Guyton and Hall Textbook of Medical Physiology 13th Ed PDF

 13TH EDITION Guyton and Hall Textbook of Medical Physiology John E. Hall, PhD Arthur C. Guyton Professor and Chair Department of Physiology and Biophysics Dir...

 13TH EDITION Guyton and Hall Textbook of Medical Physiology John E. Hall, PhD Arthur C. Guyton Professor and Chair Department of Physiology and Biophysics Director, Mississippi Center for Obesity Research University of Mississippi Medical Center Jackson, Mississippi 1600 John F. Kennedy Blvd. Ste 1800 Philadelphia, PA 19103-2899 GUYTON AND HALL TEXTBOOK OF MEDICAL PHYSIOLOGY, ISBN: 978-1-4557-7005-2 THIRTEENTH EDITION INTERNATIONAL EDITION ISBN: 978-1-4557-7016-8 Copyright © 2016 by Elsevier, Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. 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Previous editions copyrighted 2011, 2006, 2000, 1996, 1991, 1986, 1981, 1976, 1971, 1966, 1961, 1956 by Saunders, an imprint of Elsevier, Inc. Library of Congress Cataloging-in-Publication Data Hall, John E. (John Edward), 1946-, author. Guyton and Hall textbook of medical physiology / John E. Hall.—Thirteenth edition.    p. ; cm. Textbook of medical physiology Includes bibliographical references and index. ISBN 978-1-4557-7005-2 (hardcover : alk. paper) I. Title. II. Title: Textbook of medical physiology. [DNLM: 1. Physiological Phenomena. QT 104] QP34.5 612—dc23    2015002552 Senior Content Strategist: Elyse O’Grady Senior Content Development Manager: Rebecca Gruliow Publishing Services Manager: Patricia Tannian Senior Project Manager: Carrie Stetz Design Direction: Julia Dummitt Printed in The United States of America Last digit is the print number: 9 8 7 6 5 4 3 2 1  To My Family For their abundant support, for their patience and understanding, and for their love To Arthur C. Guyton For his imaginative and innovative research For his dedication to education For showing us the excitement and joy of physiology And for serving as an inspirational role model  Preface The first edition of the Textbook of Medical Physiology was that students will continue to use it during their profes- written by Arthur C. Guyton almost 60 years ago. Unlike sional careers. most major medical textbooks, which often have 20 or My hope is that this textbook conveys the majesty more authors, the first eight editions of the Textbook of of the human body and its many functions and that it Medical Physiology were written entirely by Dr. Guyton, stimulates students to study physiology throughout their with each new edition arriving on schedule for nearly careers. Physiology is the link between the basic sciences 40 years. Dr. Guyton had a gift for communicating and medicine. The great beauty of physiology is that it complex ideas in a clear and interesting manner that integrates the individual functions of all the body’s differ- made studying physiology fun. He wrote the book to help ent cells, tissues, and organs into a functional whole, the students learn physiology, not to impress his professional human body. Indeed, the human body is much more than colleagues. the sum of its parts, and life relies upon this total function, I worked closely with Dr. Guyton for almost 30 years not just on the function of individual body parts in isola- and had the privilege of writing parts of the ninth and tion from the others. tenth editions. After Dr. Guyton’s tragic death in an auto- This brings us to an important question: How are mobile accident in 2003, I assumed responsibility for the separate organs and systems coordinated to maintain completing the subsequent editions. proper function of the entire body? Fortunately, our For the thirteenth edition of the Textbook of Medical bodies are endowed with a vast network of feedback con- Physiology, I have the same goal as for previous editions— trols that achieve the necessary balances without which to explain, in language easily understood by students, how we would be unable to live. Physiologists call this high the different cells, tissues, and organs of the human body level of internal bodily control homeostasis. In disease work together to maintain life. states, functional balances are often seriously disturbed This task has been challenging and fun because our and homeostasis is impaired. When even a single distur- rapidly increasing knowledge of physiology continues to bance reaches a limit, the whole body can no longer live. unravel new mysteries of body functions. Advances in One of the goals of this text, therefore, is to emphasize molecular and cellular physiology have made it possible the effectiveness and beauty of the body’s homeostasis to explain many physiology principles in the terminology mechanisms as well as to present their abnormal func- of molecular and physical sciences rather than in tions in disease. merely a series of separate and unexplained biological Another objective is to be as accurate as possible. phenomena. Suggestions and critiques from many students, physiolo- The Textbook of Medical Physiology, however, is not a gists, and clinicians throughout the world have checked reference book that attempts to provide a compendium factual accuracy as well as balance in the text. Even so, of the most recent advances in physiology. This is a book because of the likelihood of error in sorting through many that continues the tradition of being written for students. thousands of bits of information, I wish to issue a further It focuses on the basic principles of physiology needed request to all readers to send along notations of error or to begin a career in the health care professions, such inaccuracy. Physiologists understand the importance of as medicine, dentistry, and nursing, as well as graduate feedback for proper function of the human body; so, too, studies in the biological and health sciences. It should is feedback important for progressive improvement of a also be useful to physicians and health care professionals textbook of physiology. To the many persons who have who wish to review the basic principles needed for under- already helped, I express sincere thanks. Your feedback standing the pathophysiology of human disease. has helped to improve the text. I have attempted to maintain the same unified organi- A brief explanation is needed about several features of zation of the text that has been useful to students in the the thirteenth edition. Although many of the chapters past and to ensure that the book is comprehensive enough have been revised to include new principles of physiology vii Preface and new figures to illustrate these principles, the text other information that is needed for immediate discus- length has been closely monitored to limit the book size sion but that most students will learn in more detail so that it can be used effectively in physiology courses for in other courses; (2) physiological information of special medical students and health care professionals. Many of importance to certain fields of clinical medicine; and the figures have also been redrawn and are in full color. (3) information that will be of value to those students who New references have been chosen primarily for their pre- may wish to study particular physiological mechanisms sentation of physiological principles, for the quality of more deeply. their own references, and for their easy accessibility. The I wish to express sincere thanks to many persons who selected bibliography at the end of the chapters lists have helped to prepare this book, including my colleagues papers mainly from recently published scientific journals in the Department of Physiology and Biophysics at the that can be freely accessed from the PubMed site at University of Mississippi Medical Center who provided http://www.ncbi.nlm.nih.gov/pubmed/. Use of these ref- valuable suggestions. The members of our faculty and a erences, as well as cross-references from them, can give brief description of the research and educational activities the student almost complete coverage of the entire field of the department can be found at http://physiology of physiology..umc.edu/. I am also grateful to Stephanie Lucas for The effort to be as concise as possible has, unfortu- excellent secretarial services and to James Perkins for nately, necessitated a more simplified and dogmatic excellent illustrations. Michael Schenk and Walter (Kyle) presentation of many physiological principles than I nor- Cunningham also contributed to many of the illustra- mally would have desired. However, the bibliography tions. I also thank Elyse O’Grady, Rebecca Gruliow, Carrie can be used to learn more about the controversies Stetz, and the entire Elsevier team for continued editorial and unanswered questions that remain in understanding and production excellence. the complex functions of the human body in health and Finally, I owe an enormous debt to Arthur Guyton for disease. the great privilege of contributing to the Textbook of Another feature is that the print is set in two sizes. The Medical Physiology for the past 25 years, for an exciting material in large print constitutes the fundamental physi- career in physiology, for his friendship, and for the inspi- ological information that students will require in virtually ration that he provided to all who knew him. all of their medical activities and studies. The material in small print and highlighted with a pale blue background John E. Hall is of several different kinds: (1) anatomic, chemical, and viii Guyton and Hall Textbook of Medical Physiology 13rd Edition By John E. Hall, PhD, Arthur C. Guyton Professor and Chair, Department of Physiology and Biophysics, Director, Mississippi Center for Obesity Research, University of Mississippi Medical Center, Jackson, Mississippi UNIT I - Introduction to Physiology: The Cell and General Physiology 1. Functional Organization of the Human Body and Control of the "Internal Environment" 2. The Cell and Its Functions 3. Genetic Control of Protein Synthesis, cell function, and cell reproduction UNIT II - Membrane Physiology, Nerve, and Muscle 4. Transport of Substances Through Cell Membranes 5. Membrane Potentials and Action Potentials 6. Contraction of Skeletal Muscle 7. Excitation of Skeletal Muscle: Neuromuscular Transmission and Excitation-Contraction Coupling 8. Excitation and Contraction of Smooth Muscle UNIT III - The Heart 9. Cardiac Muscle; The Heart as a Pump and Function of the Heart Valves 10. Rhythmical Excitation of the Heart 11. The Normal Electrocardiogram 12. Electrocardiographic Interpretation of Cardiac Muscle and Coronary Blood Flow Abnormalities: Vectorial Analysis 13.Cardiac Arrhythmias and Their Electrocardiographic Interpretation UNIT IV - The Circulation 14. Overview of the Circulation; Biophysics of Pressure, Flow, and Resistance 15. Vascular Distensibility and Functions of the Arterial and Venous Systems 16. The Microcirculation and Lymphatic System: Capillary Fluid Exchange, Interstitial Fluid, and Lymph Flow 17. Local and Humoral Control of Tissue Blood Flow 18. Nervous Regulation of the Circulation and Rapid Control of Arterial Pressure 19. Role of the Kidneys in Long-Term Control of Arterial Pressure and in Hypertension: The Integrated System for Aterial Pressure Regulation 20. Cardiac Output, Venous Return, and Their Regulation 21. Muscle Blood Flow and Cardiac Output During Exercise; the Coronary Circulation and Ischemic Heart Disease 22. Cardiac Failure 23. Heart Valves and Heart Sounds; Valvular and Congenital Heart Defects 24. Circulatory Shock and Its Treatment UNIT V - The Body Fluids and Kidneys 25. The Body Fluid Compartments: Extracellular and Intracellular Fluids; Edema 26. The Urinary System: Functional Anatomy and Urine Formation by the Kidneys 27. Glomerular Filtration, Renal Blood Flow, and Their Control 28. Renal Tubular Reabsorption and Secretion 29. Urine Concentration and Dilution; Regulation of Extracellular Fluid Osmolarity and Sodium Concentration 30. Renal Regulation of Potassium, Calcium, Phosphate, and Magnesium; Integration of Renal Mechanisms for Control of Blood Volume and Extracellular Fluid Volume 31. Acid-Base Regulation 32. Diuretics, Kidney Diseases UNIT VI - Blood Cells, Immunity, and Blood Coagulation 33. Red Blood Cells, Anemia, and Polycythemia 34. Resistance of the Body to Infection: I. Leukocytes, Granulocytes, the Monocyte-Macrophage System, and Inflammation 35. Resistance of the Body to Infection: II. Immunity and Allergy 36. Blood Types; Transfusion; Tissue and Organ Transplantation 37. Hemostasis and Blood Coagulation UNIT VII - Respiration 38. Pulmonary Ventilation 39. Pulmonary Circulation, Pulmonary Edema, Pleural Fluid 40. Principles of Gas Exchange; Diffusion of Oxygen and Carbon Dioxide Through the Respiratory Membrane 41. Transport of Oxygen and Carbon Dioxide in Blood and Tissue Fluids 42. Regulation of Respiration 43. Respiratory Insufficiency - Pathophysiology, Diagnosis, Oxygen Therapy UNIT VIII - Aviation, Space, and Deep-Sea Diving Physiology 44. Aviation, High Altitude, and Space Physiology 45. Physiology of Deep-Sea Diving and Other Hyperbaric Conditions UNIT IX - The Nervous System: A. General Principles and Sensory Physiology 46. Organization of the Nervous System, Basic Functions of Synapses, and Neurotransmitters 47. Sensory Receptors, Neuronal Circuits for Processing Information 48. Somatic Sensations: I. General Organization, the Tactile and Position Senses 49. Somatic sensations: II. Pain, Headache, and Thermal Sensations UNIT X - The Nervous System: B. The Special Senses 50. The Eye: I. Optics of Vision 51. The Eye: II. Receptor and Neural Function of the Retina 52. The Eye: III. Central Neurophysiology of Vision 53. The Sense of Hearing 54. The Chemical Senses - Taste and Smell UNIT XI - The Nervous System: C. Motor and Integrative Neurophysiology 55. Motor Functions of the Spinal Cord; the Cord Reflexes 56. Cortical and Brain Stem Control of Motor Function 57. Contributions of the Cerebellum and Basal Ganglia to Overall Motor Control 58. Cerebral Cortex, Intellectual Functions of the Brain, Learning, and Memory 59. Behavioral and Motivational Mechanisms of the Brain - The Limbic System and the Hypothalamus 60. States of Brain Activity - Sleep, Brain Waves, Epilepsy, Psychoses, and Dementia 61. The Autonomic Nervous System and the Adrenal Medulla 62. Cerebral Blood Flow, Cerebrospinal Fluid, and Brain Metabolism UNIT XII - Gastrointestinal Physiology 63. General Principles of Gastrointestinal Function - Motility, Nervous Control, and Blood Circulation 64. Propulsion and Mixing of Food in the Alimentary Tract 65. Secretory Functions of the Alimentary Tract 66. Digestion and Absorption in the Gastrointestinal Tract 67. Physiology of Gastrointestinal Disorders UNIT XIII - Metabolism and Temperature Regulation 68. Metabolism of Carbohydrates and Formation of Adenosine Triphosphate 69. Lipid Metabolism 70. Protein Metabolism 71. The Liver as an Organ 72. Dietary Balances; Regulation of Feeding; Obesity and Starvation; Vitamins and Minerals 73. Energetics and Metabolic Rate 74. Body Temperature Regulation and Fever UNIT XIV - Endocrinology and Reproduction 75. Introduction to Endocrinology 76. Pituitary Hormones and Their Control by the Hypopthalamus 77. Thyroid Metabolic Hormones 78. Adenocortical Hormones 79. Insulin, Glucagon, and Diabetes Mellitus 80. Parathyroid Hormone, Calcitonin, Calcium and Phosphate Metabolism, Vitamin D, Bone, and Teeth 81. Reproductive and Hormonal Functions of the Male (and Function of the Pineal Gland) 82. Female Physiology Before Pregnancy and Female Hormones 83. Pregnancy and Lactation 84. Fetal and Neonatal Physiology UNIT XV - Sports Physiology 85. Sports Physiology MISSING  CHAPTER 1 Functional Organization of the Human Body UNIT I and Control of the “Internal Environment” Physiology is the science that seeks to explain the physical required for all cells to function. Further, the general and chemical mechanisms that are responsible for the chemical mechanisms for changing nutrients into energy origin, development, and progression of life. Each type of are basically the same in all cells, and all cells deliver life, from the simplest virus to the largest tree or the products of their chemical reactions into the surrounding complicated human being, has its own functional charac- fluids. teristics. Therefore, the vast field of physiology can be Almost all cells also have the ability to reproduce addi- divided into viral physiology, bacterial physiology, cellular tional cells of their own kind. Fortunately, when cells of physiology, plant physiology, invertebrate physiology, ver- a particular type are destroyed, the remaining cells of tebrate physiology, mammalian physiology, human physi- this type usually generate new cells until the supply is ology, and many more subdivisions. replenished. Human Physiology. The science of human physiology EXTRACELLULAR FLUID—THE attempts to explain the specific characteristics and mech- “INTERNAL ENVIRONMENT” anisms of the human body that make it a living being. The fact that we remain alive is the result of complex About 60 percent of the adult human body is fluid, mainly control systems. Hunger makes us seek food, and fear a water solution of ions and other substances. Although makes us seek refuge. Sensations of cold make us look for most of this fluid is inside the cells and is called intracel- warmth. Other forces cause us to seek fellowship and to lular fluid, about one third is in the spaces outside the reproduce. The fact that we are sensing, feeling, and cells and is called extracellular fluid. This extracellular knowledgeable beings is part of this automatic sequence fluid is in constant motion throughout the body. It is of life; these special attributes allow us to exist under transported rapidly in the circulating blood and then widely varying conditions, which otherwise would make mixed between the blood and the tissue fluids by diffusion life impossible. through the capillary walls. In the extracellular fluid are the ions and nutrients needed by the cells to maintain life. Thus, all cells live in CELLS ARE THE LIVING UNITS essentially the same environment—the extracellular fluid. OF THE BODY For this reason, the extracellular fluid is also called the The basic living unit of the body is the cell. Each organ is internal environment of the body, or the milieu intérieur, an aggregate of many different cells held together by inter- a term introduced more than 150 years ago by the cellular supporting structures. great 19th-century French physiologist Claude Bernard Each type of cell is specially adapted to perform one (1813–1878). or a few particular functions. For instance, the red blood Cells are capable of living and performing their special cells, numbering about 25 trillion in each human being, functions as long as the proper concentrations of oxygen, transport oxygen from the lungs to the tissues. Although glucose, different ions, amino acids, fatty substances, the red blood cells are the most abundant of any single and other constituents are available in this internal type of cell in the body, about 75 trillion additional cells environment. of other types perform functions different from those of the red blood cell. The entire body, then, contains about Differences Between Extracellular and Intracellular 100 trillion cells. Fluids. The extracellular fluid contains large amounts of Although the many cells of the body often differ mark- sodium, chloride, and bicarbonate ions plus nutrients for edly from one another, all of them have certain basic the cells, such as oxygen, glucose, fatty acids, and amino characteristics that are alike. For instance, oxygen reacts acids. It also contains carbon dioxide that is being trans- with carbohydrate, fat, and protein to release the energy ported from the cells to the lungs to be excreted, plus 3 Unit I Introduction to Physiology: The Cell and General Physiology other cellular waste products that are being transported of the disease from the compensatory responses. For to the kidneys for excretion. example, diseases that impair the kidneys’ ability to The intracellular fluid differs significantly from the excrete salt and water may lead to high blood pressure, extracellular fluid; for example, it contains large amounts which initially helps return excretion to normal so that a of potassium, magnesium, and phosphate ions instead balance between intake and renal excretion can be main- of the sodium and chloride ions found in the extracel- tained. This balance is needed to maintain life, but over lular fluid. Special mechanisms for transporting ions long periods of time the high blood pressure can damage through the cell membranes maintain the ion concentra- various organs, including the kidneys, causing even tion differences between the extracellular and intracellu- greater increases in blood pressure and more renal lar fluids. These transport processes are discussed in damage. Thus, homeostatic compensations that ensue Chapter 4. after injury, disease, or major environmental challenges to the body may represent a “trade-off ” that is necessary to maintain vital body functions but may, in the long HOMEOSTASIS—MAINTENANCE term, contribute to additional abnormalities of body OF A NEARLY CONSTANT function. The discipline of pathophysiology seeks to INTERNAL ENVIRONMENT explain how the various physiological processes are In 1929 the American physiologist Walter Cannon altered in diseases or injury. (1871–1945) coined the term homeostasis to describe This chapter outlines the different functional systems the maintenance of nearly constant conditions in the inter- of the body and their contributions to homeostasis; we nal environment. Essentially all organs and tissues of the then briefly discuss the basic theory of the body’s control body perform functions that help maintain these rela- systems that allow the functional systems to operate in tively constant conditions. For instance, the lungs provide support of one another. oxygen to the extracellular fluid to replenish the oxygen used by the cells, the kidneys maintain constant ion EXTRACELLULAR FLUID TRANSPORT concentrations, and the gastrointestinal system provides AND MIXING SYSTEM—THE BLOOD nutrients. CIRCULATORY SYSTEM The various ions, nutrients, waste products, and other constituents of the body are normally regulated within a Extracellular fluid is transported through the body in two range of values, rather than at fixed values. For some stages. The first stage is movement of blood through the of the body’s constituents, this range is extremely small. body in the blood vessels, and the second is movement of Variations in blood hydrogen ion concentration, for fluid between the blood capillaries and the intercellular example, are normally less than 5 nanomoles per liter spaces between the tissue cells. (0.000000005 moles per liter). Blood sodium concentra- Figure 1-1 shows the overall circulation of blood. All tion is also tightly regulated, normally varying only a few the blood in the circulation traverses the entire circula- millimoles per liter even with large changes in sodium tory circuit an average of once each minute when the intake, but these variations of sodium concentration are body is at rest and as many as six times each minute when at least 1 million times greater than for hydrogen ions. a person is extremely active. Powerful control systems exist for maintaining the As blood passes through the blood capillaries, con- concentrations of sodium and hydrogen ions, as well as tinual exchange of extracellular fluid also occurs between for most of the other ions, nutrients, and substances the plasma portion of the blood and the interstitial in the body at levels that permit the cells, tissues, and fluid that fills the intercellular spaces. This process is organs to perform their normal functions despite wide shown in Figure 1-2. The walls of the capillaries are environmental variations and challenges from injury and permeable to most molecules in the plasma of the blood, diseases. with the exception of plasma proteins, which are too large A large segment of this text is concerned with how to readily pass through the capillaries. Therefore, large each organ or tissue contributes to homeostasis. Normal amounts of fluid and its dissolved constituents diffuse body functions require the integrated actions of cells, back and forth between the blood and the tissue spaces, tissues, organs, and the multiple nervous, hormonal, and as shown by the arrows. This process of diffusion is caused local control systems that together contribute to homeo- by kinetic motion of the molecules in both the plasma and stasis and good health. the interstitial fluid. That is, the fluid and dissolved mol- Disease is often considered to be a state of disrupted ecules are continually moving and bouncing in all direc- homeostasis. However, even in the presence of disease, tions within the plasma and the fluid in the intercellular homeostatic mechanisms continue to operate and main- spaces, as well as through the capillary pores. Few cells tain vital functions through multiple compensations. In are located more than 50 micrometers from a capillary, some cases, these compensations may themselves lead to which ensures diffusion of almost any substance from the major deviations of the body’s functions from the normal capillary to the cell within a few seconds. Thus, the extra- range, making it difficult to distinguish the primary cause cellular fluid everywhere in the body—both that of the 4  Chapter I Functional Organization of the Human Body and Control of the “Internal Environment” Lungs Arteriole UNIT I CO2 O2 Right Left heart heart pump pump Venule Gut Figure 1-2. Diffusion of fluid and dissolved constituents through the capillary walls and through the interstitial spaces. Nutrition Gastrointestinal Tract. A large portion of the blood and excretion pumped by the heart also passes through the walls of the gastrointestinal tract. Here different dissolved nutrients, including carbohydrates, fatty acids, and amino acids, are absorbed from the ingested food into the extracellular Kidneys fluid of the blood. Liver and Other Organs That Perform Primarily Metabolic Functions. Not all substances absorbed from the gastrointestinal tract can be used in their absorbed form by the cells. The liver changes the chemical compo- Regulation sitions of many of these substances to more usable forms, of Excretion and other tissues of the body—fat cells, gastrointestinal electrolytes mucosa, kidneys, and endocrine glands—help modify the absorbed substances or store them until they are needed. The liver also eliminates certain waste products produced Venous end Arterial end in the body and toxic substances that are ingested. Musculoskeletal System. How does the musculoskele- tal system contribute to homeostasis? The answer is obvious and simple: Were it not for the muscles, the body Capillaries could not move to obtain the foods required for nutrition. Figure 1-1. General organization of the circulatory system. The musculoskeletal system also provides motility for protection against adverse surroundings, without which plasma and that of the interstitial fluid—is continually the entire body, along with its homeostatic mechanisms, being mixed, thereby maintaining homogeneity of the could be destroyed. extracellular fluid throughout the body. REMOVAL OF METABOLIC END PRODUCTS ORIGIN OF NUTRIENTS IN THE Removal of Carbon Dioxide by the Lungs. At the EXTRACELLULAR FLUID same time that blood picks up oxygen in the lungs, carbon Respiratory System. Figure 1-1 shows that each time dioxide is released from the blood into the lung alveoli; the blood passes through the body, it also flows through the respiratory movement of air into and out of the lungs the lungs. The blood picks up oxygen in the alveoli, thus carries the carbon dioxide to the atmosphere. Carbon acquiring the oxygen needed by the cells. The membrane dioxide is the most abundant of all the metabolism between the alveoli and the lumen of the pulmonary cap- products. illaries, the alveolar membrane, is only 0.4 to 2.0 microm- eters thick, and oxygen rapidly diffuses by molecular Kidneys. Passage of the blood through the kidneys motion through this membrane into the blood. removes from the plasma most of the other substances 5 Unit I Introduction to Physiology: The Cell and General Physiology besides carbon dioxide that are not needed by the cells. and protein metabolism; and parathyroid hormone con- These substances include different end products of cel- trols bone calcium and phosphate. Thus the hormones lular metabolism, such as urea and uric acid; they also provide a system for regulation that complements the include excesses of ions and water from the food that nervous system. The nervous system regulates many mus- might have accumulated in the extracellular fluid. cular and secretory activities of the body, whereas the The kidneys perform their function by first filtering hormonal system regulates many metabolic functions. large quantities of plasma through the glomerular capil- The nervous and hormonal systems normally work laries into the tubules and then reabsorbing into the blood together in a coordinated manner to control essentially the substances needed by the body, such as glucose, all of the organ systems of the body. amino acids, appropriate amounts of water, and many of the ions. Most of the other substances that are not needed PROTECTION OF THE BODY by the body, especially metabolic waste products such as urea, are reabsorbed poorly and pass through the renal Immune System. The immune system consists of the tubules into the urine. white blood cells, tissue cells derived from white blood cells, the thymus, lymph nodes, and lymph vessels that Gastrointestinal Tract. Undigested material that enters protect the body from pathogens such as bacteria, viruses, the gastrointestinal tract and some waste products of parasites, and fungi. The immune system provides a metabolism are eliminated in the feces. mechanism for the body to (1) distinguish its own cells from foreign cells and substances and (2) destroy the Liver. Among the functions of the liver is the detoxifica- invader by phagocytosis or by producing sensitized lym- tion or removal of many drugs and chemicals that are phocytes or specialized proteins (e.g., antibodies) that ingested. The liver secretes many of these wastes into the either destroy or neutralize the invader. bile to be eventually eliminated in the feces. Integumentary System. The skin and its various appendages (including the hair, nails, glands, and other REGULATION OF BODY FUNCTIONS structures) cover, cushion, and protect the deeper tissues Nervous System. The nervous system is composed of and organs of the body and generally provide a boundary three major parts: the sensory input portion, the central between the body’s internal environment and the outside nervous system (or integrative portion), and the motor world. The integumentary system is also important for output portion. Sensory receptors detect the state of the temperature regulation and excretion of wastes, and it body or the state of the surroundings. For instance, recep- provides a sensory interface between the body and the tors in the skin alert us whenever an object touches the external environment. The skin generally comprises about skin at any point. The eyes are sensory organs that give 12 to 15 percent of body weight. us a visual image of the surrounding area. The ears are also sensory organs. The central nervous system is com- REPRODUCTION posed of the brain and spinal cord. The brain can store information, generate thoughts, create ambition, and Sometimes reproduction is not considered a homeostatic determine reactions that the body performs in response function. It does, however, help maintain homeostasis by to the sensations. Appropriate signals are then transmit- generating new beings to take the place of those that are ted through the motor output portion of the nervous dying. This may sound like a permissive usage of the term system to carry out one’s desires. homeostasis, but it illustrates that, in the final analysis, An important segment of the nervous system is called essentially all body structures are organized such that the autonomic system. It operates at a subconscious level they help maintain the automaticity and continuity of life. and controls many functions of the internal organs, including the level of pumping activity by the heart, CONTROL SYSTEMS OF THE BODY movements of the gastrointestinal tract, and secretion by many of the body’s glands. The human body has thousands of control systems. Some of the most intricate of these systems are the genetic Hormone Systems. Located in the body are eight major control systems that operate in all cells to help control endocrine glands and several organs and tissues that intracellular and extracellular functions. This subject is secrete chemical substances called hormones. Hormones discussed in Chapter 3. are transported in the extracellular fluid to other parts of Many other control systems operate within the organs the body to help regulate cellular function. For instance, to control functions of the individual parts of the organs; thyroid hormone increases the rates of most chemical others operate throughout the entire body to control the reactions in all cells, thus helping to set the tempo of interrelations between the organs. For instance, the respi- bodily activity. Insulin controls glucose metabolism; adre- ratory system, operating in association with the nervous nocortical hormones control sodium and potassium ions system, regulates the concentration of carbon dioxide in 6  Chapter I Functional Organization of the Human Body and Control of the “Internal Environment” the extracellular fluid. The liver and pancreas regulate the Reference concentration of glucose in the extracellular fluid, and the set point kidneys regulate concentrations of hydrogen, sodium, Error signal Effectors potassium, phosphate, and other ions in the extracellular Brain medulla fluid. Sympathetic Blood vessels Vasomotor nervous system Heart centers UNIT I EXAMPLES OF CONTROL MECHANISMS Feedback signal Regulation of Oxygen and Carbon Dioxide Concen­ trations in the Extracellular Fluid. Because oxygen is Baroreceptors Arterial one of the major substances required for chemical reac- pressure tions in the cells, the body has a special control mecha- Sensor Controlled variable nism to maintain an almost exact and constant oxygen Figure 1-3. Negative feedback control of arterial pressure by the concentration in the extracellular fluid. This mechanism arterial baroreceptors. Signals from the sensor (baroreceptors) are depends principally on the chemical characteristics of sent to medulla of the brain, where they are compared with a refer- hemoglobin, which is present in all red blood cells. ence set point. When arterial pressure increases above normal, this abnormal pressure increases nerve impulses from the baroreceptors Hemoglobin combines with oxygen as the blood passes to the medulla of the brain, where the input signals are compared through the lungs. Then, as the blood passes through the with the set point, generating an error signal that leads to decreased tissue capillaries, hemoglobin, because of its own strong sympathetic nervous system activity. Decreased sympathetic activity chemical affinity for oxygen, does not release oxygen into causes dilation of blood vessels and reduced pumping activity of the the tissue fluid if too much oxygen is already there. heart, which return arterial pressure toward normal. However, if the oxygen concentration in the tissue fluid is too low, sufficient oxygen is released to re-establish an adequate concentration. Thus regulation of oxygen con- of these effects decrease the arterial pressure, moving it centration in the tissues is vested principally in the chemi- back toward normal. cal characteristics of hemoglobin. This regulation is called Conversely, a decrease in arterial pressure below the oxygen-buffering function of hemoglobin. normal relaxes the stretch receptors, allowing the vaso- Carbon dioxide concentration in the extracellular fluid motor center to become more active than usual, thereby is regulated in a much different way. Carbon dioxide is a causing vasoconstriction and increased heart pumping. major end product of the oxidative reactions in cells. If all The decrease in arterial pressure also raises arterial pres- the carbon dioxide formed in the cells continued to accu- sure, moving it back toward normal. mulate in the tissue fluids, all energy-giving reactions of the cells would cease. Fortunately, a higher than normal Normal Ranges and Physical carbon dioxide concentration in the blood excites the Characteristics of Important Extracellular respiratory center, causing a person to breathe rapidly and Fluid Constituents deeply. This deep, rapid breathing increases expiration of Table 1-1 lists some of the important constituents carbon dioxide and, therefore, removes excess carbon and physical characteristics of extracellular fluid, along dioxide from the blood and tissue fluids. This process with their normal values, normal ranges, and maximum continues until the concentration returns to normal. limits without causing death. Note the narrowness of the normal range for each one. Values outside these ranges Regulation of Arterial Blood Pressure. Several systems are often caused by illness, injury, or major environmental contribute to the regulation of arterial blood pressure. challenges. One of these, the baroreceptor system, is a simple and Most important are the limits beyond which abnor- excellent example of a rapidly acting control mechanism malities can cause death. For example, an increase in the (Figure 1-3). In the walls of the bifurcation region of the body temperature of only 11°F (7°C) above normal can carotid arteries in the neck, and also in the arch of the lead to a vicious cycle of increasing cellular metabolism aorta in the thorax, are many nerve receptors called baro- that destroys the cells. Note also the narrow range for receptors that are stimulated by stretch of the arterial wall. acid-base balance in the body, with a normal pH value When the arterial pressure rises too high, the barorecep- of 7.4 and lethal values only about 0.5 on either side of tors send barrages of nerve impulses to the medulla of the normal. Another important factor is the potassium ion brain. Here these impulses inhibit the vasomotor center, concentration because whenever it decreases to less than which in turn decreases the number of impulses transmit- one-third normal, a person is likely to be paralyzed as a ted from the vasomotor center through the sympathetic result of the inability of the nerves to carry signals. nervous system to the heart and blood vessels. Lack of Alternatively, if potassium ion concentration increases to these impulses causes diminished pumping activity by the two or more times normal, the heart muscle is likely to heart and also dilation of the peripheral blood vessels, be severely depressed. Also, when calcium ion concentra- allowing increased blood flow through the vessels. Both tion falls below about one-half normal, a person is likely 7 Unit I Introduction to Physiology: The Cell and General Physiology Table 1-1 Important Constituents and Physical Characteristics of Extracellular Fluid Normal Value Normal Range Approximate Short-Term Nonlethal Limit Unit Oxygen (venous) 40 35-45 10-1000 mm Hg Carbon dioxide 45 35-45 5-80 mm Hg (venous) Sodium ion 142 138-146 115-175 mmol/L Potassium ion 4.2 3.8-5.0 1.5-9.0 mmol/L Calcium ion 1.2 1.0-1.4 0.5-2.0 mmol/L Chloride ion 106 103-112 70-130 mmol/L Bicarbonate ion 24 24-32 8-45 mmol/L Glucose 90 75-95 20-1500 mg/dl Body temperature 98.4 (37.0) 98-98.8 (37.0) 65-110 (18.3-43.3) °F (°C) Acid-base 7.4 7.3-7.5 6.9-8.0 pH to experience tetanic contraction of muscles throughout instances, these effects are negative with respect to the the body because of the spontaneous generation of excess initiating stimulus. nerve impulses in the peripheral nerves. When glucose Therefore, in general, if some factor becomes excessive concentration falls below one-half normal, a person fre- or deficient, a control system initiates negative feedback, quently exhibits extreme mental irritability and some- which consists of a series of changes that return the times even has convulsions. factor toward a certain mean value, thus maintaining These examples should give one an appreciation for homeostasis. the extreme value and even the necessity of the vast numbers of control systems that keep the body operating Gain of a Control System. The degree of effectiveness in health; in the absence of any one of these controls, with which a control system maintains constant condi- serious body malfunction or death can result. tions is determined by the gain of the negative feedback. For instance, let us assume that a large volume of blood is transfused into a person whose baroreceptor pressure CHARACTERISTICS OF CONTROL SYSTEMS control system is not functioning, and the arterial pres- The aforementioned examples of homeostatic control sure rises from the normal level of 100 mm Hg up to mechanisms are only a few of the many thousands in the 175 mm Hg. Then, let us assume that the same volume of body, all of which have certain characteristics in common blood is injected into the same person when the barore- as explained in this section. ceptor system is functioning, and this time the pressure increases only 25 mm Hg. Thus the feedback control Negative Feedback Nature of Most system has caused a “correction” of −50 mm Hg—that is, Control Systems from 175 mm Hg to 125 mm Hg. There remains an Most control systems of the body act by negative feed- increase in pressure of +25 mm Hg, called the “error,” back, which can best be explained by reviewing some of which means that the control system is not 100 percent the homeostatic control systems mentioned previously. effective in preventing change. The gain of the system is In the regulation of carbon dioxide concentration, a high then calculated by using the following formula: concentration of carbon dioxide in the extracellular Correction fluid increases pulmonary ventilation. This, in turn, de- Gain = Error creases the extracellular fluid carbon dioxide concentra- tion because the lungs expire greater amounts of carbon Thus, in the baroreceptor system example, the correc- dioxide from the body. In other words, the high concen- tion is −50 mm Hg and the error persisting is +25 mm Hg. tration of carbon dioxide initiates events that decrease Therefore, the gain of the person’s baroreceptor system the concentration toward normal, which is negative to the for control of arterial pressure is −50 divided by +25, or initiating stimulus. Conversely, a carbon dioxide concen- −2. That is, a disturbance that increases or decreases the tration that falls too low results in feedback to increase arterial pressure does so only one third as much as would the concentration. This response is also negative to the occur if this control system were not present. initiating stimulus. The gains of some other physiologic control systems In the arterial pressure–regulating mechanisms, a are much greater than that of the baroreceptor system. high pressure causes a series of reactions that promote For instance, the gain of the system controlling internal a lowered pressure, or a low pressure causes a series body temperature when a person is exposed to moder- of reactions that promote an elevated pressure. In both ately cold weather is about −33. Therefore, one can see 8  Chapter I Functional Organization of the Human Body and Control of the “Internal Environment” 5 Positive Feedback Can Sometimes Be Useful. In some instances, the body uses positive feedback to its advan- Pumping effectiveness of heart Return to tage. Blood clotting is an example of a valuable use of (Liters pumped per minute) 4 normal positive feedback. When a blood vessel is ruptured and Bled 1 liter a clot begins to form, multiple enzymes called clotting 3 factors are activated within the clot. Some of these UNIT I enzymes act on other unactivated enzymes of the imme- Bled 2 liters diately adjacent blood, thus causing more blood clotting. 2 This process continues until the hole in the vessel is plugged and bleeding no longer occurs. On occasion, this 1 mechanism can get out of hand and cause formation of unwanted clots. In fact, this is what initiates most acute Death heart attacks, which can be caused by a clot beginning on 0 the inside surface of an atherosclerotic plaque in a coro- 1 2 3 nary artery and then growing until the artery is blocked. Hours Childbirth is another instance in which positive feed- Figure 1-4. Recovery of heart pumping caused by negative feedback back is valuable. When uterine contractions become after 1 liter of blood is removed from the circulation. Death is caused by positive feedback when 2 liters of blood are removed. strong enough for the baby’s head to begin pushing through the cervix, stretching of the cervix sends signals through the uterine muscle back to the body of the uterus, that the temperature control system is much more effec- causing even more powerful contractions. Thus the tive than the baroreceptor pressure control system. uterine contractions stretch the cervix and the cervical stretch causes stronger contractions. When this process Positive Feedback Can Sometimes Cause becomes powerful enough, the baby is born. If it is not Vicious Cycles and Death powerful enough, the contractions usually die out and a Why do most control systems of the body operate by few days pass before they begin again. negative feedback rather than positive feedback? If one Another important use of positive feedback is for the considers the nature of positive feedback, it is obvious generation of nerve signals. That is, stimulation of the that positive feedback leads to instability rather than sta- membrane of a nerve fiber causes slight leakage of sodium bility and, in some cases, can cause death. ions through sodium channels in the nerve membrane to Figure 1-4 shows an example in which death can the fiber’s interior. The sodium ions entering the fiber ensue from positive feedback. This figure depicts the then change the membrane potential, which in turn pumping effectiveness of the heart, showing that the causes more opening of channels, more change of poten- heart of a healthy human being pumps about 5 liters of tial, still more opening of channels, and so forth. Thus, a blood per minute. If the person is suddenly bled 2 liters, slight leak becomes an explosion of sodium entering the the amount of blood in the body is decreased to such a interior of the nerve fiber, which creates the nerve action low level that not enough blood is available for the heart potential. This action potential in turn causes electrical to pump effectively. As a result, the arterial pressure current to flow along both the outside and the inside of falls and the flow of blood to the heart muscle through the fiber and initiates additional action potentials. This the coronary vessels diminishes. This scenario results process continues again and again until the nerve signal in weakening of the heart, further diminished pumping, goes all the way to the end of the fiber. a further decrease in coronary blood flow, and still more In each case in which positive feedback is useful, the weakness of the heart; the cycle repeats itself again and positive feedback is part of an overall negative feedback again until death occurs. Note that each cycle in the feed- process. For example, in the case of blood clotting, the back results in further weakening of the heart. In other positive feedback clotting process is a negative feedback words, the initiating stimulus causes more of the same, process for maintenance of normal blood volume. Also, which is positive feedback. the positive feedback that causes nerve signals allows the Positive feedback is better known as a “vicious cycle,” nerves to participate in thousands of negative feedback but a mild degree of positive feedback can be overcome nervous control systems. by the negative feedback control mechanisms of the body, and the vicious cycle then fails to develop. For instance, More Complex Types of Control if the person in the aforementioned example is bled only Systems—Adaptive Control 1 liter instead of 2 liters, the normal negative feedback Later in this text, when we study the nervous system, we mechanisms for controlling cardiac output and arterial shall see that this system contains great numbers of inter- pressure can counterbalance the positive feedback and connected control mechanisms. Some are simple feed- the person can recover, as shown by the dashed curve of back systems similar to those already discussed. Many are Figure 1-4. not. For instance, some movements of the body occur so 9 Unit I Introduction to Physiology: The Cell and General Physiology rapidly that there is not enough time for nerve signals to more functional systems lose their ability to contribute travel from the peripheral parts of the body all the way to their share of function. When this happens, all the cells the brain and then back to the periphery again to control of the body suffer. Extreme dysfunction leads to death; the movement. Therefore, the brain uses a principle called moderate dysfunction leads to sickness. feed-forward control to cause required muscle contrac- tions. That is, sensory nerve signals from the moving parts apprise the brain whether the movement is per- Bibliography formed correctly. If not, the brain corrects the feed- Adolph EF: Physiological adaptations: hypertrophies and superfunc- tions. Am Sci 60:608, 1972. forward signals that it sends to the muscles the next time Bernard C: Lectures on the Phenomena of Life Common to Animals the movement is required. Then, if still further correction and Plants. Springfield, IL: Charles C Thomas, 1974. is necessary, this process will be performed again for sub- Cannon WB: Organization for physiological homeostasis. Physiol Rev sequent movements. This process is called adaptive 9(3):399, 1929. control. Adaptive control, in a sense, is delayed negative Chien S: Mechanotransduction and endothelial cell homeostasis: the wisdom of the cell. Am J Physiol Heart Circ Physiol 292:H1209, feedback. 2007. Thus, one can see how complex the feedback control Csete ME, Doyle JC: Reverse engineering of biological complexity. systems of the body can be. A person’s life depends on all Science 295:1664, 2002. of them. Therefore, a major share of this text is devoted DiBona GF: Physiology in perspective: the wisdom of the body. Neural to discussing these life-giving mechanisms. control of the kidney. Am J Physiol Regul Integr Comp Physiol. 289:R633, 2005. Dickinson MH, Farley CT, Full RJ, et al: How animals move: an integra- SUMMARY—AUTOMATICITY tive view. Science 288:100, 2000. Eckel-Mahan K, Sassone-Corsi P: Metabolism and the circadian clock OF THE BODY converge. Physiol Rev 93:107, 2013. The purpose of this chapter has been to point out, first, Gao Q, Horvath TL: Neuronal control of energy homeostasis. FEBS Lett 582:132, 2008. the overall organization of the body and, second, the Guyton AC: Arterial Pressure and Hypertension. Philadelphia: WB means by which the different parts of the body operate in Saunders, 1980. harmony. To summarize, the body is actually a social Herman MA, Kahn BB: Glucose transport and sensing in the main- order of about 100 trillion cells organized into different tenance of glucose homeostasis and metabolic harmony. J Clin functional structures, some of which are called organs. Invest 116:1767, 2006. Krahe R, Gabbiani F: Burst firing in sensory systems. Nat Rev Neurosci Each functional structure contributes its share to the 5:13, 2004. maintenance of homeostatic conditions in the extracel- Orgel LE: The origin of life on the earth. Sci Am 271:76,1994. lular fluid, which is called the internal environment. As Sekirov I, Russell SL, Antunes LC, Finlay BB: Gut microbiota in health long as normal conditions are maintained in this internal and disease. Physiol Rev 90:859, 2010. environment, the cells of the body continue to live and Smith HW: From Fish to Philosopher. New York: Doubleday, 1961. function properly. Each cell benefits from homeostasis, Srinivasan MV: Honeybees as a model for the study of visually guided flight, navigation, and biologically inspired robotics. Physiol Rev and in turn, each cell contributes its share toward the 91:413, 2011. maintenance of homeostasis. This reciprocal interplay Tjian R: Molecular machines that control genes. Sci Am 272:54, provides continuous automaticity of the body until one or 1995. 10  CHAPTER 2 UNIT I The Cell and Its Functions Each of the 100 trillion cells in a human being is a living the cell membrane are required for transmission of elec- structure that can survive for months or years, provided trochemical impulses in nerve and muscle fibers. its surrounding fluids contain appropriate nutrients. Cells are the building blocks of the body, providing structure Proteins. After water, the most abundant substances for the body’s tissues and organs, ingesting nutrients and in most cells are proteins, which normally constitute 10 converting them to energy, and performing specialized to 20 percent of the cell mass. These proteins can be functions. Cells also contain the body’s hereditary code divided into two types: structural proteins and functional that controls the substances synthesized by the cells and proteins. permits them to make copies of themselves. Structural proteins are present in the cell mainly in To understand the function of organs and other struc- the form of long filaments that are polymers of many tures of the body, it is essential that we first understand individual protein molecules. A prominent use of such the basic organization of the cell and the functions of its intracellular filaments is to form microtubules that provide component parts. the “cytoskeletons” of such cellular organelles as cilia, nerve axons, the mitotic spindles of cells undergoing mitosis, and a tangled mass of thin filamentous tubules ORGANIZATION OF THE CELL that hold the parts of the cytoplasm and nucleoplasm A typical cell, as seen by the light microscope, is shown together in their respective compartments. Fibrillar pro- in Figure 2-1. Its two major parts are the nucleus and the teins are found outside the cell, especially in the collagen cytoplasm. The nucleus is separated from the cytoplasm and elastin fibers of connective tissue and in blood vessel by a nuclear membrane, and the cytoplasm is separated walls, tendons, ligaments, and so forth. from the surrounding fluids by a cell membrane, also The functional proteins are an entirely different type of called the plasma membrane. protein and are usually composed of combinations of a The different substances that make up the cell are col- few molecules in tubular-globular form. These proteins lectively called protoplasm. Protoplasm is composed are mainly the enzymes of the cell and, in contrast to the mainly of five basic substances: water, electrolytes, pro- fibrillar proteins, are often mobile in the cell fluid. Also, teins, lipids, and carbohydrates. many of them are adherent to membranous structures inside the cell. The enzymes come into direct contact with Water. The principal fluid medium of the cell is water, other substances in the cell fluid and catalyze specific which is present in most cells, except for fat cells, in a intracellular chemical reactions. For instance, the chemi- concentration of 70 to 85 percent. Many cellular chemi- cal reactions that split glucose into its component parts cals are dissolved in the water. Others are suspended in and then combine these with oxygen to form carbon the water as solid particulates. Chemical reactions take dioxide and water while simultaneously providing energy place among the dissolved chemicals or at the surfaces of for cellular function are all catalyzed by a series of protein the suspended particles or membranes. enzymes. Ions. Important ions in the cell include potassium, Lipids. Lipids are several types of substances that are magnesium, phosphate, sulfate, bicarbonate, and smaller grouped together because of their common property of quantities of sodium, chloride, and calcium. These ions being soluble in fat solvents. Especially important lipids are all discussed in more detail in Chapter 4, which con- are phospholipids and cholesterol, which together consti- siders the interrelations between the intracellular and tute only about 2 percent of the total cell mass. The sig- extracellular fluids. nificance of phospholipids and cholesterol is that they are The ions provide inorganic chemicals for cellular reac- mainly insoluble in water and therefore are used to form tions and also are necessary for operation of some of the the cell membrane and intracellular membrane barriers cellular control mechanisms. For instance, ions acting at that separate the different cell compartments. 11 Unit I Introduction to Physiology: The Cell and General Physiology water is not soluble in lipids. However, protein molecules Cell membrane in the membrane often penetrate all the way through the membrane, thus providing specialized pathways, often organized into actual pores, for passage of specific sub- Cytoplasm stances through the membrane. Also, many other mem- Nucleolus Nucleoplasm brane proteins are enzymes that catalyze a multitude of Nuclear membrane Nucleus different chemical reactions, discussed here and in sub- sequent chapters. Cell Membrane Figure 2-1. Structure of the cell as seen with the light microscope. The cell membrane (also called the plasma membrane) envelops the cell and is a thin, pliable, elastic structure In addition to phospholipids and cholesterol, some only 7.5 to 10 nanometers thick. It is composed almost cells contain large quantities of triglycerides, also called entirely of proteins and lipids. The approximate composi- neutral fat. In the fat cells, triglycerides often account for tion is proteins, 55 percent; phospholipids, 25 percent; as much as 95 percent of the cell mass. The fat stored in cholesterol, 13 percent; other lipids, 4 percent; and car- these cells represents the body’s main storehouse of bohydrates, 3 percent. energy-giving nutrients that can later be used to provide energy wherever in the body it is needed. The Cell Membrane Lipid Barrier Impedes Penetra­ tion by Water-Soluble Substances. Figure 2-3 shows Carbohydrates. Carbohydrates have little structural the structure of the cell membrane. Its basic structure function in the cell except as parts of glycoprotein mol- is a lipid bilayer, which is a thin, double-layered film of ecules, but they play a major role in nutrition of the cell. lipids—each layer only one molecule thick—that is con- Most human cells do not maintain large stores of carbo- tinuous over the entire cell surface. Interspersed in this hydrates; the amount usually averages about 1 percent of lipid film are large globular proteins. their total mass but increases to as much as 3 percent in The basic lipid bilayer is composed of three main types muscle cells and, occasionally, 6 percent in liver cells. of lipids: phospholipids, sphingolipids, and cholesterol. However, carbohydrate in the form of dissolved glucose Phospholipids are the most abundant of the cell mem- is always present in the surrounding extracellular fluid so brane lipids. One end of each phospholipid molecule is that it is readily available to the cell. Also, a small amount soluble in water; that is, it is hydrophilic. The other end is of carbohydrate is stored in the cells in the form of glyco­ soluble only in fats; that is, it is hydrophobic. The phos- gen, which is an insoluble polymer of glucose that can phate end of the phospholipid is hydrophilic, and the fatty be depolymerized and used rapidly to supply the cells’ acid portion is hydrophobic. energy needs. Because the hydrophobic portions of the phospholipid molecules are repelled by water but are mutually attracted to one another, they have a natural tendency to attach to PHYSICAL STRUCTURE OF THE CELL one another in the middle of the membrane, as shown in The cell contains highly organized physical structures, Figure 2-3. The hydrophilic phosphate portions then called intracellular organelles. The physical nature of each constitute the two surfaces of the complete cell mem- organelle is as important as the cell’s chemical constitu- brane, in contact with intracellular water on the inside of ents for cell function. For instance, without one of the the membrane and extracellular water on the outside organelles, the mitochondria, more than 95 percent of the surface. cell’s energy release from nutrients would cease immedi- The lipid layer in the middle of the membrane is ately. The most important organelles and other structures impermeable to the usual water-soluble substances, such of the cell are shown in Figure 2-2. as ions, glucose, and urea. Conversely, fat-soluble sub- stances, such as oxygen, carbon dioxide, and alcohol, can penetrate this portion of the membrane with ease. MEMBRANOUS STRUCTURES Sphingolipids, derived from the amino alcohol sphin­ OF THE CELL gosine, also have hydrophobic and hydrophilic groups and Most organelles of the cell are covered by membranes are present in small amounts in the cell membranes, espe- composed primarily of lipids and proteins. These mem- cially nerve cells. Complex sphingolipids in cell mem- branes include the cell membrane, nuclear membrane, branes are thought to serve several functions, including membrane of the endoplasmic reticulum, and membranes protection from harmful environmental factors, signal of the mitochondria, lysosomes, and Golgi apparatus. transmission, and as adhesion sites for extracellular The lipids in the membranes provide a barrier that proteins. impedes movement of water and water-soluble sub- The cholesterol molecules in the membrane are also stances from one cell compartment to another because lipids because their steroid nuclei are highly fat soluble. 12  Chapter 2 The Cell and Its Functions Chromosomes and DNA Centrioles UNIT I Secretory granule Golgi apparatus Microtubules Nuclear membrane Cell membrane Nucleolus Glycogen Ribosomes Lysosome Mitochondrion Granular Smooth Microfilaments endoplasmic (agranular) reticulum endoplasmic reticulum Figure 2-2. Reconstruction of a typical cell, showing the internal organelles in the cytoplasm and in the nucleus. These molecules, in a sense, are dissolved in the bilayer lipid bilayer. Sometimes these carrier proteins even trans- of the membrane. They mainly help determine the degree port substances in the direction opposite to their electro- of permeability (or impermeability) of the bilayer to chemical gradients for diffusion, which is called “active water-soluble constituents of body fluids. Cholesterol transport.” Still others act as enzymes. controls much of the fluidity of the membrane as well. Integral membrane proteins can also serve as recep­ tors for water-soluble chemicals, such as peptide hor- Integral and Peripheral Cell Membrane Proteins. mones, that do not easily penetrate the cell membrane. Figure 2-3 also shows globular masses floating in the Interaction of cell membrane receptors with specific lipid bilayer. These membrane proteins are mainly glyco­ ligands that bind to the receptor causes conformational proteins. There are two types of cell membrane proteins: changes in the receptor protein. This process, in turn, integral proteins that protrude all the way through the enzymatically activates the intracellular part of the protein membrane and peripheral proteins that are attached only or induces interactions between the receptor and proteins to one surface of the membrane and do not penetrate all in the cytoplasm that act as second messengers, relaying the way through. the signal from the extracellular part of the receptor Many of the integral proteins provide structural chan­ to the interior of the cell. In this way, integral proteins nels (or pores) through which water molecules and water- spanning the cell membrane provide a means of con­ soluble substances, especially ions, can diffuse between veying information about the environment to the cell the extracellular and intracellular fluids. These protein interior. channels also have selective properties that allow prefer- Peripheral protein molecules are often attached to the ential diffusion of some substances over others. integral proteins. These peripheral proteins function Other integral proteins act as carrier proteins for trans- almost entirely as enzymes or as controllers of transport porting substances that otherwise could not penetrate the of substances through the cell membrane “pores.” 13 Unit I Introduction to Physiology: The Cell and General Physiology Carbohydrate Extracellular fluid Integral protein Lipid bilayer Peripheral protein Intracellular fluid Cytoplasm Integral protein Figure 2-3. Structure of the cell membrane, showing that it is composed mainly of a lipid bilayer of phospholipid molecules, but with large numbers of protein molecules protruding through the layer. Also, carbohydrate moieties are attached to the protein molecules on the outside of the membrane and to additional protein molecules on the inside. (Modified from Lodish HF, Rothman JE: The assembly of cell membranes. Sci Am 240:48, 1979. Copyright George V. Kevin.) Membrane Carbohydrates—The Cell “Glycocalyx.” bound, this combination activates attached internal Membrane carbohydrates occur almost invariably in proteins that, in turn, activate a cascade of intracel- combination with proteins or lipids in the form of glyco­ lular enzymes. proteins or glycolipids. In fact, most of the integral 4. Some carbohydrate moieties enter into immune proteins are glycoproteins, and about one tenth of the reactions, as discussed in Chapter 35. membrane lipid molecules are glycolipids. The “glyco” portions of these molecules almost invariably protrude CYTOPLASM AND ITS ORGANELLES to the outside of the cell, dangling outward from the cell surface. Many other carbohydrate compounds, The cytoplasm is filled with both minute and large dis- called proteoglycans—which are mainly carbohydrate persed particles and organelles. The jelly-like fluid portion substances bound to small protein cores—are loosely of the cytoplasm in which the particles are dispersed is attached to the outer surface of the cell as well. Thus, the called cytosol and contains mainly dissolved proteins, entire outside surface of the cell often has a loose carbo- electrolytes, and glucose. hydrate coat called the glycocalyx. Dispersed in the cytoplasm are neutral fat globules, The carbohydrate moieties attached to the outer glycogen granules, ribosomes, secretory vesicles, and five surface of the cell have several important functions: especially important organelles: the endoplasmic reticu­ 1. Many of them have a negative electrical charge, lum, the Golgi apparatus, mitochondria, lysosomes, and which gives most cells an overall negative surface peroxisomes. charge that repels other negatively charged objects. 2. The glycocalyx of some cells attaches to the glyco- Endoplasmic Reticulum calyx of other cells, thus attaching cells to one Figure 2-2 shows a network of tubular and flat vesicular another. structures in the cytoplasm, which is the endoplasmic 3. Many of the carbohydrates act as receptor sub­ reticulum. This organelle helps process molecules made stances for binding hormones, such as insulin; when by the cell and transports them to their specific 14  Chapter 2 The Cell and Its Functions Golgi vesicles Matrix Golgi UNIT I apparatus ER vesicles Endoplasmic reticulum Granular endoplasmic Agranular reticulum endoplasmic reticulum Figure 2-5. A typical Golgi apparatus and its relationship to the endoplasmic reticulum (ER) and the nucleus. Figure 2-4. Structure of the endoplasmic reticulum. (Modified from DeRobertis EDP, Saez FA, DeRobertis EMF: Cell Biology, 6th ed. Philadelphia: WB Saunders, 1975.) is called the agranular or smooth, endoplasmic reticulum. The agranular reticulum functions for the synthesis of destinations inside or outside the cell. The tubules and lipid substances and for other processes of the cells pro- vesicles interconnect. Also, their walls are constructed of moted by intrareticular enzymes. lipid bilayer membranes that contain large amounts of proteins, similar to the cell membrane. The total surface Golgi Apparatus area of this structure in some cells—the liver cells, for The Golgi apparatus, shown in Figure 2-5, is closely instance—can be as much as 30 to 40 times the cell mem- related to the endoplasmic reticulum. It has membranes brane area. similar to those of the agranular endoplasmic reticulum. The detailed structure of a small portion of endo­ The Golgi apparatus is usually composed of four or more plasmic reticulum is shown in Figure 2-4. The space stacked layers of thin, flat, enclosed vesicles lying near one inside the tubules and vesicles is filled with endo­ side of the nucleus. This apparatus is prominent in secre- plasmic matrix, a watery medium that is different from tory cells, where it is located on the side of the cell from the fluid in the cytosol outside the endoplasmic reticu- which the secretory substances are extruded. lum. Electron micrographs show that the space inside The Golgi apparatus functions in association with the endoplasmic reticulum is connected with the space the endoplasmic reticulum. As shown in Figure 2-5, between the two membrane surfaces of the nuclear small “transport vesicles” (also called endoplasmic membrane. reticulum vesicles, or ER vesicles) continually pinch off Substances formed in some parts of the cell enter the from the endoplasmic reticulum and shortly thereafter space of the endoplasmic reticulum and are then directed fuse with the Golgi apparatus. In this way, substances to other parts of the cell. Also, the vast surface area of this entrapped in the ER vesicles are transported from the reticulum and the multiple enzyme systems attached to endoplasmic reticulum to the Golgi apparatus. The trans- its membranes provide machinery for a major share of the ported substances are then processed in the Golgi appa- metabolic functions of the cell. ratus to form lysosomes, secretory vesicles, and other cytoplasmic components that are discussed later in this Ribosomes and the Granular Endoplasmic Reticulum. chapter. Attached to the outer surfaces of many parts of the endo- plasmic reticulum are large numbers of minute granular Lysosomes particles called ribosomes. Where these particles are Lysosomes, shown in Figure 2-2, are vesicular organelles present, the reticulum is called the granular endoplasmic that form by breaking off from the Golgi apparatus and reticulum. The ribosomes are composed of a mixture of then dispersing throughout the cytoplasm. The lysosomes RNA and proteins, and they function to synthesize new provide an intracellular digestive system that allows the protein molecules in the cell, as discussed later in this cell to digest (1) damaged cellular structures, (2) food chapter and in Chapter 3. particles that have been ingested by the cell, and (3) unwanted matter such as bacteria. The lysosome is quite Agranular Endoplasmic Reticulum. Part of the endo- different in various cell types, but it is usually 250 to 750 plasmic reticulum has no attached ribosomes. This part nanometers in diameter. It is surrounded by a typical lipid 15 Unit I Introduction to Physiology: The Cell and General Physiology bilayer membrane and is filled with large numbers of Secretory small granules 5 to 8 nanometers in diameter, which are granules protein aggregates of as many as 40 different hydrolase (digestive) enzymes. A hydrolytic enzyme is capable of splitting an organic compound into two or more parts by combining hydrogen from a water molecule with one part of the compound and combining the hydroxyl portion of the water molecule with the other part of the compound. For instance, protein is hydrolyzed to form amino acids, glycogen is hydrolyzed to form glucose, and lipids are hydrolyzed to form fatty acids and glycerol. Hydrolytic enzymes are highly concentrated in lyso- somes. Ordinarily, the membrane surrounding the lyso- Figure 2-6. Secretory granules (secretory vesicles) in acinar cells of some prevents the enclosed hydrolytic enzymes from the pancreas. coming in contact with other substances in the cell and therefore prevents their digestive actions. However, some Outer membrane conditions of the cell break the membranes of some of the Inner membrane lysosomes, allowing release of the digestive enzymes. These enzymes then split the organic substances with Cristae Matrix which they come in contact into small, highly diffusible substances such as amino acids and glucose. Some of the specific functions of lysosomes are discussed later in this chapter. Peroxisomes Peroxisomes are similar physically to lysosomes, but they Oxidative are different in two important ways. First, they are believed phosphorylation to be formed by self-replication (or perhaps by budding Outer chamber enzymes off from the smooth endoplasmic reticulum) rather than Figure 2-7. Structure of a mitochondrion. (Modified from DeRobertis from the Golgi apparatus. Second, they contain oxidases EDP, Saez FA, DeRobertis EMF: Cell Biology, 6th ed. Philadelphia: WB rather than hydrolases. Several of th