Guyton and Hall Textbook of Medical Physiology 14th Edition PDF

NOTE TO INSTRUCTORS Contact your Elsevier Sales Representative for teaching resources, including slides and image banks, for Guyton and Hall Textbook of ­Medical Physiology, 14e, or request these supporting materials at: http://evolve.elsevier.com/Hall/physiology/  14TH ED...

NOTE TO INSTRUCTORS Contact your Elsevier Sales Representative for teaching resources, including slides and image banks, for Guyton and Hall Textbook of ­Medical Physiology, 14e, or request these supporting materials at: http://evolve.elsevier.com/Hall/physiology/  14TH 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 Michael E. Hall, MD, MS Associate Professor Department of Medicine, Division of Cardiovascular Diseases Associate Vice Chair for Research Department of Physiology and Biophysics University of Mississippi Medical Center Jackson, Mississippi Elsevier 1600 John F. Kennedy Blvd. Ste 1800 Philadelphia, PA 19103-­2899 GUYTON AND HALL TEXTBOOK OF MEDICAL PHYSIOLOGY, FOURTEENTH EDITION  ISBN: 978-­0-­323-­59712-­8 INTERNATIONAL EDITION  ISBN: 978-­0-­323-­67280-­1 Copyright © 2021 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. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein). Notice Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds or experiments described herein. Because of rapid advances in the medical sciences, in particular, independent verification of diagnoses and drug dosages should be made. To the fullest extent of the law, no responsibility is assumed by Elsevier, authors, editors or contributors for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. Previous editions copyrighted 2016, 2011, 2006, 2000, 1996, 1991, 1986, 1981, 1976, 1971, 1966, 1961, and 1956. Library of Congress Control Number: 2020936245 Publisher: Elyse O’Grady Senior Content Development Specialist: Jennifer Shreiner Publishing Services Manager: Julie Eddy Project Manager: Grace Onderlinde Design Direction: Margaret Reid Printed in Canada Last digit is the print number: 9 8 7 6 5 4 3 2 1  To Our Families 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 review the basic principles needed for understanding the written by Arthur C. Guyton almost 65 years ago. Unlike pathophysiology of human disease. We have attempted to most major medical textbooks, which often have 20 or maintain the same unified organization of the text that more authors, the first eight editions of the Textbook of has been useful to students in the past and to ensure that Medical Physiology were written entirely by Dr. Guyton. the book is comprehensive enough that students will con- He had a gift for communicating complex ideas in a clear tinue to use it during their professional careers. and interesting manner that made studying physiology Our hope is that the Textbook of Medical Physiology fun. He wrote the book to help students learn physiology, conveys the majesty of the human body and its many not to impress his professional colleagues. functions and that it stimulates students to study physiol- Dr. John Hall worked closely with Dr. Guyton for ogy throughout their careers. Physiology links the basic almost 30 years and had the privilege of writing parts of sciences and medicine. The great beauty of physiology is the 9th and 10th editions and of assuming sole responsi- that it integrates the individual functions of all the body’s bility for completing the subsequent editions. different cells, tissues, and organs into a functional whole, Dr. Michael Hall has joined in the preparation of the the human body. Indeed, the human body is much more 14th edition of the Textbook of Medical Physiology. He is than the sum of its parts, and life relies upon this total a physician trained in internal medicine, cardiology, and function, not just on the function of individual body parts physiology and has brought new insights that have helped in isolation from the others. greatly to achieve the same goal as for previous editions— This brings us to an important question: How are the to explain, in language easily understood by students, how separate organs and systems coordinated to maintain the different cells, tissues, and organs of the human body proper function of the entire body? Fortunately, our bod- work together to maintain life. ies are endowed with a vast network of feedback controls This task has been challenging and fun because that achieve the necessary balances without which we researchers continue to unravel new mysteries of body would be unable to live. Physiologists call this high level functions. Advances in molecular and cellular physiology of internal bodily control homeostasis. In disease states, have made it possible to explain some physiology princi- functional balances are often seriously disturbed, and ples in the terminology of molecular and physical sciences homeostasis is impaired. When even a single disturbance rather than in merely a series of separate and unexplained reaches a limit, the whole body can no longer live. One of biological phenomena. However, the molecular events the goals of this text is to emphasize the effectiveness and that underpin the functions of the body’s cells provide beauty of the body’s homeostasis mechanisms as well as only a partial explanation of human physiology. The total to present their abnormal functions in disease. function of the human body requires complex control Another objective is to be as accurate as possible. Sug- systems that communicate with each other and coordi- gestions and critiques from many students, physiologists, nate the molecular functions of the body’s cells, tissues, and clinicians throughout the world have checked factual and organs in health and disease. accuracy as well as balance in the text. Even so, because The Textbook of Medical Physiology is not a reference of the likelihood of error in sorting through many thou- book that attempts to provide a compendium of the most sands of bits of information, we issue a further request recent advances in physiology. It is a book that contin- for all readers to send notations of error or inaccuracy to ues the tradition of being written for students. It focuses us. Physiologists understand the importance of feedback on the basic principles of physiology needed to begin a for proper function of the human body; feedback is also career in the health care professions, such as medicine, important for progressive improvement of a textbook of dentistry, and nursing, as well as graduate studies in the physiology. To the many persons who have already helped, biological and health sciences. It should also be useful we express sincere thanks. Your feedback has helped to to physicians and health care professionals who wish to improve the text. vii Preface A brief explanation is needed about several features most students will learn in more detail in other courses; of the 14th edition. Although many of the chapters have (2) physiological information of special importance to been revised to include new principles of physiology and certain fields of clinical medicine; and (3) information new figures to illustrate these principles, the text length that will be of value to those students who wish to study has been closely monitored to limit the book’s size so specific physiological mechanisms more deeply. that it can be used effectively in physiology courses for The ebook version provides links to additional content medical students and health care professionals. New including video animations and self-­assessment questions references have been chosen primarily for their pre- that can be accessed with computers, smart phones, and sentation of physiological principles, for the quality of electronic tablets. For additional self-­assessment beyond their own references, and for their easy accessibility. these textbook supplements, the reader may consider The selected bibliography at the end of the chapters lists using a copy of Guyton and Hall Physiology Review, which mainly review papers from recently published scientific includes more than 1000 practice questions referenced to journals that can be freely accessed from the PubMed site the textbook. We hope that these ancillary materials will at https://www.ncbi.nlm.nih.gov/pubmed/. Use of these assist readers in testing their understanding of basic prin- references, as well as cross-­references from them, pro- ciples of physiology. vides much more extensive coverage of the entire field of We express sincere thanks to many persons who have physiology. helped to prepare this book, including our colleagues in Our effort to be as concise as possible has, unfortu- the Department of Physiology and Biophysics at the Uni- nately, necessitated a more simplified and dogmatic versity of Mississippi Medical Center who provided valu- presentation of many physiological principles than we able suggestions. The members of our faculty and a brief normally would have desired. However, the bibliogra- description of the research and educational activities of the phy can be used to learn more about the controversies department can be found at http://physiology.umc.edu/. and unanswered questions that remain in understanding We are especially grateful to Stephanie Lucas for excellent the complex functions of the human body in health and assistance and to James Perkins for excellent illustrations. disease. We also thank Elyse O’Grady, Jennifer Shreiner, Grace Another feature of the book is that the print is set Onderlinde, Rebecca Gruliow, and the entire Elsevier in two sizes. The material in large print constitutes the team for continued editorial and production excellence. fundamental physiological information that students Finally, we thank the many readers who continue to will require in virtually all of their medical studies. The help us improve the Textbook of Medical Physiology. We material in small print and highlighted with a pale lav- hope that you enjoy the current edition and find it even ender background (or identified by beginning and ending more useful than previous editions. double gray arrowheads in the ebook version) is of several different kinds: (1) anatomic, chemical, and other infor- John E. Hall mation that is needed for immediate discussion but that Michael E. Hall viii  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 physi- Each type of cell is specially adapted to perform one cal and chemical mechanisms that are responsible for the or a few particular functions. For example, the red blood origin, development, and progression of life. Each type cells, numbering about 25 trillion in each person, trans- of life, from the simplest virus to the largest tree or the port oxygen from the lungs to the tissues. Although the complicated human being, has its own functional char- red blood cells are the most abundant of any single type of acteristics. Therefore, the vast field of physiology can be cell in the body, there are also trillions of additional cells divided into viral physiology, bacterial physiology, cellular of other types that perform functions different from those physiology, plant physiology, invertebrate physiology, ver- of the red blood cell. The entire body, then, contains about tebrate physiology, mammalian physiology, human physi- 35 to 40 trillion human cells. ology, and many more subdivisions. The many cells of the body often differ markedly from one another but all have certain basic characteristics that Human Physiology. The science of human physiology are alike. For example, oxygen reacts with carbohydrate, attempts to explain the specific characteristics and mech- fat, and protein to release the energy required for all cells anisms of the human body that make it a living being. The to function. Furthermore, the general chemical mecha- fact that we remain alive is the result of complex control nisms for changing nutrients into energy are basically systems. Hunger makes us seek food, and fear makes us the same in all cells, and all cells deliver products of their seek refuge. Sensations of cold make us look for warmth. chemical reactions into the surrounding fluids. Other forces cause us to seek fellowship and to reproduce. Almost all cells also have the ability to reproduce addi- The fact that we are sensing, feeling, and knowledgeable tional cells of their own type. Fortunately, when cells of a beings is part of this automatic sequence of life; these spe- particular type are destroyed, the remaining cells of this type cial attributes allow us to exist under widely varying con- usually generate new cells until the supply is replenished. ditions that otherwise would make life impossible. Human physiology links the basic sciences with medicine Microorganisms Living in the Body Outnumber Hu- and integrates multiple functions of the cells, tissues, and man Cells. In addition to human cells, trillions of microbes organs into the functions of the living human being. This inte- inhabit the body, living on the skin and in the mouth, gut, gration requires communication and coordination by a vast and nose. The gastrointestinal tract, for example, normally array of control systems that operate at every level—from the contains a complex and dynamic population of 400 to 1000 genes that program synthesis of molecules to the complex species of microorganisms that outnumber our human nervous and hormonal systems that coordinate functions of cells. Communities of microorganisms that inhabit the cells, tissues, and organs throughout the body. Thus, the coor- body, often called microbiota, can cause diseases, but most dinated functions of the human body are much more than the of the time they live in harmony with their human hosts sum of its parts, and life in health, as well as in disease states, and provide vital functions that are essential for survival of relies on this total function. Although the main focus of this their hosts. Although the importance of gut microbiota in book is on normal human physiology, we will also discuss, the digestion of foodstuffs is widely recognized, additional to some extent, pathophysiology, which is the study of disor- roles for the body’s microbes in nutrition, immunity, and dered body function and the basis for clinical medicine. other functions are just beginning to be appreciated and represent an intensive area of biomedical research. CELLS ARE THE LIVING UNITS OF THE BODY EXTRACELLULAR FLUID—THE “INTERNAL ENVIRONMENT” The basic living unit of the body is the cell. Each tissue or organ is an aggregate of many different cells held together About 50% to 70% of the adult human body is fluid, mainly by intercellular supporting structures. a water solution of ions and other substances. Although 3 UNIT I Introduction to Physiology: The Cell and General Physiology most of this fluid is inside the cells and is called intracellu- regulated, normally varying only a few millimoles per liter, lar fluid, about one-­third is in the spaces outside the cells even with large changes in sodium intake, but these varia- and is called extracellular fluid. This extracellular fluid is tions of sodium concentration are at least 1 million times in constant motion throughout the body. It is transported greater than for hydrogen ions. rapidly in the circulating blood and then mixed between Powerful control systems exist for maintaining concen- the blood and tissue fluids by diffusion through the capil- trations of sodium and hydrogen ions, as well as for most lary walls. of the other ions, nutrients, and substances in the body at In the extracellular fluid are the ions and nutrients levels that permit the cells, tissues, and organs to perform needed by the cells to maintain life. Thus, all cells live in their normal functions, despite wide environmental varia- essentially the same environment—the extracellular fluid. tions and challenges from injury and diseases. For this reason, the extracellular fluid is also called the Much of this text is concerned with how each organ or internal environment of the body, or the milieu intérieur, a tissue contributes to homeostasis. Normal body functions term introduced by the great 19th-­century French physi- require integrated actions of cells, tissues, organs, and ologist Claude Bernard (1813–1878). multiple nervous, hormonal, and local control systems Cells are capable of living and performing their spe- that together contribute to homeostasis and good health. cial functions as long as the proper concentrations of oxygen, glucose, different ions, amino acids, fatty sub- Homeostatic Compensations in Diseases. Disease is stances, and other constituents are available in this inter- often considered to be a state of disrupted homeostasis. nal environment. However, even in the presence of disease, homeostatic mechanisms continue to operate and maintain vital func- Differences in Extracellular and Intracellular Fluids. tions through multiple compensations. In some cases, The extracellular fluid contains large amounts of sodium, these compensations may lead to major deviations of the chloride, and bicarbonate ions plus nutrients for the cells, body’s functions from the normal range, making it diffi- such as oxygen, glucose, fatty acids, and amino acids. It cult to distinguish the primary cause of the disease from also contains carbon dioxide that is being transported the compensatory responses. For example, diseases that from the cells to the lungs to be excreted, plus other cel- impair the kidneys’ ability to excrete salt and water may lular waste products that are being transported to the kid- lead to high blood pressure, which initially helps return neys for excretion. excretion to normal so that a balance between intake and The intracellular fluid contains large amounts of potas- renal excretion can be maintained. This balance is needed sium, magnesium, and phosphate ions instead of the to maintain life, but, over long periods of time, the high sodium and chloride ions found in the extracellular fluid. blood pressure can damage various organs, including the Special mechanisms for transporting ions through the cell kidneys, causing even greater increases in blood pressure membranes maintain the ion concentration differences and more renal damage. Thus, homeostatic compensa- between the extracellular and intracellular fluids. These tions that ensue after injury, disease, or major environ- transport processes are discussed in Chapter 4. mental challenges to the body may represent trade-­offs that are necessary to maintain vital body functions but, in the long term, contribute to additional abnormalities HOMEOSTASIS—MAINTENANCE OF of body function. The discipline of pathophysiology seeks A NEARLY CONSTANT INTERNAL to explain how the various physiological processes are al- ENVIRONMENT tered in diseases or injury. In 1929, the American physiologist Walter Cannon This chapter outlines the different functional systems (1871–1945) coined the term homeostasis to describe the of the body and their contributions to homeostasis. We maintenance of nearly constant conditions in the internal then briefly discuss the basic theory of the body’s control environment. Essentially, all organs and tissues of the body systems that allow the functional systems to operate in perform functions that help maintain these relatively con- support of one another. stant conditions. For example, the lungs provide oxygen to the extracellular fluid to replenish the oxygen used by EXTRACELLULAR FLUID TRANSPORT the cells, the kidneys maintain constant ion concentra- AND MIXING SYSTEM—THE BLOOD tions, and the gastrointestinal system provides nutrients CIRCULATORY SYSTEM while eliminating waste from the body. The various ions, nutrients, waste products, and other Extracellular fluid is transported through the body in two constituents of the body are normally regulated within a stages. The first stage is movement of blood through the range of values, rather than at fixed values. For some of the body in the blood vessels. The second is movement of body’s constituents, this range is extremely small. Varia- fluid between the blood capillaries and the intercellular tions in the blood hydrogen ion concentration, for exam- spaces between the tissue cells. ple, are normally less than 5 nanomoles/L (0.000000005 Figure 1-1 shows the overall circulation of blood. All the moles/L). The blood sodium concentration is also tightly blood in the circulation traverses the entire circuit an average 4  Chapter 1 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 interstitial spaces. Nutrition That is, the fluid and dissolved molecules are continually and moving and bouncing in all directions in the plasma and excretion fluid in the intercellular spaces, as well as through capil- lary pores. Few cells are located more than 50 microm- eters from a capillary, which ensures diffusion of almost any substance from the capillary to the cell within a few Kidneys seconds. Thus, the extracellular fluid everywhere in the body—both that of the plasma and that of the interstitial fluid—is continually being mixed, thereby maintaining homogeneity of extracellular fluid throughout the body. Regulation ORIGIN OF NUTRIENTS IN THE of Excretion electrolytes EXTRACELLULAR FLUID Respiratory System. Figure 1-1 shows that each time blood passes through the body, it also flows through the Venous end Arterial end lungs. The blood picks up oxygen in alveoli, thus acquiring the oxygen needed by cells. The membrane between the alveoli and the lumen of the pulmonary capillaries, the alveolar membrane, is only 0.4 to 2.0 micrometers thick, and oxygen rapidly diffuses by molecular motion through Capillaries this membrane into the blood. Figure 1-1. General organization of the circulatory system. Gastrointestinal Tract. A large portion of the blood pumped by the heart also passes through the walls of the gastrointes- of once each minute when the body is at rest and as many tinal tract. Here different dissolved nutrients, including car- as six times each minute when a person is extremely active. bohydrates, fatty acids, and amino acids, are absorbed from As blood passes through blood capillaries, continual ingested food into the extracellular fluid of the blood. exchange of extracellular fluid occurs between the plasma portion of the blood and the interstitial fluid that fills the Liver and Other Organs That Perform Primarily Meta- intercellular spaces. This process is shown in Figure 1-2. bolic Functions. Not all substances absorbed from the The capillary walls are permeable to most molecules in gastrointestinal tract can be used in their absorbed form the blood plasma, with the exception of plasma proteins, by the cells. The liver changes the chemical compositions which are too large to pass through capillaries readily. of many of these substances to more usable forms, and Therefore, large amounts of fluid and its dissolved con- other tissues of the body—fat cells, gastrointestinal mu- stituents diffuse back and forth between the blood and the cosa, kidneys, and endocrine glands—help modify the tissue spaces, as shown by the arrows in Figure 1-2. absorbed substances or store them until they are needed. This process of diffusion is caused by kinetic motion The liver also eliminates certain waste products produced of the molecules in the plasma and the interstitial fluid. in the body and toxic substances that are ingested. 5 UNIT I Introduction to Physiology: The Cell and General Physiology Musculoskeletal System. How does the musculoskeletal performs in response to the sensations. Appropriate sig- system contribute to homeostasis? The answer is obvious nals are then transmitted through the motor output por- and simple. Were it not for the muscles, the body could tion of the nervous system to carry out one’s desires. not move to obtain the foods required for nutrition. The An important segment of the nervous system is called musculoskeletal system also provides motility for protec- the autonomic system. It operates at a subconscious level tion against adverse surroundings, without which the en- and controls many functions of internal organs, including tire body, along with its homeostatic mechanisms, could the level of pumping activity by the heart, movements of be destroyed. the gastrointestinal tract, and secretion by many of the body’s glands. REMOVAL OF METABOLIC END PRODUCTS Hormone Systems. Located in the body are endocrine Removal of Carbon Dioxide by the Lungs. At the same glands, organs and tissues that secrete chemical sub- time that blood picks up oxygen in the lungs, carbon di- stances called hormones. Hormones are transported in oxide is released from the blood into lung alveoli; the res- the extracellular fluid to other parts of the body to help piratory movement of air into and out of the lungs carries regulate cellular function. For example, thyroid hormone carbon dioxide to the atmosphere. Carbon dioxide is the increases the rates of most chemical reactions in all cells, most abundant of all the metabolism products. thus helping set the tempo of bodily activity. Insulin con- trols glucose metabolism, adrenocortical hormones con- Kidneys. Passage of blood through the kidneys removes trol sodium and potassium ions and protein metabolism, most of the other substances from the plasma besides car- and parathyroid hormone controls bone calcium and bon dioxide that are not needed by cells. These substanc- phosphate. Thus, the hormones provide a regulatory sys- es include different end products of cellular metabolism, tem that complements the nervous system. The nervous such as urea and uric acid; they also include excesses of system controls many muscular and secretory activities ions and water from the food that accumulate in the ex- of the body, whereas the hormonal system regulates many tracellular fluid. metabolic functions. The nervous and hormonal systems The kidneys perform their function first by filtering normally work together in a coordinated manner to con- large quantities of plasma through the glomerular capil- trol essentially all the organ systems of the body. laries into the tubules and then reabsorbing into the blood substances needed by the body, such as glucose, amino PROTECTION OF THE BODY acids, appropriate amounts of water, and many of the ions. Most of the other substances that are not needed Immune System. The immune system includes white by the body, especially metabolic waste products such blood cells, tissue cells derived from white blood cells, the as urea and creatinine, are reabsorbed poorly and pass thymus, lymph nodes, and lymph vessels that protect the through the renal tubules into the urine. body from pathogens such as bacteria, viruses, parasites, and fungi. The immune system provides a mechanism for Gastrointestinal Tract. Undigested material that enters the body to carry out the following: (1) distinguish its own the gastrointestinal tract and some waste products of me- cells from harmful foreign cells and substances; and (2) tabolism are eliminated in the feces. destroy the invader by phagocytosis or by producing sensi- tized lymphocytes or specialized proteins (e.g., antibodies) Liver. Among the many functions of the liver is detoxifi- that destroy or neutralize the invader. cation or removal of ingested drugs and chemicals. The liver secretes many of these wastes into the bile to be Integumentary System. The skin and its various ap- eventually eliminated in the feces. pendages (including the hair, nails, glands, and other structures) cover, cushion, and protect the deeper tissues and organs of the body and generally provide a bound- REGULATION OF BODY FUNCTIONS ary between the body’s internal environment and the out- Nervous System. The nervous system is composed of side world. The integumentary system is also important three major parts—the sensory input portion, the central for temperature regulation and excretion of wastes, and nervous system (or integrative portion), and the motor out- it provides a sensory interface between the body and the put portion. Sensory receptors detect the state of the body external environment. The skin generally comprises about and its surroundings. For example, receptors in the skin 12% to 15% of body weight. alert us whenever an object touches the skin. The eyes are sensory organs that give us a visual image of the sur- REPRODUCTION rounding area. The ears are also sensory organs. The cen- tral nervous system is composed of the brain and spinal Although reproduction is sometimes not considered a cord. The brain stores information, generates thoughts, homeostatic function, it helps maintain homeostasis by creates ambition, and determines reactions that the body generating new beings to take the place of those that are 6  Chapter 1 Functional Organization of the Human Body and Control of the “Internal Environment” dying. This may sound like a permissive usage of the term Reference homeostasis, but it illustrates that in the final analysis, set point essentially all body structures are organized to help main- Error signal Effectors tain the automaticity and continuity of life. Brain medulla Sympathetic Blood vessels Vasomotor nervous system Heart centers CONTROL SYSTEMS OF THE BODY UNIT I The human body has thousands of control systems. Some Feedback signal of the most intricate of these systems are genetic control systems that operate in all cells to help regulate intracel- Baroreceptors Arterial lular and extracellular functions. This subject is discussed pressure in Chapter 3. Sensor Controlled variable Many other control systems operate within the organs Figure 1-3. Negative feedback control of arterial pressure by the ar- to regulate functions of the individual parts of the organs; terial baroreceptors. Signals from the sensor (baroreceptors) are sent others operate throughout the entire body to control the to the medulla of the brain, where they are compared with a refer- interrelationships between the organs. For example, the ence set point. When arterial pressure increases above normal, this abnormal pressure increases nerve impulses from the baroreceptors respiratory system, operating in association with the to the medulla of the brain, where the input signals are compared nervous system, regulates the concentration of carbon with the set point, generating an error signal that leads to decreased dioxide in the extracellular fluid. The liver and pancreas sympathetic nervous system activity. Decreased sympathetic activity control glucose concentration in the extracellular fluid, causes dilation of blood vessels and reduced pumping activity of the and the kidneys regulate concentrations of hydrogen, heart, which return arterial pressure toward normal. sodium, potassium, phosphate, and other ions in the extracellular fluid. Regulation of Arterial Blood Pressure. Several systems contribute to arterial blood pressure regulation. One of these, the baroreceptor system, is an excellent example of EXAMPLES OF CONTROL MECHANISMS a rapidly acting control mechanism (Figure 1-3). In the Regulation of Oxygen and Carbon Dioxide Concen- walls of the bifurcation region of the carotid arteries in trations in the Extracellular Fluid. Because oxygen is the neck, and also in the arch of the aorta in the thorax, one of the major substances required for chemical reac- are many nerve receptors called baroreceptors that are tions in cells, the body has a special control mechanism to stimulated by stretch of the arterial wall. When arterial maintain an almost exact and constant oxygen concentra- pressure rises too high, the baroreceptors send barrages tion in the extracellular fluid. This mechanism depends of nerve impulses to the medulla of the brain. Here, these principally on the chemical characteristics of hemoglobin, impulses inhibit the vasomotor center, which in turn de- which is present in red blood cells. Hemoglobin com- creases the number of impulses transmitted from the bines with oxygen as the blood passes through the lungs. vasomotor center through the sympathetic nervous sys- Then, as the blood passes through the tissue capillaries, tem to the heart and blood vessels. Lack of these impulses hemoglobin, because of its own strong chemical affinity causes diminished pumping activity by the heart and dila- for oxygen, does not release oxygen into the tissue fluid tion of peripheral blood vessels, allowing increased blood if too much oxygen is already there. However, if oxygen flow through the vessels. Both these effects decrease the concentration in the tissue fluid is too low, sufficient oxy- arterial pressure, moving it back toward normal. gen is released to re-­establish an adequate concentration. Conversely, a decrease in arterial pressure below nor- Thus, regulation of oxygen concentration in the tissues mal relaxes the stretch receptors, allowing the vasomotor relies to a great extent on the chemical characteristics of center to become more active than usual, thereby causing hemoglobin. This regulation is called the oxygen-­buffering vasoconstriction and increased heart pumping. The initial function of hemoglobin. decrease in arterial pressure thus initiates negative feed- Carbon dioxide concentration in the extracellular fluid back mechanisms that raise arterial pressure back toward is regulated in a much different way. Carbon dioxide is a normal. major end product of oxidative reactions in cells. If all the carbon dioxide formed in the cells continued to accumu- Normal Ranges and Physical late in the tissue fluids, all energy-­giving reactions of the Characteristics of Important Extracellular cells would cease. Fortunately, a higher than normal car- Fluid Constituents bon dioxide concentration in the blood excites the respira- Table 1-1 lists some important constituents and physical tory center, causing a person to breathe rapidly and deeply. characteristics of extracellular fluid, along with their nor- This deep rapid breathing increases expiration of carbon mal values, normal ranges, and maximum limits without dioxide and, therefore, removes excess carbon dioxide causing death. Note the narrowness of the normal range from the blood and tissue fluids. This process continues for each one. Values outside these ranges are often caused until the concentration returns to normal. by illness, injury, or major environmental challenges. 7 UNIT I Introduction to Physiology: The Cell and General Physiology Table 1-1  Important Constituents and Physical Characteristics of Extracellular Fluid Constituent Normal Value Normal Range Approximate Short-­Term Nonlethal Limit Unit Oxygen (venous) 40 25–40 10–1000 mm Hg Carbon dioxide (venous) 45 41–51 5–80 mm Hg Sodium ion 142 135–145 115–175 mmol/L Potassium ion 4.2 3.5–5.3 1.5–9.0 mmol/L Calcium ion 1.2 1.0–1.4 0.5–2.0 mmol/L Chloride ion 106 98–108 70–130 mmol/L Bicarbonate ion 24 22–29 8–45 mmol/L Glucose 90 70–115 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 (venous) 7.4 7.3–7.5 6.9–8.0 pH Most important are the limits beyond which abnor- the extracellular fluid carbon dioxide concentration malities can cause death. For example, an increase in the because the lungs expire greater amounts of carbon diox- body temperature of only 11°F (7°C) above normal can ide from the body. Thus, the high concentration of carbon lead to a vicious cycle of increasing cellular metabolism dioxide initiates events that decrease the concentration that destroys the cells. Note also the narrow range for toward normal, which is negative to the initiating stimu- acid–base balance in the body, with a normal pH value lus. Conversely, a carbon dioxide concentration that falls of 7.4 and lethal values only about 0.5 on either side of too low results in feedback to increase the concentration. normal. Whenever the potassium ion concentration This response is also negative to the initiating stimulus. decreases to less than one-­third normal, paralysis may In the arterial pressure–regulating mechanisms, a high result from the inability of the nerves to carry signals. pressure causes a series of reactions that promote reduced Alternatively, if potassium ion concentration increases pressure, or a low pressure causes a series of reactions that to two or more times normal, the heart muscle is likely promote increased pressure. In both cases, these effects to be severely depressed. Also, when the calcium ion are negative with respect to the initiating stimulus. concentration falls below about one-­half normal, a per- Therefore, in general, if some factor becomes exces- son is likely to experience tetanic contraction of muscles sive or deficient, a control system initiates negative feed- throughout the body because of the spontaneous genera- back, which consists of a series of changes that return tion of excess nerve impulses in peripheral nerves. When the factor toward a certain mean value, thus maintaining the glucose concentration falls below one-­half normal, a homeostasis. person frequently exhibits extreme mental irritability and sometimes even has convulsions. Gain of a Control System. The degree of effectiveness These examples should give one an appreciation for with which a control system maintains constant condi- the necessity of the vast numbers of control systems that tions is determined by the gain of negative feedback. keep the body operating in health. In the absence of any For example, let us assume that a large volume of blood one of these controls, serious body malfunction or death is transfused into a person whose baroreceptor pressure can result. control system is not functioning, and the arterial pres- sure rises from the normal level of 100 mm Hg up to 175 mm Hg. Then, let us assume that the same volume of CHARACTERISTICS OF CONTROL SYSTEMS blood is injected into the same person when the barore- The aforementioned examples of homeostatic control ceptor system is functioning, and this time the pressure mechanisms are only a few of the many thousands in the increases by only 25 mm Hg. Thus, the feedback control body, all of which have some common characteristics, as system has caused a “correction” of −50 mm Hg, from explained in this section. 175 mm Hg to 125 mm Hg. There remains an increase in pressure of +25 mm Hg, called the “error,” which means Negative Feedback Nature of Most that the control system is not 100% effective in preventing Control Systems change. The gain of the system is then calculated by using Most control systems of the body act by negative feed- the following formula: back, which can be explained by reviewing some of the Correction Gain = homeostatic control systems mentioned previously. In Error the regulation of carbon dioxide concentration, a high Thus, in the baroreceptor system example, the correc- concentration of carbon dioxide in the extracellular fluid tion is −50 mm Hg, and the error persisting is +25 mm Hg. increases pulmonary ventilation. This, in turn, decreases Therefore, the gain of the person’s baroreceptor system 8  Chapter 1 Functional Organization of the Human Body and Control of the “Internal Environment” 5 overcome by the negative feedback control mechanisms of the body, and the vicious cycle then fails to develop. Pumping effectiveness of heart Return to For example, if the person in the aforementioned example (Liters pumped per minute) 4 normal bleeds only 1 liter instead of 2 liters, the normal negative Bled 1 liter feedback mechanisms for controlling cardiac output and 3 arterial pressure can counterbalance the positive feedback UNIT I and the person can recover, as shown by the dashed curve Bled 2 liters of Figure 1-4. 2 Positive Feedback Can Sometimes Be Useful. The body 1 sometimes uses positive feedback to its advantage. Blood clotting is an example of a valuable use of positive feed- Death back. When a blood vessel is ruptured, and a clot begins to 0 form, multiple enzymes called clotting factors are activated 1 2 3 within the clot. Some of these enzymes act on other inac- Hours tivated enzymes of the immediately adjacent blood, thus Figure 1-4. Recovery of heart pumping caused by negative feedback causing more blood clotting. This process continues until after 1 liter of blood is removed from the circulation. Death is caused by positive feedback when 2 liters or more blood is removed. the hole in the vessel is plugged and bleeding no longer occurs. On occasion, this mechanism can get out of hand for control of arterial pressure is −50 divided by +25, or and cause formation of unwanted clots. In fact, this is what −2. That is, a disturbance that increases or decreases the initiates most acute heart attacks, which can be caused by arterial pressure does so only one-third as much as would a clot beginning on the inside surface of an atherosclerotic occur if this control system were not present. plaque in a coronary artery and then growing until the ar- The gains of some other physiological control systems tery is blocked. are much greater than that of the baroreceptor system. Childbirth is another situation in which positive feed- For example, the gain of the system controlling internal back is valuable. When uterine contractions become body temperature when a person is exposed to moder- strong enough for the baby’s head to begin pushing ately cold weather is about −33. Therefore, one can see through the cervix, stretching of the cervix sends signals that the temperature control system is much more effec- through the uterine muscle back to the body of the uterus, tive than the baroreceptor pressure control system. causing even more powerful contractions. Thus, the uter- ine contractions stretch the cervix, and cervical stretch Positive Feedback May Cause Vicious causes stronger contractions. When this process becomes Cycles and Death powerful enough, the baby is born. If they are not pow- Why do most control systems of the body operate by erful enough, the contractions usually die out, and a few negative feedback rather than by positive feedback? If days pass before they begin again. one considers the nature of positive feedback, it is obvi- Another important use of positive feedback is for the ous that positive feedback leads to instability rather than generation of nerve signals. Stimulation of the mem- stability and, in some cases, can cause death. brane of a nerve fiber causes slight leakage of sodium ions Figure 1-4 shows an example in which death can ensue through sodium channels in the nerve membrane to the from positive feedback. This figure depicts the pumping fiber’s interior. The sodium ions entering the fiber then effectiveness of the heart, showing the heart of a healthy change the membrane potential, which, in turn, causes human pumping about 5 liters of blood per minute. If the more opening of channels, more change of potential, still person suddenly bleeds a total of 2 liters, the amount of more opening of channels, and so forth. Thus, a slight leak blood in the body is decreased to such a low level that becomes an explosion of sodium entering the interior of not enough blood is available for the heart to pump effec- the nerve fiber, which creates the nerve action potential. tively. As a result, the arterial pressure falls, and the flow This action potential, in turn, causes electrical current to of blood to the heart muscle through the coronary ves- flow along the outside and inside of the fiber and initiates sels diminishes. This scenario results in weakening of the additional action potentials. This process continues until heart, further diminished pumping, a further decrease the nerve signal goes all the way to the end of the fiber. in coronary blood flow, and still more weakness of the In each case in which positive feedback is useful, the heart; the cycle repeats itself again and again until death positive feedback is part of an overall negative feedback occurs. Note that each cycle in the feedback results in process. For example, in the case of blood clotting, the further weakening of the heart. In other words, the initi- positive feedback clotting process is a negative feedback ating stimulus causes more of the same, which is positive process for the maintenance of normal blood volume. feedback. Also, the positive feedback that causes nerve signals Positive feedback is sometimes known as a “vicious allows the nerves to participate in thousands of negative cycle,” but a mild degree of positive feedback can be feedback nervous control systems. 9 UNIT I Introduction to Physiology: The Cell and General Physiology More Complex Types of Control for understanding normal physiology as well as for treat- Systems—Feed-­Forward and Adaptive ment of diseases. Control Age-­related and ethnic or racial differences in physiol- Later in this text, when we study the nervous system, we ogy also have important influences on body composition, shall see that this system contains great numbers of inter- physiological control systems, and pathophysiology of connected control mechanisms. Some are simple feedback diseases. For example, in a lean young male the total body systems similar to those already discussed. Many are not. water is about 60% of body weight. As a person grows and For example, some movements of the body occur so rap- ages, this percentage gradually decreases, partly because idly that there is not enough time for nerve signals to travel aging is usually associated with declining skeletal muscle from the peripheral parts of the body all the way to the mass and increasing fat mass. Aging may also cause a brain and then back to the periphery again to control the decline in the function and effectiveness of some organs movement. Therefore, the brain uses a mechanism called and physiological control systems. feed-­forward control to cause required muscle contrac- These sources of physiological variability—sex differ- tions. Sensory nerve signals from the moving parts apprise ences, aging, ethnic, and racial—are complex but impor- the brain about whether the movement is performed cor- tant considerations when discussing normal physiology rectly. If not, the brain corrects the feed-­forward signals and the pathophysiology of diseases. that it sends to the muscles the next time the movement is required. Then, if still further correction is necessary, SUMMARY—AUTOMATICITY OF THE this process will be performed again for subsequent move- BODY ments. This process is called adaptive control. Adaptive control, in a sense, is delayed negative feedback. The main purpose of this chapter has been to discuss Thus, one can see how complex the feedback control briefly the overall organization of the body and the means systems of the body can be. A person’s life depends on all whereby the different parts of the body operate in har- of them. Therefore, much of this text is devoted to dis- mony. To summarize, the body is actually a social order of cussing these life-­giving mechanisms. about 35 to 40 trillion cells organized into different func- tional structures, some of which are called organs. Each functional structure contributes its share to the mainte- PHYSIOLOGICAL VARIABILITY nance of homeostasis in the extracellular fluid, which is Although some physiological variables, such as plasma called the internal environment. As long as normal con- concentrations of potassium, calcium, and hydrogen ditions are maintained in this internal environment, the ions, are tightly regulated, others, such as body weight cells of the body continue to live and function properly. and adiposity, show wide variation among different indi- Each cell benefits from homeostasis and, in turn, each viduals and even in the same individual at different stages cell contributes its share toward the maintenance of of life. Blood pressure, cardiac pumping, metabolic rate, homeostasis. This reciprocal interplay provides continu- nervous system activity, hormones, and other physi- ous automaticity of the body until one or more functional ological variables change throughout the day as we move systems lose their ability to contribute their share of func- about and engage in normal daily activities. Therefore, tion. When this happens, all the cells of the body suffer. when we discuss “normal” values, it is with the under- Extreme dysfunction leads to death; moderate dysfunc- standing that many of the body’s control systems are con- tion leads to sickness. stantly reacting to perturbations, and that variability may exist among different individuals, depending on body weight and height, diet, age, sex, environment, genetics, Bibliography and other factors. Adolph EF: Physiological adaptations: hypertrophies and superfunc- For simplicity, discussion of physiological functions tions. Am Sci 60:608, 1972. often focuses on the “average” 70-­kg young, lean male. Bentsen MA, Mirzadeh Z, Schwartz MW: Revisiting how the brain senses glucose-and why. Cell Metab 29:11, 2019. However, the American male no longer weighs an aver- Bernard C: Lectures on the Phenomena of Life Common to Animals age of 70 kg; he now weighs over 88 kg, and the average and Plants. Springfield, IL: Charles C Thomas, 1974. American female weighs over 76 kg, more than the aver- Cannon WB: Organization for physiological homeostasis. Physiol Rev age man in the 1960s. Body weight has also increased sub- 9:399, 1929. stantially in most other industrialized countries during Chien S: Mechanotransduction and endothelial cell homeostasis: the wisdom of the cell. Am J Physiol Heart Circ Physiol 292:H1209, 2007. the past 40 to 50 years. DiBona GF: Physiology in perspective: the wisdom of the body. Neu- Except for reproductive and hormonal functions, ral control of the kidney. Am J Physiol Regul Integr Comp Physiol many other physiological functions and normal values 289:R633, 2005. are often discussed in terms of male physiology. However, Dickinson MH, Farley CT, Full RJ, et al: How animals move: an integra- there are clearly differences in male and female physiology tive view. Science 288:100, 2000. Eckel-Mahan K, Sassone-Corsi P: Metabolism and the circadian clock beyond the obvious differences that relate to reproduc- converge. Physiol Rev 93:107, 2013. tion. These differences can have important consequences 10  Chapter 1 Functional Organization of the Human Body and Control of the “Internal Environment” Guyton AC: Arterial Pressure and Hypertension. Philadelphia: WB Nishida AH, Ochman H: A great-ape view of the gut microbiome. Nat Saunders, 1980. Rev Genet 20:185, 2019. Herman MA, Kahn BB: Glucose transport and sensing in the mainte- Orgel LE: The origin of life on the earth. Sci Am 271:76,1994. nance of glucose homeostasis and metabolic harmony. J Clin Invest Reardon C, Murray K, Lomax AE: Neuroimmune communication in 116:1767, 2006. health and disease. Physiol Rev 98:2287-2316, 2018. Kabashima K, Honda T, Ginhoux F, Egawa G: The immunological Sender R, Fuchs S, Milo R: Revised estimates for the number of human anatomy of the skin. Nat Rev Immunol 19:19, 2019. and bacteria cells in the body. PLoS Biol 14(8):e1002533, 2016. UNIT I Khramtsova EA, Davis LK, Stranger BE: The role of sex in the genom- Smith HW: From Fish to Philosopher. New York: Doubleday, 1961. ics of human complex traits. Nat Rev Genet 20: 173, 2019. Kim KS, Seeley RJ, Sandoval DA: Signalling from the periphery to the brain that regulates energy homeostasis. Nat Rev Neurosci 19:185, 2018. 11  CHAPTER 2 UNIT I The Cell and Its Functions Each of the trillions of cells in a human being is a living 20% of the cell mass. These proteins can be divided into structure that can survive for months or years, provided two types, structural proteins and functional proteins. its surrounding fluids contain appropriate nutrients. Cells Structural proteins are present in the cell mainly in the are the building blocks of the body, providing structure form of long filaments that are polymers of many indi- for the body’s tissues and organs, ingesting nutrients and vidual protein molecules. A prominent use of such intra- converting them to energy, and performing specialized cellular filaments is to form microtubules, which provide functions. Cells also contain the body’s hereditary code, the cytoskeletons of cellular organelles such as cilia, nerve which controls the substances synthesized by the cells axons, the mitotic spindles of cells undergoing mitosis, and permits them to make copies of themselves. and a tangled mass of thin filamentous tubules that hold the parts of the cytoplasm and nucleoplasm together in their respective compartments. Fibrillar proteins are ORGANIZATION OF THE CELL found outside the cell, especially in the collagen and elas- A schematic drawing of a typical cell, as seen by the light tin fibers of connective tissue, and elsewhere, such as in microscope, is shown in Figure 2-1. Its two major parts blood vessel walls, tendons, and ligaments. are the nucleus and the cytoplasm. The nucleus is sepa- The functional proteins are usually composed of com- rated from the cytoplasm by a nuclear membrane, and the binations of a few molecules in tubular-­globular form. cytoplasm is separated from the surrounding fluids by a These proteins are mainly the enzymes of the cell and, in cell membrane, also called the plasma membrane. contrast to the fibrillar proteins, are often mobile in the The different substances that make up the cell are cell fluid. Also, many of them are adherent to membra- collectively called protoplasm. Protoplasm is composed nous structures inside the cell and catalyze specific intra- mainly of five basic substances—water, electrolytes, pro- cellular chemical reactions. For example, the chemical teins, lipids, and carbohydrates. reactions that split glucose into its component parts and then combine these with oxygen to form carbon diox- Water. Most cells, except for fat cells, are comprised ide and water while simultaneously providing energy for mainly of water in a concentration of 70% to 85%. Many cellular function are all catalyzed by a series of protein cellular chemicals are dissolved in the water. Others are enzymes. suspended in the water as solid particulates. Chemical re- actions take place among the dissolved chemicals or at the Lipids. Lipids are several types of substances that are surfaces of the suspended particles or membranes. grouped together because of their common property of being soluble in fat solvents. Especially important lipids Ions. Important ions in the cell include potassium, magne- sium, phosphate, sulfate, bicarbonate, and smaller quanti- ties of sodium, chloride, and calcium. These ions are all Cell discussed in Chapter 4, which considers the interrelations membrane between the intracellular and extracellular fluids. The ions provide inorganic chemicals for cellular reac- Cytoplasm tions and are necessary for the operation of some cellular Nucleolus control mechanisms. For example, ions acting at the cell Nucleoplasm Nuclear membrane are required for the transmission of electro- membrane Nucleus chemical impulses in nerve and muscle fibers. Proteins. After water, the most abundant substances in most cells are proteins, which normally constitute 10% to Figure 2-1. Illustration of cell structures visible with a light microscope. 13 UNIT I Introduction to Physiology: The Cell and General Physiology Chromosomes and DNA Centrioles Secretory granule Golgi apparatus Microtubules Nuclear membrane Cell membrane Nucleolus Glycogen Ribosomes Lysosome Mitochondrion Rough (granular) Smooth (agranular) Microfilaments endoplasmic endoplasmic reticulum reticulum Figure 2-2. Reconstruction of a typical cell, showing the internal organelles in the cytoplasm and nucleus. are phospholipids and cholesterol, which together consti- that it is readily available to the cell. Also, a small amount tute only about 2% of the total cell mass. Phospholipids of carbohydrate is stored in cells as glycogen, an insoluble and cholesterol are mainly insoluble in water and there- polymer of glucose that can be depolymerized and used fore are used to form the cell membrane and intracellular rapidly to supply the cell’s energy needs. membrane barriers that separate the different cell com- partments. CELL STRUCTURE In addition to phospholipids and cholesterol, some cells contain large quantities of triglycerides, also called The cell contains highly organized physical structures neutral fats. In fat cells (adipocytes), triglycerides often called intracellular organelles, which are critical for cell account for as much as 95% of the cell mass. The fat stored function. For example, without one of the organelles, the in these cells represents the body’s main storehouse of mitochondria, more than 95% of the cell’s energy release energy-­giving nutrients that can later be used to provide from nutrients would cease immediately. The most energy wherever it is needed in the body. important organelles and other structures of the cell are shown in Figure 2-2. Carbohydrates. Carbohydrates play a major role in cell nutrition and, as parts of glycoprotein molecules, have MEMBRANOUS STRUCTURES OF THE CELL structural functions. Most human cells do not maintain large stores of carbohydrates; the amount usually averages Most organelles of the cell are covered by membranes only about 1% of their total mass but increases to as much composed primarily of lipids and proteins. These mem- as 3% in muscle cells and, occasionally, to 6% in liver cells. branes include the cell membrane, nuclear membrane, However, carbohydrate in the form of dissolved glucose membrane of the endoplasmic reticulum, and membranes is always present in the surrounding extracellular fluid so of the mitochondria, lysosomes, and Golgi apparatus. 14  Chapter 2 The Cell and Its Functions Carbohydrate Extracellular fluid UNIT I 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. The lipids in membranes provide a barrier that c­ontinuous over the entire cell surface. Interspersed in impedes movement of water and water-­ soluble sub- this lipid film are large globular proteins. stances from one cell compartment to another because The basic lipid bilayer is composed of three main types water is not soluble in lipids. However, protein mole- of lipids—phospholipids, sphingolipids, and cholesterol. cules often penetrate all the way through membranes, Phospholipids are the most abundant cell membrane thus providing specialized pathways, often organized lipids. One end of each phospholipid molecule is hydro- into actual pores, for passage of specific substances philic and soluble in water. The other end is hydropho- through membranes. Also, many other membrane bic and soluble only in fats. The phosphate end of the proteins are enzymes, which catalyze a multitude of phospholipid is hydrophilic, and the fatty acid portion is different chemical reactions, discussed here and in sub- hydrophobic. sequent chapters. Because the hydrophobic portions of the phospholipid molecules are repelled by water but are mutually attracted Cell Membrane to one another, they have a natural tendency to attach to The cell membrane (also called the plasma membrane) one another in the middle of the membrane, as shown in envelops the cell and is a thin, pliable, elastic structure Figure 2-3. The hydrophilic phosphate portions then con- only 7.5 to 10 nanometers thick. It is composed almost stitute the two surfaces of the complete cell membrane, in entirely of proteins and lipids. The approximate composi- contact with intracellular water on the inside of the mem- tion is 55% proteins, 25% phospholipids, 13% cholesterol, brane and extracellular water on the outside surface. 4% other lipids, and 3% carbohydrates. The lipid layer in the middle of the membrane is impermeable to the usual water-­soluble substances, such The Cell Membrane Lipid Barrier Impedes Penetra- as ions, glucose, and urea. Conversely, fat-­soluble sub- tion by Water-­Soluble Substances. Figure 2-3 shows stances, such as oxygen, carbon dioxide, and alcohol, can the structure of the cell membrane. Its basic structure penetrate this portion of the membrane with ease. is a lipid bilayer, which is a thin, double-­layered film Sphingolipids, derived from the amino alcohol sphin- of lipids—each layer only one molecule thick—that is gosine, also have hydrophobic and hydrophilic groups and 15 UNIT I Introduction to Physiology: The Cell and General Physiology are present in small amounts in the cell membranes, espe- these molecules almost invariably protrude to the outside cially nerve cells. Complex sphingolipids in cell mem- of the cell, dangling outward from the cell surface. Many branes are thought to serve several functions, including other carbohydrate compounds, called proteoglycans— protection from harmful environmental factors, signal which are mainly carbohydrates bound to small protein transmission, and adhesion sites for extracellular proteins. cores—are loosely attached to the outer surface of the cell Cholesterol molecules in membranes are also lipids as well. Thus, the entire outside surface of the cell often because their steroid nuclei are highly fat-­soluble. These has a loose carbohydrate coat called the glycocalyx. molecules, in a sense, are dissolved in the bilayer of the The carbohydrate moieties attached to the outer sur- membrane. They mainly help determine the degree of face of the cell have several important functions: permeability (or impermeability) of the bilayer to water-­ 1. Many of them have a negative electrical charge, soluble constituents of body fluids. Cholesterol controls which gives most cells an overall negative surface much of the fluidity of the membrane as well. charge that repels other negatively charged objects. 2. The glycocalyx of some cells attaches to the glycoca- Integral and Peripheral Cell Membrane Proteins. lyx of other cells, thus attaching cells to one another. Figure 2-3 also shows globular masses floating in the 3. Many of the carbohydrates act as receptors for bind- lipid bilayer. These membrane proteins are mainly glyco- ing hormones, such as insulin. When bound, this proteins. There are two types of cell membrane proteins, combination activates attached internal proteins that integral proteins, which protrude all the way through in turn activate a cascade of intracellular enzymes. the membrane, and peripheral proteins, which are 4. Some carbohydrate moieties enter into immune re- attached only to one surface of the membrane and do actions, as discussed in Chapter 35. not penetrate all the way through. Many of the integral proteins provide structural chan- CYTOPLASM AND ITS ORGANELLES nels (or pores) through which water molecules and water-­ soluble substances, especially ions, can diffuse between The cytoplasm is filled with minute and large dispersed extracellular and intracellular fluids. These protein chan- particles and organelles. The jelly-­like fluid portion of the nels also have selective properties that allow preferential cytoplasm in which the particles are dispersed is called diffusion of some substances over others. cytosol and contains mainly dissolved proteins, electro- Other integral proteins act as carrier proteins for trans- lytes, and glucose. porting substances that otherwise could not penetrate Dispersed in the cytoplasm are neutral fat globules, the lipid bilayer. Sometimes, these carrier proteins even glycogen granules, ribosomes, secretory vesicles, and five transport substances in the direction opposite to their especially important organelles—the endoplasmic reticu- electrochemical gradients for diffusion, which is called lum, the Golgi apparatus, mitochondria, lysosomes, and active transport. Still others act as enzymes. peroxisomes. Integral membrane proteins can also serve as receptors for water-­soluble chemicals, such as peptide hormones, Endoplasmic Reticulum that do not easily penetrate the cell membrane. Interac- Figure 2-2 shows the endoplasmic reticulum, a network tion of cell membrane receptors with specific ligands that of tubular structures called cisternae and flat vesicular bind to the receptor causes conformational changes in structures in the cytoplasm. This organelle helps pro- the receptor protein. This process, in turn, enzymatically cess molecules made by the cell and transports them to activates the intracellular part of the protein or induces their specific destinations inside or outside the cell. The interactions between the receptor and proteins in the tubules and vesicles interconnect. Also, their walls are cytoplasm that act as second messengers, relaying the sig- constructed of lipid bilayer membranes that contain large nal from the extracellular part of the receptor to the inte- amounts of proteins, similar to the cell membrane. The rior of the cell. In this way, integral proteins spanning the total surface area of this structure in some cells—the liver cell membrane provide a means of conveying information cells, for example—can be as much as 30 to 40 times the about the environment to the cell interior. cell membrane area. Peripheral protein molecules are often attached to The detailed structure of a small portion of endoplas- integral proteins. These peripheral proteins function mic reticulum is shown in Figure 2-4. The space inside almost entirely as enzymes or as controllers of transport the tubules and vesicles is filled with endoplasmic matrix, of substances through cell membrane pores. a watery medium that is different from fluid in the cytosol outside the endoplasmic reticulum. Electron micrographs Membrane Carbohydrates—The Cell “Glycocalyx.” show that the space inside the endoplasmic reticulum is Membrane carbohydrates occur almost invariably in com- connected with the space between the two membrane bination with proteins or lipids in the form of glycopro- surfaces of the nuclear membrane. teins or glycolipids. In fact, most of the integral proteins Substances formed in some parts of the cell enter the are glycoproteins, and about one-tenth of the membrane space of the endoplasmic reticulum and are then directed lipid molecules are glycolipids. The glyco-­ portions of to other parts of the cell. Also, the vast surface area of this 16  Chapter 2 The Cell and Its Functions Ribosome Golgi vesicles Matrix Golgi UNIT I apparatus ER vesicles Endoplasmic reticulum Rough (granular) endoplasmic reticulum Smooth (agranular) endoplasmic Figure 2-5. A typical Golgi apparatus and its relationship to the reticulum endoplasmic reticulum (ER) and the nucleus. Figure 2-4. Structure of the endoplasmic reticulum. vesicles are transported from the endoplasmic reticulum reticulum and the multiple enzyme systems attached to to the Golgi apparatus. The transported substances are its membranes provide the mechanisms for a major share then processed in the Golgi apparatus to form lysosomes, of the cell’s metabolic functions. secretory vesicles, and other cytoplasmic components (discussed later in this chapter). Ribosomes and the Rough (Granular) Endoplasmic Reticulum. Attached to the outer surfaces of many parts Lysosomes of the endoplasmic reticulum are large numbers of minute Lysosomes, shown in Figure 2-2, are vesicular organ- granular particles called ribosomes. Where these particles elles that form by breaking off from the Golgi appara- are present, the reticulum is called the rough (granular) tus; they then disperse throughout the cytoplasm. The endoplasmic reticulum. The ribosomes are composed of a lysosomes provide an intracellular digestive system that mixture of RNA and proteins; they function to synthesize allows the cell to digest the following: (1) damaged cellu- new protein molecules in the cell, as discussed later in this lar structures; (2) food particles that have been ingested chapter and in Chapter 3. by the cell; and (3) unwanted matter such as bacteria. Lysosome are different in various cell types but are usu- Smooth (Agranular) Endoplasmic Reticulum. Part of ally 250 to 750 nanometers in diameter. They are sur- the endoplasmic reticulum has no attached ribosomes. rounded by typical lipid bilayer membranes and are filled This part is called the smooth, or agranular, endoplasmic with large numbers of small granules, 5 to 8 nanometers reticulum. The smooth reticulum functions for the syn- in diameter, which are protein aggregates of as many as thesis of lipid substances and for other processes of the 40 different hydrolase (digestive) enzymes. A hydrolytic cells promoted by intrareticular enzymes. enzyme is capable of splitting an organic compound into two or more parts by combining hydrogen from a water Golgi Apparatus molecule with one part of the compound and combin- The Golgi apparatus, shown in Figure 2-5, is closely ing the hydroxyl portion of the water molecule with the related to the endoplasmic reticulum. It has membranes other part of the compound. For example, protein is similar to those of the smooth endoplasmic reticulum. hydrolyzed to form amino acids, glycogen is hydrolyzed The Golgi apparatus is usually composed of four or more to form glucose, and lipids are hydrolyzed to form fatty stacked layers of thin, flat, enclosed vesicles lying near one acids and glycerol. side of the nucleus. This apparatus is prominent in secre- Hydrolytic enzymes are highly concentrated in lyso- tory cells, where it is located on the side of the cell from somes. Ordinarily, the membrane surrounding the lyso- which secretory substances are extruded. some prevents the enclosed hydrolytic enzymes from The Golgi apparatus functions in association with the coming into contact with other substances in the cell and endoplasmic reticulum. As shown in Figure 2-5, small therefore prevents their digestive actions. However, some transport vesicles (also called endoplasmic reticulum conditions of the cell break the membranes of lysosomes, vesicles [ER vesicles]) continually pinch off from the endo- allowing release of the digestive enzymes. These enzymes plasmic reticulum and shortly thereafter fuse with the then split the organic substances with which they come Golgi apparatus. In this way, substances entrapped in ER in contact into small, highly diffusible substances such as 17 UNIT I Introduction to Physiology: The Cell and General Physiology Secretory Outer membrane granules Inner membrane Cristae Matrix Oxidative phosphorylation Outer chamber enzymes Figure 2-6. Secretory granules (secretory vesicles) in acinar cells of the pancreas. Figure 2-7. Structure of a mitochondrion. amino acids and glucose. Some of the specific functions of Mitochondria are present in all areas of each cell’s lysosomes are discussed later in this chapter. cytoplasm, but the total number per cell varies from less than 100 up to several thousand, depending on the energy Peroxisomes requirements of the cell. Cardiac muscle cells (cardiomyo- Peroxisomes are physically similar to lysosomes, but cytes), for example, use large amounts of energy and have they are different in two important ways. First, they are far more mitochondria than fat cells (adipocytes), which believed to be formed by self-­replication (or perhaps by are much less active and use less energy. Furthermore, budding off from the smooth endoplasmic reticulum) the mitochondria are concentrated in those portions rather than from the Golgi apparatus. Second, they con- of the cell responsible for the major share of its energy tain oxidases rather than hydrolases. Several of the oxi- metabolism. They are also variable in size and shape. dases are capable of combining oxygen with hydrogen Some mitochondria are only a few hundred nanometers ions derived from different intracellular chemicals to in diameter and are globular in shape, whereas others are form hydrogen peroxide (H2O2). Hydrogen peroxide is a elongated and are as large as 1 micrometer in diameter highly oxidizing substance and is used in association with and 7 micrometers long. Still others are branching and catalase, another oxidase enzyme present in large quan- filamentous. tities in peroxisomes, to oxidize many substances that The basic structure of the mitochondrion, shown might otherwise be poisonous to the cell. For example, in Figure 2-7, is composed mainly of two lipid bilayer-­ about half the alcohol that a person drinks is detoxified protein membranes, an outer membrane and an inner into acetaldehyde by the peroxisomes of the liver cells in membrane. Many infoldings of the inner membrane form this manner. A major function of peroxisomes is to catab- shelves or tubules called cristae onto which oxidative olize long-­chain fatty acids. enzymes are attached. The cristae provide a large surface area for chemical reactions to occur. In addition, the inner Secretory Vesicles cavity of the mitochondrion is filled with a matrix that One of the important functions of many cells is secretion contains large quantities of dissolved enzymes necessary of special chemical substances. Almost all such secretory for extracting energy from nutrients. These enzymes oper- substances are formed by the endoplasmic reticulum– ate in associati