Receptors & Stimuli

An important recent event was the isolation of vanilloid receptor-1 (VR1). Vanillins are a group of compounds, including capsaicin, that cause pain. This necessitated revision of the concept that a single pathway carries pain and only pain to the cerebral cortex. The VR1 receptors respond not only to the pain-causing agents such as capsaicin but also to protons and to potentially harmful temperatures above 43 °C. Another receptor, VRL-1, which responds to temperatures above 50 °C but not to capsaicin, has been isolated from C fibers. There may be many types of receptors on single peripheral C fiber endings, so single fibers can respond to many different noxious stimuli. However, the different properties of the VR1 and the VRL-1 receptors make it likely that there are many different nociceptor C fibers systems as well.

Receptors & Pathways

The sense organs for pain are the naked nerve endings found in almost every tissue of the body. Pain impulses are transmitted to the CNS by two fiber systems. One nociceptor system is made up of small myelinated Aδ fibers 2-5 um in diameter, which conduct at rates of 12-30 m/s. The other consists of unmyelinated C fibers 0.4-1.2 um in diameter. These latter fibers are found in the lateral division of the dorsal roots and are often called dorsal root C fibers. They conduct at the low rate of 0.5-2 m/s. Both fiber groups end in the dorsal horn; Aδ fibers terminate primarily on neurons in laminas I and V, whereas the dorsal root C fibers terminate on neurons in laminas I and II. The synaptic transmitter secreted by primary afferent fibers subserving fast mild pain (see below) is glutamate, and the transmitter subserving slow severe pain is substance P.

The synaptic junctions between the peripheral nociceptor fibers and the dorsal horn cells in the spinal cord are the sites of considerable plasticity. For this reason, the dorsal horn has been called a gate, where pain impulses can be "gated," ie, modified.

Some of the axons of the dorsal horn neurons end in the spinal cord and brain stem. Others enter the anterolateral system, including the lateral spinothalamic tract. A few ascend in the posterolateral portion of the cord. Some of the ascending fibers project to the ventral posterior nuclei, which are the specific sensory relay nuclei of the thalamus, and from there to the cerebral cortex. PET and fMRI studies in normal humans indicate that pain activates cortical areas SI, SII, and the cingulate gyrus on the side opposite the stimulus. In addition, the mediofrontal cortex, the insular cortex, and the cerebellum are activated.

Pain was called by Sherrington "the physical adjunct of an imperative protective reflex." Painful stimuli generally initiate potent withdrawal and avoidance responses. Furthermore, pain is unique among the sensations in that it has a "built-in" unpleasant affect.

TEMPERATURE

Mapping experiments show that there are discrete cold-sensitive and heat-sensitive spots in the skin. There are four to ten times as many cold-sensitive as heat-sensitive spots. Cold receptors respond from 10 °C to 38 °C and heat receptors from 30 °C to over 45 °C. The afferents for cold are Aδ and C fibers, whereas the afferents for heat are C fibers. Temperature has generally been regarded as closely related to touch, but new evidence indicates that in addition to ending in the postcentral gyrus, thermal fibers from the thalamus end in the ipsilateral insular cortex. It has even been suggested that this is the true primary thermal receiving area.

Three receptors involved in temperature perception have been cloned. The receptor for moderate cold is the cold- and menthol-sensitive receptor 1 (CMR 1). Two receptors respond to high, potentially noxious heat: VR1, which also responds to the pain-producing chemical capsaicin and is clearly a nociceptor; and VRL-1, a closely related receptor that does not respond to capsaicin but is probably a nociceptor as well. All three are members of the TRP family of cation channels . The receptor that responds to moderate heat (warmth receptor) could be the ATP P2X receptor because injection of ATP causes a feeling of warmth, and mice in which the P2X receptor gene has been knocked out do not show the activity in the spinal cord normally produced by mild skin warming.

Because the sense organs are located subepithelially, it is the temperature of the subcutaneous tissues that determines the responses. Cool metal objects feel colder than wooden objects of the same temperature because the metal conducts heat away from the skin more rapidly, cooling the subcutaneous tissues to a greater degree.

PROPRIOCEPTION

roprioceptive information is transmitted up the spinal cord in the dorsal columns. A good deal of the proprioceptive input goes to the cerebellum, but some passes via the medial lemnisci and thalamic radiations to the cortex. Diseases of the dorsal columns produce ataxia because of the interruption of proprioceptive input to the cerebellum.

There is some evidence that proprioceptive information passes to consciousness in the anterolateral columns of the spinal cord. Conscious awareness of the positions of the various parts of the body in space depends in part upon impulses from sense organs in and around the joints. The organs involved are slowly adapting "spray" endings, structures that resemble Golgi tendon organs, and probably pacinian corpuscles in the synovia and ligaments. Impulses from these organs, touch receptors in the skin and other tissues, and muscle spindles are synthesized in the cortex into a conscious picture of the position of the body in space. Microelectrode studies indicate that many of the neurons in the sensory cortex respond to particular movements, not just to touch or static position. In this regard, the sensory cortex is organized like the visual cortex .

touch

As noted in , pressure is maintained touch. Touch is present in areas that have no visible specialized receptors. However, pacinian corpuscles and possibly other putative receptors may subsume special functions related to touch. Touch receptors are most numerous in the skin of the fingers and lips and relatively scarce in the skin of the trunk. There are many receptors around hair follicles in addition to those in the subcutaneous tissues of hairless areas. When a hair is moved, it acts as a lever with its fulcrum at the edge of the follicle, so that slight movements of the hairs are magnified into relatively potent stimuli to the nerve endings around the follicles. The stiff vibrissae on the snouts of some animals are highly developed examples of hairs that act as levers to magnify tactile stimuli.

The Na⁺ channel BNC1 is closely associated with touch receptors. This channel is one of the degenerins, so called because when they are hyperexpressed they cause the neurons they are in to degenerate. However, it is not known if BNC1 is part of the receptor complex or the neural fiber at the point of initiation of the spike potential. The receptor may be opened mechanically by pressure on the skin.

The Aβ sensory fibers that transmit impulses from touch receptors to the central nervous system are 5-12 um in diameter and have conduction velocities of 30-70 m/s. Some touch impulses are also conducted via C fibers.

Touch information is transmitted in both the lemniscal and anterolateral pathways, so that only very extensive lesions completely interrupt touch sensation. However, there are differences in the type of touch information transmitted in the two systems. When the dorsal columns are destroyed, vibratory sensation and proprioception are reduced, the touch threshold is elevated, and the number of touch-sensitive areas in the skin is decreased. In addition, localization of touch sensation is impaired. An increase in touch threshold and a decrease in the number of touch spots in the skin are also observed after interrupting the spinothalamic tracts, but the touch deficit is slight and touch localization remains normal. The information carried in the lemniscal system is concerned with the detailed localization, spatial form, and temporal pattern of tactile stimuli. The information carried in the spinothalamic tracts, on the other hand, is concerned with poorly localized, gross tactile sensations.

Effects of Cortical Lesions

Ablation of SI in animals causes deficits in position sense and in the ability to discriminate size and shape. Ablation of SII causes deficits in learning based on tactile discrimination. Ablation of SI causes deficits in sensory processing in SII, whereas ablation of SII has no gross effect on processing in SI. Thus, it seems clear that SI and SII process sensory information in series rather than in parallel and that SII is concerned with further elaboration of sensory data. SI also projects to the posterior parietal cortex , and lesions of this association area produce complex abnormalities of spatial orientation on the contralateral side of the body .

It is worth emphasizing that in experimental animals and humans, cortical lesions do not abolish somatic sensation. Proprioception and fine touch are most affected by cortical lesions. Temperature sensibility is less affected, and pain sensibility is only slightly affected. Thus, perception is possible in the absence of the cortex.

Cortical Representation

Mapping of cortical areas involved in sensation has been carried out in experimental animals and during neurosurgical procedures in humans, but it has also been carried out more recently in intact humans by techniques such as positron emission tomography (PET) and functional magnetic resonance imaging (fMRI). These techniques, which are described in and referenced in the , have led to major advances not only in sensory physiology but also in all aspects of cortical function in normal humans.

From the specific sensory nuclei of the thalamus, neurons carrying sensory information project in a highly specific way to the two somatic sensory areas of the cortex: somatic sensory area I (SI) in the postcentral gyrus and somatic sensory area II (SII) in the wall of the sylvian fissure. In addition, SI projects to SII. SI corresponds to Brodmann's areas 1, 2, and 3. Brodmann was a histologist who painstakingly divided the cerebral cortex into numbered areas based on their histologic characteristics.

The arrangement of the thalamic fibers in SI is such that the parts of the body are represented in order along the postcentral gyrus, with the legs on top and the head at the foot of the gyrus (. Not only is there detailed localization of the fibers from the various parts of the body in the postcentral gyrus, but also the size of the cortical receiving area for impulses from a particular part of the body is proportionate to the number of receptors in the part. The relative sizes of the cortical receiving areas are shown dramatically in , in which the proportions of the homunculus have been distorted to correspond to the size of the cortical receiving areas for each. Note that the cortical areas for sensation from the trunk and back are small, whereas very large areas are concerned with impulses from the hand and the parts of the mouth concerned with speech.

Studies of the sensory receiving area emphasize the very discrete nature of the point-for-point localization of peripheral areas in the cortex and provide further evidence for the general validity of the doctrine of specific nerve energies . Stimulation of the various parts of the postcentral gyrus gives rise to sensations projected to appropriate parts of the body. The sensations produced are usually numbness, tingling, or a sense of movement, but with fine enough electrodes it has been possible to produce relatively pure sensations of touch, warmth, and cold. The cells in the postcentral gyrus are organized in vertical columns, like cells in the visual cortex . The cells in a given column are all activated by afferents from a given part of the body, and all respond to the same sensory modality.

SII is located in the superior wall of the sylvian fissure, the fissure that separates the temporal from the frontal and parietal lobes. The head is represented at the inferior end of the postcentral gyrus, and the feet at the bottom of the sylvian fissure. The representation of the body parts is not as complete or detailed as it is in the postcentral gyrus.

The Cathode Ray Oscilloscope

The cathode ray oscilloscope (CRO) is used to measure the electrical events in living tissue. In the CRO, electrons emitted from a cathode are directed into a focused beam that strikes the face of the glass tube in which the cathode is located . The face is coated with one of a number of substances (phosphors) that emit light when struck by electrons. A vertical metal plate is placed on either side of the electron beam. When a voltage is applied across these plates, the negatively charged electrons are drawn toward the positively charged plate and repelled by the negatively charged plate. If the voltage applied to the vertical plates (X plates) is increased slowly and then reduced suddenly and increased again, the beam moves steadily toward the positive plate, snaps back to its former position, and moves toward the positive plate again. Application of a "saw-tooth voltage" of this type thus causes the beam to sweep across the face of the tube, and the speed of the sweep is proportionate to the rate of rise of the applied voltage.

Another set of plates (Y plates) is arranged horizontally, with one plate above and one below the beam. Voltages applied to these plates deflect the beam up and down as it sweeps across the face of the tube, and the magnitude of the vertical deflection is proportionate to the potential difference between the horizontal plates. When these plates are connected to electrodes on a nerve, any changes in potential occurring in the nerve are recorded as vertical deflections of the beam as it moves across the tube.

EXCITATION & CONDUCTION

Nerve cells have a low threshold for excitation. The stimulus may be electrical, chemical, or mechanical. Two types of physicochemical disturbances are produced: local, nonpropagated potentials called, depending on their location, synaptic, generator, or electrotonic potentials; and propagated disturbances, the action potentials (or nerve impulses). These are the only electrical responses of neurons and other excitable tissues, and they are the main language of the nervous system. They are due to changes in the conduction of ions across the cell membrane that are produced by alterations in ion channels.

The impulse is normally transmitted (conducted) along the axon to its termination. Nerves are not "telephone wires" that transmit impulses passively; conduction of nerve impulses, although rapid, is much slower than that of electricity. Nerve tissue is in fact a relatively poor passive conductor, and it would take a potential of many volts to produce a signal of a fraction of 1 V at the other end of a 1-m axon in the absence of active processes in the nerve. Conduction is an active, self-propagating process, and the impulse moves along the nerve at a constant amplitude and velocity. The process is often compared to what happens when a match is applied to one end of a train of gunpowder; by igniting the powder particles immediately in front of it, the flame moves steadily down the train to its end.

The electrical events in neurons are rapid, being measured in milliseconds (ms); and the potential changes are small, being measured in millivolts (mV). In addition to development of microelectrodes with a tip diameter of less than 1 um, the principal advances that made detailed study of the electrical activity in nerves possible were the development of electronic amplifiers and the cathode ray oscilloscope. Modern amplifiers magnify potential changes 1000 times or more, and the cathode ray oscilloscope provides an almost inertia-less and almost instantaneously responding "lever" for recording electrical events.

Excitable Tissue: Nerve

The human central nervous system (CNS) contains about 10¹¹ (100 billion) neurons. It also contains 10-50 times this number of glial cells. It is a complex organ; it has been calculated that 40% of the human genes participate, at least to a degree, in its formation. The neurons, the basic building blocks of the nervous system, have evolved from primitive neuroeffector cells that respond to various stimuli by contracting. In more complex animals, contraction has become the specialized function of muscle cells, whereas integration and transmission of nerve impulses have become the specialized functions of neurons. This chapter is concerned with the ways these neurons are excited and the way they integrate and transmit impulses.

BONE MARROW

In the adult, red blood cells, many white blood cells, and platelets are formed in the bone marrow. In the fetus, blood cells are also formed in the liver and spleen, and in adults such extramedullary hematopoiesis may occur in diseases in which the bone marrow becomes destroyed or fibrosed. In children, blood cells are actively produced in the marrow cavities of all the bones. By age 20, the marrow in the cavities of the long bones, except for the upper humerus and femur, has become inactive . Active cellular marrow is called red marrow; inactive marrow that is infiltrated with fat is called yellow marrow.

The bone marrow is actually one of the largest organs in the body, approaching the size and weight of the liver. It is also one of the most active. Normally, 75% of the cells in the marrow belong to the white blood cell-producing myeloid series and only 25% are maturing red cells, even though there are over 500 times as many red cells in the circulation as there are white cells. This difference in the marrow reflects the fact that the average life span of white cells is short, whereas that of red cells is long.

The bone marrow contains multipotent uncommitted stem cells (pluripotential stem cells) that differentiate into one or another type of committed stem cells (progenitor cells). These in turn form the various differentiated types of blood cells. There are separate pools of progenitor cells for megakaryocytes, lymphocytes, erythrocytes, eosinophils, and basophils, whereas neutrophils and monocytes arise from a common precursor. The bone marrow stem cells are also the source of osteoclasts , Kupffer cells , mast cells, dendritic cells, and Langerhans cells (see below).

The pluripotential cells are few in number but are capable of completely replacing the bone marrow when injected into a host whose own bone marrow has been completely destroyed. The best current source for these hematopoietic stem cells is umbilical cord blood.

The pluripotential cells are derived from uncommitted, totipotent stem cells that at least in theory can be stimulated to form any cell in the body. There are a few of these in adults, but they are more readily obtained from the blastocysts of embryos. Totipotential cells from human embryos have now been cultured, and there is immense interest in stem cell research. However, there are ethical as well as scientific issues involved, and debate on these issues will undoubtedly continue.

Surfactant

The low surface tension when the alveoli are small is due to the presence in the fluid lining the alveoli of surfactant, a lipid surface-tension-lowering agent. Surfactant is a mixture of dipalmitoylphosphatidylcholine (DPPC), other lipids, and proteins (. If the surface tension is not kept low when the alveoli become smaller during expiration, they collapse in accordance with the law of Laplace. In spherical structures like the alveoli, the distending pressure equals 2 times the tension divided by the radius (P = 2T/r); if T is not reduced as r is reduced, the tension overcomes the distending pressure. Surfactant also helps to prevent pulmonary edema. It has been calculated that if it were not present, the unopposed surface tension in the alveoli would produce a 20 mm Hg force favoring transudation of fluid from the blood into the alveoli.

Phospholipids, which have a hydrophilic "head" and two parallel hydrophobic fatty acids "tails" , line up in the alveoli with their tails facing the alveolar lumen , and surface tension is inversely proportionate to their concentration per unit area. They move farther apart as the alveoli enlarge during inspiration, and surface tension increases, whereas it decreases when they move closer together during expiration.

Surfactant is produced by type II alveolar epithelial cells . Typical lamellar bodies, membrane-bound organelles containing whorls of phospholipid, are formed in these cells and secreted into the alveolar lumen by exocytosis. Tubes of lipid called tubular myelin form from the extruded bodies, and the tubular myelin in turn forms the phospholipid film. Some of the protein-lipid complexes in surfactant are taken up by endocytosis in type II alveolar cells and recycled.

Formation of the phospholipid film is greatly facilitated by the proteins in surfactant. This material contains four unique proteins, SP-A, SP-B, SP-C, and SP-D. SP-A is a large glycoprotein and has a collagen-like domain within its structure. It probably has multiple functions, including regulation of the feedback uptake of surfactant by the type II alveolar epithelial cells that secrete it. SP-B and SP-C are smaller proteins, which facilitate formation of the monomolecular film of phospholipid. A mutation of the gene for SP-C has been reported to be associated with familial interstitial lung disease. Like SP-A, SP-D is a glycoprotein. Its function is uncertain. However, SP-A and SP-D are members of the collectin family of proteins that are involved in innate immunity in other parts of the body.

Surfactant is important at birth. The fetus makes respiratory movements in utero, but the lungs remain collapsed until birth. After birth, the infant makes several strong inspiratory movements and the lungs expand. Surfactant keeps them from collapsing again. Surfactant deficiency is an important cause of infant respiratory distress syndrome (IRDS; hyaline membrane disease), the serious pulmonary disease that develops in infants born before their surfactant system is functional. Surface tension in the lungs of these infants is high, and there are many areas in which the alveoli are collapsed (atelectasis). An additional factor in IRDS is retention of fluid in the lungs. During fetal life, Cl^- is secreted with fluid by the pulmonary epithelial cells. At birth, there is a shift to Na⁺ absorption by these cells via the epithelial Na⁺ channels (ENaCs), and fluid is absorbed with the Na⁺. Prolonged immaturity of the ENaCs contributes to the pulmonary abnormalities in IRDS.

Administration of phospholipid alone by inhalation has little value in the treatment of IRDS. However, a synthetic surfactant and a surfactant preparation derived from bovine lungs are available for use by inhalation. Used prophylactically at birth and as replacement therapy, they decrease the severity of IRDS and the severity but not the incidence of chronic lung disease in survivors.

Maturation of surfactant in the lungs is accelerated by glucocorticoid hormones. There is an increase in fetal and maternal cortisol near term, and the lungs are rich in glucocorticoid receptors.

Patchy atelectasis is also associated with surfactant deficiency in patients who have undergone cardiac surgery involving use of a pump oxygenator and interruption of the pulmonary circulation. In addition, surfactant deficiency may play a role in some of the abnormalities that develop following occlusion of a main bronchus, occlusion of one pulmonary artery, or long-term inhalation of 100% O₂. There is a decrease in surfactant in the lungs of cigarette smokers.

An interesting recent finding is the presence of excess surfactant lipids and proteins in mice with the GM-CSF gene knocked out. The role of GM-CSF in hematopoiesis is discussed. The pathologic findings in the lungs of the knockout mice resemble those in the lungs of humans with pulmonary alveolar proteinosis.

Differences in Ventilation & Blood Flow in Different Parts of the Lung

In the upright position, ventilation per unit lung volume is greater at the base of the lung than at the apex. The reason for this is that at the start of inspiration, intrapleural pressure is less negative at the base than at the apex , and since the intrapulmonary-intrapleural pressure difference is less than at the apex, the lung is less expanded. Conversely, at the apex, the lung is more expanded; ie, the percentage of maximum lung volume is greater. Because of the stiffness of the lung, the increase in lung volume per unit increase in pressure is smaller when the lung is initially more expanded, and ventilation is consequently greater at the base. Blood flow is also greater at the base than the apex (see below). The relative change in blood flow from the apex to the base is greater than the relative change in ventilation, so the ventilation/perfusion ratio is low at the base and high at the apex.

The ventilation and perfusion differences from the apex to the base of the lung have usually been attributed to gravity; they tend to disappear in the supine position, and the weight of the lung would be expected to make the intrapleural pressure lower at the base in the upright position. However, the inequalities of ventilation and blood flow in humans were found to persist to a remarkable degree in the weightlessness of space. Therefore, other as yet unknown factors apparently also play a role in producing the inequalities.

It should be noted that at very low lung volumes such as those after forced expiration, intrapleural pressure at the bases of the lungs can actually exceed the atmospheric pressure in the airways, and the small airways such as respiratory bronchioles collapse (airway closure). In older people and in those with chronic lung disease, some of the elastic recoil is lost, with a resulting decrease in intrapleural pressure. Consequently, airway closure may occur in the bases of the lungs in the upright position without forced expiration, at volumes as high as the functional residual capacity.

Glottis

The abductor muscles in the larynx contract early in inspiration, pulling the vocal cords apart and opening the glottis. During swallowing or gagging, there is reflex contraction of the adductor muscles that closes the glottis and prevents aspiration of food, fluid, or vomitus into the lungs. In unconscious or anesthetized patients, glottic closure may be incomplete and vomitus may enter the trachea, causing an inflammatory reaction in the lung (aspiration pneumonia).

The laryngeal muscles are supplied by the vagus nerves. When the abductors are paralyzed, there is inspiratory stridor. When the adductors are paralyzed, food and fluid enter the trachea, causing aspiration pneumonia and edema. Bilateral cervical vagotomy in animals causes the slow development of fatal pulmonary congestion and edema. The edema is due at least in part to aspiration, although some edema develops even if a tracheostomy is performed before the vagotomy.

Partial Pressures

Unlike liquids, gases expand to fill the volume available to them, and the volume occupied by a given number of gas molecules at a given temperature and pressure is (ideally) the same regardless of the composition of the gas. Therefore, the pressure exerted by any one gas in a mixture of gases (its partial pressure) is equal to the total pressure times the fraction of the total amount of gas it represents.

The composition of dry air is 20.98% O₂, 0.04% CO₂, 78.06% N₂, and 0.92% other inert constituents such as argon and helium. The barometric pressure (P_B) at sea level is 760 mm Hg (1 atmosphere). The partial pressure (indicated by the symbol P) of O₂ in dry air is therefore 0.21 × 760, or 160 mm Hg at sea level. The partial pressure of N₂ and the other inert gases is 0.79 × 760, or 600 mm Hg; and the PCO₂ is 0.0004 × 760, or 0.3 mm Hg. The water vapor in the air in most climates reduces these percentages, and therefore the partial pressures, to a slight degree. Air equilibrated with water is saturated with water vapor, and inspired air is saturated by the time it reaches the lungs. The PH₂O at body temperature (37 °C) is 47 mm Hg. Therefore, the partial pressures at sea level of the other gases in the air reaching the lungs are PO₂, 149 mm Hg; PCO₂, 0.3 mm Hg; and PN₂ (including the other inert gases), 564 mm Hg.

Gas diffuses from areas of high pressure to areas of low pressure, the rate of diffusion depending upon the concentration gradient and the nature of the barrier between the two areas. When a mixture of gases is in contact with and permitted to equilibrate with a liquid, each gas in the mixture dissolves in the liquid to an extent determined by its partial pressure and its solubility in the fluid. The partial pressure of a gas in a liquid is that pressure which in the gaseous phase in equilibrium with the liquid would produce the concentration of gas molecules found in the liquid.

Energy Balance

The first law of thermodynamics, the principle which states that energy is neither created nor destroyed when it is converted from one form to another, applies to living organisms as well as inanimate systems. One may therefore speak of an energy balance between caloric intake and energy output. If the caloric content of the food ingested is less than the energy output—ie, if the balance is negative—endogenous stores are utilized. Glycogen, body protein, and fat are catabolized, and the individual loses weight. If the caloric value of the food intake exceeds energy loss due to heat and work and the food is properly digested and absorbed—ie, if the balance is positive—energy is stored, and the individual gains weight.

To balance basal output so that the energy-consuming tasks essential for life can be performed, the average adult must take in about 2000 kcal/d. Caloric requirements above the basal level depend upon the individual's activity. The average sedentary student (or professor) needs another 500 kcal, whereas a lumberjack needs up to 3000 additional kcal per day.

Calorimetry

The energy released by combustion of foodstuffs outside the body can be measured directly (direct calorimetry) by oxidizing the compounds in an apparatus such as a bomb calorimeter, a metal vessel surrounded by water inside an insulated container. The food is ignited by an electric spark. The change in the temperature of the water is a measure of the calories produced. Similar measurements of the energy released by combustion of compounds in living animals and humans are much more complex, but calorimeters have been constructed that can physically accommodate human beings. The heat produced by their bodies is measured by the change in temperature of the water in the walls of the calorimeter.

The caloric values of the common foodstuffs, as measured in a bomb calorimeter, are found to be 4.1 kcal/g of carbohydrate, 9.3 kcal/g of fat, and 5.3 kcal/g of protein. In the body, similar values are obtained for carbohydrate and fat, but the oxidation of protein is incomplete, the end products of protein catabolism being urea and related nitrogenous compounds in addition to CO₂ and H₂O (see below). Therefore, the caloric value of protein in the body is only 4.1 kcal/g.

Calories

The standard unit of heat energy is the calorie (cal), defined as the amount of heat energy necessary to raise the temperature of 1 g of water 1 degree, from 15 °C to 16 °C. This unit is also called the gram calorie, small calorie, or standard calorie. The unit commonly used in physiology and medicine is the Calorie (kilocalorie; kcal), which equals 1000 cal.

Energy Balance, Metabolism, & Nutrition

The endocrine system, like the nervous system, adjusts and correlates the activities of the various body systems, making them appropriate to the changing demands of the external and internal environment. Endocrine integration is brought about by ductless glands and transported in the circulation to target cells. Other types of chemical messengers are discussed. Some of the hormones are amines, and others are amino acids, polypeptides, proteins, or steroids.

The hormones regulate metabolic processes. The term metabolism, meaning literally "change," is used to refer to all the chemical and energy transformations that occur in the body.

The animal organism oxidizes carbohydrates, proteins, and fats, producing principally CO₂, H₂O, and the energy necessary for life processes. CO₂, H₂O, and energy are also produced when food is burned outside the body. However, in the body, oxidation is not a one-step, semiexplosive reaction but a complex, slow, stepwise process called catabolism, which liberates energy in small, usable amounts. Energy can be stored in the body in the form of special energy-rich phosphate compounds and in the form of proteins, fats, and complex carbohydrates synthesized from simpler molecules. Formation of these substances by processes that take up rather than liberate energy is called anabolism. This chapter sets the stage for consideration of endocrine function by providing a brief summary of the production and utilization of energy and the metabolism of carbohydrates, proteins, and fats.

The environment of a dissociable group affects its pKa. The pKa values of the R groups of free amino acids in aqueous solution (Table 3–1) thus provid

The environment of a dissociable group affects its pK_a. The pK_a values of the R groups of free amino acids in aqueous solution (Table 3–1) thus provide only an approximate guide to the pK_a values of the same amino acids when present in proteins. A polar environment favors the charged form (R—COO^– or R—NH₃⁺), and a nonpolar environment favors the uncharged form (R—COOH or R—NH₂). A nonpolar environment thus raises the pK_a of a carboxyl group (making it a weaker acid) but lowers that of an amino group (making it a stronger acid). The presence of adjacent charged groups can reinforce or counteract solvent effects. The pK_a of a functional group thus will depend upon its location within a given protein. Variations in pK_a can encompass whole pH units (Table 3–2). pK_a values that diverge from those listed by as much as 3 pH units are common at the active sites of enzymes. An extreme example, a buried aspartic acid of thioredoxin, has a pK_a above 9—a shift of more than 6 pH units!

pKa Values Express the Strengths of Weak Acids

The acid strengths of weak acids are expressed as their pK_a. For molecules with multiple dissociable protons, the pK_a for each acidic group is designated by replacing the subscript "a" with a number (Table 3–1). The imidazole group of histidine and the guanidino group of arginine exist as resonance hybrids with positive charge distributed between both nitrogens (histidine) or all three nitrogens (arginine) (Figure 3–2). The net charge on an amino acid—the algebraic sum of all the positively and negatively charged groups present—depends upon the pK_a values of its functional groups and on the pH of the surrounding medium. Altering the charge on amino acids and their derivatives by varying the pH facilitates the physical separation of amino acids, peptides, and proteins

Genetic Code Specifies 20 L--Amino Acids

Of the over 300 naturally occurring amino acids, 20 constitute the monomer units of proteins. While a nonredundant three-letter genetic code could accommodate more than 20 amino acids, its redundancy limits the available codons to the 20 L--amino acids listed in Table 3–1, classified according to the polarity of their R groups. Both one- and three-letter abbreviations for each amino acid can be used to represent the amino acids in peptides (Table 3–1). Some proteins contain additional amino acids that arise by modification of an amino acid already present in a peptide. Examples include conversion of peptidyl proline and lysine to 4-hydroxyproline and 5-hydroxylysine; the conversion of peptidyl glutamate to -carboxyglutamate; and the methylation, formylation, acetylation, prenylation, and phosphorylation of certain aminoacyl residues. These modifications extend the biologic diversity of proteins by altering their solubility, stability, and interaction with other proteins.

Relationship of the Electrocardiogram to the Cardiac Cycle

They are electrical voltages generated by the heart and recorded by the electrocardiograph from the surface of the body.

The P wave is caused by spread of depolarization through the atria, and this is followed by atrial contraction, which causes a slight rise in the atrial pressure curve immediately after the electrocardiographic P wave.

About 0.16 second after the onset of the P wave, the QRS waves appear as a result of electrical depolarization of the ventricles, which initiates contraction of the ventricles and causes the ventricular pressure to begin rising, as also shown in the figure. Therefore, the QRS complex begins slightly before the onset of ventricular systole.

Finally, one observes the ventricular T wave in the electrocardiogram. This represents the stage of repolarization of the ventricles when the ventricular muscle fibers begin to relax. Therefore, the T wave occurs slightly before the end of ventricular contraction.

The Cardiac Cycle

The cardiac events that occur from the beginning of one heartbeat to the beginning of the next are called the cardiac cycle. Each cycle is initiated by spontaneous generation of an action potential in the sinus node,. This node is located in the superior lateral wall of the right atrium near the opening of the superior vena cava, and the action potential travels from here rapidly through both atria and then through the A-V bundle into the ventricles. Because of this special arrangement of the conducting system from the atria into the ventricles, there is a delay of more than 0.1 second during passage of the cardiac impulse from the atria into the ventricles. This allows the atria to contract ahead of ventricular contraction, thereby pumping blood into the ventricles before the strong ventricular contraction begins. Thus, the atria act as primer pumps for the ventricles, and the ventricles in turn provide the major source of power for moving blood through the body's vascular system.

Duration of Contraction.

Cardiac muscle begins to contract a few milliseconds after the action potential begins and continues to contract until a few milliseconds after the action potential ends. Therefore, the duration of contraction of cardiac muscle is mainly a function of the duration of the action potential, including the plateau-about 0.2 second in atrial muscle and 0.3 second in ventricular muscle.

Excitation-Contraction Coupling-Function of Calcium Ions and the Transverse Tubules

As is true for skeletal muscle, when an action potential passes over the cardiac muscle membrane, the action potential spreads to the interior of the cardiac muscle fiber along the membranes of the transverse (T) tubules. The T tubule action potentials in turn act on the membranes of the longitudinal sarcoplasmic tubules to cause release of calcium ions into the muscle sarcoplasm from the sarcoplasmic reticulum. In another few thousandths of a second, these calcium ions diffuse into the myofibrils and catalyze the chemical reactions that promote sliding of the actin and myosin filaments along one another; this produces the muscle contraction.

Thus far, this mechanism of excitation-contraction coupling is the same as that for skeletal muscle, but there is a second effect that is quite different. In addition to the calcium ions that are released into the sarcoplasm from the cisternae of the sarcoplasmic reticulum, a large quantity of extra calcium ions also diffuses into the sarcoplasm from the T tubules themselves at the time of the action potential. Indeed, without this extra calcium from the T tubules, the strength of cardiac muscle contraction would be reduced considerably because the sarcoplasmic reticulum of cardiac muscle is less well developed than that of skeletal muscle and does not store enough calcium to provide full contraction. Conversely, the T tubules of cardiac muscle have a diameter 5 times as great as that of the skeletal muscle tubules, which means a volume 25 times as great. Also, inside the T tubules is a large quantity of mucopolysaccharides that are electronegatively charged and bind an abundant store of calcium ions, keeping these always available for diffusion to the interior of the cardiac muscle fiber when a T tubule action potential appears.

The strength of contraction of cardiac muscle depends to a great extent on the concentration of calcium ions in the extracellular fluids. The reason for this is that the openings of the T tubules pass directly through the cardiac muscle cell membrane into the extracellular spaces surrounding the cells, allowing the same extracellular fluid that is in the cardiac muscle interstitium to percolate through the T tubules as well. Consequently, the quantity of calcium ions in the T tubule system-that is, the availability of calcium ions to cause cardiac muscle contraction-depends to a great extent on the extracellular fluid calcium ion concentration.

(By way of contrast, the strength of skeletal muscle contraction is hardly affected by moderate changes in extracellular fluid calcium concentration because skeletal muscle contraction is caused almost entirely by calcium ions released from the sarcoplasmic reticulum inside the skeletal muscle fiber itself.)

At the end of the plateau of the cardiac action potential, the influx of calcium ions to the interior of the muscle fiber is suddenly cut off, and the calcium ions in the sarcoplasm are rapidly pumped back out of the muscle fibers into both the sarcoplasmic reticulum and the T tubule-extracellular fluid space. As a result, the contraction ceases until a new action potential comes along.

What Causes the Long Action Potential and the Plateau?

At least two major differences between the membrane properties of cardiac and skeletal muscle account for the prolonged action potential and the plateau in cardiac muscle. First, the action potential of skeletal muscle is caused almost entirely by sudden opening of large numbers of so-called fast sodium channels that allow tremendous numbers of sodium ions to enter the skeletal muscle fiber from the extracellular fluid. These channels are called "fast" channels because they remain open for only a few thousandths of a second and then abruptly close. At the end of this closure, repolarization occurs, and the action potential is over within another thousandth of a second or so.

In cardiac muscle, the action potential is caused by opening of two types of channels: (1) the same fast sodium channels as those in skeletal muscle and (2) another entirely different population of slow calcium channels, which are also called calcium-sodium channels. This second population of channels differs from the fast sodium channels in that they are slower to open and, even more important, remain open for several tenths of a second. During this time, a large quantity of both calcium and sodium ions flows through these channels to the interior of the cardiac muscle fiber, and this maintains a prolonged period of depolarization, causing the plateau in the action potential. Further, the calcium ions that enter during this plateau phase activate the muscle contractile process, while the calcium ions that cause skeletal muscle contraction are derived from the intracellular sarcoplasmic reticulum.

The second major functional difference between cardiac muscle and skeletal muscle that helps account for both the prolonged action potential and its plateau is this: Immediately after the onset of the action potential, the permeability of the cardiac muscle membrane for potassium ions decreases about fivefold, an effect that does not occur in skeletal muscle. This decreased potassium permeability may result from the excess calcium influx through the calcium channels just noted. Regardless of the cause, the decreased potassium permeability greatly decreases the outflux of positively charged potassium ions during the action potential plateau and thereby prevents early return of the action potential voltage to its resting level. When the slow calcium-sodium channels do close at the end of 0.2 to 0.3 second and the influx of calcium and sodium ions ceases, the membrane permeability for potassium ions also increases rapidly; this rapid loss of potassium from the fiber immediately returns the membrane potential to its resting level, thus ending the action potential.

Physiology of Cardiac Muscle

The heart is composed of three major types of cardiac muscle: atrial muscle, ventricular muscle, and specialized excitatory and conductive muscle fibers. The atrial and ventricular types of muscle contract in much the same way as skeletal muscle, except that the duration of contraction is much longer. Conversely, the specialized excitatory and conductive fibers contract only feebly because they contain few contractile fibrils; instead, they exhibit either automatic rhythmical electrical discharge in the form of action potentials or conduction of the action potentials through the heart, providing an excitatory system that controls the rhythmical beating of the heart.

Automaticity of the Body

The purpose of this chapter has been to point out, first, the overall organization of the body and, second, the means by which the different parts of the body operate in harmony. To summarize, the body is actually a social order of about 100 trillion cells organized into different functional structures, some of which are called organs. Each functional structure contributes its share to the maintenance of homeostatic conditions in the extracellular fluid, which is called the internal environment. As long as normal conditions are maintained in this internal environment, the cells of the body continue to live and function properly. Each cell benefits from homeostasis, and in turn, each cell contributes its share toward the maintenance of homeostasis. This reciprocal interplay provides continuous automaticity of the body until one or more functional systems lose their ability to contribute their share of function. When this happens, all the cells of the body suffer. Extreme dysfunction leads to death; moderate dysfunction leads to sickness.

More Complex Types of Control Systems-Adaptive Control

Later in this text, when we study the nervous system, we shall see that this system contains great numbers of interconnected control mechanisms. Some are simple feedback systems similar to those already discussed. Many are not. For instance, some movements of the body occur so rapidly that there is not enough time for nerve signals to travel from the peripheral parts of the body all the way to the brain and then back to the periphery again to control the movement. Therefore, the brain uses a principle called feed-forward control to cause required muscle contractions. That is, sensory nerve signals from the moving parts apprise the brain whether the movement is performed correctly. If not, the brain corrects the feed-forward signals that it sends to the muscles the next time the movement is required. Then, if still further correction is needed, this will be done again for subsequent movements. This is called adaptive control. Adaptive control, in a sense, is delayed negative feedback.

Thus, one can see how complex the feedback control systems of the body can be. A person's life depends on all of them. Therefore, a major share of this text is devoted to discussing these life-giving mechanisms.

Positive Feedback Can Sometimes Be Useful

. In some instances, the body uses positive feedback to its advantage. Blood clotting is an example of a valuable use of positive feedback. When a blood vessel is ruptured and a clot begins to form, multiple enzymes called clotting factors are activated within the clot itself. Some of these enzymes act on other unactivated enzymes of the immediately adjacent blood, thus causing more blood clotting. This process continues until the hole in the vessel is plugged and bleeding no longer occurs. On occasion, this mechanism can get out of hand and cause the formation of unwanted clots. In fact, this is what initiates most acute heart attacks, which are caused by a clot beginning on the inside surface of an atherosclerotic plaque in a coronary artery and then growing until the artery is blocked.

page 8

page 9

Childbirth is another instance in which positive feedback plays a valuable role. When uterine contractions become strong enough for the baby's head to begin pushing through the cervix, stretch of the cervix sends signals through the uterine muscle back to the body of the uterus, causing even more powerful contractions. Thus, the uterine contractions stretch the cervix, and the cervical stretch causes stronger contractions. When this process becomes powerful enough, the baby is born. If it is not powerful enough, the contractions usually die out, and a few days pass before they begin again.

Another important use of positive feedback is for the generation of nerve signals. That is, when the membrane of a nerve fiber is stimulated, this causes slight leakage of sodium ions through sodium channels in the nerve membrane to the fiber's interior. The sodium ions entering the fiber then change the membrane potential, which in turn causes more opening of channels, more change of potential, still more opening of channels, and so forth. Thus, a slight leak becomes an explosion of sodium entering the interior of the nerve fiber, which creates the nerve action potential. This action potential in turn causes electrical current to flow along both the outside and the inside of the fiber and initiates additional action potentials. This process continues again and again until the nerve signal goes all the way to the end of the fiber.

In each case in which positive feedback is useful, the positive feedback itself is part of an overall negative feedback process. For example, in the case of blood clotting, the positive feedback clotting process is a negative feedback process for maintenance of normal blood volume. Also, the positive feedback that causes nerve signals allows the nerves to participate in thousands of negative feedback nervous control systems.

"Gain" of a Control System.

The degree of effectiveness with which a control system maintains constant conditions 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 control system is not functioning, and the arterial pressure rises from the normal level of 100 mm Hg up to 175 mm Hg. Then, let us assume that the same volume of blood is injected into the same person when the baroreceptor system is functioning, and this time the pressure increases only 25 mm Hg. Thus, the feedback control system has caused a "correction" of -50 mm Hg-that is, from 175 mm Hg to 125 mm Hg. There remains an increase in pressure of +25 mm Hg, called the "error," which means that the control system is not 100 per cent effective in preventing change. The gain of the system is then calculated by the following formula: Thus, in the baroreceptor system example, the correction is -50 mm Hg and the error persisting is +25 mm Hg. Therefore, the gain of the person's baroreceptor system for control of arterial pressure is -50 divided by +25, or -2. That is, a disturbance that increases or decreases the arterial pressure does so only one third as much as would occur if this control system were not present.

The gains of some other physiologic control systems are much greater than that of the baroreceptor system. For instance, the gain of the system controlling internal body temperature when a person is exposed to moderately cold weather is about -33. Therefore, one can see that the temperature control system is much more effective than the baroreceptor pressure control system.

Negative Feedback Nature of Most Control Systems

Most control systems of the body act by negative feedback, which can best be explained by reviewing some of the homeostatic control systems mentioned previously. In the regulation of carbon dioxide concentration, a high concentration of carbon dioxide in the extracellular fluid increases pulmonary ventilation. This, in turn, decreases the extracellular fluid carbon dioxide concentration because the lungs expire greater amounts of carbon dioxide from the body. In other words, the high concentration of carbon dioxide initiates events that decrease the concentration toward normal, which is negative to the initiating stimulus. Conversely, if the carbon dioxide concentration falls too low, this causes feedback to increase the concentration. This response also is negative to the initiating stimulus.

Normal Ranges and Physical Characteristics of Important Extracellular Fluid Constituents

Most important are the limits beyond which abnormalities can cause death. For example, an increase in the body temperature of only 11°F (7°C) above normal can lead to a vicious cycle of increasing cellular metabolism that destroys the cells. Note also the narrow range for acid-base balance in the body, with a normal pH value of 7.4 and lethal values only about 0.5 on either side of normal. Another important factor is the potassium ion concentration, because whenever it decreases to less than one third normal, a person is likely to be paralyzed as a result of the nerves' inability to carry signals. Alternatively, if the potassium ion concentration increases to two or more times normal, the heart muscle is likely to be severely depressed. Also, when the calcium ion concentration falls below about one half of normal, a person is likely to experience tetanic contraction of muscles throughout the body because of the spontaneous generation of excess nerve impulses in the peripheral nerves. When the glucose concentration falls below one half of normal, a person frequently develops extreme mental irritability and sometimes even convulsions.

Regulation of Arterial Blood Pressure.

Several systems contribute to the regulation of arterial blood pressure. One of these, the baroreceptor system, is a simple and excellent example of a rapidly acting control mechanism. In the walls of the bifurcation region of the carotid arteries in the neck, and also in the arch of the aorta in the thorax, are many nerve receptors called baroreceptors, which are stimulated by stretch of the arterial wall. When the arterial pressure rises too high, the baroreceptors send barrages of nerve impulses to the medulla of the brain. Here these impulses inhibit the vasomotor center, which in turn decreases the number of impulses transmitted from the vasomotor center through the sympathetic nervous system to the heart and blood vessels. Lack of these impulses causes diminished pumping activity by the heart and also dilation of the peripheral blood vessels, allowing increased blood flow through the vessels. Both of these effects decrease the arterial pressure back toward normal.

Regulation of Oxygen and Carbon Dioxide Concentrations in the Extracellular Fluid.

Because oxygen is one of the major substances required for chemical reactions in the cells, it is fortunate that the body has a special control mechanism to maintain an almost exact and constant oxygen concentration in the extracellular fluid. This mechanism depends principally on the chemical characteristics of hemoglobin, which is present in all red blood cells. Hemoglobin combines with oxygen as the blood passes through the lungs. Then, as the blood passes through the tissue capillaries, hemoglobin, because of its own strong chemical affinity for oxygen, does not release oxygen into the tissue fluid if too much oxygen is already there. But 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 concentration in the tissues is vested principally in the chemical characteristics of hemoglobin itself. This regulation is called the oxygen-buffering function of hemoglobin.

Reproduction

Sometimes reproduction is not considered a homeostatic function. It does, however, help maintain homeostasis by generating new beings to take the place of those that are dying. This may sound like a permissive usage of the term homeostasis, but it illustrates that, in the final analysis, essentially all body structures are organized such that they help maintain the automaticity and continuity of life.

Hormonal System of Regulation.

Located in the body are eight major endocrine glands that secrete chemical substances called hormones. Hormones are transported in the extracellular fluid to all parts of the body to help regulate cellular function. For instance, thyroid hormone increases the rates of most chemical reactions in all cells, thus helping to set the tempo of bodily activity. Insulin controls glucose metabolism; adrenocortical hormones control sodium ion, potassium ion, and protein metabolism; and parathyroid hormone controls bone calcium and phosphate. Thus, the hormones are a system of regulation that complements the nervous system. The nervous system regulates mainly muscular and secretory activities of the body, whereas the hormonal system regulates many metabolic functions

Nervous System.

The nervous system is composed of three major parts: the sensory input portion, the central nervous system (or integrative portion), and the motor output portion. Sensory receptors detect the state of the body or the state of the surroundings. For instance, receptors in the skin apprise one whenever an object touches the skin at any point. The eyes are sensory organs that give one a visual image of the surrounding area. The ears also are sensory organs. The central nervous system is composed of the brain and spinal cord. The brain can store information, generate thoughts, create ambition, and determine reactions that the body performs in response to the sensations. Appropriate signals are then transmitted through the motor output portion of the nervous system to carry out one's desires.

Kidneys.

Passage of the blood through the kidneys removes from the plasma most of the other substances besides carbon dioxide that are not needed by the cells. These substances include different end products of cellular metabolism, such as urea and uric acid; they also include excesses of ions and water from the food that might have accumulated in the extracellular fluid.

Removal of Carbon Dioxide by the Lungs.

At the same time that blood picks up oxygen in the lungs, carbon dioxide is released from the blood into the lung alveoli; the respiratory movement of air into and out of the lungs carries the carbon dioxide to the atmosphere. Carbon dioxide is the most abundant of all the end products of metabolism

Musculoskeletal System.

Sometimes the question is asked, How does the musculoskeletal system fit into the homeostatic functions of the body? The answer is obvious and simple: Were it not for the muscles, the body could not move to the appropriate place at the appropriate time to obtain the foods required for nutrition. The musculoskeletal system also provides motility for protection against adverse surroundings, without which the entire body, along with its homeostatic mechanisms, could be destroyed instantaneously.

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 compositions of many of these substances to more usable forms, and other tissues of the body-fat cells, gastrointestinal mucosa, kidneys, and endocrine glands-help modify the absorbed substances or store them until they are needed.

Extracellular Fluid Transport and Mixing System-The Blood Circulatory System

Extracellular fluid is transported through all parts of the body in two stages. The first stage is movement of blood through the body in the blood vessels, and the second is movement of fluid between the blood capillaries and the intercellular spaces between the tissue cells.

All the blood in the circulation traverses the entire circulatory circuit an average of once each minute when the body is at rest and as many as six times each minute when a person is extremely active.

Homeostasis

The term homeostasis is used by physiologists to mean maintenance of nearly constant conditions in the internal environment. Essentially all organs and tissues of the body perform functions that help maintain these constant conditions. For instance, the lungs provide oxygen to the extracellular fluid to replenish the oxygen used by the cells, the kidneys maintain constant ion concentrations, and the gastrointestinal system provides nutrients.

A large segment of this text is concerned with the manner in which each organ or tissue contributes to homeostasis. To begin this discussion, the different functional systems of the body and their contributions to homeostasis are outlined in this chapter; then we briefly outline the basic theory of the body's control systems that allow the functional systems to operate in support of one another.

Differences Between Extracellular and Intracellular Fluids

The extracellular fluid contains large amounts of sodium, chloride, and bicarbonate ions plus nutrients for the cells, such as oxygen, glucose, fatty acids, and amino acids. It also contains carbon dioxide that is being transported from the cells to the lungs to be excreted, plus other cellular waste products that are being transported to the kidneys for excretion.

The intracellular fluid differs significantly from the extracellular fluid; specifically, it contains large amounts of potassium, magnesium, and phosphate ions instead of the sodium and chloride ions found in the extracellular fluid. Special mechanisms for transporting ions through the cell membranes maintain the ion concentration differences between the extracellular and intracellular fluids.

Extracellular Fluid-The "Internal Environment"

About 60 per cent of the adult human body is fluid, mainly a water solution of ions and other substances. Although most of this fluid is inside the cells and is called intracellular fluid, about one third is in the spaces outside the cells and is called extracellular fluid. This extracellular fluid is in constant motion throughout the body. It is transported rapidly in the circulating blood and then mixed between the blood and the tissue fluids by diffusion through the capillary walls.

In the extracellular fluid are the ions and nutrients needed by the cells to maintain cell life. Thus, all cells live in essentially the same environment-the extracellular fluid. For this reason, the extracellular fluid is also called the internal environment of the body, or the milieu intérieur, a term introduced more than 100 years ago by the great 19th-century French physiologist Claude Bernard.

Cells as the Living Units of the Body

The basic living unit of the body is the cell. Each organ is an aggregate of many different cells held together by intercellular supporting structures.

Each type of cell is specially adapted to perform one or a few particular functions. For instance, the red blood cells, numbering 25 trillion in each human being, transport oxygen from the lungs to the tissues. Although the red cells are the most abundant of any single type of cell in the body, there are about 75 trillion additional cells of other types that perform functions different from those of the red cell. The entire body, then, contains about 100 trillion cells.

Although the many cells of the body often differ markedly from one another, all of them have certain basic characteristics that are alike. For instance, in all cells, oxygen reacts with carbohydrate, fat, and protein to release the energy required for cell function. Further, the general chemical mechanisms for changing nutrients into energy are basically the same in all cells, and all cells deliver end products of their chemical reactions into the surrounding fluids.

phisioology

The goal of physiology is to explain the physical and chemical factors that are responsible for the origin, development, and progression of life. Each type of life, from the simple virus to the largest tree or the complicated human being, has its own functional characteristics. Therefore, the vast field of physiology can be divided into viral physiology, bacterial physiology, cellular physiology, plant physiology, human physiology, and many more subdivisions.