinizing hormone (LH) Lidocaine, 53 Ligand, 16, 605f, 607, 647f, 660, 662f gated channels, 20, 607 ionotropic ligand receptors, 20 ligand-binding domain of, 706 metabotropic ligand receptors, 20 osteoprotegerin, 646 Ligand-gated channels, 20 Limbic system, 108 α-Limit dextrins, 584–586 Lipase, 507, 521, 594, 595, 629, 692 gastric and pancreatic, positional specificity, 594f Lipases, 517 Lipid assimilation epithelial events in brush border events, 596–597 intracellular processing, 597 lymphatic uptake of absorbed lipid, 597–598 fat-soluble vitamins, absorption, 598 intraluminal digestion bile acids/micelles, role of, 596 gastric digestion, 594 intestinal digestion, 594–596 intestinal handling of cholesterol, 597f intestinal lipolysis, mediators of, 595t role of colipase, 595f principles dietary and endogenous sources, 593–594 hydrophobic molecules, assimilation barriers, 593 role and significance, 593 Lipids, 593 bilayer, 1, 15, 596 droplets, 2 flip-flop, 16 lamellar phase, 596 long-chain triglycerides, 593 phosphatidylcholine, 594 phospholipids, 593 rafts, 16 Lipolysis, 692. See also Lipase products of, 593 Lipopolysaccharides, 731 Lithium treatment, 620 Lithocholic acid, 566 Liver ammonia metabolism, principles extraintestinal production, 579 intestinal production, 578–579 role and significance, 578 urea cycle, 579 urea disposition, 579–580 bilirubin homeostasis bacterial metabolism, 577

hyperbilirubinemia, 578 urinary elimination, 577–578 bilirubin metabolism cellular heme metabolism, 575–576 hepatic transport mechanisms, 576 hepatocyte conjugation, 576–577 role and significance, 575 blood vessels, bile ducts, and hepatocytes arrangement, 561f cirrhosis, 620 engineering considerations biliary tract and gallbladder, 562 blood supply, 560–561 hepatic parenchyma and sinusoids, 561–562 functions lipid-soluble waste products, excretion, 560 metabolism and detoxification, 559–560 protein metabolism and synthesis, 560 gluconeogenesis, 559 glucose buffer function, 559 splanchnic circulation, 560f Loading spindle, 127 Local circuit interneurons, 121f Location of stimulus, 117 Long-QT (LQT) syndrome, 52, 243 Long-term bed rest cardiovascular mechanisms involved, 298f responses to cardiovascular system, 297–298 Long-term depression (LTD), 76, 193 Long-term memory, 76, 192f, 194 Long-term potentiation (LTP), 76, 192–193 production of, 193f Loop diuretic, 442, 489 Loop of Henle. See Henle’s loop Loperamide, 530 Loudness, 152 Lou Gehrig’s disease, 86, 176 Low-density lipoprotein (LDL), 707 Lower esophageal sphincter (LES), 495, 508, 544 Lower motor neurons, 168 Low-pressure receptors, 289 Low-resistance electrical, 214 Low vascular volume, responses to, 454f L-type (voltage-gated) calcium channels, 94, 101 Luminal epithelial cell membrane, 619 Luminal/mucosal membrane, 29 Luminal proteolysis gastric, 588 intestinal, 588 Lung compliance, 318–321, 754 Lung volumes, 331 measurement of, 332–333 body plethysmography, 334 helium-dilution technique, 334 nitrogen-washout technique, 333 pulmonary function tests, 333 spirometry, 333 and pulmonary vascular resistance, 343–344 standard lung volumes, 331 expiratory reserve volume (ERV), 332 functional residual capacity (FRC), 332 inspiratory capacity (IC), 332 inspiratory reserve volume (IRV), 332 residual volume (RV), 332 tidal volume(VT), 331 total lung capacity (TLC), 332 vital capacity (VC), 332 Lusitropic effect, positive, 221

INDEX

Luteinizing hormone (LH), 64, 602, 615, 623, 626, 683, 686, 697–699, 702, 711, 726, 750 Lymph, 4, 255, 350, 377, 496, 563 Lymphatic system, 4, 255, 311, 350, 552 Lymphedema, 255, 262 Lymphocytes, 536 Lymphoid tissues/MALT, 535 Lysergic acid diethylamide (LSD), 64 Lysosomal enzymes, 307 Lysosomes, 2, 23, 311, 431, 608, 628, 646f, 703 M Macroglia, 105 Macrophages, 105, 307, 311, 350, 536, 703, 731, 732f Macula densa cells, 406, 452 Macula lutea, 134 Macular sparing, 142 Magnetic resonance image (MRI) scan, 112, 121, 631 Magnocellular cells, 141 Magnocellular neurons, 614f, 615–617, 619f Magnocellular pathway, 141 Main pancreatic duct, 518 Major histocompatibility complex (MHC), 536 Malabsorption, 496, 512, 521 Male reproductive system, 684f Male sexual differentiation, 689f Malignant hyperthermia, 57 Maltose, 584, 585f Maltotriose, 584, 585f, 586 Mamillary bodies, 193 Mammalian muscle spindle, 127f Mammalian nerve fibers, 107, 109t Mammalian target of rapamycin (mTOR), 675 Manubrium, 147 Mass balance system, 729 concept of, 5f Mast cells, 64 Maximum voluntary ventilation (MVV) test, 387 M cells, 141, 535 Mean arterial blood pressure (MABP), 258, 297, 619f, 747, 749 Mean circulatory filling pressure, 276–277 Mean electrical axis, 239f Mean pulmonary artery pressure, 345f Mean quantal content, 69, 70 Mechanical nociceptors, 115 Mechanoreceptors, 115, 289, 722 afferents, 746 Mechanosensitive channels, 11, 18 Mechanosensory transduction, 43 Medial and lateral descending brain stem pathways, 170f Medial geniculate bodies, 108, 153 Medial lemniscal system, 118 Medial lemniscus, 118 Median eminence, 613, 623 Median nerve, 122 Median preoptic nucleus, 619 Medium-chain fatty acids, 596 Medulla oblongata, 287 Medullary cardiovascular centers, 287 Medullary collecting tubule, 406 Medullary interstitial fluid, composition, 444 Medullary osmotic gradient, components of, 444 Medullary pyramids, 168 Medullary raphe neurons, 183 Medullary respiratory center, 311, 385 Meissner’s corpuscles, 115 Melanocortin receptors (MCRs), 626 Melanocyte-stimulating hormone, 626

α-Melanocyte-stimulating hormone (α-MSH), 721 Melatonin, 188, 188f, 189, 615, 624 Membrane-bound hydrolases, 584 Membrane capacitance, 34, 39 Membrane conductance, 35 Membrane potentials, 10, 34 changes in, 39, 44f measurement, 34 Membrane proteins, 1, 17, 26, 66, 485, 590 Membrane pumps, localization, 23t Membrane receptors, 24 enzyme-linked, 25 G protein–coupled, 25 Membrane resistance, 39–41 Membrane transport, 4, 521, 532, 568, 576 active pathways, characteristics of, 528t protein, MRP2, 576 Membranous labyrinth, 149 Ménière disease, 156 Meningiomas, 161 Menopause, 301, 652, 711, 755 Menstrual cycle, 99, 611f, 696, 697, 701f, 703, 706, 708, 713 Merkel cells, 115 Messenger RNA (mRNA) synthesis of proteins, 2 Metabolic acidosis, 377, 379, 382, 392, 481, 679, 725, 737, 749 causes, 379t renal response to, 482 Metabolic alkalosis, 379, 481–483, 483f, 725 causes, 379t Metabolic clearance rate, 417 Metabolic functions of the liver, 559 Metabolic syndrome, 435, 719 Metabolic waste, excretion, 398 Metabotropic, 59 Metabotropic glutamate receptor (mGluR4), 163 Methemoglobin, 364, 368 Methemoglobinemia, 383 Methimazole, 639 Metrorrhagia, 713 Micelles, 565, 567, 568, 594, 596, 598 Michaelis–Menten equation, 27 Microbiota, 538 controlling factors, 538–539 Microelectrode, 34 Microglia, 105, 112 Microtubules, 66 Microvillous membrane, 584, 596 Midcollicular decerebration, 171 Midline nuclei, 108 Mifepristone, 708 Migrating motor complex (MMC), 548, 551, 551f, 553, 554, 554f Milliosmoles, calculation of, 28 Mineralocorticoids, 626, 662 diseases, 664 synthesis and release, 658–659 Miniature endplate potentials (MEPPs), 69 Minute ventilation, 335 Minute volume, 335 Miosis, 182 Mitochondria, 2, 15, 23, 64, 66, 68, 93, 509, 579, 580, 679f, 688f, 691 Mitogen-activated protein kinase (MAPK), 674 Mitral cells, 159 Mitral regurgitation, 247 Mitral stenosis, 246, 247, 349

775

Mitral valve prolapse, 247 Mixed micelles, 565 Mixed venous PO2, 737 Mixed venous blood, 305 MLC kinase, 100 Modality, 117 Modiolus, 149 Monge’s disease, 742 Monitor peptide, 517, 519 Monoamine oxidase (MAO), 63, 64, 665 Monoamine transporters, 665 Monoiodinated tyrosine (MIT), 636 Monomer of glutamate receptor channels (gluR), 20 Monophasic action, 54 Monosodium glutamate (MSG), 163 Monosynaptic reflex, 125–126 Morphine, 64, 120 Mossy fibers, 175 Motilin, 499, 501, 551 Motility, 72, 491, 495, 502, 529 esophageal, 545–547 gastric, 547–548 intestinal, 552–556 Motoneuron, repetitive firing, 75f Motor cortex, 169 premotor cortex, 169 primary motor cortex, 169 supplementary motor cortex, 169 Motor endplate, 68, 74, 85f, 86, 101, 128f, 544 Motor homunculus, 169 Motor neurons, 9, 85 areflexia, 168 axon, 10 dendrites of, 9 fasciculations, 168 flaccid paralysis, 168 hyporeflexia, 168 hypotonia, 168 in facial nuclei, 168 in hypoglossal nuclei, 168 in trigeminal nuclei, 168 muscular atrophy, 168 spasticity, 168 synapse, 10 with myelinated axon, 107 α-Motor neurons, 171 γ-Motor neurons (nerves), 45, 170 Motor unit, 68, 85, 89, 91, 385 Mountain sickness, acute, 736 Mountain sickness, chronic, 742 MRP2. See Multiple organic anion transporter (MOAT) Mucins, 523 Mucociliary escalator, 308 Mucosa-associated lymphoid tissues (MALT), 535 Mucosal immune system, 535 CD4 cell, 536 CD8 cell, 536 enteric antigens, immune response to, 537 autoimmunity, 538 immune responsiveness, 538 oral tolerance, 537–538 features, 535 functional anatomy adaptive immunity, cellular mediators, 536 innate immunity, cellular mediators, 535–536 lymphoid tissues, organization, 536

776

INDEX

Mucosal immune system (continued) IgE, 536 IgG, 536 secretory IgA system IgA, secretion, 537f IgA, structural aspects, 536–537 physiological functions, 537 protective effects, mechanisms, 537 Mucus, 161, 307 Multidrug resistance protein 3 (MDR3), 568 Multidrug resistance (MDR) transporter, 24 Multiple organic anion transporter (MOAT), 568t, 569 Multiple sclerosis (MS), 53, 107, 112, 162 Multiple system atrophy (MSA), 183 Murmurs, 258 Muscarine, 60 Muscarinic receptors, 102, 179, 206, 510, 524 AChRs, 20, 60 Muscimol, 63 Muscle cell membrane, depolarization of, 6 Muscles contraction changes in strength of, 80 period, 80 Muscles of respiration, 305 Muscle spindles, 45, 117, 125, 390 discharge, various conditions, 128f function, 127–128 structure, 126–127 Muscle tone, 129–130 Muscle weakness, 723 Muscular atrophy, 168, 175 Muscular dystrophy, 85, 340 Muscularis mucosa, 493f, 494, 497f, 502, 553 Myasthenia gravis, 68, 70, 77, 86, 91, 382 Mydriasis, 182 Myelin, 68, 105, 106, 106f, 112 Myelination, 52 Myenteric plexus, 494 Myocardial contractility, 232 Myocardial infarction, 210, 282, 350, 360 Myocardial infarcts, 270 Myocardial ischemia, 272, 360 Myocardial oxygen consumption determinants, 231–232 Myocytes, 93 Myoepithelial cells, 617 Myofibroblasts, 503, 523, 529 Myogenic response mechanism, 81, 265, 415, 547 Myoglobin (Mb), 90, 91, 93, 368, 369, 412, 575 Myometrium, 696f, 708 Myopia, 136, 138f Myosin, 83 Myosin ATPase activity, 99 Myosin filament, 80, 83 Myosin light chain kinase (MLCK), 99, 100, 100f Myosin light chain phosphatase, 99, 100, 100f Myotonia, 57 N Na–Ca antiporter, 486 Na/Ca exchanger (NCX), 24 Na/choline cotransporter, 61 Na–Cl symporter, 443 Na–glucose cotransporter (SGLT), 24 Na/glutamate cotransporter, 24 Na-GLUT antiporter, 27 Na-H antiporters (NHE3), 441, 455, 475 sodium–hydrogen exchanger, 531

Na–HCO3— symporters, 475 Na+/K+-adenosine triphosphatase (ATPase), 662 Na,K-ATPase, 531 Na,K-ATPase pumps, 425, 438, 455, 456, 465, 531 plasma membrane pumps, 464 Na–K–2Cl multiporter, 465, 479 Na–K–2Cl symporter (NKCC2), 442 Na/K pump, 37 cycle, 22f Named potentials, 10 Narcolepsy, 187 Nasal hairs, 308 Nasal turbinates, 307 Na/serotonin cotransporter, 24 Nasopharynx, 307 Natriuretic peptides and hormones, 405, 457, 739 atrial natriuretic peptide (ANP), 457 brain natriuretic peptide (BNP), 457 Nausea, 551. See also Vomiting NaV channels, 75 N-CAMs, 26 NE. See Norepinephrine (NE) Near point of vision, 137 Nearsightedness. See Myopia Necrotizing enterocolitis, 598 Negative base excess, 381 Negative-feedback system, 12, 390 Negative-pressure breathing, 313 Neocortex, 108, 161, 192f, 194, 195 Neomycin, 581 Neospinothalamic tract, 120 Neostigmine, 70 Neosynephrine, 64 Nephrogenic, 620 Nephrogenic diabetes insipidus, 620 Nephron basic structure, 402f collecting ducts, 399 components, 400f juxtaglomerular apparatus, 403 extraglomerular mesangial cells, 403 glomerular filtration rate (GFR), 403 granular cells, 403 juxtamedullary nephron, 403 macula densa cells, 403 renin, 403 renal corpuscle, 399, 400, 401f afferent arteriole, 400 Bowman’s capsule, 400 efferent arteriole, 400 glomerulus (glomeruli), 400 mesangial cell, 400 tubule, 400–403 ascending thin limb, 400 connecting tubule, 402 descending thin limb, 400 distal convoluted tubule, 402 inner medullary collecting duct cells, 403 intercalated cells, 403 loop of Henle, 400 macula densa, 402 peritubular capillaries, 402, 405, 409, 426 principal cells, 403 proximal convoluted tubule, 400 proximal straight tubule, 400 proximal tubule, 400 thick ascending limb, 400 Nephrotic syndrome, 620 Nernst equilibrium potential, 36 Nernst potential, 38, 39, 67, 74 generation of, 36–37

Nerve fiber, 107 mammalian, classification of, 109t relative susceptibility, 110t Nerve gases, 86 Nerve growth factor (NGF), 111 Nervous system, 4, 45, 66, 623 types of glial cells in, 106f Net filtration pressure (NFP), 412 Net influx, 27 Neuroblastomas, 161 Neuroendocrine regulation, 715 counterregulation to acute stress, 718 energy metabolism during fasted state, 716 fat, 716–717 glucose, 716 protein, 717–718 energy metabolism during fed state, 715 fat, 716 glucose, 715–716 protein, 716 long-term energy balance and fat storage, maintenance of, 718–722 of stress response, 725 chronic/severe stress, 726f Neuroendocrine system, 609, 692 Neurofibrillary tangles, 194, 753, 755 Neurogenic shock, 80, 301 Neurogenic tone, 267 Neurohormones, 615 hypophysiotropic, 623 hypothalamic, 623 magnocellular neurons, 614f Neurohumoral regulation, 498 Neurohypophysis, 613 Neurokinin A, 503, 554 Neurological disorders Bell’s palsy, 162 familial dysautonomia, 162 multiple sclerosis, 162 primary amoeboid meningoencephalopathy, 162 vestibular schwannoma, 162 Neurological examination, 120–121 Neuromuscular irritability, 647 Neuromuscular junction, 67f, 85–86, 85f Neuromuscular synapse, 10 Neuromuscular system, 497 enteric nervous system, 497 Neuronal depolarization, 613 Neurons, 9, 105–107 types, in mammalian nervous system, 108 Neuropeptides, 64, 717f anorexigenic, 721 hypothalamic, 615, 719 produced by magnocellular neurons, 616 as potential prolactin-releasing factors, 629 from sensory terminals, 121f that function as hormones, 613 Neuropeptide Y, 721 Neurophysins, 616 Neurotensin (NT), 630 Neurotransmitters, 6, 60f, 63, 64, 75, 106, 179, 499, 500, 530, 610f, 673, 720 enteric, 503 intestinal epithelial transport regulated by, 529 VIP and nitric oxide as, 548 Neurotrophins, 110 Neutrophil, 307 NHE3 sodium-hydrogen exchanger, 531 Nicotine, 60 Nicotinic acetylcholine receptor channels (nAChR), 20, 60

INDEX

Nicotinic cholinergic receptor, 86 Nicotinic receptors, 86, 89, 503, 544 Niemann–Pick C1-like 1 (NPC1L1) gene product, 596 Night blindness, 598 Night terrors, 187 Night vision, 134 Nigrostriatal dopaminergic system, 171 Nitric oxide (NO), 75, 100, 265, 292, 346, 368, 545, 692, 738 Nitrogen narcosis, 741 Nitrogen-washout technique, 333 Nitroglycerin, 272 Nitrous oxide, 350 N-methyl-d-aspartate (NMDA) receptors, 193 channel, 74, 76, 193 N1 nicotinic cholinergic receptors, 179 N2 nicotinic cholinergic receptors, 179 Nociception, 116 Nociceptive stimuli, 130 Nociceptors, 45, 115, 118f, 119, 121f Nocturnal enuresis, 187 Nodes of Ranvier, 52, 106 Nod2 molecule, 536 Nonchloride anions, 468 Nonessential amino acids, 560 Non-NMDA channels, 74 Nonrespiratory acidosis, 379 Nonsteroidal anti-inflammatory drugs (NSAIDs), 30, 116, 117, 435, 514 Noradrenergic neurons, 179 Norepinephrine (NE), 56, 63, 178, 188, 189, 217, 229, 268, 300, 346, 405, 665 receptors, 71 Normal saline, 372 NO synthase, 265 NREM sleep, 186–190, 391 Nuclear bag fiber dynamic and static, 126 Nuclear chain fiber, 126 Nuclear envelope, 3 Nucleases, 517 Nucleation, 572 Nucleolus, 3 Nucleotide–gated cation channel, 163 Nucleus, 3 Nucleus ambiguus, 287, 386, 544 Nucleus basalis of Meynert, 193–194 Nucleus of the tractus solitarius (NTS), 162, 386 Nucleus para-ambigualis, 386 Nucleus parabrachialis medialis, 387 Nucleus retroambigualis, 386 Nucleus retrofacialis, 544 Nucleus tractus solitarius, 287, 509, 545 Nystagmus, 155 O Obesity, 190, 292, 630, 718–719, 721 Obligatory water loss, 440 Obstructive diseases, 326, 333 Obstructive sleep apnea (OSA), 187, 189, 329, 391 Occipital lobe, 141 Occlusion, 130 Octreotide, 631 Ocular dominance columns, 142 Oculomotor nerves, 143, 178 Odorant receptors, 159 Off-center cell, 139 Olfaction, 307 Olfactory bulbs, 159 basic neural circuits in, 160f

Olfactory cortex, 159–161 amygdala, 159 anterior olfactory nucleus, 159 entorhinal cortex, 159 frontal cortex, 160 olfactory tubercle, 159 orbitofrontal cortex, 160 piriform cortex, 159 thalamus, 160 Olfactory discrimination, 161 Olfactory epithelium, 159, 160f Olfactory glomeruli, 159 Olfactory nerve, 165 Olfactory pathway, 161f Olfactory receptors, 25 Olfactory sensory neurons, 159, 159f, 160f Oligoclonal bands, 112 Oligodendrocytes, 105, 106f, 183 Oligomenorrhea, 750 Oligospermia, 693 Olivocochlear bundle, 153 Omeprazole (Prilosec), 23 On-center cell, 139 Oncotic pressure, 254, 412 in glomerular capillary plasma, 412–413 of fluid in Bowman’s capsule, 412 of interstitial fluid, 254 of intracapillary fluid, 254 Oogenesis, 699–701 follicle growth and development, 702f and formation of dominant follicle, 699–701 Open-angle glaucoma, 133 Opiate drugs, 530 Opioid peptides, 120 Optic chiasm, 141 Optic disk, 134 Optic neuritis, 112 Optic tract, 139 Oral cavity, 495 Oral rehydration solutions, 529 Oral tolerance, 537–538 Organelles, 2, 3, 15, 23, 79, 95, 217 Organic anions, 431t Organic anion transporting polypeptide (OATP), 569, 576 Organic cations, 432t Organic cation transporter (OCT), 432 Organic substances, renal handling of, 429 organic anions, proximal secretion, 431–432 urate, 432 organic cations, proximal secretion, 432–433 passive reabsorption/secretion, pH dependence, 433 proximal reabsorption, 429 glucose, 430 proteins and peptides, 430–431 urea, 433–435 Organification, 634 Organ of Corti, 149 Organomegaly, 631 Organum vasculosum lamina terminalis, 619 Orientation columns, 142 Ornithine, 430, 579f Oropharyngeal dysphagia, 556 Oropharynx, 307 Orthostatic/postural hypotension, 183, 298, 448, 620 Osmolarity, 28, 29, 208, 302, 441, 499, 620, 722, 725 Osmoreceptor neurons, 619 Osmoreceptors, 459 Osmosis, 4, 27 Osmotic diuresis, 441, 468

777

Osmotic pressure, 28, 254, 412 Ossicular conduction, 152 OST, bile acid transporter, 569 Osteoblasts, 648f Osteoclast-differentiating factor (ODF), 646 Osteoclasts, 648f Osteocytes, 487, 648f Osteomalacia, 598, 650 Osteonecrosis, 741 Osteopenia, 755 Osteoporosis, 406, 487, 489, 638, 711, 750, 753, 755 postmenopausal, 652, 713 prevention of, 652–653 Osteosclerosis, 154 Otitis externa, 154 Otitis media, 154 Otoconia, 150 Otolithic organ (macula), 150 Otoliths, 150 Ouabain, 22, 37 Oval window, 147 Ovarian cycle, 699 Ovarian follicle, 695 Ovarian hormones, 713 overproduction and undersecretion, 713 physiologic effects of, 705 estrogen, 705–707 placenta, 708–709 progesterone, 707–708 synthesis, 697 activin, 698 androgens, 697 estrogen, 697 follistatin, 698 inhibin, 698 progesterone, 697–698 Ovulation, 701 corpus luteum, formation of, 703 follicle growth and development, 702f luteolysis, 703 β-Oxidation of fatty acids, 678 Oxidative phosphorylation, 79, 80, 90, 91, 93, 100, 383, 745 of glucose, 745 Oxidative stress, 176, 580 Oxygen carrying capacity of hemoglobin, 364, 737 consumption, 269, 336, 746, 747 debt, 745 delivery, 737 inspired and alveolar partial pressures, 736 toxicity, 742 transport, factors affecting, 367–368 Oxygen-carrying capacity, 364, 737 Oxygen consumption, 269, 336, 746, 747 Oxygen content of the mixed venous blood, 355 Oxygen debt, 745 Oxygen delivery, 737 Oxygen extraction, 269 Oxygen loading in lung, 365–366 Oxygen toxicity, 742 Oxyhemoglobin dissociation curve, 364–367, 737, 749 Oxyntic glands, 508 Oxytocin, 64, 615 physiologic effects of, 617 release control of, 617 physiologic effects and regulation of, 617f synthesis and processing of, 616f

778

INDEX

P Pacemaker, 93. See also Cardiac pacemaker; Gastric pacemaker potential, 55 Pacinian corpuscles, 44, 115 Packed red blood cells, 372 Pain inflammatory pain, 116 neuropathic pain, 116 pathological/chronic pain, 116 physiological/acute pain, 116 Pain transmission, modulation of, 120 Paleospinothalamic tract, 120 Palpitations, 640, 667, 668, 678, 732, 736 Pancreas, 492 acini, 518 duct of Santorini, 518 islets of Langerhans, 518 main pancreatic duct (See Wirsung’s duct) phases of secretion cephalic and gastric phases, 519 intestinal phase, 519 sphincter of Oddi, 518 structure, 518f Pancreatic acinar cells, 518, 595 receptors, 521f secretory products, 518t zymogen granules, 518 Pancreatic amylase, 587 Pancreatic hormones, 671, 672 diseases associated with, 678–680 Pancreatic insufficiency, 525, 584 Pancreatic juice, ionic composition, 520f Pancreatic polypeptide, 502, 671, 677, 678 Pancreatic proteases, activation avoiding mechanism, 589f Pancreatic secretion anatomic considerations acinar cells, 518 ductular cells, 518 cellular basis acinar cells, 520–521 ductular cells, 521 pathophysiology, 521–522 principles pancreatic secretory products, 517–518 role and significance, 517 regulation phases of, 519 role of CCK, 519 role of secretin, 519–520 Pancreatitis, 525 Paneth cells, 494 Pannexons, 22 Papillae, 162, 399 circumvallate papillae, 162 foliate papillae, 162 fungiform papillae, 162 Para-aminohippurate (PAH), 418, 432 Paracrine, 499 communication, 500 signaling, 6 Paradoxical potassium retention, 470 Paradoxical reflex, 388 Parafollicular cells, 633 Parageusia, 163 Parallel fibers, 174 Paralytic ileus, 723 Paraplegia, 131 Parasomnias, 187 Parasternal intercartilaginous muscles, 311

Parasternal intercostal muscle, 315 Parasympathetic ganglia, 60, 71 Parasympathetic nerves, 286 Parasympathetic nervous system (PNS), 80, 101, 177, 180f, 523, 692 Parasympathetic tone, 216 Parasympathetic vasodilator nerves, 268 Parathyroid adenoma, 653 Parathyroid Ca2+-sensing receptor, 644f Parathyroid gland hyperplasia, 653 Parathyroid glands, 487, 489, 602f, 611, 643, 644, 649, 653 Parathyroid hormone (PTH), 487–489, 643 cellular effects of, 645–646 clinical evaluation of abnormalities in, 652t hyperplasia of, 653 hypocalcemia, 487 mediated osteoclast differentiation, 647f mobilization of bone calcium, 646–647 production, diseases of primary hyperparathyroidism, 653 pseudohypoparathyroidism, 653 secondary hyperparathyroidism, 653 release, regulation of, 643–644, 644f, 645t and renal calcium rabsorption, 645f and renal inorganic phosphate (Pi) reabsorption, 646f target organs and physiologic effects, 644–645f Paraventricular nucleus, 183, 459, 614f, 615t, 617f, 626 Paresthesia, 122 Parietal cells, 494, 508 ion transport proteins, 513f receptors, schematic representation, 511f ultrastructural appearance, 509f Parietal glands, 508 Parietal lobe, 169 Parkinsonism, 183 Parkinson’s disease, 64, 172, 183 Parotid glands, 522, 523 Paroxysmal hypertension, 667 Paroxysmal nocturnal dyspnea, 283 Partial pressure of alveolar oxygen, 754 Partial seizures, 185, 196 Parturition, 617 Parvocellular cells, 141 Parvocellular neurons, 615 Parvo (P) cells, 141 Passive diffusion, 253 Passive electrical properties, 39 long cylindrical cell, 39–41 small round cell, 39 Passive transport, 26 Patent foramen ovale, 741 Pathologic anatomic shunts, 355 Pathophysiology, 1 Peak expiratory flow (PEF), 326, 384 Pedicels, 411 Pelvic nerves, 554 Penile meatus, 692 Pepsin, 507 secretion, regulation, 511f cephalic phase, 511 gastric phase, 512 intestinal phase, 512 Pepsinogen, 507 PEPT1, 531, 590 Peptic ulcer disease, 514 Peptides, 64, 504 disposition in intestinal epithelial cells, 590f

luminal digestion, 589f transporters, 589–590 peptide transporter 1 (PEPT1), 531, 589 Peptide YY, 502 Percentage of inspired oxygen (FIO2), 355 Percussion, 329 Periaqueductal gray matter (PAG), 120 Pericardium, 203 Periglomerular cells, 159 Perilymph, 149 Perineurium, 112 Peripheral chemoreceptors, 392 Peripheral edema, 742 Peripheral motor control system, 130f Peripheral nervous system, 66, 105–107, 601 Peripheral neuropathy, 126 Peripheral peaking of pulse pressure, 258 Peripheral thermoreceptors, 730 Peripheral vascular system, 252 arterioles, 207 blood vessels, control of, 207 capacitance vessels, 207 capillaries, 207 conduit vessels, 207 structural characteristics, 206 transmural distending pressure, 207 Peripheral venous compartment, 275 Peripheral venous pool, 258 Peripheral venous pressure, 259, 262, 278, 288f, 299 influence on venous return, 279 Peristalsis, 544–547, 555 control of, 546f, 547f primary, 546f secondary, 546, 547f Peritoneal cavity, 399, 563 Permeability, 4, 21, 26, 253 glomerular, 431 hydraulic, 412 ionic, 35 to K+, 37 passive, 524 to sodium ions, 48 to water, 438, 443, 444, 459, 618 Permeable membrane, 26 permeant/permeate substance, 26 Pernicious anemia, 120 Peroxisome proliferator-activated receptor-γ (PPAR-γ), 719 Perturbation, 1, 6, 459 of acid–base balance, 471 in renal handling of potassium, 468–470 Pertussis, 25 Peyer’s patches, 535, 536 structure, 536f PGF2α, 346 Phalen’s sign, 122 Pharyngeal dilator muscles, 322 Pharyngeal dilator reflex, 390 Pharynx, 544, 545 movement of food, 546f Phasic contractions, 548 Phenobarbital, 63 Pheochromocytomas, 665, 667, 668 Phonation, 306 Phosphate, 643 balance, 485–486 regulation, 485, 651 renal phosphate handling, 489 homeostasis, 651 Phosphatidylcholine (PC), 15, 568, 594

INDEX

Phosphatidylethanolamine (PE), 15 Phosphatidylinositol (PIP2), 15, 16, 101 Phosphatidylinositol bisphosphate, 607 Phosphatidylserine (PS), 15, 16 Phosphodiesterase (PDE), 607, 638, 675, 692 Phospholamban, 57, 94, 221 Phospholipase (PLCβ), 25 Phospholipase A2, 595 Phospholipase C (PLC), 21, 101, 607, 658 Phospholipids, 593 bilayer, organization of, 2 translocators, 15, 16 Phosphosphingolipid, 15 Photoreceptors, 43, 115 mechanism, 138–139 current flow in visual receptors, effect of light on, 138 photosensitive compounds, 139 phototransduction in rods and cones, 139f potentials, ionic basis of, 138 Photosensitive compounds opsin and retinal, 139 rhodopsin, 139 scotopsin, 139 Phrenic nerves, 315 Physiological stresses, 738, 739 cardiovascular responses to, 286 Physiologic dead space, 335 Physiologic reserves, 750 Physiologic shunt, 355 Physostigmine, 70, 77 Picrotoxin, 63 Pigment epithelium, 134 Pigment stones, 572 Pillar cells, 149 Pilocarpine, 524 Pineal gland, 188f, 189, 615 Pinealocytes, 189 Pineal sand, 189 Pituitary, 623 adenoma, 144, 630 and hypothalamus, anatomic and functional relationship, 614f insufficiency, 630 tumor, 144 Pituitary adenoma, 144, 630 Pituitary adenylate cyclase activating peptide (PACAP), 503 Pituitary insufficiency, 630 Pituitary tumors, 142 Placenta, 299, 625 structure and physiologic function, 708 Planum temporale, 195 Plaques, 272 Plasma calcium concentration, physiological responses, 488f Plasma creatinine, 419 steady-state relation, 420f Plasma norepinephrine, 183 Plasma osmolality, 755 Plasma potassium, 467 Plasma transcobalamin II (TC II), 591 Plasma volume, 749 Plateau phase, 55 Platelet-activating factor, 307 Platelet aggregation, 208, 272 Pleural effusion, 282 P loop, 17 Plug formation, 208 Pneumonia, 176, 360, 556, 756 Pneumothorax, 321, 329, 330, 349, 360

PNS. See Parasympathetic nervous system (PNS) Podocytes, 411 Poiseuille equation, 203, 258, 322 Poiseuille’s law, 203, 258, 322 Polio or Poliomyelitis, 66, 340 Polycythemia, 742 Polydipsia, 448, 678 Polymeric immunoglobulin receptor (pIgR), 536 Polymodal nociceptors, 116 Polyphagia, 678 Polysomnogram (PSG), 189 Polysynaptic reflexes, 125, 130 Polyuria, 620, 678 Pons, 387 Pontine respiratory groups, 387 Pores of Kohn, 310 Portal circulation, 492 Portal hypertension, 563, 580 Portal triads, 561 Portal vein, 560 Position agnosia, 121 Positive end-expiratory pressure (PEEP), 321, 348 Positive feedback system, 7, 12 Positive-pressure ventilation or breathing, 313, 620 Positive-pressure ventilation with positive end-expiratory pressure, 336 Positive-pressure ventilators, 321 Positron emission tomography (PET), 191 Posterior pituitary gland, 268, 448, 459, 613 anatomic and functional relationship, 614 hormones of, 616–617, 618t synthesis and processing of, 616f Postganglionic fibers, nerves, or neurons, 71, 177, 286 Postmenopausal osteoporosis, 652 Postobstructive polyuria, 644 Postsynaptic cell, 10, 59 Postsynaptic inhibition, 128 Postsynaptic potential (PSP), 11, 59 Postsynaptic processes, 66–67 Post-tetanic potentiation, 71, 192 Posttraumatic diabetes insipidus, 620 Posture, 167 Potassium balance, regulation intracellular and extracellular compartments, 463–464 hormonal regulation of, 724 renal potassium handling, 464–466 distal nephron secretion and regulation, 466–468 perturbations in, 468–470 Potassium channel (KACh), 56 Potassium equilibrium potential, 212 Potassium excretion, 731 Potassium retention, paradoxical, 470 Potassium transport, 466f Potential, membrane, 34 Potentiation, 7 P1 receptors, 21 Precocious puberty, 692, 713 Prednisone, 53, 77, 662, 732 Preganglionic fibers or nerves, 71, 286 Pregnancy, 299, 696 and lacatation, 709 fetoplacental unit hormone synthesis, 710f hormonal control of milk secretion, 711 mammary gland development, 710–711 parturition, hormonal control of, 709–710 tests, 709 Preload, 87

779

cardiac, 228, 230 muscle, 88, 95 shifts, 96 venous return, 747 ventricular, 226 effect of changes, 228 larger, 228 Premature ventricular contractions (PVCs), 243 Preoptic neurons, 188 Presbycusis, 154 Presbyopia, 137 Pressure, 5 transmural, 5 Pressure natriuresis, 455 Pressure–volume curve, 318 Presynaptic cell, 9 Presynaptic inhibition, 75 Presynaptic neuron, 59 Presynaptic processes, 60, 72 Presynaptic terminals, 106 Prevertebral/collateral ganglia, 178 Primary active transport, 27 Primary adrenal insufficiency, 664. See also Adrenal gland Primary amoeboid meningoencephalopathy, 162 Primary colors, 142 Primary/essential hypertension, 292 Primary hyperaldosteronism, 664 Primary hyperparathyroidism, 489 Primary hyperthyroidism, 732 Primary metabolic acidosis, 394. See also Metabolic alkalosis Primary somatosensory area, 169 Primary spontaneous pneumothorax, 330 Primary uncompensated disorder, 481 Primary visual cortex, 141 Principal cells, 403, 443, 466 potassium secretion, 466f Procedural memory, 76 Processivity, 66 Procolipase, 595 Progesterone, 378, 697, 709 antiestrogen actions, 708 metabolic fate of, 705f physiologic actions, 630f, 707–708 receptor–mediated effects, 707–708 receptors, 707 Programmed cell death, 493. See Apoptosis Prolactin, 615, 623, 711 family, 624 physiologic effects of, 630, 630f prolactin release, regulation of, 629–630 Prolactinomas, 630, 631, 692 Prolonged QT intervals, 243 Proopiomelanocortin (POMC), 624, 626 processing, 627f Proopiomelanocortin-derived hormones adrenocorticotropic hormone, 626 β−endorphin, 626 melanocyte-stimulating hormone, 626 Prophospholipase A2, 518 Propranolol, 273 Proprioception, 117, 126 Proprioceptors, 9, 11, 156, 387, 748 Proptosis, 639, 733 Propylthiouracil, 639 Prosopagnosia, 196 Prostacyclin, 346 Prostaglandin 15-dehydrogenase, 708 Prostaglandin E2, 117, 307

780

INDEX

Prostaglandins, 117, 307, 529, 533, 708, 732 synthesis of, 617 Prostaglandins G2 and H2, 307 Prostate, 683 Prostatic hyperplasia, 687 Proteases, 517 Protein kinase A, 25, 57, 94, 97, 100, 231, 607, 618, 675 Protein kinase C, 101–102, 607 Protein kinase G, 100, 103 Protein/peptide hormones, 602 synthesis, 603f Protein assimilation basic principles, 587–590 barriers to water-soluble macromolecules, 584 brush border hydrolysis, 588–589 luminal proteolysis, 588 oligopeptides/amino acids, uptake mechanisms, 589–590 regulation, 590 role and significance, 583 vs. carbohydrate assimilation, 587–588 digestion and absorption, 583 Proteinuria, 427 Protein zero (P0), 106 Prothrombin, 209 Proton pump, 512 inhibitor, 514 Protoplasmic astrocytes, 105 Proximal convoluted tubule, 405 Proximal stump, 112 Proximal tubule, 405, 423, 429, 737 Pseudohypoparathyroidism, 653 Psilocin, 64 Psilocybin, 64 Psychogenic polydipsia, 448 PTH. See Parathyroid hormone (PTH) PTH-related protein (PTHrP), 489, 645 Ptosis, 91 P-type E1–E2 pumps, 23 P-type pumps, 22 Puberty, 189, 629, 690, 707, 711 Puborectalis muscle, 556 Pudendal nerves, 554 Pulmonary blood flow, 341, 355 interaction of gravity and extravascular pressure, 347–348 positive endexpiratory pressure (PEEP), 348 regional distribution, 346–347 zones of lung, 347f Pulmonary capillary blood volume, 360 Pulmonary capillary hydrostatic pressure, 349 Pulmonary circulation, 342 nonrespiratory functions, 350 Pulmonary edema, 30, 247, 283, 348–349, 360 conditions leading to, 349–350 Pulmonary emboli, 336 Pulmonary embolism, 262, 307, 360, 361 Pulmonary embolus, 354, 360 Pulmonary function tests, 333 Pulmonary resistance, 322 Pulmonary sarcoidosis, 322 Pulmonary stretch receptors, 388, 390 Pulmonary surfactant, 307, 321 Pulmonary tissue resistance, 322 Pulmonary vascular congestion, 351 Pulmonary vascular resistance (PVR), 300, 342–343, 748 active influences on, 346t distribution of, 343

lung volume and, 343–344 passive influences on, 346t recruitment and distention, 344–345 Pulmonary vascular smooth muscle control of, 345–346 Pulmonary wedge pressure, 282 Pulse oximetry, 750 Pumps, 16, 22–23 Pupillary light reflex, 143 Purinergic channels, 102 Purinergic (P2) receptors, 21, 179, 456 Purines, 64, 435 Purkinje cells, 174 Purkinje fibers, 54, 214, 216 Purkinje system, 236 PVR. See Pulmonary vascular resistance (PVR) P wave, 216, 224 P2X receptors (P2XRs), 21 P2X ATP receptors, 64 P2X4 receptors, 45 P2X3 receptor channels, 45 Pyelogram, 447 Pylorus, 494, 508, 548 Pyramidal cells, 108, 159 Pyramids, 399 Pyrogens, 731, 732f Q QRS complex, 216, 238–239 Quadriplegia, 131 Quanta of ACh, 69 Quisqualate channel, 74 R Rabies, 66 Radiation, 730 Radioactive iodine uptake test, 733 Raloxifene, 652 Raphe magnus nucleus, 120 Raphe nucleus, 287 Rapid eye movement (REM) sleep, 185 Rapidly adapting pulmonary stretch receptors, 390 Rapidly adapting (phasic) receptors, 118 Rapture of deep, 741 Rarefaction, 292, 754 RAS. See Renin-angiotensin systems (RAS) Rathke’s pouch, 623 RBF. See Renal blood flow (RBF) R-binding protein, 591 Reaction time, 127, 130 Reactive/post-occlusion hyperemia, 265 Rebound phenomenon, 175 Receptive field, 43, 117 Receptive relaxation process, 495, 549 Receptor, 24 Receptor activator of nuclear factor-κβ ligand (RANKL), 646 Receptor desensitization, 667 Receptor downregulation, 608 Receptor kinase, 606f Receptor-linked kinase receptors, 606f, 607 Receptor-mediated endocytosis, 30 Receptor potential, 161 Receptor protein tyrosine kinases, 607 Receptors, 1, 59, 390, 524, 551. See also Cell membrane receptors in airways and lungs, 390 cardiovascular, 390 5HT1 receptors, 551

5HT3 receptors, 551 in muscle, tendons, skin, and viscera, 390 potential, 43 pulmonary vascular, 390 regulating activity of intracellular proteins, 607 Receptor tyrosine kinases (RTK), 25 Reciprocal innervation, 128 Recompression, 741 Recruitment, spatial and temporal, 89 Rectoanal inhibitory reflex, 554 Rectum 553f Rectus abdominis, 311, 556 Red blood cell production, regulation, 398 5α-Reductase inhibitors, 687 Referred pain, 120 Reflection coefficient, 28, 349 Reflex arc, 125, 126f, 131, 499 Reflexes, 1. See also Respiratory reflexes cardiovascular, 288 chemoreceptor, 289 hyperactive stretch, 169 intrinsic, 549, 550 inverse stretch, 128, 129 local, 545 from receptors in heart & lungs, 289 respiratory, 388–390, 389t vagovagal, 510, 519, 546, 549, 550 Reflux, 495 disease, 547 Refraction, 136, 137f Refractory fiber, 89 Refractory period absolute/relative, 51 Regulatory hypothalamic factor, 625 Regulatory systems, 529 Reissner’s membrane, 149 REM sleep, 186–188 Renal acid–base processing, 471–484 Renal angiogram, 461 Renal artery, 399, 409, 414 angioplasty, 462 blockage, 462 obstruction in, 419 pressure, 415, 455 stenosis, 453, 462 Renal artery stenosis, 453, 462 Renal blood flow (RBF), 409–410, 449 afferent arterioles, 409 arcuate arteries, 409 autoregulation, 415–416, 415f cortical radial arteries, 409 efferent arterioles, 409 kidneys flow, resistance, and blood pressure, 410–411 peritubular capillaries, 409 vasa recta, 410 Renal clearance, 417, 418 Renal compensatory mechanisms, 380 Renal failure, 482, 580 chronic, 406, 489 Renal function curves, 292 Renal insufficiency, 630, 664, 722 Renal-MAP set point, 290 Renal microcirculation, 410f Renal plasma flow (RPF), 414, 754 Renal processes. See also Nephron catabolism, 403 chloride reabsorption, 439

INDEX

excretion, 403 filtration, 403 average values, 405t individual tubular segments collecting duct system, 443–444 distal convoluted tubule, 443 Henle’s loop, 442–443 proximal tubule, 440–442 metabolism by tubules, 405 for sodium, chloride, and water, 437 fundamental elements, 404f glomerular filtration, 404 reabsorption, 403 average values, 405t tubular reabsorption, 404 regional function, overview of, 405–406 renal function, regulation, 405 secretion, 403 tubular secretion, 404–405 sodium reabsorption, 438–439 synthesis, of secreted substances, 403 urinary concentration urea, 445–447 vasa recta, 445 water reabsorption, 439–440 Renal tubular acidosis, 427 Renin, 658 secretion, control, 453f Renin–angiotensin–aldosterone system, 658, 722 aldosterone release, regulation, 661f Renin-angiotensin system, 406, 451–453, 482 ACE inhibitors, 453 angiotensin II receptor blockers (ARB), 453 components of, 452f Renovascular hypertension, 462 Renshaw cell, 130 Reserpine, 64 Reserve, 95 Residual volume (RV), 325, 332 Resistance, 5 Resistance vessels, 207 Resistance work of breathing, 737 Resonator, 152 Respiratory acidosis, 377, 378, 481 causes, 378t Respiratory alkalosis, 378–379, 481, 736 causes, 379t Respiratory compensatory mechanisms, 380 Respiratory control system, 385 organization of, 386f response to carbon dioxide, 390–392 hydrogen ions, 392–393 hypoxia, 394 spontaneous rhythmicity, 386–388 Respiratory gases partial pressures of, 336–337 Respiratory pump, 299, 302 Respiratory rate, 329, 330, 339, 340, 350, 360, 372, 385, 388, 394, 427 Respiratory reflexes, 388, 389t cardiovascular receptors, 390 j receptors, 390 pulmonary stretch receptors, 388, 390 receptors in airways, 390 in muscle, tendons, skin, and viscera, 390 Respiratory rhythm generator, 387 Respiratory system, 305–396 airway resistance, 322

assessment of, 325–329 (see also Flowvolume curves) distribution of, 322 increased, clinical consequences of, 329 lung volume and, 323 alveolar pressure, 314 dynamic compression of airways, 324–325 functions acid–base balance, 306 filtration and removal of inspired particles, by airways, 309 gas exchange, 305, 306f handling of bioactive materials, 307 phonation, 306 pulmonary defense mechanisms, 306–307 pulmonary metabolism, 307 removal of material, from alveolar surface, 311 hypoxia of altitude, 736–737 intrapleural pressure, 314 mechanical interaction between lung and chest wall, 314, 314f, 321–322, 338 medullary respiratory center, 311 muscles of, 311, 315 bronchial smooth muscle, control of, 322–323 expiratory muscles, 317 inspiratory muscles, 315–316 normal tidal breath, events involved in, 317t volume, pressure, and airflow changes during, 318f pressure, flow, and resistance, relationship among, 322 pressure-volume relationships in, 318 alveolar interdependence, 321 clinical evaluation of compliance, 319 compliance of lung and, 318–319 elastic recoil, 319–321 pulmonary surfactant, 321 structure, 307 airways, 307–309 alveolar–capillary unit, 309–310 alveolar septum, 310f human lung parenchyma, 309f pulmonary capillary, 310f transpulmonary pressure, 314 ventilatory response to exercise, 747–749, 748t work of breathing, 329 Respiratory zone, 308 Resting membrane potential, 34, 80, 102, 212, 214 of hair cells, 150 hyperpolarization, 216 Resting potential, 10, 34, 37–38 generation, 35 Kir channels supporting, 38 Restrictive disease, 326, 333, 340 Reticular activating system, 110, 188 Reticular formation, 110, 386 Reticular lamina, 149 Reticuloendothelial system, 575 Reticulospinal tracts, 167, 170 Retina, 134 amacrine cells, 134 bipolar cells, 134 cones, 134 extrafoveal portion, neural components of, 135f ganglion cells, 134 projections from right hemiretina of, 141f

781

responses to light, 140f horizontal cells, 134 optic nerve, 134 processing of visual information in, 139 projection, on primary visual cortex, 141f rod and cone density, 136f rods, 134 visual receptors in, 134–135 Retraction, 316 Retrograde amnesia, 192 Retrograde giant contraction, 552 Retrograde transport, 110 Retropulsion, 550, 551 Reversal potential, 67 Reverse T3 (rT3), 637 Rhodopsin, 44f Rho kinase pathway, 100 Rhythmicity, 240–241 Ribosomes, 2, 603f Rickets, 598, 650 Right atrial pressure (RAP), 747 Right axis deviation, 742 Right heart failure, 284 Right ventricular failure, 742 Right ventricular hypertrophy, 738 Rods of Corti, 149 ROMK potassium channels, 466 activity, 467f Rostral ventrolateral medulla, 183, 287 Rough endoplasmic reticulum (RER), 2, 60, 66, 597 Round window, 149 Rubrospinal tracts, 167 Ruffini corpuscles, 115 Rugae, 508 Ryanodine receptors (RyR), 21, 80, 86, 86f, 94, 101 S Saccades, 143 Saccules, 134, 147, 150, 151f, 154 Safety factor, 53, 350, 366 Saliva constituents, 523 ionic composition, 524f Salivary amylase, 523, 584 Salivary glands, 492, 495, 523 salivatory center, 523 salivatory nuclei, 523 salivary gland anatomy acinar cells, 523 ductular cells, 523 salivary secretion acinar cells, 524 ductular cells, 524 neural regulation, 523–524 role and significance, 522 salivary secretory products, 522–523 Salivary secretory products, 522–523 Salivatory center, 523 Salivatory nuclei, 523 Salmonella, 534 Salt appetite, 461 Saltatory conduction, 52, 106 Salt restriction, 293 SA node, 289 Sarcoidosis, 319, 322, 329, 360, 382 Sarcolemma (SL), 79, 85, 100 sarcoplasmic reticulum (SR) interaction, 93 Sarcomeres, 83 pattern of striation, 84f

782

INDEX

Sarcopenia, 753 Sarcoplasmic reticulum (SR), 79, 86, 101, 217, 231 Scalae, 149 Scala media, 149 Scala tympani, 149 Scala vestibuli, 149 Scalene muscles, 311, 315 Scanning speech, 175 Scar formation, 112 S cells, 519 Schaffer collateral LTP, 193 Schizophrenia, 64, 195 Schwann cells, 105, 106, 107f, 112 Scleroderma, 360 Scoliosis, 340 Scuba, 740 Secondary active transport, 27 Secondary hyperparathyroidism, 651 Secondary hypoaldosteronism, 664 Secondary hypothyroidism, 639 Secondary peristalsis, 546 Secondary respiratory alkalosis, 394 Secondary spontaneous pneumothorax, 330 Secondary transporter, 23 Secondary tympanic membrane, 149 Second-degree heart block, 242 Secretin, 499, 501, 519, 568 function, 520f Secretory component, 537 Secretory diarrheal disease, 530f Secretory granules, 2 Secretory immunoglobulin (IgA) molecules, 535 Segmental propulsion, 555 Segmentation, 555 Selectins, 26 Selective estrogen receptor modulators (SERMs), 652 Selective serotonin reuptake inhibitors, 64 Self-contained underwater breathing apparatus (Scuba), 740 Semen, 684 Semicircular canals, 147 Seminal fluid, 684 Seminiferous tubules, 683 Senescence, 690 Senile dementia, 194–195 Sense organ, 115 Sensitization, 541 Sensors, 9, 12 central thermoreceptors, 730 peripheral thermoreceptors, 730 Sensory adaptation, 45 fast and slow, 45f Sensory coding, 117–118 Sensory endings primary (group I) ending, 126 secondary (group II) endings, 126 Sensory fibers, 110 numerical classification for, 110t Sensory generator potential, 10, 43 all-or-none, 10 encoded, 43 graded, 10 Sensory hair cells, 44 Sensory homunculus, 120 Sensory information from peripheral receptors to cerebral cortex, 119f Sensory neuron, 9, 12f, 108, 111, 117, 119f, 149, 159, 160, 162, 502f

Sensory receptors, 115, 125 cutaneous mechanoreceptors, 115 nociceptors and thermoreceptors, 115–117 sensory receptors in skeletal muscles & joints, 115–117 Sensory systems, 4 code elementary attributes of, 116f, 117 improving discrimination, 139 Sensory transduction, 43 Sensory unit, 117 Sepsis, 618 Septal ischemia, 222 SERCA pump, 23 Serosal/peritubular membrane, 29 Serotonin (5-HT), 63, 116, 188, 307, 503 receptors, 20 Sertoli cells, 683, 684 Set point, 6, 731 Set point for temperature regulation, 289 Severe sweating, coordinated response to, 461f Sex hormone–binding globulin (SHBG), 686 Sex hormone synthesis, 626 SGLT-1, 531 Shallow water blackout, 740 Shear stress, 257 Sheehan syndrome, 630 Shivering thermogenesis, 730 Shock, 80, 379, 618, 665 Shock lung syndrome, 321 Short bowel syndrome, 598 Shortening maximum velocity of, 88 Short stature, 631 Short-term memory, 76, 192, 196 Shunt equation, 355 Shunt flow, 355 Shunt fraction, 355 Shuntlike states, 355 Shunts, 383 Shy–Drager syndrome, 183 Sickle cell disease, 350, 364 Sildenafil, 692 Silicosis, 329 Simple cells, 142 Simple diffusion, 26 Sinoatrial (SA) node, 54, 93, 212, 228, 236 Sinusoidal endothelium, 561, 562 Sinusoids, 560–563, 569 Sitosterolemia, 596 ABCG5 transporters, 596 ABCG8 transporters, 596 Skeletal muscle, 79–81, 83–91 cell, 9 excitation–contraction coupling, 86 fiber (cell) types, comparison of, 90 glycogenolysis, 715 neuromuscular junction, 85–86 pattern of sarcomeres, 83–84 pump, 269, 297, 747 regulation of contraction in skeletal muscle, 89–90 contraction-length-tension, 88–89 sarcomere within, 84 types of contractions, 86–88 voluntary, 80, 85 Skeletal muscle pump, 269, 297, 747 Sleep and arousal, neurochemical mechanisms promoting, 188 disorders, 187 cataplexy, 187

central sleep apnea, 187 hypersomnolence, 187 narcolepsy, 187 night terrors, 187 nocturnal enuresis, 187 parasomnias, 187 somnambulism, 187 stages, 186–187 distribution of, 187 K complexes, 186 PET scans during REM sleep, 187 pontogeniculooccipital (PGO) spikes, 187 slow-wave sleep, 186 theta rhythm, 186 Sleep–wake cycle, 187–188 circadian rhythms and, 187–189 and melatonin, 189 Slit diaphragms, 411 Slowly adapting (tonic) receptors, 118 Slow-wave sleep, 186, 624 SL voltage-gated calcium channels, 80 Small intestine, 496 chloride secretion, 532f electroneutral NaCl absorption, 532f epithelial layers, morphology of, 493f ion transport mechanisms, 528ft jejunum and ileum, 496 role, 552 Small skeletal muscles stapedius, 147 tensor tympani, 147 Smooth muscle, 79–81, 99–103 contraction, 99–100 influences on, 102f energy, for contraction and relaxation, 100 multiunit versus unitary, 100–101 smooth muscle cell types, comparison of, 100 stimulation, methods of, 101–103 vascular versus visceral, 100–101 Smooth pursuit movements, 144 SNAP-25, 65 SNARE proteins, 65 Sneeze, 390 S-nitrosohemoglobin (SNO-Hb), 368 SNS. See Sympathetic nervous system (SNS) Sodium excretion, regulation and angiotensin II, 454–455 and autoregulation, 456–457 and ECF volume, 453–454 glomerular filtration rate, 453 important variables, 458f long-term control, 455–456 natriuretic peptides, 457–458 pressure natriuresis and diuresis, 455 renin–angiotensin systems, 451–453 summary, 458 vascular resistance, renal control of, 451 intake and loss, normal routes, 438t reabsorption, 731 collecting duct system, 438 comparison with water reabsorption, 439t distal convoluted tubule, 438 Henle’s loop, 438 Na,K-ATPase pumps, 438 pathways for, 440f proximal tubule, 438 summary of mechanisms, 441t transport pathways, 442f, 443f

INDEX

Sodium-bicarbonate cotransporter (NBC), 521 Sodium channels inactivated, 48 repolarized, 48 Sodium-coupled cotransporters SVCT1/SVCT2, 590 Sodium-coupled nutrient absorption, 531f Sodium-dependent glucose symporter (SGLUT), 430 Sodium/glucose cotransporter SGLT-1 transporter, 531, 586, 587 Sodium–hydrogen exchanger (NHE-1), 513 Sodium–iodide (Na+/I-) symporter, 635 Sodium/potassium/2 chloride cotransporter (NKCC1), 532 Sodium–proton antiporter (NHE3), 426 Sodium reabsorption, 731 Sodium taurocholate cotransporting polypeptide (NTCP), 569 Soluble N-ethylmaleimide-sensitive factor attachment protein (SNAP)-receptor proteins, 65 Soma, 72 Somatic sensory areas somatic sensory area I (SI), 118 somatic sensory area II (SII), 118 Somatomedins, 629 Somatomotor, 183, 290 peripheral organization and transmitters released by, 178f Somatosensory pathways, 118 dorsal column pathway, 118–119 dorsal horn, 118 Somatostatin (SST), 503, 509, 627, 676, 677 Somatotopic organization, 169 Somnambulism, 187 Sound amplitude, 152 bels, 152 decibel scale, 152 frequency, 152 pitch, 152 Sound localization, 153–154 Space constant, 40 Space of Disse, 562, 576 Spasticity, 110, 129, 131, 168, 171, 173 Spatial and temporal facilitation, 130 Spatial recruitment, 89, 90 Spatial summation, 73 Specificity, 24, 576, 605 of CCK and gastrin, 501 of cholesterol esterase, 595 and high affinity, for hormones, 605 of pepsins, 588 positional, of lipases, 594f Specific sensory relay nuclei, 108 Sperm, 683 and accessory organs for production, 684t Spermatogenesis, 690–691 key events in, 691f and functional importance, 691t regulation of, 691 Spermatogonia, 683 Spermatozoa, 683 Spermiation, 690 Sphincter of Oddi, 494, 518, 562 Sphincters, 494, 554 external anal sphincter, 554 ileocecal valve, 554 internal anal sphincter, 554 lower esophageal sphincter (LES), 495, 508, 544

rectoanal inhibitory reflex, 554 upper esophageal sphincter, 544 Sphingolipids, 15 Sphingomyelin, 15 Sphygmomanometry, 297 Spina bifida, 340 Spinal cord, 105, 385 lateral spinothalamic tract, 119 Spinal cord injury (SCI), 131 Spinal integration, 131 Spinal motor neurons, 167 Spinal nerves, 107 Spinal shock, 131 Spinal ventral roots, 125 Spindle sensitivity, 129 Spinocerebellum, 174 Spinoreticular pathway, 119 Spinothalamic tract, 115 Spiny stellate cells, 109 Spiral ganglion, 149 Splanchnic circulation schematic anatomy, 497f Splanchnic nerve, 548 Spleen, 560f, 575, 740 Stagnant hypoxia, 383 Staircase phenomenon, 94 Standard 12-lead electrocardiogram, 240 Standard lung capacities, 331 Standard lung volumes, 331 Starch, 584 Starling equation, 348 Starling forces, 426 Starling hypothesis, 254 Starling’s law of heart, 205, 277 Stasis, 360 Static compliance, 319 Static response, 126 Steady state, 37 Steatorrhea, 512 Stellate cells, 175, 561 Stenosis, 272, 462 aortic, 246, 248 mitral, 246f, 247, 349 renal artery, 453, 462 Stents, 273, 750 Stercobilinogens, 577 Stercobilins, 577 Stereocilia, 150 Stereognosis, 121 Sternocleidomastoid, 311 Steroid hormone receptors, 24 and mineralocorticoid specificity, 662f Steroid hormones, 602 alterations in synthesis, 659f androgens, 655 cholesterol esterase, 656 corticosterone, 656 cortisol, 656 cytochrome P450 sidechain cleavage (SCC) enzyme, 656 DHEA and DHEA sulfate (DHEAS), 656 glucocorticoids, 655 mineralocorticoids, 655 receptors and mineralocorticoid specificity, 662f steroidogenic acute regulatory (StAR) protein, 656 synthesis and metabolism, key enzymes, 658t target organ cellular effects, 660–661 zona fasciculata, 656

783

zona glomerulosa, 656 zona reticularis, 656 Steroidogenesis. See Sex hormone synthesis Steroidogenic acute regulatory (STAR) protein, 656 Steroid receptor superfamily, 607 Stethoscope, 226 Stimulatory G proteins, 217 Stimulus-secretion reflex, 629 Stomach, 495, 547 antrum, 548 cardia, 495, 548 corpus, 548 functional regions, 495f, 548f antrum, 508 cardia, 508 fundus, 508 gastric glands, 508 gastric pits, 508 gastrin, 508 lower esophageal sphincter, 508 oxyntic glands, 508 rugae, 508 fundus, 548 gastric glands, 495 intrinsic and vagovagal reflexes, 550f phasic and tonic contractions, 548 pylorus, 548 receptive relaxation, 495 Stones. See also Gallstone disease; Kidney, stone formation, 485 Storage-operated channels (SOC), 102 Strabismus, 137 Stratified squamous epithelium, 493 Strenuous exercise blood flow in skeletal muscle, 271 cardiac output, 227, 270, 359 diffusion limitation of oxygen transfer during, 359 lactic acidosis associated with, 474 left ventricular output, distribution of, 747f oxygen consumption rate, 270 Stretch receptors, 386, 388 Stretch reflex, 12, 125–126 pathways responsible for, 128f Striatum, 171 Stricture, 556 Stroke, 130 Stroke volume (SV), 95, 228, 258 influences on, 228 cardiac muscle contractility, 229–230 cardiac output, 230f Starling’s law, 228 ventricular afterload, 228–229 Strong acid, 375 Structural interdependence of alveoli, 321 Strychnine, 63 ST segment depression, 750 Subfornical organ, 619 Sublingual gland, 523 Submandibular gland, 523 Submucosal gland cells, 307 Substance P, 116, 265, 503, 545 Substantia gelatinosa, 118 Sucrase, 585 Sucrase-isomaltase, 586 Sucrose, 584, 586 bush border digestion ad assimilation, 586f Sulfonyl urea receptor, 673 Sulfur-containing amino acids, 473 Summation, 89

784

INDEX

Suppression scotoma, 137 Suprachiasmatic nucleus, 188, 615, 623 Supraventricular abnormalities, 240–241 Supraventricular arrhythmias, 242f Supraventricular tachycardia, 232, 241, 242 Surface mucous cells, 509 Surface tension, 319 Sustaining collateral, 111 SVR. See Systemic vascular resistance (SVR) Swallowing center, 544 Sweat glands, 730 Sylvian fissure, 118, 119, 195 Sympathetically mediated vasoconstriction, 738 Sympathetic celiac plexus, 405 Sympathetic chain, 178 Sympathetic ganglia, 71 Sympathetic nerves, 286 Sympathetic nervous system (SNS), 80, 94, 101, 177, 180f, 268, 524, 745 Sympathetic paravertebral ganglion, 178 Sympathetic preganglionic and postganglionic fibers, 179f Sympathetic tone, 216 Sympathetic vasoconstrictor nerves, 267 Sympathomimetic effects, 638 Synapse, 6, 10, 40, 59, 62, 67, 71, 73, 74, 119, 126, 178, 188, 497, 571 Synaptic cleft, 11, 59, 68 Synaptic currents integration, 73–74 Synaptic knobs, 106 Synaptic plasticity, 192 Synaptic release, 64–66 Synaptic transmission depression, 70, 71f facilitation, 70–71, 71f posttetanic potentiation (PTP) of, 71f Synaptic vesicle docking, 60f Synaptotagmin, 66 Syncope, 210, 289, 290 Syncytium, 93, 205 Syndrome of inappropriate ADH secretion, 620 Synovial fluid, 4 Systemic anaphylaxis, 541 Systemic and pulmonary circulations differences in pressure, 343 Systemic cardiovascular circuit, 276f Systemic hypertension, 292 Systemic vascular resistance (SVR), 258, 343, 638, 739, 747 Systole, 56, 204, 221, 224, 225, 229, 247, 269, 270 Systolic compression, 269 Systolic heart failure, 245, 282, 283f T Tachycardia, 232, 241, 242f, 243f, 301, 350, 361, 640, 667 Tachykinins, 503 neurokinin A, 503 substance P, 503 Tachyphylaxis, 667 Tachypnea, 350, 361, 372, 427 Tactile acuity, 117 Tactile agnosia, 121 Taenia coli, 553 Taste buds, 161–163 basal cells, 161 dark cells, 162 intermediate cells, 162 light cells, 162

Taste cells type I, II, and III, 162 Taste modalities, 162 Taste pathways, 161–162, 164f Tau protein, 194, 755 T-cells, 535 receptor, 536 Tectospinal tracts, 167, 170f Temperature-regulating mechanisms, 731f Temporal bone, 149 Temporal lobe, 191, 195, 196 Temporal recruitment, 89 Temporal summation, 39, 73 Tension, 86–88 developed tension, 88 passive tension, 88 total tension, 88 Tension pneumothorax, 330 Terminal buttons/boutons, 106 Testosterone, 683 biosynthesis and metabolism, 688f diseases of, 692–693 receptor-mediated effects of, 687f specific actions of, 689t Tetanic contractions, 89 Tetanus, 66, 89 toxin, 63 Tetany, 52, 653 Tetraiodothyronine (T4), 602, 634 Tetrodotoxin (TTX), 53 Thalamic fasciculus, 171 Thalamic reticular nucleus, 108 Thalamostriatal pathway, 171 Thalamus, 107, 108, 111, 119, 154, 160, 161f, 164f, 167, 171, 173 Thermal nociceptors, 115 Thermoreceptors, 115 cold and warm receptors, 115 Thermoregulation, 715 Thermostatic set point, 6 Thermostat signals, 6 Theta rhythm, 186 Thiazide diuretics, 443 Thiazolidinedione drugs, 719 Third degree (total) AV nodal heart block, 221 Third-degree heart block, 242 Thoracic duct, 597–598 Thoracoabdominal pump, 299, 747 Threshold, 47 Thrombi, 272 Thrombin, 209 Thromboembolus, 361 Thrombolytic drugs, 361 Thrombophlebitis, 262 Thrombosis, 360 Thromboxane, 208, 346 Thymectomy, 77 Thyroglobulin, 633, 634 Thyroid autoimmune disease, 634 Thyroid-binding globulin (TBG), 637 Thyroidectomy, 733 Thyroid gland calcitonin, 633 colloid, 633 euthyroid, 638 follicular (epithelial) cells, 633 functional anatomy thyroid follicle, 633 hypothalamic–pituitary–thyroid axis, evaluation, 640 iodide concentration, mechanism, 635f

iodine metabolism in thyroid follicular cell, regulation, 635–636 key features of, 636t parafollicular cells, 633 regulation and function, 636t thyroglobulin, 633 thyroid hormone, 731, 732 Thyroid hormone, 731, 732 biologic effects, 637–638 diseases of, 638 hyperthyroidism, 639 hypothyroidism, 638–639 inotropic and chronotropic effects of, 638 iodine metabolism, 639–640 metabolism, 637, 637f organ-specific effects, 638 release, regulation, 636 synthesis, 634–635, 636f transport and tissue delivery, 637 Thyroid hyperplasia, 634 Thyroiditis, 634, 639 chronic, 640 Thyroid peroxidase, 636 Thyroid-stimulating hormone (TSH), 615, 623, 633, 634, 640, 732 Thyroid-stimulating immunoglobulins (TSI), 639 Thyroid storm, 731, 733. See Hyperthyroidism Thyrotoxicosis, 732 thyroid storm, 733 Thyrotropin releasing hormone (TRH), 625, 633 Thyrotropin-secreting tumors, 630 Thyroxine, 732 Thyroxine-binding globulin, 707 Tidal volume (VT), 329, 331 Tight junctions, 6, 29 Time constant, 39 Tinel’s sign, 122 Tinnitus, 156 Tip links, 150 Tissue plasminogen activator (tPA), 209 Tissue pressure hypothesis, 266 Titin, 85 Titratable acidity, 480 Toll-like receptors, 536 Tonic–clonic seizure, 185 Tonic contractions, 548 Tonicity, 28 Tonsils, 308 Total body water, 200, 755 Total cholesterol, 707 Total CO2, 377 Total lung capacity (TLC), 322, 332, 750 Total peripheral resistance (TPR), 232, 258, 264, 285, 292, 299, 302, 343, 450, 451, 453, 460 Toxic nodules, 635 Tracheobronchial tree, 307 Transcapillary fluid movement, 254–255 Transcapillary solute diffusion, 253–254 pathways, 253f Transcellular processes, 425 Transcortin, 658, 707 Transcytosis, 30 Transducers, 43, 115 Transducin, 44f, 45, 139, 139f Transepithelial transport mechanisms, 527 Transient ischemic attack (TIA), 210 Transient receptor potential (TRP), 45 Transient shrinking, 29 Transitional zone, 308 Transmembrane protein, 2f, 194, 607

INDEX

Transmembrane solute transport, mechanisms, 424f Transmitter–receptor interaction, 69–70 Transmitters, 10–11, 59 Transmural distending pressure, 207 Transmural pressure gradient, 265, 314, 343 Transport across cell membranes, 26 active, 27 facilitated, 27 passive, 26–27 Transport across epithelial cells, 29–30 Transporters, 16, 23, 424 types of, 24f Transport mechanisms classification, 426 Transpulmonary pressure, 314, 318, 338–339 Transthyretin, 637 Transverse tubules, 11 Traumatic pneumothorax, 330 Traveler’s diarrhea, 534 Trefoil factors, 507 Tremor, 171, 173 Tremor at rest, 173 Treppe, 94 T1R3 family, 163 T2R family, 163 Triiodothyronine (T3), 602f, 634, 733 Trochlear nerves, 143 Tropic hormones, 623 Tropomyosin, 83 Troponin, 80, 83, 94 TnC, 83 TnI, 83 TnT, 83 Trousseau’s sign, 648 Trypsin, 517, 588 Trypsin inhibitors, 517 Trypsinogen, 517, 588 Tryptophan hydroxylase, 64 T score, 652 TSH receptor, 733 t-SNARE syntaxin, 65 T-tubule, 86, 94 T-type calcium channels, 55 D-Tubocurare, 70 Tubular maximum (Tm), 418, 426 Tubular osmolality, 447f Tubular potassium transport, 465t Tubular transport mechanisms limits on rate Tm and gradient-limited systems, 426–427 paracellular route, 424 proximal tubule reabsorption, 423–426 transcellular and paracellular reabsorption, 424f transcellular route, 424 Tubuloglomerular feedback, 456 Tubulovesicles, 509, 512 Tufted cells, 159 Tumor necrosis factor, 731 Turbulent flow, 257, 322 T wave, 215f, 216, 226, 236, 237, 239, 241, 242, 248, 360 Twitch, 88 Two-point discrimination test, 117 Tympanic membrane, 147 Tympanic reflex, 152 Type A intercalated cells, 475 Type B intercalated cells, 476 Type 1 diabetes mellitus, 394, 587 Type 2 diabetes mellitus, 292, 406 Type I alveolar cells, 310

Type II alveolar epithelial cells, 307 Tyrosine hydroxylase (TH), 63, 665 Tyrosine kinases, 629 Tyrosine-tyrosine, 502 U UDP glucuronyl transferase (UGT), 576 Ulcerative, 538 Ulcerative colitis, 534 Unacclimatized person, 736 Uncal herniation, 171 Uncompensated respiratory alkalosis, 361, 384 Unidirectional efflux, 27 Unidirectional influx, 27 Uniporters (UT family) transports, 434 Unloading oxygen, at tissues, 366 Upper endoscopy, 556 Upper esophageal sphincter, 544 Upper motor neuron lesion, 130 Upper motor neurons, 168 Urate, 432–433 Urea, 433–435, 445–447 Urea cycle, 578, 579, 580f. See also KrebsHenseleit cycle Urea disposition, 579–580 Ureases, 579 Uremia, 434, 653 Ureter, 399f, 400, 403, 414, 435, 444, 447 Urethra, 399f, 684 Uric acid, 208, 398, 405, 432, 435 Urinary system anatomy, 399 in female, 399f Urobilinogens, 539, 577 Urobilins, 577 Urolithiasis, 653 Ursodeoxycholic acid, 566 Uterine contractility, 708 Utricle, 147, 149f, 150, 154, 155f V Vagal communication, 503 Vagovagal reflexes, 510, 529 Vagus nerves, 60, 162, 178, 216, 323, 390, 503, 509, 545, 547, 552f Valsalva maneuver, 299 Valve abnormalities, common, 246 Vanilloid receptor, 45 VR1 for, 45 Vanillylmandelic acid (VMA), 665 Variable obstructions, 326 Varicocele, 692 Vasa recta, 409, 445 Vascular bed, 753 stiffening (see Arteriosclerosis) Vascular control mechanisms, 269 in specific organs, 269 cerebral blood flow, 271–272 coronary blood flow, 269–270 skeletal muscle blood flow, 270–271 Vascular function, basic, 255 arteries and veins, elastic properties, 259 blood flow velocities, peripheral, 256–258 blood volumes, peripheral, 258 and flow in networks of vessels, 255–256 resistance, 255–256 vascular resistances, peripheral, 258 Vascular pressure effect of gravity on, 296f responses to changes in body position, 296–297

785

Vascular smooth muscle, 263–264 Vascular tone, 264 Vasculature, 206–207, 257, 267, 336, 404, 445, 451, 563, 619 blood vessels, control of, 207 Vas deferens, 683 Vasoactive intestinal polypeptide (VIP), 64, 265, 501, 503, 521, 529, 547, 630 Vasopressin, 64, 268, 302 Vasovagal syncope, 210, 289 Venoconstriction, 268 Venous admixture, 355 Venous capacitance, 747 Venous function curve, 278 Venous return, 277, 747f Venous tone control of, 268–269 Ventilation–perfusion mismatch, 355 Ventilation-perfusion ratio, 748 matching, 737 mismatching, 754 Ventilation–perfusion ratio line, 355 Ventilation-perfusion ratio matching, 737 Ventilation-perfusion relationships and ratios, 353–356 alveolar–arterial oxygen difference, 355–356 increased, causes of, 356t mismatched, testing for, 355 physiologic dead space, 355 physiologic shunts, 355 shunt equation, 355 regional differences in lung, 356–357 distribution, 357f ventilation–perfusion ratios, 353–355 high and low, consequences of, 353–355 Ventral anterior/lateral nuclei, 108 Ventral cochlear nuclei, 153 Ventral posterior lateral (VPL), 108 nucleus, 118 Ventral posteromedial, 108 nucleus, 162 Ventral respiratory groups (VRG), 386 Ventricular abnormalities, 242–244 Ventricular arrhythmias, 243f Ventricular depolarization, 238, 239 and generation of QRS complex, 239f Ventricular fibrillation, 243 Ventricular gallop rhythm, 226 Ventricular repolarization, 239 and T wave, 239f Ventricular systole, 225 Ventricular tachycardia, 243 Ventrolateral spinothalamic tract, 119–120 Verapamil, 273 Vermis, 174, 175 Vertigo, 156, 552 Vesicles, 10, 60 Vestibular movements, 144 Vestibular schwannoma, 162 Vestibular system, 154 Deiters’ nucleus, 154 vestibular apparatus, 154 vestibular nuclei, 154 Vestibulo-ocular reflex, 155 Vestibulospinal tracts, 167 Vibratory sensibility, 120 Vibrio cholerae, 533 Vibrissae, 308 Villus structures, 493 VIP. See Vasoactive intestinal polypeptide (VIP) Virilization, 657

786

INDEX

Visceral senses, 159 Visual acuity, 134 Visual agnosia, 121 Visual evoked potential test, 112 Visual field exam, 144 Visual pathways, 139–141, 140f optic pathways, effect of lesions in, 142 macular sparing, 142 primary visual cortex, 141–142 Vital capacity (VC), 325, 332, 334 Vitamin A, 139 Vitamin B12, 507 Vitamin D toxicity, 650 Vitamins, 590 homeostasis, 590 vitamin A, retinoic acid, 594 vitamin B12, 507, 591 deficiencies, 120 gastrointestinal absorption, 591f vitamin C, 590 (See also Ascorbic acid) vitamin D, 486, 643 abnormal levels, 650 active form, 398 analogs, 653 calciferol, 594 cellular effects of, 650 1,25-(OH)2D; calcitriol, 487 insufficiency, 755 metabolism and physiologic effects at, 649f production, regulation, 398 synthesis and activation, 649–650 vitamin E, tocopherol, 594 vitamin K, 594 Vmax, 88, 96, 96f Voltage-activated L-type CaV channels, 54

Voltage clamping, 49–51 circuit for squid giant axon, 49 Voltage-dependent Ca2+ channels, 673 Voltage-dependent K channels (KV), 49 topology of monomer, 19f Voltage-dependent Na (NaV) channels, 19, 48 Voltage-gated channels, 213, 485 Voltage-sensitive Ca2+ channels (CaV), 19 Voltage-sensitive channels, 11 voltage-sensitive Ca2+ channels (CaV), 11, 19 voltage-sensitive Na channels (NaV), 11, 19 role of, 47–49 Voltage-sensitive Na channels (NaV), 11, 19 role of, 47–49 Voluntary movement, 167, 168f, 169 Voluntary muscle, 80, 85 Vomiting, 156, 279, 379, 394, 474, 489, 551–552, 563 neural pathways, 552f v-SNARE synaptobrevin, 65 V-type H+ pump, 23, 60 W Wallerian degeneration, 66, 111 Warfarin, 262 Wasting syndrome, 718 Water balance concept, regulation, 397–398 diuresis, 444 excretion, regulation, 458 ADH secretion, baroreceptor control, 459–460 ADH secretion, osmoreceptor control, 459 goals, 449 mechanism, 459f, 460f

plasma volume pathway, 457f thirst and salt appetite, 460–461 gain and loss, normal routes, 439t insensible loss, 439 obligatory water loss, 440 reabsorption, 439–440 pathways for, 440f Water-soluble vitamins, 429 assimilation, 590–591 vitamin B12 (cobalamin), 591 vitamin C, 590 digestion and absorption, 583 Weak acid, 375 Weber and Schwabach tests, 154 Wernicke’s area, 195 White rami communicans, 178 Willebrand factor, 208 Wirsung’s duct, 518 Withdrawal reflex, 116 Wolff-Chaikoff effect, 636 Working memory, 192–194 Work of breathing, 329, 748 X Xenobiotics, 560 Z Zones of the lung, 346–348 Zone-specific, adrenal steroid hormone synthetic pathway, 657f Z score, 652 Zymogen granules, 518