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37 C Acid–Base Regulation and Causes of Hypoxia Michael Levitzky H A P T E R O B J E C T I V E S ■ ■ ■ ■ ■ ■ ■ Define acids, bases, and buffers List the buffer systems available in the human body State the normal ranges of arterial pH, PCO2, and bicarbonate concentration, and define alkalosis and acidosis List the potential causes of respiratory acidosis and alkalosis and metabolic acidosis and alkalosis Discuss the respiratory mechanisms that help compensate for acidosis and alkalosis Evaluate blood gas data to determine acid–base status Classify and explain the causes of tissue hypoxia The respiratory and renal systems maintain the balance of acids and bases in the body This chapter will introduce the major concepts of the respiratory system’s contribution to acid–base balance; Chapter 47 addresses the renal system contribution to acid–base balance and includes a more detailed discussion of the basic chemistry of acid–base physiology, buffers, and the chemistry of the CO2–bicarbonate system INTRODUCTION TO ACID–BASE CHEMISTRY An acid can be simply defined as a substance that can donate a hydrogen ion (a proton) to another substance and a base as a substance that can accept a hydrogen ion from another substance A strong acid is a substance that is completely or almost completely dissociated into a hydrogen ion and its corresponding or conjugate base in dilute aqueous solution; a weak acid is only slightly ionized in aqueous solution In general, a strong acid has a weak conjugate base and a weak acid has a strong conjugate base The strength of an acid or a base should not be confused with its concentration A buffer is a mixture of substances in aqueous solution (usually a combination of a weak acid and its conjugate base) that can resist changes in hydrogen ion concentration when Ch37_375-384.indd 375 strong acids or bases are added; that is, the changes in hydrogen ion concentration that occur when a strong acid or base is added to a buffer system are much smaller than those that would occur if the same amount of acid or base were added to pure water or another nonbuffer solution The hydrogen ion activity of pure water is about 1.0 × 10–7 mol/L By convention, solutions with hydrogen ion activities above 10–7 mol/L are considered to be acid; those with hydrogen ion activities below 10–7 are considered to be alkaline The range of hydrogen ion concentrations or activities in the body is normally from about 10–1 for gastric acid to about 10–8 for the most alkaline pancreatic secretion This wide range of hydrogen ion activities necessitates the use of the more convenient pH scale The pH of a solution is the negative logarithm of its hydrogen ion activity With the exception of the highly concentrated gastric acid, in most instances in the body, the hydrogen ion activity is about equal to the hydrogen ion concentration The pH of arterial blood is normally close to 7.40, with a normal range considered to be about 7.35–7.45 An arterial pH (pHa) less than 7.35 is considered acidemia; a pHa greater than 7.45 is considered alkalemia The underlying condition characterized by hydrogen ion retention or by loss of bicarbonate or other bases is referred to as acidosis; the underlying condition characterized by hydrogen ion loss or retention of 375 11/29/10 4:40:09 PM 376 SECTION VI Pulmonary Physiology TABLE 37–1 The pH scale pH Concentration (nmol/L) 6.90 126 7.00 100 7.10 79 7.20 63 7.30 50 7.40 40 7.50 32 7.60 25 7.70 20 7.80 16 Reproduced with permission from Levitzky MG: Pulmonary Physiology, 7th ed New York: McGraw-Hill Medical, 2007 base is referred to as alkalosis Under pathologic conditions, the extremes of arterial blood pH have been noted to range as high as 7.8 and as low as 6.9 These correspond to hydrogen ion concentrations as seen in Table 37–1 (hydrogen ion concentrations are expressed as nanomoles [10–9 mol/L] for convenience) Note that the pH scale is “inverted” by the negative sign and is also logarithmic as it is defined An increase in pH represents a decrease in hydrogen ion concentration In fact, an increase of only 0.3 pH units indicates that the hydrogen ion concentration was cut in half Hydrogen ions are the most reactive cations in body fluids, and they interact with negatively charged regions of other molecules, such as those of body proteins Interactions of hydrogen ions with negatively charged functional groups of proteins can lead to marked changes in protein structural conformations with resulting alterations in the behavior of the proteins An example of this was already seen in Chapter 36, where hemoglobin was noted to combine with less oxygen at a lower pH (the Bohr effect) Alterations in the structural conformations and charges of protein enzymes affect their activities, with resulting alterations in the functions of body tissues Extreme changes in the hydrogen ion concentration of the body can result in loss of organ system function and may be fatal Under normal circumstances, cellular metabolism is the main source of acids in the body These acids are the waste products of substances ingested as foodstuffs The greatest source of hydrogen ions is the carbon dioxide produced as one of the end products of the oxidation of glucose and fatty acids during aerobic metabolism The hydration of carbon dioxide results in the formation of carbonic acid, which then can dissociate into a hydrogen ion and a bicarbonate ion, as discussed in Chapter 36 This process is reversed in the pulmonary capillaries, and CO2 then diffuses through the alveolar–capillary barrier into the alveoli, from which it is removed by alveolar ventilation Carbonic acid is therefore said to be a volatile acid because it can be converted into a gas and then removed from an open system such as the body Very great amounts of carbon dioxide can be removed from the lungs by alveolar ventilation: under normal circumstances, about 15,000–25,000 mmol of carbon dioxide is removed via the lungs daily A much smaller quantity of fixed or nonvolatile acids is also normally produced during the course of the metabolism of foodstuffs The fixed acids produced by the body include sulfuric acid, which originates from the oxidation of sulfurcontaining amino acids such as cysteine; phosphoric acid from the oxidation of phospholipids and phosphoproteins; hydrochloric acid, which is produced during the conversion of ingested ammonium chloride to urea and by other reactions; and lactic acid from the anaerobic metabolism of glucose Other fixed acids may be ingested accidentally or formed in abnormally large quantities by disease processes, such as the acetoacetic and butyric acid formed during diabetic ketoacidosis (see Chapter 66) About 70 mEq of fixed acids is normally removed from the body each day (about mEq/kg/body weight per day); the range is 50–100 mEq A vegetarian diet may produce significantly less fixed acid and may even result in no net production of fixed acids The removal of fixed acids is accomplished mainly by the kidneys, as will be discussed in Chapter 47 Some may also be removed via the gastrointestinal tract Fixed acids normally represent only about 0.2% of the total body acid production The body contains a variety of substances that can act as buffers in the physiologic pH range These include bicarbonate, phosphate, and proteins in the blood, the interstitial fluid, and inside cells (discussed in greater detail in Chapter 47) The isohydric principle states that all the buffer pairs in a homogeneous solution are in equilibrium with the same hydrogen ion concentration For this reason, all the buffer pairs in the plasma behave similarly, so that the detailed analysis of a single buffer pair, like the bicarbonate buffer system, can reveal a great deal about the chemistry of all the plasma buffers The main buffers of the blood are bicarbonate, phosphate, and proteins The bicarbonate buffer system consists of the buffer pair of the weak acid, carbonic acid, and its conjugate base, bicarbonate The ability of the bicarbonate system to function as a buffer of fixed acids in the body is largely due to the ability of the lungs to remove carbon dioxide from the body In a closed system, bicarbonate would not be nearly as effective At a temperature of 37°C, about 0.03 mmol of carbon dioxide per mm Hg of Pco2 will dissolve in a liter of plasma (Note that the solubility of CO2 was expressed as milliliters of CO2 per 100 mL of plasma in Chapter 36.) Therefore, the carbon dioxide dissolved in the plasma, expressed as millimoles per liter, is equal to 0.03 x Pco2 At body temperature in the plasma, the equilibrium of the reaction is such that there is roughly 1,000 times more carbon dioxide physically dissolved in the plasma than there is in the form of carbonic acid The dissolved carbon dioxide is in equilibrium with the carbonic acid, though, so both the dissolved carbon dioxide and the carbonic CHAPTER 37 Acid–Base Regulation and Causes of Hypoxia acid are considered as the undissociated HA in the Henderson–Hasselbalch equation (see Chapter 47) for the bicarbonate system: [HCO3–]p pH = pK + log _ [CO + H CO ] 2 (1) where [HCO3−]p stands for plasma bicarbonate concentration The concentration of carbonic acid is negligible, so we have: [HCO3–]p pH = pK′ + log _ 0.03 P (2) co2 where pK′ is the pK of the HCO3−–CO2 system in blood The pK′ of this system at physiologic pH values and at 37°C is 6.1 Therefore, at a pHa of 7.40 and an arterial Pco2 of 40 mm Hg, we have: [HCO3–]p 7.40 = 6.1 + log _ (3) 1.2 mmol/L Therefore, the arterial plasma bicarbonate concentration is about 24 mmol/L (the normal range is 23–28 mmol/L) because the logarithm of 20 is equal to 1.3 Note that the term total CO2 refers to the dissolved carbon dioxide (including carbonic acid) plus the carbon dioxide present as bicarbonate A useful way to display the interrelationships among the variables of pH, Pco2, and bicarbonate concentration of the plasma, as expressed by the Henderson–Hasselbalch equation, is the pH–bicarbonate diagram shown in Figure 37–1 As can be seen from Figure 37–1, pH is on the abscissa of the pH–bicarbonate diagram, and the plasma bicarbonate concentration in millimoles per liter is on the ordinate For 100 40 80 70 [H ϩ] (nmol/L) 50 40 60 30 20 16 ba r A iso ba B Hg m m ϭ 40 m m 60 ϭ CO ϭ CO r ba C P CO P 25 r iso Hg mm 80 30 P [HCO3Ϫ]p (mmol/L) Hg ba r iso 35 20 D ϭ P CO E 15 10 7.0 m 7.1 7.2 7.3 7.4 pH Hg iso 0m 2 7.5 Normal buffer line 7.6 7.7 FIGURE 37–1 Acid–Base Chemistry, 6th ed 1974.) each value of pH and bicarbonate ion concentration, there is a single corresponding Pco2 on the graph Conversely, for any particular pH and Pco2, only one bicarbonate ion concentration will satisfy the Henderson–Hasselbalch equation If the Pco2 is held constant, for example, at 40 mm Hg, an isobar line can be constructed, connecting the resulting points as the pH is varied The representative isobars shown in Figure 37–1 give an indication of the potential alterations of acid–base status when alveolar ventilation is increased or decreased If everything else remains constant, hypoventilation leads to acidosis; hyperventilation leads to alkalosis The bicarbonate buffer system is a poor buffer for carbonic acid The presence of hemoglobin makes blood a much better buffer The buffer value of plasma in the presence of hemoglobin is four to five times that of plasma separated from erythrocytes Therefore, the slope of the normal in vivo buffer line shown in Figures 37–1 is mainly determined by the nonbicarbonate buffers present in the body The phosphate buffer system mainly consists of the buffer pair of the dihydrogen phosphate (H2PO4−) and the monohydrogen phosphate (HPO42−) anions Although several potential buffering groups are found on proteins, only one large group has pK in the pH range encountered in the blood These are the imidazole groups in the histidine residues of the peptide chains The protein present in the greatest quantity in the blood is hemoglobin As already noted, deoxyhemoglobin is a weaker acid than is oxyhemoglobin Thus, as oxygen leaves hemoglobin in the tissue capillaries, the imidazole group removes hydrogen ions from the erythrocyte interior, allowing more carbon dioxide to be transported as bicarbonate This process is reversed in the lungs The bicarbonate buffer system is the major buffer found in the interstitial fluid, including the lymph The phosphate buffer pair is also found in the interstitial fluid The volume of the interstitial compartment is much larger than that of the plasma, so the interstitial fluid may play an important role in buffering The extracellular portion of bone contains very large deposits of calcium and phosphate salts, mainly in the form of hydroxyapatite In an otherwise healthy adult, where bone growth and resorption are in a steady state, bone salts can buffer hydrogen ions in chronic acidosis Chronic buffering of hydrogen ions by the bone salts may therefore lead to demineralization of bone The intracellular proteins and organic phosphates of most cells can function to buffer both fixed acids and carbonic acid Of course, buffering by the hemoglobin in erythrocytes is intracellular 7.8 The pH–bicarbonate diagram with PCO isobars Note the hydrogen ion concentration in nanomoles per liter at the top of the figure corresponding to the pH values on the abscissa Points A to E correspond to different pH values and bicarbonate concentrations all falling on the same PCO isobar (Modified with permission of the University of Chicago Press from Davenport HW: The ABC of 377 ACIDOSIS AND ALKALOSIS Acid–base disorders can be divided into four major categories: respiratory acidosis, respiratory alkalosis, metabolic acidosis, and metabolic alkalosis These primary acid–base disorders may occur singly (“simple”) or in combination (“mixed”) or may be altered by compensatory mechanisms 378 SECTION VI Pulmonary Physiology RESPIRATORY ACIDOSIS TABLE 37–2 Common causes of respiratory acidosis The arterial Pco2 is normally maintained at or near 40 mm Hg (normal range is 35–45 mm Hg) by the mechanisms that regulate breathing Sensors exposed to the arterial blood and to the cerebrospinal fluid provide the central controllers of breathing with the information necessary to regulate the arterial Pco2 at or near 40 mm Hg (see Chapter 38) Any short-term alterations (i.e., those which occur without renal compensation) in alveolar ventilation that result in an increase in alveolar and therefore also in arterial Pco2 tend to lower the pHa, resulting in respiratory acidosis This can be appreciated by examining the Pco2 = 60 and 80 mm Hg isobars in Figure 37–1 The pHa at any Paco2 depends on the bicarbonate and other buffers present in the blood Pure changes in arterial Pco2 caused by changes in ventilation travel along the normal in vivo buffer line (Figures 37–1 and 37–2) Pure uncompensated respiratory acidosis would correspond with point C in Figure 37–2 (at the intersection of an elevated Pco2 isobar and the normal buffer line) In respiratory acidosis, the ratio of bicarbonate to CO2 decreases Yet, as can be seen at point C in Figure 37–2, in uncompensated primary (simple) respiratory acidosis, the absolute plasma bicarbonate concentration does increase somewhat because of the buffering of some of the hydrogen ions liberated by the dissociation of carbonic acid by nonbicarbonate buffers Any impairment of alveolar ventilation can cause respiratory acidosis As shown in Table 37–2, depression of the respiratory centers in the medulla (see Chapter 38) by anesthetic agents, narcotics, hypoxia, central nervous system disease or trauma, or even greatly increased PaCo2 itself results in hypoventilation and respiratory acidosis Interference with the neural transmission to the respiratory muscles by disease Metabolic alkalosis and respiratory acidosis F 35 [HCO3Ϫ]p (mmol/L) D 25 20 15 Uncompensated metabolic alkalosis Metabolic alkalosis Uncompensated E respiratory acidosis Metabolic alkalosis C and respiratory alkalosis Metabolic acidosis A and respiratory acidosis Normal buffer line I Metabolic G acidosis B Uncompensated Uncompensated metabolic acidosis respiratory alkalosis Metabolic acidosis H and respiratory alkalosis 10 7.0 7.1 FIGURE 37–2 7.2 7.3 7.4 pH 7.5 7.6 7.7 7.8 Acid–base paths in vivo (Modified with permission of the University of Chicago Press from Davenport HW: The ABC of Acid–Base Chemistry, 6th ed 1974.) Neuromuscular disorders Spinal cord injury Phrenic nerve injury Poliomyelitis, Guillain–Barré syndrome, etc Botulism, tetanus Myasthenia gravis Administration of curarelike drugs Diseases affecting the respiratory muscles Chest wall restriction Kyphoscoliosis Extreme obesity Lung restriction Pulmonary fibrosis Sarcoidosis Pneumothorax, pleural effusions, etc Pulmonary parenchymal diseases Pneumonia, etc Pulmonary edema Airway obstruction Chronic obstructive pulmonary disease Upper airway obstruction Reproduced with permission from Levitzky MG: Pulmonary Physiology, 7th ed New York: McGraw-Hill Medical, 2007 processes, drugs or toxins, or dysfunctions or deformities of the respiratory muscles or the chest wall can result in respiratory acidosis Restrictive, obstructive, and obliterative diseases of the lungs can also result in respiratory acidosis RESPIRATORY ALKALOSIS 40 30 Depression of the respiratory control centers Anesthetics Sedatives Opiates Brain injury or disease Severe hypercapnia, hypoxia Alveolar ventilation in excess of that needed to keep pace with body’s carbon dioxide production results in alveolar and arterial Pco2 below 35 mm Hg Such hyperventilation leads to respiratory alkalosis Uncompensated primary respiratory alkalosis results in movement to a lower Pco2 isobar along the normal buffer line, as seen at point B in Figure 37–2 The decreased Paco2 shifts the equilibrium of the series of reactions describing carbon dioxide hydration and carbonic acid dissociation to the left This results in a decreased arterial hydrogen ion concentration, increased pH, and a decreased plasma bicarbonate concentration The ratio of bicarbonate to carbon dioxide increases The causes of respiratory alkalosis include anything leading to hyperventilation As shown in Table 37–3, hyperventilation syndrome, a psychological dysfunction of unknown cause, results in chronic or recurrent episodes of hyperventilation and respiratory alkalosis Drugs, hormones (such as progesterone), toxic substances, central nervous system diseases or disorders, CHAPTER 37 Acid–Base Regulation and Causes of Hypoxia TABLE 37–3 Common causes of respiratory alkalosis 379 TABLE 37–4 Common causes of metabolic acidosis Central nervous system Anxiety Hyperventilation syndrome Inflammation (encephalitis, meningitis) Cerebrovascular disease Tumors Ingested drugs or toxic substances Methanol Ethanol Salicylates Ethylene glycol Ammonium chloride Drugs or hormones Salicylates Progesterone Loss of bicarbonate ions Diarrhea Pancreatic fistulas Renal dysfunction Bacteremias, fever Pulmonary diseases Acute asthma Pulmonary vascular diseases (pulmonary embolism) Overventilation with mechanical ventilators Hypoxia; high altitude Reproduced with permission from Levitzky MG: Pulmonary Physiology, 7th ed New York: McGraw-Hill Medical, 2007 bacteremias, fever, overventilation by mechanical ventilators (or the clinician), or ascent to high altitude may all result in respiratory alkalosis Lactic acidosis Hypoxemia Anemia, carbon monoxide Shock (hypovolemic, cardiogenic, septic, etc.) Severe exercise Acute respiratory distress syndrome (ARDS) Ketoacidosis Diabetes mellitus Alcoholism Starvation Inability to excrete hydrogen ions Renal dysfunction Reproduced with permission from Levitzky MG: Pulmonary Physiology, 7th ed New York: McGraw-Hill Medical, 2007 METABOLIC ACIDOSIS Metabolic acidosis may be thought of as nonrespiratory acidosis It can be caused by the ingestion, infusion, or production of a fixed acid; decreased renal excretion of hydrogen ions; the movement of hydrogen ions from the intracellular to the extracellular compartment; or the loss of bicarbonate or other bases from the extracellular compartment As can be seen in Figure 37–2, primary uncompensated metabolic acidosis results in a downward movement along the Pco2 = 40 mm Hg isobar to point G, that is, a net loss of buffer establishes a new blood–buffer line lower than and parallel to the normal blood–buffer line Pco2 is unchanged, hydrogen ion concentration is increased, and the ratio of bicarbonate concentration to CO2 is decreased As shown in Table 37–4, ingestion of methyl alcohol or salicylates can cause metabolic acidosis by increasing the fixed acids in the blood (Salicylate poisoning—for example, aspirin overdose—causes both metabolic acidosis and later respiratory alkalosis.) Diarrhea can cause significant bicarbonate losses, resulting in metabolic acidosis Renal dysfunction can lead to an inability to excrete hydrogen ions, as well as an inability to reabsorb bicarbonate ions, as will be discussed in the next section True “metabolic” acidosis may be caused by an accumulation of lactic acid in severe hypoxemia or shock and by diabetic ketoacidosis METABOLIC ALKALOSIS Metabolic, or nonrespiratory, alkalosis occurs when there is an excessive loss of fixed acids from the body, or it may occur as a consequence of the ingestion, infusion, or excessive renal reabsorption of bases such as bicarbonate Figure 37–2 shows that primary uncompensated metabolic alkalosis results in an upward movement along the Pco2 = 40 mm Hg isobar to point D, that is, a net gain of buffer establishes a new blood–buffer line higher than and parallel to the normal blood–buffer line Pco2 is unchanged, hydrogen ion concentration is decreased, and the ratio of bicarbonate concentration to carbon dioxide is increased As shown in Table 37–5, loss of gastric juice by vomiting results in a loss of hydrogen ions and may cause metabolic alkalosis Excessive ingestion of bicarbonate or other bases (e.g., stomach antacids) or overinfusion of bicarbonate by the clinician may cause metabolic alkalosis In addition, TABLE 37–5 Common causes of metabolic alkalosis Loss of hydrogen ions Vomiting Gastric fistulas Diuretic therapy Treatment with or overproduction of steroids (aldosterone or other mineralocorticoids) Ingestion or administration of excess bicarbonate or other bases Intravenous bicarbonate Ingestion of bicarbonate or other bases (e.g., antacids) Reproduced with permission from Levitzky MG: Pulmonary Physiology, 7th ed New York: McGraw-Hill Medical, 2007 380 SECTION VI Pulmonary Physiology diuretic therapy, treatment with steroids (or the overproduction of endogenous steroids), and conditions leading to severe potassium depletion may also cause metabolic alkalosis mechanism or the breathing apparatus itself Compensation for acidosis or alkalosis in these conditions must therefore come from outside the respiratory system The respiratory compensatory mechanism can operate very rapidly (within minutes) to partially correct metabolic acidosis or alkalosis COMPENSATORY MECHANISMS Uncompensated primary acid–base disturbances, such as those indicated by points B–D and G in Figure 37–2, seldom occur because respiratory and renal compensatory mechanisms are called into play to offset these disturbances The two main compensatory mechanisms are functions of the respiratory and renal systems RESPIRATORY COMPENSATORY MECHANISMS The respiratory system can compensate for metabolic acidosis or alkalosis by altering alveolar ventilation As discussed in Chapter 33, if carbon dioxide production is constant, the alveolar Pco2 is inversely proportional to the alveolar ventilation In metabolic acidosis, the increased blood hydrogen ion concentration stimulates chemoreceptors, which, in turn, increase alveolar ventilation, thus decreasing arterial Pco2 This causes an increase in pHa, returning it toward normal (The mechanisms by which ventilation is regulated are discussed in detail in Chapter 38.) These events can be better understood by looking at Figure 37–2 Point G represents uncompensated metabolic acidosis As the respiratory compensation for the metabolic acidosis occurs, in the form of an increase in ventilation, the arterial Pco2 decreases The point representing blood pHa, Paco2, and bicarbonate concentration would then move a short distance along the lower-than-normal buffer line (from point G toward point H) until a new lower Paco2 is attained This returns the pHa toward normal; complete compensation does not occur The respiratory compensation for metabolic acidosis occurs almost simultaneously with the development of the acidosis The blood pH, Pco2, and bicarbonate concentration point does not really move first from the normal (point A) to point G and then move a short distance along line GH; instead, the compensation begins to occur as the acidosis develops, so the point takes an intermediate pathway between the two lines The respiratory compensation for metabolic alkalosis is to decrease alveolar ventilation, thus increasing Paco2 This decreases pHa toward normal, as can be seen in Figure 37–2 Point D represents uncompensated metabolic alkalosis; respiratory compensation would move the blood pHa, PaCo2, and bicarbonate concentration point a short distance along the new higher-than-normal blood–buffer line toward point F Again the compensation occurs as the alkalosis develops, with the point moving along an intermediate course Under most circumstances, the cause of respiratory acidosis or alkalosis is a dysfunction in the ventilatory control RENAL COMPENSATORY MECHANISMS The kidneys can compensate for respiratory acidosis and metabolic acidosis of nonrenal origin by excreting fixed acids and by retaining filtered bicarbonate They can also compensate for respiratory alkalosis or metabolic alkalosis of nonrenal origin by decreasing hydrogen ion excretion and by decreasing the retention of filtered bicarbonate These mechanisms are discussed in Chapter 47 Renal compensatory mechanisms for acid–base disturbances operate much more slowly than respiratory compensatory mechanisms For example, the renal compensatory responses to sustained respiratory acidosis or alkalosis may take 3–6 days The kidneys help regulate acid–base balance by altering the excretion of fixed acids and the retention of the filtered bicarbonate; the respiratory system helps regulate body acid–base balance by adjusting alveolar ventilation to alter alveolar Pco2 For these reasons, the Henderson–Hasselbalch equation is in effect: Kidneys pH = Constant + Lungs (4) CLINICAL INTERPRETATION OF ARTERIAL BLOOD GASES Samples of arterial blood are usually analyzed clinically to determine the “arterial blood gases”: the arterial Po2, Pco2, and pH The plasma bicarbonate can then be calculated from the pH and Pco2 by using the Henderson–Hasselbalch equation This can be done directly, or by using a nomogram, or by graphical analysis such as the pH–bicarbonate diagram (the “Davenport plot,” after its popularizer), the pH– Pco2 diagram (the “Siggaard-Andersen”), or the composite acid–base diagram Blood gas analyzers perform these calculations automatically Table 37–6 summarizes the changes in pHa, Paco2, and plasma bicarbonate concentration that occur in simple, mixed, and partially compensated acid–base disturbances It contains the same information shown in Figure 37–2, depicted differently A thorough understanding of the patterns shown in Table 37–6 coupled with knowledge of a patient’s Pco2 and other clinical findings can reveal a great deal about the underlying pathophysiologic processes in progress A simple approach to interpreting a blood gas set is to first look at the pH to determine whether the predominant problem is acidosis or alkalosis (Note that an acidemia could represent more than one cause of acidosis, an acidosis with some compensation, or even an acidosis and a separate underlying CHAPTER 37 Acid–Base Regulation and Causes of Hypoxia TABLE 37–6 Acid–base disturbances pH PCO2 HCO3− Uncompensated respiratory acidosis ↓↓ ↑↑ ↑ Uncompensated respiratory alkalosis ↑↑ ↓↓ ↓ Uncompensated metabolic acidosis ↓↓ ↔ ↓↓ Uncompensated metabolic alkalosis ↑↑ ↔ ↑↑ Partially compensated respiratory acidosis ↓ ↑↑ ↑↑ Partially compensated respiratory alkalosis ↑ ↓↓ ↓↓ Partially compensated metabolic acidosis ↓ ↓↓ ↓↓ Partially compensated metabolic alkalosis ↑ ↑↑ ↑↑ Respiratory and metabolic acidosis ↓↓ ↑↑ ↓ Respiratory and metabolic alkalosis ↑↑ ↓↓ ↑ Reproduced with permission from Levitzky MG: Pulmonary Physiology, 7th ed New York: McGraw-Hill Medical, 2007 alkalosis Similarly, an alkalemia could represent more than one cause of alkalosis, an alkalosis with some compensation, or even an alkalosis and a separate underlying acidosis.) After evaluating the pH, look at the arterial Pco2 to see if it explains the pH For example, if the pH is low and the Pco2 is increased, then the primary problem is respiratory acidosis If the pH is low and the Pco2 is near 40 mm Hg, then the primary problem is metabolic acidosis with little or no compensation If both the pH and the Pco2 are low, there is metabolic acidosis with respiratory compensation Then look at the bicarbonate concentration to confirm your diagnosis It should be slightly increased in uncompensated respiratory acidosis, high in partially compensated respiratory acidosis, and low in metabolic acidosis If the pH is high and the Pco2 is low, then the primary problem is respiratory alkalosis If the pH is high and the Pco2 is near 40 mm Hg, then the problem is uncompensated metabolic alkalosis If both the pH and the Pco2 are high, then there is partially compensated metabolic alkalosis The bicarbonate should be slightly decreased in respiratory alkalosis, decreased in partially compensated respiratory alkalosis, and increased in metabolic alkalosis BASE EXCESS Calculation of the base excess or base deficit may be very useful in determining the therapeutic measures to be admin- 381 istered to a patient The base excess or base deficit is the number of milliequivalents of acid or base needed to titrate L of blood to pH 7.4 at 37°C if the Paco2 were held constant at 40 mm Hg It is not, therefore, just the difference between the plasma bicarbonate concentration of the sample in question and the normal plasma bicarbonate concentration because respiratory adjustments also cause a change in bicarbonate concentration: the arterial Pco2 must be considered, although in most cases the vertical deviation of the bicarbonate level above or below the blood–buffer line on the Davenport diagram at the pH of the sample is a reasonable estimate Base excess can be determined by actually titrating a sample or by using a nomogram, diagram, or calculator program Most blood gas analyzers calculate the base excess automatically The base excess is expressed in milliequivalents per liter above or below the normal buffer-base range—it therefore has a normal value of ± mEq/L A base deficit is also called a negative base excess The base deficit can be used to estimate how much sodium bicarbonate (in mEq) should be given to a patient by multiplying the base deficit (in mEq/L) times the patient’s estimated extracellular fluid (ECF) space (in liters), which is the distribution space for the bicarbonate The ECF is usually estimated to be 0.3 times the lean body mass in kilograms ANION GAP Calculation of the anion gap can be helpful in determining the cause of a patient’s metabolic acidosis It is determined by subtracting the sum of a patient’s plasma chloride and bicarbonate concentrations (in mEq/L) from his or her plasma sodium concentration: Anion gap =[Na+]–([C1–]+[HCO3–]) (5) The anion gap is normally 12 ± mEq/L The sum of all of the plasma cations must equal the sum of all of the plasma anions, so the anion gap exists only because all of the plasma cations and anions are not measured when standard blood chemistry is done Sodium, chloride, and bicarbonate concentrations are almost always reported The normal anion gap is a result of the presence of more unmeasured anions than unmeasured cations in normal blood: [Na+]+[Unmeasured cations]= [ C1 ]+[HCO3–]+[Unmeasured anions] (6) [Na+]–([ C1–]+[HCO3–])= [Unmeasured anions]–[Unmeasured cations] (7) – The anion gap is therefore the difference between the unmeasured anions and the unmeasured cations The negative charges on the plasma proteins probably make up most of the normal anion gap, because the total charges of the other plasma cations (K+, Ca2+, Mg2+) are approximately equal to the total charges of the other anions (PO43−, SO42−, organic anions) 382 SECTION VI Pulmonary Physiology An increased anion gap usually indicates an increased number of unmeasured anions (those other than C1– and HCO3−) or a decreased number of unmeasured cations (K+, Ca2+, or Mg2+), or both This is most likely to happen when the measured anions, [HCO3−] or [Cl–], are lost and replaced by unmeasured anions For example, the buffering by HCO3− of H+ from ingested or metabolically produced acids produces an increased anion gap Thus, metabolic acidosis with an abnormally great anion gap (i.e., greater than 16 mEq/L) would probably be caused by lactic acidosis or ketoacidosis; ingestion of organic anions such as salicylate, methanol, and ethylene glycol; or renal retention of anions such as sulfate, phosphate, and urate THE CAUSES OF HYPOXIA Thus far, only two of the three variables referred to as the arterial blood gases, the arterial Pco2, and pH have been discussed Many abnormal conditions or diseases can cause a low arterial Po2 They are discussed in the following section about the causes of tissue hypoxia in the discussion of hypoxic hypoxia The causes of tissue hypoxia can be classified (in some cases rather arbitrarily) into four or five major groups (Table 37–7) The underlying physiology of most of these types of hypoxia has already been discussed in this or previous chapters HYPOXIC HYPOXIA Hypoxic hypoxia refers to conditions in which the arterial Po2 is abnormally low Because the amount of oxygen that will combine with hemoglobin is mainly determined by the Po2, such conditions may lead to decreased oxygen delivery to the tissues if reflexes or other responses cannot adequately increase the cardiac output or hemoglobin concentration of the blood Low Alveolar PO2 Conditions causing low alveolar Po2 inevitably lead to low arterial Po2 and oxygen contents because the alveolar Po2 determines the upper limit of arterial Po2 Hypoventilation leads to both alveolar hypoxia and hypercapnia (high CO2), as discussed in Chapter 33 Hypoventilation can be caused by depression or injury of the respiratory centers in the brain (discussed in Chapter 38), interference with the nerves supplying the respiratory muscles, as in spinal cord injury, neuromuscular junction diseases such as myasthenia gravis, and altered mechanics of the lung or chest wall, as in noncompliant lungs due to sarcoidosis, reduced chest wall mobility because of kyphoscoliosis or obesity, and airway obstruction Ascent to high altitude causes alveolar hypoxia because of the reduced total barometric pressure encountered above sea level Reduced FIo2 (fractional concentration of inspired oxygen) has a similar effect Alveolar carbon dioxide is decreased because of the reflex increase in ventilation caused by hypoxic stimulation, as will be discussed in Chapter 71 Hypoventilation and ascent to high altitude lead to decreased venous Po2 and oxygen content as oxygen is extracted from the already hypoxic arterial blood Administration of increased oxygen concentrations in the inspired gas can alleviate the alveolar and arterial hypoxia in hypoventilation and in ascent to high altitude, but it cannot reverse the hypercapnia of hypoventilation In fact, administration of increased FIo2 to spontaneously breathing patients hypoventilating because of a depressed central response to carbon dioxide (see Chapter 38) can further depress ventilation Diffusion Impairment Alveolar–capillary diffusion is discussed in greater detail in Chapter 35 Conditions such as interstitial fibrosis and interstitial or alveolar edema can lead to low arterial Po2 and contents with normal or elevated alveolar Po2 High FIo2 that increases the alveolar Po2 to very high levels may increase the TABLE 37–7 A classification of the causes of hypoxia PAO2 PaO2 CaO2 P –V O2 C–V O2 Increased FIO2 Helpful? Low Low Low Low Low Yes Diffusion impairment N Low Low Low Low Yes Right-to-left shunts N Low Low Low Low No ˙V/ Q ˙ mismatch N Low Low Low Low Yes Anemic hypoxia N N Low Low Low No CO poisoning N N Low Low Low Possibly Hypoperfusion hypoxia N N N Low Low No Histotoxic hypoxia N N N High High No Classification Hypoxic hypoxia Low alveolar PO N, normal Reproduced with permission from Levitzky MG: Pulmonary Physiology, 7th ed New York: McGraw-Hill Medical, 2007 CHAPTER 37 Acid–Base Regulation and Causes of Hypoxia arterial Po2 by increasing the partial pressure gradient for oxygen diffusion Shunts True right-to-left shunts, such as anatomic shunts and absolute intrapulmonary shunts, can cause decreased arterial Po2 with normal or even increased alveolar Po2 Patients with intrapulmonary shunts have low arterial Po2, but may not have significantly increased Pco2 if they are able to increase their alveolar ventilation or if they are mechanically ventilated This is a result of the different shapes of the oxyhemoglobin dissociation curve (see Figure 36–1) and the carbon dioxide dissociation curve (see Figure 36–5) The carbon dioxide dissociation curve is almost linear in the normal range of arterial Pco2, and arterial Pco2 is very tightly regulated by the respiratory control system (see Chapter 38) Carbon dioxide retained in the shunted blood stimulates increased alveolar ventilation, and because the carbon dioxide dissociation curve is nearly linear, increased ventilation will allow more carbon dioxide to diffuse from the nonshunted blood into well-ventilated alveoli and be exhaled On the other hand, increasing alveolar ventilation will not get any more oxygen into the shunted blood and, because of the shape of the oxyhemoglobin dissociation curve, very little more into the unshunted blood This is because the hemoglobin of well-ventilated and perfused alveoli is nearly saturated with oxygen, and little more will dissolve in the plasma Similarly, arterial hypoxemia caused by true shunts is not relieved by high FIo2 because the shunted blood does not come into contact with the high levels of oxygen The hemoglobin of the unshunted blood is nearly completely saturated with oxygen at a normal FIo2 of 0.21, and the small additional volume of oxygen dissolved in the blood at high FIo2 cannot make up for the low hemoglobin saturation of the shunted blood VENTILATION–PERFUSION MISMATCH ˙ /Q ˙) Alveolar–capillary units with low ventilation–perfusion (V ratios contribute to arterial hypoxia, as already discussed Units ˙ /Q ˙ not by themselves lead to arterial hypoxia, of with high V course, but large lung areas that are underperfused are usually associated either with overperfusion of other units or with low cardiac outputs (see the section “Hypoperfusion Hypoxia”) Hypoxic pulmonary vasoconstriction (discussed in Chapter 34) and local airway responses (discussed in Chapter 32) nor˙/Q ˙ mismatch mally help minimize V ˙/Q ˙ mismatch Note that diffusion impairment, shunts, and V increase the alveolar–arterial Po2 difference (see Table 35–1 and the first two columns in Table 37–7) ANEMIC HYPOXIA Anemic hypoxia is caused by a decrease in the amount of functioning hemoglobin, which can be a result of decreased hemoglobin or erythrocyte production, the production of abnormal hemoglobin or red blood cells, pathologic destruction of eryth- 383 rocytes, or interference with the chemical combination of oxygen and hemoglobin Carbon monoxide poisoning, for example, results from the greater affinity of hemoglobin for carbon monoxide than for oxygen Methemoglobinemia is a condition in which the iron in hemoglobin has been altered from the Fe2+ to the Fe3+ form, which does not combine with oxygen Anemic hypoxia results in a decreased oxygen content when both alveolar and arterial Po2 are normal Standard analysis of arterial blood gases could therefore give normal values unless blood oxygen content is measured independently Venous Po2 and oxygen content are both decreased Administration of high FIo2 is not effective in greatly increasing the arterial oxygen content (except possibly in carbon monoxide poisoning) HYPOPERFUSION HYPOXIA Hypoperfusion hypoxia (sometimes called stagnant hypoxia) results from low blood flow This can occur either locally, in a particular vascular bed, or systemically, in the case of a low cardiac output The alveolar Po2 and the arterial Po2 and oxygen content may be normal, but the reduced oxygen delivery to the tissues may result in tissue hypoxia Venous Po2 and oxygen content are low Increasing the FIo2 is of little value in hypoperfusion hypoxia (unless it directly increases the perfusion) because the blood flowing to the tissues is already oxygenated normally HISTOTOXIC HYPOXIA Histotoxic hypoxia refers to a poisoning of the cellular machinery that uses oxygen to produce energy Cyanide, for example, binds to cytochrome oxidase in the respiratory chain and effectively blocks oxidative phosphorylation Alveolar Po2 and arterial Po2 and oxygen content may be normal (or even increased, because low doses of cyanide increase ventilation by stimulating the arterial chemoreceptors) Venous Po2 and oxygen content are increased because oxygen is not utilized in the tissues THE EFFECTS OF HYPOXIA Hypoxia can result in reversible tissue injury or even tissue death The outcome of an hypoxic episode depends on whether the tissue hypoxia is generalized or localized, how severe the hypoxia is, the rate of development of the hypoxia (see Chapter 71), and the duration of the hypoxia Different cell types have different susceptibilities to hypoxia; unfortunately, brain cells and heart cells are the most susceptible CLINICAL CORRELATION A 15-year-old adolescent entered the emergency department with dyspnea (shortness of breath), a feeling of chest tightness, coughing, wheezing, and anxiety His nail beds and lips were blue (cyanosis) 384 SECTION VI Pulmonary Physiology He has had frequent episodes of dyspnea and wheezing for several years, especially in the spring, and has been diagnosed with asthma Pulmonary function tests done at the time of his diagnosis showed lower-than-predicted forced expiratory volume in the first second (FEV1), forced vital capacity (FVC), FEV1/FVC, and peak expiratory flow (PEF) Inhaling a bronchodilator improved all of these An arterial blood gas was obtained to help determine the severity of the episode The arterial Po2 was 55 mm Hg, the arterial Pco2 was 32 mm Hg, the arterial pH was 7.52, and the bicarbonate was 25 mEq/L, indicating hypoxemia and uncompensated respiratory alkalosis Asthma is an episodic obstructive disease and it is reasonable to assume that it would cause CO2 retention and therefore respiratory acidosis during attacks This is true in very severe asthma attacks, but most asthma attacks result in hypocapnia and respiratory alkalosis As the asthma attack occurs, bronchial smooth muscle spasm and mucus secretion obstruct the ventilation to some alveoli Although some hypoxic pulmonary vasoconstriction may occur, it is not sufficient to divert all of the mixed venous blood flow away from these poorly ventilated alveoli This results in a right-to-left shunt or shuntlike state (Chapter 35), which would therefore be expected to cause the arterial Po2 to decrease and the arterial Pco2 to increase However, the Pco2 decreases because the patient increases alveolar ventilation if he or she is able to Irritant receptors in the airways are stimulated by the mucus and by chemical mediators released during the attack Hypoxia caused by the shunt stimulates the arterial chemoreceptors; the patient also has the feeling of dyspnea (many asthma attacks have an emotional component) All of these factors cause increased breathing and therefore increased alveolar ventilation Increasing ventilation will get more CO2 out of the blood perfusing ventilated alveoli (and therefore out of the body) but it will not get much oxygen into alveoli supplied by obstructed airways, nor will it get much more oxygen into the blood of the unobstructed alveoli because of the shape of the oxyhemoglobin dissociation curve Remember that the hemoglobin is already 97.4% saturated with oxygen and not much more will dissolve in the plasma Therefore, during the attack the patient has hypoxemia, hypocapnia, and respiratory alkalosis It is only when the attack is so severe that the patient cannot the additional work of breathing that hypercapnia and respiratory acidosis occur Acute treatment of asthma is aimed at dilating the airways with a bronchodilator, such as a β2-adrenergic agonist, and relieving the hypoxemia with oxygen Mechanical ventilation may be used in more severe cases Chronic treatment includes bronchodilators such as β2-adrenergic agonists; anticholinergics, to block parasympathetically mediated constriction and mucus production; antileukotriene drugs and inhaled corticosteroids, to prevent inflammation; and inhibition of mast cells to prevent them from releasing cytokines CHAPTER SUMMARY ■ ■ ■ ■ ■ ■ Hypoventilation causes respiratory acidosis; the compensation for respiratory acidosis is renal retention of base and excretion of hydrogen ions Hyperventilation causes respiratory alkalosis; the compensation for respiratory alkalosis is renal excretion of base and retention of hydrogen ions Ingestion, infusion, overproduction, or decreased renal excretion of hydrogen ions, or loss of bicarbonate ions, can cause metabolic acidosis; the compensation for metabolic acidosis is increased alveolar ventilation Ingestion, infusion, or excessive renal reabsorption of bases, or loss of hydrogen ions, can cause metabolic alkalosis; the compensation for metabolic alkalosis is decreased alveolar ventilation Metabolic acidosis with an abnormally elevated anion gap indicates an increased plasma concentration of anions other than chloride and bicarbonate or a decreased plasma concentration of potassium, calcium, or magnesium ions Tissue hypoxia can be a result of low alveolar Po2, diffusion impairment, right-to-left shunts, or ventilation–perfusion mismatch (hypoxic hypoxia), decreased functional hemoglobin (anemic hypoxia), low blood flow (hypoperfusion hypoxia), or an inability of the mitochondria to use oxygen (histotoxic hypoxia) STUDY QUESTIONS 1–4 Match each of the following sets of blood gas data to one of the underlying problems listed below Assume the body temperature to be 37°C, and the hemoglobin concentration to be 15 g Hb/100 mL blood FIo2 is 0.21 (room air) A) acute methanol ingestion B) diarrhea C) accidental hypoventilation of a patient on a mechanical ventilator for 10 minutes D) chronic obstructive pulmonary disease pHa = 7.25, Paco2 = 50 mm Hg , [HCO3−] = 26 mEq/L, Pao2 = 70 mm Hg, anion gap = 11 mEq/L pHa = 7.34, Paco2 = 65 mm Hg, [HCO3−] = 40 mEq/L, Pao2 = 65 mm Hg, anion gap = 11 mEq/L pHa = 7.25, Paco2 = 30 mm Hg, [HCO3−] = 15 mEq/L, Pao2 = 95 mm Hg, anion gap = 10 mEq/L pHa = 7.25, Paco2 = 30 mm Hg, [HCO3−] = 15 mEq/L, Pao2 = 95 mm Hg, anion gap = 25mEq/L 772 INDEX Herpes simplex, 66 Heteronymous hemianopia, 142, 144 Heterotrimeric guanine-binding (G) proteins, 161, 607 Hexamethonium, 71, 179 H/glutamate antiporter, 24, 27 High altitude pulmonary edema, 736 High-amplitude propagating contractions, 555 High-pressure nervous syndrome (HPNS), 741, 742 Hippocampus, 76, 108f, 191, 192f, 193–196 Histamine, 63, 64, 116, 188, 255, 307, 323, 346, 510, 529 H2 receptors, 510 antagonists, 510 Histotoxic hypoxia, 383 H–K antiporters, 465 H+,K+-ATPase, 475, 512 See also Proton pump H/K pump, 23 Holter monitor, 210 Homeostasis, 1, 11 energy, brain’s signals to control regulation, 720f and feedback control, 12 Homeotherms, 729 Homovanillic acid, 665 Homunculus, 118 Hooke’s law, Hormone-producing tumors, 678 Hormone–receptor agonists/antagonists, 605 Hormone–receptor complex, 604, 605, 607, 608, 628, 661 Hormones, 498 See also Endocrine physiology; Endocrine system; Gastrointestinal hormones; Ovarian hormones; Steroid hormones affinity, 605 of anterior pituitary, 624–630 autocrine, 603 biologic effect, 603 endocrine, 603 events, during ovarian and endometrial cycles, 701f free/unbound hormone, 603 half-life, 603 interpretation of measurements, 610–611, 611t intracrine, 603 neural control, 610f paracrine, 603 precursor, 604 product, 625 receptor function, 611 release patterns, 609f regulation of, 615–616 sensitivity, 611f specificity, 605 Hormone-sensitive lipase (HSL), 638, 675 hPL See Human placental lactogen (hPL) H2 receptor antagonists, 510 5HT1 receptors, 551 5HT3 receptors, 64, 551 Human body, 3f Human chorionic gonadotropin (hCG), 602, 625, 688, 699, 703, 709 Human language, 195 Human placental lactogen (hPL), 626, 707f, 709, 711 Human taste modalities bitter, 163 salt, 163 sour, 163 sweet, 163 umami, 163 Humoral hypercalcemia of malignancy, 489 Huntington’s disease, 63 Hydraulic pressure in Bowman’s capsule, 412 Hydrogen ions excretion of, 477f, 478 secretion generic model, 474f tubular segments, contributions, 475t Hydrophobic groups, 16 Hydrostatic forces, Hydrostatic pressure, 5, 28, 254, 258, 348, 349, 412, 413 of interstitial fluid, 254 of intracapillary fluid, 254 Hydroxyapatite, 377, 487, 646 deposition of, 488 resorption of, 488 11β-Hydroxylase, 657 enzymatic deficiency, 659f 21-Hydroxylase, 657 enzymatic deficiency, 659f 11β-Hydroxysteroid dehydrogenase, 658 type I, 658 type II, 658 5-Hydroxytryptamine (5-HT), (also see serotonin) 64, 503, 529, 550 Hyperaldosteronism primary, 470, 664 Hyperalgesia, 116 Hyperbaria, 738 Hyperbaric chambers, 738 Hyperbaric oxygen therapy (HBOT), 738 Hyperbilirubinemia, 577, 578 Hypercalcemia, 653 Hypercalcemia of malignancy, 645 Hypercalciuria, 653 Hypercapnia, 346 Hypercoagulable, 262 Hyperemia, 265 Hyperglycemia, 406 See also Diabetes mellitus Hypergonadotropic hypergonadism, 713 Hyperkalemia,38, 222, 463, 658, 665, 725 Hyperkalemic periodic paralysis (HyperKPP), 52 Hypernatremia, 620 Hyperopia, 136 Hyperosmolarity, 722 Hyperparathyroidism primary, 488, 489 (see also Thyroid gland) secondary, 489, 651 Hyperphosphatemia, 489, 653 Hyperpnea, 388, 747 Hyperpolarization, 38 Hyperpolarization-activated current, 55 Hyperprolactinemia, 640, 693 Hyperreninemic hypoaldosteronism, 664 Hyperresonant, 329 Hypersensitivity, 111 Hypersomnolence, 187 Hypertension, 229, 282, 290, 292, 470, 640, 657, 664, 718 Hyperthyroidism, 634, 638, 731, 732 Graves’ disease, 639 primary, 732 TSH-secreting adenomas, 639 Hypertonia, 169 Hypertonic (spastic) muscle, 129 Hypertonic solutions, 28 Hypertrophy, 292 Hyperventilation, 361, 378, 735, 740 syndrome, 378 Hyperventilation syndrome, 378 Hypesthesia, 161 Hypoaldosteronism, 664 Hypocalcemia, 52, 57, 68, 484, 487, 644, 647, 653 Hypocalcemic tetany, 653 Hypocapnia, 372, 384, 736, 737 Hypogeusia, 162, 165 Hypoglycemia, 626, 627, 676, 717, 718, 726 Hypogonadism, 580, 630, 692, 693 Hypogonadotropic hypogonadism, 692, 693, 713 Hypokalemia, 463, 620, 664, 724, 725, 731 Hypomagnesemia, 644 Hyponatremia, 30, 620, 665, 749 Hyponatremic encephalopathy, 30 Hypoparathyroidism, 652t, 653 Hypoperfusion hypoxia, 383 Hypophosphatemia, 651 Hypophysiotropic hormones, 613, 615 key aspects of, 615t Hypophysis, 623 Hypopituitarism, 630, 639 Hyporeflexia, 168, 176 Hyporeninemic hypoaldosteronism, 664 Hyposmia, 161 Hypothalamic integration, 719 Hypothalamic neurons, 613 Hypothalamic neuropeptides, 615 Hypothalamic nuclei, 613–615 Hypothalamic peptides, 625 Hypothalamic–pituitary–adrenal axis, 660f Hypothalamic–pituitary–ovarian axis, 695, 700f Hypothalamic–pituitary–thyroid axis, 634, 634f Hypothalamic tumors, 692 Hypothalamohypophysial tract, 613, 615 Hypothalamo-pituitary hormone-mediated effects cellular signaling pathways, 625f Hypothalamus, 161f, 183, 188, 189f, 287, 385, 450f, 501, 509, 602, 613, 614f, 626, 630 anatomic and functional relationship, 614f endocrine functions of, 615 supraoptic/paraventricular nuclei, 459 Hypothermia, 716, 731 Hypothyroidism, 638 primary hypothyroidism, 638–639 secondary hypothyroidism, 639 Hypotonia, 168, 175, 176 Hypotonic encephalopathy, 30 Hypotonic muscle, 129 Hypotonic solutions, 28 Hypoventilation, 366, 377, 382, 480 Hypovolemia, 484 Hypovolemic shock, 301 Hypoxemia, 321, 379, 384 Hypoxia, 321, 346, 382, 391, 394, 730, 735 altitude and acclimatization altitude, acute effects, 736 cardiovascular system, 736 respiratory system, 736–738 anemic hypoxia, 383 classification of causes, 382t effects of, 383 histotoxic hypoxia, 383 hypoperfusion hypoxia, 383 hypoxic hypoxia, 382–383, 735 Hypoxic hypoxia, 382, 735 diffusion impairment, 382–383 INDEX low alveolar PO2, 382 shunts, 383 Hypoxic pulmonary vasoconstriction, 384, 736 chronic, 742 Hysteresis, 319, 320 I IgA system, 537 See also Mucosal immune system physiological functions, 537 secretion of IgA across, 535, 537f, 568, 569 structural aspects of IgA, 536–537 IGF receptor, 629 Ileal brake, 502 Ileal-fatty acid binding protein (I-FABP), 597 Ileocecal valve, 494, 554 Ileum, 496 Immune communication, 500 Immune responses, alterations in, 725 Impaired glucose tolerance, 631 Implicit memory, 76 Implicit/nondeclarative memory, 191 Impotence, 631 Inactivation gate, 213 Incontinence, 183, 754t, 755 Incretin, 501, 675 Infant respiratory distress syndrome, 321 Inferior colliculi, 153 Inferior olivary nuclei, 175 Inflammation, 112 Inflammatory bowel diseases, 534, 538 Crohn’s disease, 534, 538 ulcerative colitis, 534, 538 Inhibin B, 685 Inhibitory G proteins, 216 Inhibitory postsynaptic potentials (IPSPs), 11, 67, 125 Inhibitory spinal pathways, 287 Innocent murmurs, 300 Inositol triphosphate (IP3) receptor (IP3R), 21 Inositol trisphosphate (IP3), 607 Inotropic, 220, 638 Input–process–output structural framework, 10 Inspiratory capacity (IC), 332 Inspiratory neurons, 386 Inspiratory reserve volume (IRV), 332 Insulin, 394, 464, 587, 671, 715, 724 effects at target organs, 674 early effects, 674 intermediate effects, 675 long-term effects, 675 effects on carbohydrate, fat, and protein metabolism, 674 effects on hepatic glucose metabolism, 676f glucose-induced stimulation of, 673 physiologic effects of, 673 receptor, 25, 674 substrates, 674 regulation of release, 672, 673f resistance, 662, 678–680 sensitivity, 755 synthesis, 672 Insulin/glucagon ratios, 716 Insulin-like growth factor-1 (IGF-1), 627–629, 755 Insulin-like growth factor binding proteins (IGFBPs), 629 Insulinoma, 678 Insulin resistance, 662 Integrins, 26 Intensity, 118 Intention tremor, 175 Intercalated cells, 403, 466 type A, 475, 476f type B, 476, 476f Intercalated disks, 214 Intercalated ducts, 523 Intercellular adhesion molecules (ICAMs), 26 Intercostal muscles, 305 Interdependence of alveolar units, 315 Interferon therapy, 563 Interleukins, 629, 646, 699, 700f, 719, 726f, 731, 732f Intermediolateral column (IML), 177 Internal anal sphincter, 554 Interstitial/alveolar edema, 382 Interstitial cells of Cajal, 549 Interstitial fibrosis, 382 Interstitial fluid, 4, 28 Interstitial hydrostatic pressure, 349 Interstitium, 399, 477f, 479f, 487, 499, 603f, 663f, 664 Intestinal calcium absorption, 644 Intestinal flatus, composition, 540f Intestinal fluid transport anatomical considerations innervation and regulatory cells, 528–529 intestinal surface area, amplification of, 528 cellular basis absorptive mechanisms, 531–532 secretory mechanisms, 532–533 endogenous regulators, 529t integration of influences, 530f principles electrolytes involved, 527–528 role and significance, 527 water and electrolyte transport, regulation acute regulation, 530 chronic adaptation, 531 regulatory strata, 529–530 Intestinal lipolysis, mediators, 595t Intestinal microecology gas generation in intestine, 540 intestinal microbiota, development, 538–539 microbiota, physiological functions, 539–540 Intestinal motility basic principles role and significance in colon, 553 role and significance in small intestine, 552–553 esophageal musculature, functional anatomy innervation, 544 muscle layers, 544 features of colonic motility, 555 defecation, 556 fed versus fasted patterns, 554–555 mixing and segmentation, 555 peristalsis, 555 functional anatomy enteric nervous system, 554 muscle layers, 553 sphincters, 554 Intestinal pathogens, pathophysiological mechanisms, 540t Intestinal phase, 519 Intestine organization, 493f Intracellular fluid (ICF), 437 Intracellular receptors, 606f Intraepithelial, 536 Intraepithelial lymphocytes, 536 Intrafusal fibers, 126 Intralaminar nuclei, 108 Intralobular ducts, 523 773 Intrapleural pressure, 309, 314, 739 Intrapulmonary shunts, 355, 366 Intrarenal chemical messengers, 405 Intrinsic factor, 507, 513 Intrinsic factor-cobalamin receptor (IFCR), 591 Intrinsic proteins, 16 Intubated patient, 309 Inulin, 418 renal handling, 419f Invasion of immune cell, 112 Inverse stretch reflex, 129 Inward-going pacemaker current, 216 Inward rectifier, 17, 18 Inward rectifier K channel (Kir), 17, 18f, 55 Iodide channel, 635 Iodine, uptake and organification, 634 Ion movements factors controlling, 35–36 receptors channels allowing, 102 Ionotropic ligand receptors, 20 Ions of importance, across muscle cell membrane, 35t Ion transport pathways, 522f, 525f IP3 receptors, 101, 102f, 677f, 698 IPSPs See Inhibitory postsynaptic potentials (IPSPs) Ischemia, 22, 63, 117, 248, 289, 302, 360, 372, 630, 703 Ischemic heart disease, 711 Ischemic stroke, 63 Islets of Langerhans, 518 Isohydric principle, 376 Isohydric shift, 370 Isomaltase, 585, 586 Isometric contraction, 85, 86 Iso-osmotic process, 423 Isopotential, 40 Isoproterenol, 346, 350 Isosmotic solution, 28 Isotonic contraction, 85, 86 Isotonic solution, 28 Ito cells, 562 J Jaundice, 575 differential diagnosis, 578f J chain, 536 Jejunum, 496, 499, 500, 552, 554 J receptors, 390 Juxtaglomerular (JG) apparatus, 403, 451 baroreceptor, 658 components, 403f extraglomerular mesangial cells, 403 glomerular filtration rate (GFR), 403 granular cells, 403 juxtamedullary nephron, 403 macula densa cells, 403 renin, 403 Juxtaglomerular cells, 401f, 403, 451 K KAch channels, 216 Kainate channels, 74 Kallmann syndrome, 692 K channels, 18, 37, 55, 74, 102, 214, 673f Kernicterus, 575 Ketoacidosis, 376, 379, 382, 394 Ketogenesis, 674–676, 680 enzymes involved in, 680t in insulin deficiency, 679f Ketone bodies, 93, 394, 474, 676, 678, 679, 717 774 INDEX Kidney, 397–490 anatomy, 399 calyces, 399 cortex, 399 functions, 397 glucose handling by, 430f Henle’s loop, 486 hilum, 399 influence of, 450f medulla, 399 pyramids, 399 stone, 435 structural components, 399f urea handling, 434f Kinesins, 66 Kinocilium, 150 Klinefelter syndrome, 692 Knee-jerk reflex, 12, 126 Kölliker-Fuse nucleus, 387 Korotkoff sounds, 260 Krebs–Henseleit cycle, 578 Kupffer cells, 559, 561, 562, 575 Kyphoscoliosis, 319, 340, 382 Kyphosis, 340 L Labyrinth See Inner ear Labyrinth righting reflexes, 156 Lacrimal duct, 134 Lacrimal gland, 134 Lactase, 585, 586 Lactated Ringer’s solution, 474 Lactation, 617, 630, 651, 696, 703, 707f, 708, 709, 711 Lactic acid, 91, 474 production, 745 Lactic acidosis, 382, 474 Lactic acid production, 745 Lactoferrin, 523 Lactose, 584, 586 bush border digestion ad assimilation, 586f in dairy products, 591 Lactose intolerance, 591, 592 Lactotrophs, 629 Lactulose, 580 Lambert–Eaton syndrome, 70 Lamina propria, 528 Laminar flow, 257, 322 Language disorders, 196 hemisphere concerned with, 195f physiology of, 195 hemisphere concerned with, 195f path taken by impulses, 196f and speech, 195 Laplace’s law, 320 Large intestine anatomy, 496f L-arginine, 265 Laron syndrome, 631 Latch state, 100, 101 Latent pacemaker, 214 Lateral corticospinal tracts, 167 Lateral geniculate bodies, 108, 139 Lateral inhibition, 117, 139, 161 Lateral olfactory stria, 159 Lateral sacs, 86 Law of Laplace, 221, 232 L-DOPA (levodopa), 173, 666 Lead pipe rigidity, 173 Lean body mass, 755 Learning, 191 synaptic plasticity and, 192–193 habituation, 192 sensitization, 192 Left heart failure, 283 Left ventricular failure, 226, 349, 390 Left ventricular hypertrophy, 247, 282 Length constant (λ), 40 Length–tension relationship, 81, 88, 95, 95f Lenticular nucleus, 171 Leptin, 501, 719–721, 750 Leptin receptor, 721 Leukotrienes, 307, 323 Levator ani muscles, 556 Leydig cells, 683 LH See Luteinizing hormone (LH) Lidocaine, 53 Ligand, 16, 605f, 607, 647f, 660, 662f gated channels, 20, 607 ionotropic ligand receptors, 20 ligand-binding domain of, 706 metabotropic ligand receptors, 20 osteoprotegerin, 646 Ligand-gated channels, 20 Limbic system, 108 α-Limit dextrins, 584–586 Lipase, 507, 521, 594, 595, 629, 692 gastric and pancreatic, positional specificity, 594f Lipases, 517 Lipid assimilation epithelial events in brush border events, 596–597 intracellular processing, 597 lymphatic uptake of absorbed lipid, 597–598 fat-soluble vitamins, absorption, 598 intraluminal digestion bile acids/micelles, role of, 596 gastric digestion, 594 intestinal digestion, 594–596 intestinal handling of cholesterol, 597f intestinal lipolysis, mediators of, 595t role of colipase, 595f principles dietary and endogenous sources, 593–594 hydrophobic molecules, assimilation barriers, 593 role and significance, 593 Lipids, 593 bilayer, 1, 15, 596 droplets, flip-flop, 16 lamellar phase, 596 long-chain triglycerides, 593 phosphatidylcholine, 594 phospholipids, 593 rafts, 16 Lipolysis, 692 See also Lipase products of, 593 Lipopolysaccharides, 731 Lithium treatment, 620 Lithocholic acid, 566 Liver ammonia metabolism, principles extraintestinal production, 579 intestinal production, 578–579 role and significance, 578 urea cycle, 579 urea disposition, 579–580 bilirubin homeostasis bacterial metabolism, 577 hyperbilirubinemia, 578 urinary elimination, 577–578 bilirubin metabolism cellular heme metabolism, 575–576 hepatic transport mechanisms, 576 hepatocyte conjugation, 576–577 role and significance, 575 blood vessels, bile ducts, and hepatocytes arrangement, 561f cirrhosis, 620 engineering considerations biliary tract and gallbladder, 562 blood supply, 560–561 hepatic parenchyma and sinusoids, 561–562 functions lipid-soluble waste products, excretion, 560 metabolism and detoxification, 559–560 protein metabolism and synthesis, 560 gluconeogenesis, 559 glucose buffer function, 559 splanchnic circulation, 560f Loading spindle, 127 Local circuit interneurons, 121f Location of stimulus, 117 Long-QT (LQT) syndrome, 52, 243 Long-term bed rest cardiovascular mechanisms involved, 298f responses to cardiovascular system, 297–298 Long-term depression (LTD), 76, 193 Long-term memory, 76, 192f, 194 Long-term potentiation (LTP), 76, 192–193 production of, 193f Loop diuretic, 442, 489 Loop of Henle See Henle’s loop Loperamide, 530 Loudness, 152 Lou Gehrig’s disease, 86, 176 Low-density lipoprotein (LDL), 707 Lower esophageal sphincter (LES), 495, 508, 544 Lower motor neurons, 168 Low-pressure receptors, 289 Low-resistance electrical, 214 Low vascular volume, responses to, 454f L-type (voltage-gated) calcium channels, 94, 101 Luminal epithelial cell membrane, 619 Luminal/mucosal membrane, 29 Luminal proteolysis gastric, 588 intestinal, 588 Lung compliance, 318–321, 754 Lung volumes, 331 measurement of, 332–333 body plethysmography, 334 helium-dilution technique, 334 nitrogen-washout technique, 333 pulmonary function tests, 333 spirometry, 333 and pulmonary vascular resistance, 343–344 standard lung volumes, 331 expiratory reserve volume (ERV), 332 functional residual capacity (FRC), 332 inspiratory capacity (IC), 332 inspiratory reserve volume (IRV), 332 residual volume (RV), 332 tidal volume(VT), 331 total lung capacity (TLC), 332 vital capacity (VC), 332 Lusitropic effect, positive, 221 INDEX Luteinizing hormone (LH), 64, 602, 615, 623, 626, 683, 686, 697–699, 702, 711, 726, 750 Lymph, 4, 255, 350, 377, 496, 563 Lymphatic system, 4, 255, 311, 350, 552 Lymphedema, 255, 262 Lymphocytes, 536 Lymphoid tissues/MALT, 535 Lysergic acid diethylamide (LSD), 64 Lysosomal enzymes, 307 Lysosomes, 2, 23, 311, 431, 608, 628, 646f, 703 M Macroglia, 105 Macrophages, 105, 307, 311, 350, 536, 703, 731, 732f Macula densa cells, 406, 452 Macula lutea, 134 Macular sparing, 142 Magnetic resonance image (MRI) scan, 112, 121, 631 Magnocellular cells, 141 Magnocellular neurons, 614f, 615–617, 619f Magnocellular pathway, 141 Main pancreatic duct, 518 Major histocompatibility complex (MHC), 536 Malabsorption, 496, 512, 521 Male reproductive system, 684f Male sexual differentiation, 689f Malignant hyperthermia, 57 Maltose, 584, 585f Maltotriose, 584, 585f, 586 Mamillary bodies, 193 Mammalian muscle spindle, 127f Mammalian nerve fibers, 107, 109t Mammalian target of rapamycin (mTOR), 675 Manubrium, 147 Mass balance system, 729 concept of, 5f Mast cells, 64 Maximum voluntary ventilation (MVV) test, 387 M cells, 141, 535 Mean arterial blood pressure (MABP), 258, 297, 619f, 747, 749 Mean circulatory filling pressure, 276–277 Mean electrical axis, 239f Mean pulmonary artery pressure, 345f Mean quantal content, 69, 70 Mechanical nociceptors, 115 Mechanoreceptors, 115, 289, 722 afferents, 746 Mechanosensitive channels, 11, 18 Mechanosensory transduction, 43 Medial and lateral descending brain stem pathways, 170f Medial geniculate bodies, 108, 153 Medial lemniscal system, 118 Medial lemniscus, 118 Median eminence, 613, 623 Median nerve, 122 Median preoptic nucleus, 619 Medium-chain fatty acids, 596 Medulla oblongata, 287 Medullary cardiovascular centers, 287 Medullary collecting tubule, 406 Medullary interstitial fluid, composition, 444 Medullary osmotic gradient, components of, 444 Medullary pyramids, 168 Medullary raphe neurons, 183 Medullary respiratory center, 311, 385 Meissner’s corpuscles, 115 Melanocortin receptors (MCRs), 626 Melanocyte-stimulating hormone, 626 α-Melanocyte-stimulating hormone (α-MSH), 721 Melatonin, 188, 188f, 189, 615, 624 Membrane-bound hydrolases, 584 Membrane capacitance, 34, 39 Membrane conductance, 35 Membrane potentials, 10, 34 changes in, 39, 44f measurement, 34 Membrane proteins, 1, 17, 26, 66, 485, 590 Membrane pumps, localization, 23t Membrane receptors, 24 enzyme-linked, 25 G protein–coupled, 25 Membrane resistance, 39–41 Membrane transport, 4, 521, 532, 568, 576 active pathways, characteristics of, 528t protein, MRP2, 576 Membranous labyrinth, 149 Ménière disease, 156 Meningiomas, 161 Menopause, 301, 652, 711, 755 Menstrual cycle, 99, 611f, 696, 697, 701f, 703, 706, 708, 713 Merkel cells, 115 Messenger RNA (mRNA) synthesis of proteins, Metabolic acidosis, 377, 379, 382, 392, 481, 679, 725, 737, 749 causes, 379t renal response to, 482 Metabolic alkalosis, 379, 481–483, 483f, 725 causes, 379t Metabolic clearance rate, 417 Metabolic functions of the liver, 559 Metabolic syndrome, 435, 719 Metabolic waste, excretion, 398 Metabotropic, 59 Metabotropic glutamate receptor (mGluR4), 163 Methemoglobin, 364, 368 Methemoglobinemia, 383 Methimazole, 639 Metrorrhagia, 713 Micelles, 565, 567, 568, 594, 596, 598 Michaelis–Menten equation, 27 Microbiota, 538 controlling factors, 538–539 Microelectrode, 34 Microglia, 105, 112 Microtubules, 66 Microvillous membrane, 584, 596 Midcollicular decerebration, 171 Midline nuclei, 108 Mifepristone, 708 Migrating motor complex (MMC), 548, 551, 551f, 553, 554, 554f Milliosmoles, calculation of, 28 Mineralocorticoids, 626, 662 diseases, 664 synthesis and release, 658–659 Miniature endplate potentials (MEPPs), 69 Minute ventilation, 335 Minute volume, 335 Miosis, 182 Mitochondria, 2, 15, 23, 64, 66, 68, 93, 509, 579, 580, 679f, 688f, 691 Mitogen-activated protein kinase (MAPK), 674 Mitral cells, 159 Mitral regurgitation, 247 Mitral stenosis, 246, 247, 349 775 Mitral valve prolapse, 247 Mixed micelles, 565 Mixed venous PO2, 737 Mixed venous blood, 305 MLC kinase, 100 Modality, 117 Modiolus, 149 Monge’s disease, 742 Monitor peptide, 517, 519 Monoamine oxidase (MAO), 63, 64, 665 Monoamine transporters, 665 Monoiodinated tyrosine (MIT), 636 Monomer of glutamate receptor channels (gluR), 20 Monophasic action, 54 Monosodium glutamate (MSG), 163 Monosynaptic reflex, 125–126 Morphine, 64, 120 Mossy fibers, 175 Motilin, 499, 501, 551 Motility, 72, 491, 495, 502, 529 esophageal, 545–547 gastric, 547–548 intestinal, 552–556 Motoneuron, repetitive firing, 75f Motor cortex, 169 premotor cortex, 169 primary motor cortex, 169 supplementary motor cortex, 169 Motor endplate, 68, 74, 85f, 86, 101, 128f, 544 Motor homunculus, 169 Motor neurons, 9, 85 areflexia, 168 axon, 10 dendrites of, fasciculations, 168 flaccid paralysis, 168 hyporeflexia, 168 hypotonia, 168 in facial nuclei, 168 in hypoglossal nuclei, 168 in trigeminal nuclei, 168 muscular atrophy, 168 spasticity, 168 synapse, 10 with myelinated axon, 107 α-Motor neurons, 171 γ-Motor neurons (nerves), 45, 170 Motor unit, 68, 85, 89, 91, 385 Mountain sickness, acute, 736 Mountain sickness, chronic, 742 MRP2 See Multiple organic anion transporter (MOAT) Mucins, 523 Mucociliary escalator, 308 Mucosa-associated lymphoid tissues (MALT), 535 Mucosal immune system, 535 CD4 cell, 536 CD8 cell, 536 enteric antigens, immune response to, 537 autoimmunity, 538 immune responsiveness, 538 oral tolerance, 537–538 features, 535 functional anatomy adaptive immunity, cellular mediators, 536 innate immunity, cellular mediators, 535–536 lymphoid tissues, organization, 536 776 INDEX Mucosal immune system (continued) IgE, 536 IgG, 536 secretory IgA system IgA, secretion, 537f IgA, structural aspects, 536–537 physiological functions, 537 protective effects, mechanisms, 537 Mucus, 161, 307 Multidrug resistance protein (MDR3), 568 Multidrug resistance (MDR) transporter, 24 Multiple organic anion transporter (MOAT), 568t, 569 Multiple sclerosis (MS), 53, 107, 112, 162 Multiple system atrophy (MSA), 183 Murmurs, 258 Muscarine, 60 Muscarinic receptors, 102, 179, 206, 510, 524 AChRs, 20, 60 Muscimol, 63 Muscle cell membrane, depolarization of, Muscles contraction changes in strength of, 80 period, 80 Muscles of respiration, 305 Muscle spindles, 45, 117, 125, 390 discharge, various conditions, 128f function, 127–128 structure, 126–127 Muscle tone, 129–130 Muscle weakness, 723 Muscular atrophy, 168, 175 Muscular dystrophy, 85, 340 Muscularis mucosa, 493f, 494, 497f, 502, 553 Myasthenia gravis, 68, 70, 77, 86, 91, 382 Mydriasis, 182 Myelin, 68, 105, 106, 106f, 112 Myelination, 52 Myenteric plexus, 494 Myocardial contractility, 232 Myocardial infarction, 210, 282, 350, 360 Myocardial infarcts, 270 Myocardial ischemia, 272, 360 Myocardial oxygen consumption determinants, 231–232 Myocytes, 93 Myoepithelial cells, 617 Myofibroblasts, 503, 523, 529 Myogenic response mechanism, 81, 265, 415, 547 Myoglobin (Mb), 90, 91, 93, 368, 369, 412, 575 Myometrium, 696f, 708 Myopia, 136, 138f Myosin, 83 Myosin ATPase activity, 99 Myosin filament, 80, 83 Myosin light chain kinase (MLCK), 99, 100, 100f Myosin light chain phosphatase, 99, 100, 100f Myotonia, 57 N Na–Ca antiporter, 486 Na/Ca exchanger (NCX), 24 Na/choline cotransporter, 61 Na–Cl symporter, 443 Na–glucose cotransporter (SGLT), 24 Na/glutamate cotransporter, 24 Na-GLUT antiporter, 27 Na-H antiporters (NHE3), 441, 455, 475 sodium–hydrogen exchanger, 531 Na–HCO3— symporters, 475 Na+/K+-adenosine triphosphatase (ATPase), 662 Na,K-ATPase, 531 Na,K-ATPase pumps, 425, 438, 455, 456, 465, 531 plasma membrane pumps, 464 Na–K–2Cl multiporter, 465, 479 Na–K–2Cl symporter (NKCC2), 442 Na/K pump, 37 cycle, 22f Named potentials, 10 Narcolepsy, 187 Nasal hairs, 308 Nasal turbinates, 307 Na/serotonin cotransporter, 24 Nasopharynx, 307 Natriuretic peptides and hormones, 405, 457, 739 atrial natriuretic peptide (ANP), 457 brain natriuretic peptide (BNP), 457 Nausea, 551 See also Vomiting NaV channels, 75 N-CAMs, 26 NE See Norepinephrine (NE) Near point of vision, 137 Nearsightedness See Myopia Necrotizing enterocolitis, 598 Negative base excess, 381 Negative-feedback system, 12, 390 Negative-pressure breathing, 313 Neocortex, 108, 161, 192f, 194, 195 Neomycin, 581 Neospinothalamic tract, 120 Neostigmine, 70 Neosynephrine, 64 Nephrogenic, 620 Nephrogenic diabetes insipidus, 620 Nephron basic structure, 402f collecting ducts, 399 components, 400f juxtaglomerular apparatus, 403 extraglomerular mesangial cells, 403 glomerular filtration rate (GFR), 403 granular cells, 403 juxtamedullary nephron, 403 macula densa cells, 403 renin, 403 renal corpuscle, 399, 400, 401f afferent arteriole, 400 Bowman’s capsule, 400 efferent arteriole, 400 glomerulus (glomeruli), 400 mesangial cell, 400 tubule, 400–403 ascending thin limb, 400 connecting tubule, 402 descending thin limb, 400 distal convoluted tubule, 402 inner medullary collecting duct cells, 403 intercalated cells, 403 loop of Henle, 400 macula densa, 402 peritubular capillaries, 402, 405, 409, 426 principal cells, 403 proximal convoluted tubule, 400 proximal straight tubule, 400 proximal tubule, 400 thick ascending limb, 400 Nephrotic syndrome, 620 Nernst equilibrium potential, 36 Nernst potential, 38, 39, 67, 74 generation of, 36–37 Nerve fiber, 107 mammalian, classification of, 109t relative susceptibility, 110t Nerve gases, 86 Nerve growth factor (NGF), 111 Nervous system, 4, 45, 66, 623 types of glial cells in, 106f Net filtration pressure (NFP), 412 Net influx, 27 Neuroblastomas, 161 Neuroendocrine regulation, 715 counterregulation to acute stress, 718 energy metabolism during fasted state, 716 fat, 716–717 glucose, 716 protein, 717–718 energy metabolism during fed state, 715 fat, 716 glucose, 715–716 protein, 716 long-term energy balance and fat storage, maintenance of, 718–722 of stress response, 725 chronic/severe stress, 726f Neuroendocrine system, 609, 692 Neurofibrillary tangles, 194, 753, 755 Neurogenic shock, 80, 301 Neurogenic tone, 267 Neurohormones, 615 hypophysiotropic, 623 hypothalamic, 623 magnocellular neurons, 614f Neurohumoral regulation, 498 Neurohypophysis, 613 Neurokinin A, 503, 554 Neurological disorders Bell’s palsy, 162 familial dysautonomia, 162 multiple sclerosis, 162 primary amoeboid meningoencephalopathy, 162 vestibular schwannoma, 162 Neurological examination, 120–121 Neuromuscular irritability, 647 Neuromuscular junction, 67f, 85–86, 85f Neuromuscular synapse, 10 Neuromuscular system, 497 enteric nervous system, 497 Neuronal depolarization, 613 Neurons, 9, 105–107 types, in mammalian nervous system, 108 Neuropeptides, 64, 717f anorexigenic, 721 hypothalamic, 615, 719 produced by magnocellular neurons, 616 as potential prolactin-releasing factors, 629 from sensory terminals, 121f that function as hormones, 613 Neuropeptide Y, 721 Neurophysins, 616 Neurotensin (NT), 630 Neurotransmitters, 6, 60f, 63, 64, 75, 106, 179, 499, 500, 530, 610f, 673, 720 enteric, 503 intestinal epithelial transport regulated by, 529 VIP and nitric oxide as, 548 Neurotrophins, 110 Neutrophil, 307 NHE3 sodium-hydrogen exchanger, 531 Nicotine, 60 Nicotinic acetylcholine receptor channels (nAChR), 20, 60 INDEX Nicotinic cholinergic receptor, 86 Nicotinic receptors, 86, 89, 503, 544 Niemann–Pick C1-like (NPC1L1) gene product, 596 Night blindness, 598 Night terrors, 187 Night vision, 134 Nigrostriatal dopaminergic system, 171 Nitric oxide (NO), 75, 100, 265, 292, 346, 368, 545, 692, 738 Nitrogen narcosis, 741 Nitrogen-washout technique, 333 Nitroglycerin, 272 Nitrous oxide, 350 N-methyl-d-aspartate (NMDA) receptors, 193 channel, 74, 76, 193 N1 nicotinic cholinergic receptors, 179 N2 nicotinic cholinergic receptors, 179 Nociception, 116 Nociceptive stimuli, 130 Nociceptors, 45, 115, 118f, 119, 121f Nocturnal enuresis, 187 Nodes of Ranvier, 52, 106 Nod2 molecule, 536 Nonchloride anions, 468 Nonessential amino acids, 560 Non-NMDA channels, 74 Nonrespiratory acidosis, 379 Nonsteroidal anti-inflammatory drugs (NSAIDs), 30, 116, 117, 435, 514 Noradrenergic neurons, 179 Norepinephrine (NE), 56, 63, 178, 188, 189, 217, 229, 268, 300, 346, 405, 665 receptors, 71 Normal saline, 372 NO synthase, 265 NREM sleep, 186–190, 391 Nuclear bag fiber dynamic and static, 126 Nuclear chain fiber, 126 Nuclear envelope, Nucleases, 517 Nucleation, 572 Nucleolus, Nucleotide–gated cation channel, 163 Nucleus, Nucleus ambiguus, 287, 386, 544 Nucleus basalis of Meynert, 193–194 Nucleus of the tractus solitarius (NTS), 162, 386 Nucleus para-ambigualis, 386 Nucleus parabrachialis medialis, 387 Nucleus retroambigualis, 386 Nucleus retrofacialis, 544 Nucleus tractus solitarius, 287, 509, 545 Nystagmus, 155 O Obesity, 190, 292, 630, 718–719, 721 Obligatory water loss, 440 Obstructive diseases, 326, 333 Obstructive sleep apnea (OSA), 187, 189, 329, 391 Occipital lobe, 141 Occlusion, 130 Octreotide, 631 Ocular dominance columns, 142 Oculomotor nerves, 143, 178 Odorant receptors, 159 Off-center cell, 139 Olfaction, 307 Olfactory bulbs, 159 basic neural circuits in, 160f Olfactory cortex, 159–161 amygdala, 159 anterior olfactory nucleus, 159 entorhinal cortex, 159 frontal cortex, 160 olfactory tubercle, 159 orbitofrontal cortex, 160 piriform cortex, 159 thalamus, 160 Olfactory discrimination, 161 Olfactory epithelium, 159, 160f Olfactory glomeruli, 159 Olfactory nerve, 165 Olfactory pathway, 161f Olfactory receptors, 25 Olfactory sensory neurons, 159, 159f, 160f Oligoclonal bands, 112 Oligodendrocytes, 105, 106f, 183 Oligomenorrhea, 750 Oligospermia, 693 Olivocochlear bundle, 153 Omeprazole (Prilosec), 23 On-center cell, 139 Oncotic pressure, 254, 412 in glomerular capillary plasma, 412–413 of fluid in Bowman’s capsule, 412 of interstitial fluid, 254 of intracapillary fluid, 254 Oogenesis, 699–701 follicle growth and development, 702f and formation of dominant follicle, 699–701 Open-angle glaucoma, 133 Opiate drugs, 530 Opioid peptides, 120 Optic chiasm, 141 Optic disk, 134 Optic neuritis, 112 Optic tract, 139 Oral cavity, 495 Oral rehydration solutions, 529 Oral tolerance, 537–538 Organelles, 2, 3, 15, 23, 79, 95, 217 Organic anions, 431t Organic anion transporting polypeptide (OATP), 569, 576 Organic cations, 432t Organic cation transporter (OCT), 432 Organic substances, renal handling of, 429 organic anions, proximal secretion, 431–432 urate, 432 organic cations, proximal secretion, 432–433 passive reabsorption/secretion, pH dependence, 433 proximal reabsorption, 429 glucose, 430 proteins and peptides, 430–431 urea, 433–435 Organification, 634 Organ of Corti, 149 Organomegaly, 631 Organum vasculosum lamina terminalis, 619 Orientation columns, 142 Ornithine, 430, 579f Oropharyngeal dysphagia, 556 Oropharynx, 307 Orthostatic/postural hypotension, 183, 298, 448, 620 Osmolarity, 28, 29, 208, 302, 441, 499, 620, 722, 725 Osmoreceptor neurons, 619 Osmoreceptors, 459 Osmosis, 4, 27 Osmotic diuresis, 441, 468 777 Osmotic pressure, 28, 254, 412 Ossicular conduction, 152 OST, bile acid transporter, 569 Osteoblasts, 648f Osteoclast-differentiating factor (ODF), 646 Osteoclasts, 648f Osteocytes, 487, 648f Osteomalacia, 598, 650 Osteonecrosis, 741 Osteopenia, 755 Osteoporosis, 406, 487, 489, 638, 711, 750, 753, 755 postmenopausal, 652, 713 prevention of, 652–653 Osteosclerosis, 154 Otitis externa, 154 Otitis media, 154 Otoconia, 150 Otolithic organ (macula), 150 Otoliths, 150 Ouabain, 22, 37 Oval window, 147 Ovarian cycle, 699 Ovarian follicle, 695 Ovarian hormones, 713 overproduction and undersecretion, 713 physiologic effects of, 705 estrogen, 705–707 placenta, 708–709 progesterone, 707–708 synthesis, 697 activin, 698 androgens, 697 estrogen, 697 follistatin, 698 inhibin, 698 progesterone, 697–698 Ovulation, 701 corpus luteum, formation of, 703 follicle growth and development, 702f luteolysis, 703 β-Oxidation of fatty acids, 678 Oxidative phosphorylation, 79, 80, 90, 91, 93, 100, 383, 745 of glucose, 745 Oxidative stress, 176, 580 Oxygen carrying capacity of hemoglobin, 364, 737 consumption, 269, 336, 746, 747 debt, 745 delivery, 737 inspired and alveolar partial pressures, 736 toxicity, 742 transport, factors affecting, 367–368 Oxygen-carrying capacity, 364, 737 Oxygen consumption, 269, 336, 746, 747 Oxygen content of the mixed venous blood, 355 Oxygen debt, 745 Oxygen delivery, 737 Oxygen extraction, 269 Oxygen loading in lung, 365–366 Oxygen toxicity, 742 Oxyhemoglobin dissociation curve, 364–367, 737, 749 Oxyntic glands, 508 Oxytocin, 64, 615 physiologic effects of, 617 release control of, 617 physiologic effects and regulation of, 617f synthesis and processing of, 616f 778 INDEX P Pacemaker, 93 See also Cardiac pacemaker; Gastric pacemaker potential, 55 Pacinian corpuscles, 44, 115 Packed red blood cells, 372 Pain inflammatory pain, 116 neuropathic pain, 116 pathological/chronic pain, 116 physiological/acute pain, 116 Pain transmission, modulation of, 120 Paleospinothalamic tract, 120 Palpitations, 640, 667, 668, 678, 732, 736 Pancreas, 492 acini, 518 duct of Santorini, 518 islets of Langerhans, 518 main pancreatic duct (See Wirsung’s duct) phases of secretion cephalic and gastric phases, 519 intestinal phase, 519 sphincter of Oddi, 518 structure, 518f Pancreatic acinar cells, 518, 595 receptors, 521f secretory products, 518t zymogen granules, 518 Pancreatic amylase, 587 Pancreatic hormones, 671, 672 diseases associated with, 678–680 Pancreatic insufficiency, 525, 584 Pancreatic juice, ionic composition, 520f Pancreatic polypeptide, 502, 671, 677, 678 Pancreatic proteases, activation avoiding mechanism, 589f Pancreatic secretion anatomic considerations acinar cells, 518 ductular cells, 518 cellular basis acinar cells, 520–521 ductular cells, 521 pathophysiology, 521–522 principles pancreatic secretory products, 517–518 role and significance, 517 regulation phases of, 519 role of CCK, 519 role of secretin, 519–520 Pancreatitis, 525 Paneth cells, 494 Pannexons, 22 Papillae, 162, 399 circumvallate papillae, 162 foliate papillae, 162 fungiform papillae, 162 Para-aminohippurate (PAH), 418, 432 Paracrine, 499 communication, 500 signaling, Paradoxical potassium retention, 470 Paradoxical reflex, 388 Parafollicular cells, 633 Parageusia, 163 Parallel fibers, 174 Paralytic ileus, 723 Paraplegia, 131 Parasomnias, 187 Parasternal intercartilaginous muscles, 311 Parasternal intercostal muscle, 315 Parasympathetic ganglia, 60, 71 Parasympathetic nerves, 286 Parasympathetic nervous system (PNS), 80, 101, 177, 180f, 523, 692 Parasympathetic tone, 216 Parasympathetic vasodilator nerves, 268 Parathyroid adenoma, 653 Parathyroid Ca2+-sensing receptor, 644f Parathyroid gland hyperplasia, 653 Parathyroid glands, 487, 489, 602f, 611, 643, 644, 649, 653 Parathyroid hormone (PTH), 487–489, 643 cellular effects of, 645–646 clinical evaluation of abnormalities in, 652t hyperplasia of, 653 hypocalcemia, 487 mediated osteoclast differentiation, 647f mobilization of bone calcium, 646–647 production, diseases of primary hyperparathyroidism, 653 pseudohypoparathyroidism, 653 secondary hyperparathyroidism, 653 release, regulation of, 643–644, 644f, 645t and renal calcium rabsorption, 645f and renal inorganic phosphate (Pi) reabsorption, 646f target organs and physiologic effects, 644–645f Paraventricular nucleus, 183, 459, 614f, 615t, 617f, 626 Paresthesia, 122 Parietal cells, 494, 508 ion transport proteins, 513f receptors, schematic representation, 511f ultrastructural appearance, 509f Parietal glands, 508 Parietal lobe, 169 Parkinsonism, 183 Parkinson’s disease, 64, 172, 183 Parotid glands, 522, 523 Paroxysmal hypertension, 667 Paroxysmal nocturnal dyspnea, 283 Partial pressure of alveolar oxygen, 754 Partial seizures, 185, 196 Parturition, 617 Parvocellular cells, 141 Parvocellular neurons, 615 Parvo (P) cells, 141 Passive diffusion, 253 Passive electrical properties, 39 long cylindrical cell, 39–41 small round cell, 39 Passive transport, 26 Patent foramen ovale, 741 Pathologic anatomic shunts, 355 Pathophysiology, Peak expiratory flow (PEF), 326, 384 Pedicels, 411 Pelvic nerves, 554 Penile meatus, 692 Pepsin, 507 secretion, regulation, 511f cephalic phase, 511 gastric phase, 512 intestinal phase, 512 Pepsinogen, 507 PEPT1, 531, 590 Peptic ulcer disease, 514 Peptides, 64, 504 disposition in intestinal epithelial cells, 590f luminal digestion, 589f transporters, 589–590 peptide transporter (PEPT1), 531, 589 Peptide YY, 502 Percentage of inspired oxygen (FIO2), 355 Percussion, 329 Periaqueductal gray matter (PAG), 120 Pericardium, 203 Periglomerular cells, 159 Perilymph, 149 Perineurium, 112 Peripheral chemoreceptors, 392 Peripheral edema, 742 Peripheral motor control system, 130f Peripheral nervous system, 66, 105–107, 601 Peripheral neuropathy, 126 Peripheral peaking of pulse pressure, 258 Peripheral thermoreceptors, 730 Peripheral vascular system, 252 arterioles, 207 blood vessels, control of, 207 capacitance vessels, 207 capillaries, 207 conduit vessels, 207 structural characteristics, 206 transmural distending pressure, 207 Peripheral venous compartment, 275 Peripheral venous pool, 258 Peripheral venous pressure, 259, 262, 278, 288f, 299 influence on venous return, 279 Peristalsis, 544–547, 555 control of, 546f, 547f primary, 546f secondary, 546, 547f Peritoneal cavity, 399, 563 Permeability, 4, 21, 26, 253 glomerular, 431 hydraulic, 412 ionic, 35 to K+, 37 passive, 524 to sodium ions, 48 to water, 438, 443, 444, 459, 618 Permeable membrane, 26 permeant/permeate substance, 26 Pernicious anemia, 120 Peroxisome proliferator-activated receptor-γ (PPAR-γ), 719 Perturbation, 1, 6, 459 of acid–base balance, 471 in renal handling of potassium, 468–470 Pertussis, 25 Peyer’s patches, 535, 536 structure, 536f PGF2α, 346 Phalen’s sign, 122 Pharyngeal dilator muscles, 322 Pharyngeal dilator reflex, 390 Pharynx, 544, 545 movement of food, 546f Phasic contractions, 548 Phenobarbital, 63 Pheochromocytomas, 665, 667, 668 Phonation, 306 Phosphate, 643 balance, 485–486 regulation, 485, 651 renal phosphate handling, 489 homeostasis, 651 Phosphatidylcholine (PC), 15, 568, 594 INDEX Phosphatidylethanolamine (PE), 15 Phosphatidylinositol (PIP2), 15, 16, 101 Phosphatidylinositol bisphosphate, 607 Phosphatidylserine (PS), 15, 16 Phosphodiesterase (PDE), 607, 638, 675, 692 Phospholamban, 57, 94, 221 Phospholipase (PLCβ), 25 Phospholipase A2, 595 Phospholipase C (PLC), 21, 101, 607, 658 Phospholipids, 593 bilayer, organization of, translocators, 15, 16 Phosphosphingolipid, 15 Photoreceptors, 43, 115 mechanism, 138–139 current flow in visual receptors, effect of light on, 138 photosensitive compounds, 139 phototransduction in rods and cones, 139f potentials, ionic basis of, 138 Photosensitive compounds opsin and retinal, 139 rhodopsin, 139 scotopsin, 139 Phrenic nerves, 315 Physiological stresses, 738, 739 cardiovascular responses to, 286 Physiologic dead space, 335 Physiologic reserves, 750 Physiologic shunt, 355 Physostigmine, 70, 77 Picrotoxin, 63 Pigment epithelium, 134 Pigment stones, 572 Pillar cells, 149 Pilocarpine, 524 Pineal gland, 188f, 189, 615 Pinealocytes, 189 Pineal sand, 189 Pituitary, 623 adenoma, 144, 630 and hypothalamus, anatomic and functional relationship, 614f insufficiency, 630 tumor, 144 Pituitary adenoma, 144, 630 Pituitary adenylate cyclase activating peptide (PACAP), 503 Pituitary insufficiency, 630 Pituitary tumors, 142 Placenta, 299, 625 structure and physiologic function, 708 Planum temporale, 195 Plaques, 272 Plasma calcium concentration, physiological responses, 488f Plasma creatinine, 419 steady-state relation, 420f Plasma norepinephrine, 183 Plasma osmolality, 755 Plasma potassium, 467 Plasma transcobalamin II (TC II), 591 Plasma volume, 749 Plateau phase, 55 Platelet-activating factor, 307 Platelet aggregation, 208, 272 Pleural effusion, 282 P loop, 17 Plug formation, 208 Pneumonia, 176, 360, 556, 756 Pneumothorax, 321, 329, 330, 349, 360 PNS See Parasympathetic nervous system (PNS) Podocytes, 411 Poiseuille equation, 203, 258, 322 Poiseuille’s law, 203, 258, 322 Polio or Poliomyelitis, 66, 340 Polycythemia, 742 Polydipsia, 448, 678 Polymeric immunoglobulin receptor (pIgR), 536 Polymodal nociceptors, 116 Polyphagia, 678 Polysomnogram (PSG), 189 Polysynaptic reflexes, 125, 130 Polyuria, 620, 678 Pons, 387 Pontine respiratory groups, 387 Pores of Kohn, 310 Portal circulation, 492 Portal hypertension, 563, 580 Portal triads, 561 Portal vein, 560 Position agnosia, 121 Positive end-expiratory pressure (PEEP), 321, 348 Positive feedback system, 7, 12 Positive-pressure ventilation or breathing, 313, 620 Positive-pressure ventilation with positive end-expiratory pressure, 336 Positive-pressure ventilators, 321 Positron emission tomography (PET), 191 Posterior pituitary gland, 268, 448, 459, 613 anatomic and functional relationship, 614 hormones of, 616–617, 618t synthesis and processing of, 616f Postganglionic fibers, nerves, or neurons, 71, 177, 286 Postmenopausal osteoporosis, 652 Postobstructive polyuria, 644 Postsynaptic cell, 10, 59 Postsynaptic inhibition, 128 Postsynaptic potential (PSP), 11, 59 Postsynaptic processes, 66–67 Post-tetanic potentiation, 71, 192 Posttraumatic diabetes insipidus, 620 Posture, 167 Potassium balance, regulation intracellular and extracellular compartments, 463–464 hormonal regulation of, 724 renal potassium handling, 464–466 distal nephron secretion and regulation, 466–468 perturbations in, 468–470 Potassium channel (KACh), 56 Potassium equilibrium potential, 212 Potassium excretion, 731 Potassium retention, paradoxical, 470 Potassium transport, 466f Potential, membrane, 34 Potentiation, P1 receptors, 21 Precocious puberty, 692, 713 Prednisone, 53, 77, 662, 732 Preganglionic fibers or nerves, 71, 286 Pregnancy, 299, 696 and lacatation, 709 fetoplacental unit hormone synthesis, 710f hormonal control of milk secretion, 711 mammary gland development, 710–711 parturition, hormonal control of, 709–710 tests, 709 Preload, 87 779 cardiac, 228, 230 muscle, 88, 95 shifts, 96 venous return, 747 ventricular, 226 effect of changes, 228 larger, 228 Premature ventricular contractions (PVCs), 243 Preoptic neurons, 188 Presbycusis, 154 Presbyopia, 137 Pressure, transmural, Pressure natriuresis, 455 Pressure–volume curve, 318 Presynaptic cell, Presynaptic inhibition, 75 Presynaptic neuron, 59 Presynaptic processes, 60, 72 Presynaptic terminals, 106 Prevertebral/collateral ganglia, 178 Primary active transport, 27 Primary adrenal insufficiency, 664 See also Adrenal gland Primary amoeboid meningoencephalopathy, 162 Primary colors, 142 Primary/essential hypertension, 292 Primary hyperaldosteronism, 664 Primary hyperparathyroidism, 489 Primary hyperthyroidism, 732 Primary metabolic acidosis, 394 See also Metabolic alkalosis Primary somatosensory area, 169 Primary spontaneous pneumothorax, 330 Primary uncompensated disorder, 481 Primary visual cortex, 141 Principal cells, 403, 443, 466 potassium secretion, 466f Procedural memory, 76 Processivity, 66 Procolipase, 595 Progesterone, 378, 697, 709 antiestrogen actions, 708 metabolic fate of, 705f physiologic actions, 630f, 707–708 receptor–mediated effects, 707–708 receptors, 707 Programmed cell death, 493 See Apoptosis Prolactin, 615, 623, 711 family, 624 physiologic effects of, 630, 630f prolactin release, regulation of, 629–630 Prolactinomas, 630, 631, 692 Prolonged QT intervals, 243 Proopiomelanocortin (POMC), 624, 626 processing, 627f Proopiomelanocortin-derived hormones adrenocorticotropic hormone, 626 β−endorphin, 626 melanocyte-stimulating hormone, 626 Prophospholipase A2, 518 Propranolol, 273 Proprioception, 117, 126 Proprioceptors, 9, 11, 156, 387, 748 Proptosis, 639, 733 Propylthiouracil, 639 Prosopagnosia, 196 Prostacyclin, 346 Prostaglandin 15-dehydrogenase, 708 Prostaglandin E2, 117, 307 780 INDEX Prostaglandins, 117, 307, 529, 533, 708, 732 synthesis of, 617 Prostaglandins G2 and H2, 307 Prostate, 683 Prostatic hyperplasia, 687 Proteases, 517 Protein kinase A, 25, 57, 94, 97, 100, 231, 607, 618, 675 Protein kinase C, 101–102, 607 Protein kinase G, 100, 103 Protein/peptide hormones, 602 synthesis, 603f Protein assimilation basic principles, 587–590 barriers to water-soluble macromolecules, 584 brush border hydrolysis, 588–589 luminal proteolysis, 588 oligopeptides/amino acids, uptake mechanisms, 589–590 regulation, 590 role and significance, 583 vs carbohydrate assimilation, 587–588 digestion and absorption, 583 Proteinuria, 427 Protein zero (P0), 106 Prothrombin, 209 Proton pump, 512 inhibitor, 514 Protoplasmic astrocytes, 105 Proximal convoluted tubule, 405 Proximal stump, 112 Proximal tubule, 405, 423, 429, 737 Pseudohypoparathyroidism, 653 Psilocin, 64 Psilocybin, 64 Psychogenic polydipsia, 448 PTH See Parathyroid hormone (PTH) PTH-related protein (PTHrP), 489, 645 Ptosis, 91 P-type E1–E2 pumps, 23 P-type pumps, 22 Puberty, 189, 629, 690, 707, 711 Puborectalis muscle, 556 Pudendal nerves, 554 Pulmonary blood flow, 341, 355 interaction of gravity and extravascular pressure, 347–348 positive endexpiratory pressure (PEEP), 348 regional distribution, 346–347 zones of lung, 347f Pulmonary capillary blood volume, 360 Pulmonary capillary hydrostatic pressure, 349 Pulmonary circulation, 342 nonrespiratory functions, 350 Pulmonary edema, 30, 247, 283, 348–349, 360 conditions leading to, 349–350 Pulmonary emboli, 336 Pulmonary embolism, 262, 307, 360, 361 Pulmonary embolus, 354, 360 Pulmonary function tests, 333 Pulmonary resistance, 322 Pulmonary sarcoidosis, 322 Pulmonary stretch receptors, 388, 390 Pulmonary surfactant, 307, 321 Pulmonary tissue resistance, 322 Pulmonary vascular congestion, 351 Pulmonary vascular resistance (PVR), 300, 342–343, 748 active influences on, 346t distribution of, 343 lung volume and, 343–344 passive influences on, 346t recruitment and distention, 344–345 Pulmonary vascular smooth muscle control of, 345–346 Pulmonary wedge pressure, 282 Pulse oximetry, 750 Pumps, 16, 22–23 Pupillary light reflex, 143 Purinergic channels, 102 Purinergic (P2) receptors, 21, 179, 456 Purines, 64, 435 Purkinje cells, 174 Purkinje fibers, 54, 214, 216 Purkinje system, 236 PVR See Pulmonary vascular resistance (PVR) P wave, 216, 224 P2X receptors (P2XRs), 21 P2X ATP receptors, 64 P2X4 receptors, 45 P2X3 receptor channels, 45 Pyelogram, 447 Pylorus, 494, 508, 548 Pyramidal cells, 108, 159 Pyramids, 399 Pyrogens, 731, 732f Q QRS complex, 216, 238–239 Quadriplegia, 131 Quanta of ACh, 69 Quisqualate channel, 74 R Rabies, 66 Radiation, 730 Radioactive iodine uptake test, 733 Raloxifene, 652 Raphe magnus nucleus, 120 Raphe nucleus, 287 Rapid eye movement (REM) sleep, 185 Rapidly adapting pulmonary stretch receptors, 390 Rapidly adapting (phasic) receptors, 118 Rapture of deep, 741 Rarefaction, 292, 754 RAS See Renin-angiotensin systems (RAS) Rathke’s pouch, 623 RBF See Renal blood flow (RBF) R-binding protein, 591 Reaction time, 127, 130 Reactive/post-occlusion hyperemia, 265 Rebound phenomenon, 175 Receptive field, 43, 117 Receptive relaxation process, 495, 549 Receptor, 24 Receptor activator of nuclear factor-κβ ligand (RANKL), 646 Receptor desensitization, 667 Receptor downregulation, 608 Receptor kinase, 606f Receptor-linked kinase receptors, 606f, 607 Receptor-mediated endocytosis, 30 Receptor potential, 161 Receptor protein tyrosine kinases, 607 Receptors, 1, 59, 390, 524, 551 See also Cell membrane receptors in airways and lungs, 390 cardiovascular, 390 5HT1 receptors, 551 5HT3 receptors, 551 in muscle, tendons, skin, and viscera, 390 potential, 43 pulmonary vascular, 390 regulating activity of intracellular proteins, 607 Receptor tyrosine kinases (RTK), 25 Reciprocal innervation, 128 Recompression, 741 Recruitment, spatial and temporal, 89 Rectoanal inhibitory reflex, 554 Rectum 553f Rectus abdominis, 311, 556 Red blood cell production, regulation, 398 5α-Reductase inhibitors, 687 Referred pain, 120 Reflection coefficient, 28, 349 Reflex arc, 125, 126f, 131, 499 Reflexes, See also Respiratory reflexes cardiovascular, 288 chemoreceptor, 289 hyperactive stretch, 169 intrinsic, 549, 550 inverse stretch, 128, 129 local, 545 from receptors in heart & lungs, 289 respiratory, 388–390, 389t vagovagal, 510, 519, 546, 549, 550 Reflux, 495 disease, 547 Refraction, 136, 137f Refractory fiber, 89 Refractory period absolute/relative, 51 Regulatory hypothalamic factor, 625 Regulatory systems, 529 Reissner’s membrane, 149 REM sleep, 186–188 Renal acid–base processing, 471–484 Renal angiogram, 461 Renal artery, 399, 409, 414 angioplasty, 462 blockage, 462 obstruction in, 419 pressure, 415, 455 stenosis, 453, 462 Renal artery stenosis, 453, 462 Renal blood flow (RBF), 409–410, 449 afferent arterioles, 409 arcuate arteries, 409 autoregulation, 415–416, 415f cortical radial arteries, 409 efferent arterioles, 409 kidneys flow, resistance, and blood pressure, 410–411 peritubular capillaries, 409 vasa recta, 410 Renal clearance, 417, 418 Renal compensatory mechanisms, 380 Renal failure, 482, 580 chronic, 406, 489 Renal function curves, 292 Renal insufficiency, 630, 664, 722 Renal-MAP set point, 290 Renal microcirculation, 410f Renal plasma flow (RPF), 414, 754 Renal processes See also Nephron catabolism, 403 chloride reabsorption, 439 INDEX excretion, 403 filtration, 403 average values, 405t individual tubular segments collecting duct system, 443–444 distal convoluted tubule, 443 Henle’s loop, 442–443 proximal tubule, 440–442 metabolism by tubules, 405 for sodium, chloride, and water, 437 fundamental elements, 404f glomerular filtration, 404 reabsorption, 403 average values, 405t tubular reabsorption, 404 regional function, overview of, 405–406 renal function, regulation, 405 secretion, 403 tubular secretion, 404–405 sodium reabsorption, 438–439 synthesis, of secreted substances, 403 urinary concentration urea, 445–447 vasa recta, 445 water reabsorption, 439–440 Renal tubular acidosis, 427 Renin, 658 secretion, control, 453f Renin–angiotensin–aldosterone system, 658, 722 aldosterone release, regulation, 661f Renin-angiotensin system, 406, 451–453, 482 ACE inhibitors, 453 angiotensin II receptor blockers (ARB), 453 components of, 452f Renovascular hypertension, 462 Renshaw cell, 130 Reserpine, 64 Reserve, 95 Residual volume (RV), 325, 332 Resistance, Resistance vessels, 207 Resistance work of breathing, 737 Resonator, 152 Respiratory acidosis, 377, 378, 481 causes, 378t Respiratory alkalosis, 378–379, 481, 736 causes, 379t Respiratory compensatory mechanisms, 380 Respiratory control system, 385 organization of, 386f response to carbon dioxide, 390–392 hydrogen ions, 392–393 hypoxia, 394 spontaneous rhythmicity, 386–388 Respiratory gases partial pressures of, 336–337 Respiratory pump, 299, 302 Respiratory rate, 329, 330, 339, 340, 350, 360, 372, 385, 388, 394, 427 Respiratory reflexes, 388, 389t cardiovascular receptors, 390 j receptors, 390 pulmonary stretch receptors, 388, 390 receptors in airways, 390 in muscle, tendons, skin, and viscera, 390 Respiratory rhythm generator, 387 Respiratory system, 305–396 airway resistance, 322 assessment of, 325–329 (see also Flowvolume curves) distribution of, 322 increased, clinical consequences of, 329 lung volume and, 323 alveolar pressure, 314 dynamic compression of airways, 324–325 functions acid–base balance, 306 filtration and removal of inspired particles, by airways, 309 gas exchange, 305, 306f handling of bioactive materials, 307 phonation, 306 pulmonary defense mechanisms, 306–307 pulmonary metabolism, 307 removal of material, from alveolar surface, 311 hypoxia of altitude, 736–737 intrapleural pressure, 314 mechanical interaction between lung and chest wall, 314, 314f, 321–322, 338 medullary respiratory center, 311 muscles of, 311, 315 bronchial smooth muscle, control of, 322–323 expiratory muscles, 317 inspiratory muscles, 315–316 normal tidal breath, events involved in, 317t volume, pressure, and airflow changes during, 318f pressure, flow, and resistance, relationship among, 322 pressure-volume relationships in, 318 alveolar interdependence, 321 clinical evaluation of compliance, 319 compliance of lung and, 318–319 elastic recoil, 319–321 pulmonary surfactant, 321 structure, 307 airways, 307–309 alveolar–capillary unit, 309–310 alveolar septum, 310f human lung parenchyma, 309f pulmonary capillary, 310f transpulmonary pressure, 314 ventilatory response to exercise, 747–749, 748t work of breathing, 329 Respiratory zone, 308 Resting membrane potential, 34, 80, 102, 212, 214 of hair cells, 150 hyperpolarization, 216 Resting potential, 10, 34, 37–38 generation, 35 Kir channels supporting, 38 Restrictive disease, 326, 333, 340 Reticular activating system, 110, 188 Reticular formation, 110, 386 Reticular lamina, 149 Reticuloendothelial system, 575 Reticulospinal tracts, 167, 170 Retina, 134 amacrine cells, 134 bipolar cells, 134 cones, 134 extrafoveal portion, neural components of, 135f ganglion cells, 134 projections from right hemiretina of, 141f 781 responses to light, 140f horizontal cells, 134 optic nerve, 134 processing of visual information in, 139 projection, on primary visual cortex, 141f rod and cone density, 136f rods, 134 visual receptors in, 134–135 Retraction, 316 Retrograde amnesia, 192 Retrograde giant contraction, 552 Retrograde transport, 110 Retropulsion, 550, 551 Reversal potential, 67 Reverse T3 (rT3), 637 Rhodopsin, 44f Rho kinase pathway, 100 Rhythmicity, 240–241 Ribosomes, 2, 603f Rickets, 598, 650 Right atrial pressure (RAP), 747 Right axis deviation, 742 Right heart failure, 284 Right ventricular failure, 742 Right ventricular hypertrophy, 738 Rods of Corti, 149 ROMK potassium channels, 466 activity, 467f Rostral ventrolateral medulla, 183, 287 Rough endoplasmic reticulum (RER), 2, 60, 66, 597 Round window, 149 Rubrospinal tracts, 167 Ruffini corpuscles, 115 Rugae, 508 Ryanodine receptors (RyR), 21, 80, 86, 86f, 94, 101 S Saccades, 143 Saccules, 134, 147, 150, 151f, 154 Safety factor, 53, 350, 366 Saliva constituents, 523 ionic composition, 524f Salivary amylase, 523, 584 Salivary glands, 492, 495, 523 salivatory center, 523 salivatory nuclei, 523 salivary gland anatomy acinar cells, 523 ductular cells, 523 salivary secretion acinar cells, 524 ductular cells, 524 neural regulation, 523–524 role and significance, 522 salivary secretory products, 522–523 Salivary secretory products, 522–523 Salivatory center, 523 Salivatory nuclei, 523 Salmonella, 534 Salt appetite, 461 Saltatory conduction, 52, 106 Salt restriction, 293 SA node, 289 Sarcoidosis, 319, 322, 329, 360, 382 Sarcolemma (SL), 79, 85, 100 sarcoplasmic reticulum (SR) interaction, 93 Sarcomeres, 83 pattern of striation, 84f 782 INDEX Sarcopenia, 753 Sarcoplasmic reticulum (SR), 79, 86, 101, 217, 231 Scalae, 149 Scala media, 149 Scala tympani, 149 Scala vestibuli, 149 Scalene muscles, 311, 315 Scanning speech, 175 Scar formation, 112 S cells, 519 Schaffer collateral LTP, 193 Schizophrenia, 64, 195 Schwann cells, 105, 106, 107f, 112 Scleroderma, 360 Scoliosis, 340 Scuba, 740 Secondary active transport, 27 Secondary hyperparathyroidism, 651 Secondary hypoaldosteronism, 664 Secondary hypothyroidism, 639 Secondary peristalsis, 546 Secondary respiratory alkalosis, 394 Secondary spontaneous pneumothorax, 330 Secondary transporter, 23 Secondary tympanic membrane, 149 Second-degree heart block, 242 Secretin, 499, 501, 519, 568 function, 520f Secretory component, 537 Secretory diarrheal disease, 530f Secretory granules, Secretory immunoglobulin (IgA) molecules, 535 Segmental propulsion, 555 Segmentation, 555 Selectins, 26 Selective estrogen receptor modulators (SERMs), 652 Selective serotonin reuptake inhibitors, 64 Self-contained underwater breathing apparatus (Scuba), 740 Semen, 684 Semicircular canals, 147 Seminal fluid, 684 Seminiferous tubules, 683 Senescence, 690 Senile dementia, 194–195 Sense organ, 115 Sensitization, 541 Sensors, 9, 12 central thermoreceptors, 730 peripheral thermoreceptors, 730 Sensory adaptation, 45 fast and slow, 45f Sensory coding, 117–118 Sensory endings primary (group I) ending, 126 secondary (group II) endings, 126 Sensory fibers, 110 numerical classification for, 110t Sensory generator potential, 10, 43 all-or-none, 10 encoded, 43 graded, 10 Sensory hair cells, 44 Sensory homunculus, 120 Sensory information from peripheral receptors to cerebral cortex, 119f Sensory neuron, 9, 12f, 108, 111, 117, 119f, 149, 159, 160, 162, 502f Sensory receptors, 115, 125 cutaneous mechanoreceptors, 115 nociceptors and thermoreceptors, 115–117 sensory receptors in skeletal muscles & joints, 115–117 Sensory systems, code elementary attributes of, 116f, 117 improving discrimination, 139 Sensory transduction, 43 Sensory unit, 117 Sepsis, 618 Septal ischemia, 222 SERCA pump, 23 Serosal/peritubular membrane, 29 Serotonin (5-HT), 63, 116, 188, 307, 503 receptors, 20 Sertoli cells, 683, 684 Set point, 6, 731 Set point for temperature regulation, 289 Severe sweating, coordinated response to, 461f Sex hormone–binding globulin (SHBG), 686 Sex hormone synthesis, 626 SGLT-1, 531 Shallow water blackout, 740 Shear stress, 257 Sheehan syndrome, 630 Shivering thermogenesis, 730 Shock, 80, 379, 618, 665 Shock lung syndrome, 321 Short bowel syndrome, 598 Shortening maximum velocity of, 88 Short stature, 631 Short-term memory, 76, 192, 196 Shunt equation, 355 Shunt flow, 355 Shunt fraction, 355 Shuntlike states, 355 Shunts, 383 Shy–Drager syndrome, 183 Sickle cell disease, 350, 364 Sildenafil, 692 Silicosis, 329 Simple cells, 142 Simple diffusion, 26 Sinoatrial (SA) node, 54, 93, 212, 228, 236 Sinusoidal endothelium, 561, 562 Sinusoids, 560–563, 569 Sitosterolemia, 596 ABCG5 transporters, 596 ABCG8 transporters, 596 Skeletal muscle, 79–81, 83–91 cell, excitation–contraction coupling, 86 fiber (cell) types, comparison of, 90 glycogenolysis, 715 neuromuscular junction, 85–86 pattern of sarcomeres, 83–84 pump, 269, 297, 747 regulation of contraction in skeletal muscle, 89–90 contraction-length-tension, 88–89 sarcomere within, 84 types of contractions, 86–88 voluntary, 80, 85 Skeletal muscle pump, 269, 297, 747 Sleep and arousal, neurochemical mechanisms promoting, 188 disorders, 187 cataplexy, 187 central sleep apnea, 187 hypersomnolence, 187 narcolepsy, 187 night terrors, 187 nocturnal enuresis, 187 parasomnias, 187 somnambulism, 187 stages, 186–187 distribution of, 187 K complexes, 186 PET scans during REM sleep, 187 pontogeniculooccipital (PGO) spikes, 187 slow-wave sleep, 186 theta rhythm, 186 Sleep–wake cycle, 187–188 circadian rhythms and, 187–189 and melatonin, 189 Slit diaphragms, 411 Slowly adapting (tonic) receptors, 118 Slow-wave sleep, 186, 624 SL voltage-gated calcium channels, 80 Small intestine, 496 chloride secretion, 532f electroneutral NaCl absorption, 532f epithelial layers, morphology of, 493f ion transport mechanisms, 528ft jejunum and ileum, 496 role, 552 Small skeletal muscles stapedius, 147 tensor tympani, 147 Smooth muscle, 79–81, 99–103 contraction, 99–100 influences on, 102f energy, for contraction and relaxation, 100 multiunit versus unitary, 100–101 smooth muscle cell types, comparison of, 100 stimulation, methods of, 101–103 vascular versus visceral, 100–101 Smooth pursuit movements, 144 SNAP-25, 65 SNARE proteins, 65 Sneeze, 390 S-nitrosohemoglobin (SNO-Hb), 368 SNS See Sympathetic nervous system (SNS) Sodium excretion, regulation and angiotensin II, 454–455 and autoregulation, 456–457 and ECF volume, 453–454 glomerular filtration rate, 453 important variables, 458f long-term control, 455–456 natriuretic peptides, 457–458 pressure natriuresis and diuresis, 455 renin–angiotensin systems, 451–453 summary, 458 vascular resistance, renal control of, 451 intake and loss, normal routes, 438t reabsorption, 731 collecting duct system, 438 comparison with water reabsorption, 439t distal convoluted tubule, 438 Henle’s loop, 438 Na,K-ATPase pumps, 438 pathways for, 440f proximal tubule, 438 summary of mechanisms, 441t transport pathways, 442f, 443f INDEX Sodium-bicarbonate cotransporter (NBC), 521 Sodium channels inactivated, 48 repolarized, 48 Sodium-coupled cotransporters SVCT1/SVCT2, 590 Sodium-coupled nutrient absorption, 531f Sodium-dependent glucose symporter (SGLUT), 430 Sodium/glucose cotransporter SGLT-1 transporter, 531, 586, 587 Sodium–hydrogen exchanger (NHE-1), 513 Sodium–iodide (Na+/I-) symporter, 635 Sodium/potassium/2 chloride cotransporter (NKCC1), 532 Sodium–proton antiporter (NHE3), 426 Sodium reabsorption, 731 Sodium taurocholate cotransporting polypeptide (NTCP), 569 Soluble N-ethylmaleimide-sensitive factor attachment protein (SNAP)-receptor proteins, 65 Soma, 72 Somatic sensory areas somatic sensory area I (SI), 118 somatic sensory area II (SII), 118 Somatomedins, 629 Somatomotor, 183, 290 peripheral organization and transmitters released by, 178f Somatosensory pathways, 118 dorsal column pathway, 118–119 dorsal horn, 118 Somatostatin (SST), 503, 509, 627, 676, 677 Somatotopic organization, 169 Somnambulism, 187 Sound amplitude, 152 bels, 152 decibel scale, 152 frequency, 152 pitch, 152 Sound localization, 153–154 Space constant, 40 Space of Disse, 562, 576 Spasticity, 110, 129, 131, 168, 171, 173 Spatial and temporal facilitation, 130 Spatial recruitment, 89, 90 Spatial summation, 73 Specificity, 24, 576, 605 of CCK and gastrin, 501 of cholesterol esterase, 595 and high affinity, for hormones, 605 of pepsins, 588 positional, of lipases, 594f Specific sensory relay nuclei, 108 Sperm, 683 and accessory organs for production, 684t Spermatogenesis, 690–691 key events in, 691f and functional importance, 691t regulation of, 691 Spermatogonia, 683 Spermatozoa, 683 Spermiation, 690 Sphincter of Oddi, 494, 518, 562 Sphincters, 494, 554 external anal sphincter, 554 ileocecal valve, 554 internal anal sphincter, 554 lower esophageal sphincter (LES), 495, 508, 544 rectoanal inhibitory reflex, 554 upper esophageal sphincter, 544 Sphingolipids, 15 Sphingomyelin, 15 Sphygmomanometry, 297 Spina bifida, 340 Spinal cord, 105, 385 lateral spinothalamic tract, 119 Spinal cord injury (SCI), 131 Spinal integration, 131 Spinal motor neurons, 167 Spinal nerves, 107 Spinal shock, 131 Spinal ventral roots, 125 Spindle sensitivity, 129 Spinocerebellum, 174 Spinoreticular pathway, 119 Spinothalamic tract, 115 Spiny stellate cells, 109 Spiral ganglion, 149 Splanchnic circulation schematic anatomy, 497f Splanchnic nerve, 548 Spleen, 560f, 575, 740 Stagnant hypoxia, 383 Staircase phenomenon, 94 Standard 12-lead electrocardiogram, 240 Standard lung capacities, 331 Standard lung volumes, 331 Starch, 584 Starling equation, 348 Starling forces, 426 Starling hypothesis, 254 Starling’s law of heart, 205, 277 Stasis, 360 Static compliance, 319 Static response, 126 Steady state, 37 Steatorrhea, 512 Stellate cells, 175, 561 Stenosis, 272, 462 aortic, 246, 248 mitral, 246f, 247, 349 renal artery, 453, 462 Stents, 273, 750 Stercobilinogens, 577 Stercobilins, 577 Stereocilia, 150 Stereognosis, 121 Sternocleidomastoid, 311 Steroid hormone receptors, 24 and mineralocorticoid specificity, 662f Steroid hormones, 602 alterations in synthesis, 659f androgens, 655 cholesterol esterase, 656 corticosterone, 656 cortisol, 656 cytochrome P450 sidechain cleavage (SCC) enzyme, 656 DHEA and DHEA sulfate (DHEAS), 656 glucocorticoids, 655 mineralocorticoids, 655 receptors and mineralocorticoid specificity, 662f steroidogenic acute regulatory (StAR) protein, 656 synthesis and metabolism, key enzymes, 658t target organ cellular effects, 660–661 zona fasciculata, 656 783 zona glomerulosa, 656 zona reticularis, 656 Steroidogenesis See Sex hormone synthesis Steroidogenic acute regulatory (STAR) protein, 656 Steroid receptor superfamily, 607 Stethoscope, 226 Stimulatory G proteins, 217 Stimulus-secretion reflex, 629 Stomach, 495, 547 antrum, 548 cardia, 495, 548 corpus, 548 functional regions, 495f, 548f antrum, 508 cardia, 508 fundus, 508 gastric glands, 508 gastric pits, 508 gastrin, 508 lower esophageal sphincter, 508 oxyntic glands, 508 rugae, 508 fundus, 548 gastric glands, 495 intrinsic and vagovagal reflexes, 550f phasic and tonic contractions, 548 pylorus, 548 receptive relaxation, 495 Stones See also Gallstone disease; Kidney, stone formation, 485 Storage-operated channels (SOC), 102 Strabismus, 137 Stratified squamous epithelium, 493 Strenuous exercise blood flow in skeletal muscle, 271 cardiac output, 227, 270, 359 diffusion limitation of oxygen transfer during, 359 lactic acidosis associated with, 474 left ventricular output, distribution of, 747f oxygen consumption rate, 270 Stretch receptors, 386, 388 Stretch reflex, 12, 125–126 pathways responsible for, 128f Striatum, 171 Stricture, 556 Stroke, 130 Stroke volume (SV), 95, 228, 258 influences on, 228 cardiac muscle contractility, 229–230 cardiac output, 230f Starling’s law, 228 ventricular afterload, 228–229 Strong acid, 375 Structural interdependence of alveoli, 321 Strychnine, 63 ST segment depression, 750 Subfornical organ, 619 Sublingual gland, 523 Submandibular gland, 523 Submucosal gland cells, 307 Substance P, 116, 265, 503, 545 Substantia gelatinosa, 118 Sucrase, 585 Sucrase-isomaltase, 586 Sucrose, 584, 586 bush border digestion ad assimilation, 586f Sulfonyl urea receptor, 673 Sulfur-containing amino acids, 473 Summation, 89 784 INDEX Suppression scotoma, 137 Suprachiasmatic nucleus, 188, 615, 623 Supraventricular abnormalities, 240–241 Supraventricular arrhythmias, 242f Supraventricular tachycardia, 232, 241, 242 Surface mucous cells, 509 Surface tension, 319 Sustaining collateral, 111 SVR See Systemic vascular resistance (SVR) Swallowing center, 544 Sweat glands, 730 Sylvian fissure, 118, 119, 195 Sympathetically mediated vasoconstriction, 738 Sympathetic celiac plexus, 405 Sympathetic chain, 178 Sympathetic ganglia, 71 Sympathetic nerves, 286 Sympathetic nervous system (SNS), 80, 94, 101, 177, 180f, 268, 524, 745 Sympathetic paravertebral ganglion, 178 Sympathetic preganglionic and postganglionic fibers, 179f Sympathetic tone, 216 Sympathetic vasoconstrictor nerves, 267 Sympathomimetic effects, 638 Synapse, 6, 10, 40, 59, 62, 67, 71, 73, 74, 119, 126, 178, 188, 497, 571 Synaptic cleft, 11, 59, 68 Synaptic currents integration, 73–74 Synaptic knobs, 106 Synaptic plasticity, 192 Synaptic release, 64–66 Synaptic transmission depression, 70, 71f facilitation, 70–71, 71f posttetanic potentiation (PTP) of, 71f Synaptic vesicle docking, 60f Synaptotagmin, 66 Syncope, 210, 289, 290 Syncytium, 93, 205 Syndrome of inappropriate ADH secretion, 620 Synovial fluid, Systemic anaphylaxis, 541 Systemic and pulmonary circulations differences in pressure, 343 Systemic cardiovascular circuit, 276f Systemic hypertension, 292 Systemic vascular resistance (SVR), 258, 343, 638, 739, 747 Systole, 56, 204, 221, 224, 225, 229, 247, 269, 270 Systolic compression, 269 Systolic heart failure, 245, 282, 283f T Tachycardia, 232, 241, 242f, 243f, 301, 350, 361, 640, 667 Tachykinins, 503 neurokinin A, 503 substance P, 503 Tachyphylaxis, 667 Tachypnea, 350, 361, 372, 427 Tactile acuity, 117 Tactile agnosia, 121 Taenia coli, 553 Taste buds, 161–163 basal cells, 161 dark cells, 162 intermediate cells, 162 light cells, 162 Taste cells type I, II, and III, 162 Taste modalities, 162 Taste pathways, 161–162, 164f Tau protein, 194, 755 T-cells, 535 receptor, 536 Tectospinal tracts, 167, 170f Temperature-regulating mechanisms, 731f Temporal bone, 149 Temporal lobe, 191, 195, 196 Temporal recruitment, 89 Temporal summation, 39, 73 Tension, 86–88 developed tension, 88 passive tension, 88 total tension, 88 Tension pneumothorax, 330 Terminal buttons/boutons, 106 Testosterone, 683 biosynthesis and metabolism, 688f diseases of, 692–693 receptor-mediated effects of, 687f specific actions of, 689t Tetanic contractions, 89 Tetanus, 66, 89 toxin, 63 Tetany, 52, 653 Tetraiodothyronine (T4), 602, 634 Tetrodotoxin (TTX), 53 Thalamic fasciculus, 171 Thalamic reticular nucleus, 108 Thalamostriatal pathway, 171 Thalamus, 107, 108, 111, 119, 154, 160, 161f, 164f, 167, 171, 173 Thermal nociceptors, 115 Thermoreceptors, 115 cold and warm receptors, 115 Thermoregulation, 715 Thermostatic set point, Thermostat signals, Theta rhythm, 186 Thiazide diuretics, 443 Thiazolidinedione drugs, 719 Third degree (total) AV nodal heart block, 221 Third-degree heart block, 242 Thoracic duct, 597–598 Thoracoabdominal pump, 299, 747 Threshold, 47 Thrombi, 272 Thrombin, 209 Thromboembolus, 361 Thrombolytic drugs, 361 Thrombophlebitis, 262 Thrombosis, 360 Thromboxane, 208, 346 Thymectomy, 77 Thyroglobulin, 633, 634 Thyroid autoimmune disease, 634 Thyroid-binding globulin (TBG), 637 Thyroidectomy, 733 Thyroid gland calcitonin, 633 colloid, 633 euthyroid, 638 follicular (epithelial) cells, 633 functional anatomy thyroid follicle, 633 hypothalamic–pituitary–thyroid axis, evaluation, 640 iodide concentration, mechanism, 635f iodine metabolism in thyroid follicular cell, regulation, 635–636 key features of, 636t parafollicular cells, 633 regulation and function, 636t thyroglobulin, 633 thyroid hormone, 731, 732 Thyroid hormone, 731, 732 biologic effects, 637–638 diseases of, 638 hyperthyroidism, 639 hypothyroidism, 638–639 inotropic and chronotropic effects of, 638 iodine metabolism, 639–640 metabolism, 637, 637f organ-specific effects, 638 release, regulation, 636 synthesis, 634–635, 636f transport and tissue delivery, 637 Thyroid hyperplasia, 634 Thyroiditis, 634, 639 chronic, 640 Thyroid peroxidase, 636 Thyroid-stimulating hormone (TSH), 615, 623, 633, 634, 640, 732 Thyroid-stimulating immunoglobulins (TSI), 639 Thyroid storm, 731, 733 See Hyperthyroidism Thyrotoxicosis, 732 thyroid storm, 733 Thyrotropin releasing hormone (TRH), 625, 633 Thyrotropin-secreting tumors, 630 Thyroxine, 732 Thyroxine-binding globulin, 707 Tidal volume (VT), 329, 331 Tight junctions, 6, 29 Time constant, 39 Tinel’s sign, 122 Tinnitus, 156 Tip links, 150 Tissue plasminogen activator (tPA), 209 Tissue pressure hypothesis, 266 Titin, 85 Titratable acidity, 480 Toll-like receptors, 536 Tonic–clonic seizure, 185 Tonic contractions, 548 Tonicity, 28 Tonsils, 308 Total body water, 200, 755 Total cholesterol, 707 Total CO2, 377 Total lung capacity (TLC), 322, 332, 750 Total peripheral resistance (TPR), 232, 258, 264, 285, 292, 299, 302, 343, 450, 451, 453, 460 Toxic nodules, 635 Tracheobronchial tree, 307 Transcapillary fluid movement, 254–255 Transcapillary solute diffusion, 253–254 pathways, 253f Transcellular processes, 425 Transcortin, 658, 707 Transcytosis, 30 Transducers, 43, 115 Transducin, 44f, 45, 139, 139f Transepithelial transport mechanisms, 527 Transient ischemic attack (TIA), 210 Transient receptor potential (TRP), 45 Transient shrinking, 29 Transitional zone, 308 Transmembrane protein, 2f, 194, 607 INDEX Transmembrane solute transport, mechanisms, 424f Transmitter–receptor interaction, 69–70 Transmitters, 10–11, 59 Transmural distending pressure, 207 Transmural pressure gradient, 265, 314, 343 Transport across cell membranes, 26 active, 27 facilitated, 27 passive, 26–27 Transport across epithelial cells, 29–30 Transporters, 16, 23, 424 types of, 24f Transport mechanisms classification, 426 Transpulmonary pressure, 314, 318, 338–339 Transthyretin, 637 Transverse tubules, 11 Traumatic pneumothorax, 330 Traveler’s diarrhea, 534 Trefoil factors, 507 Tremor, 171, 173 Tremor at rest, 173 Treppe, 94 T1R3 family, 163 T2R family, 163 Triiodothyronine (T3), 602f, 634, 733 Trochlear nerves, 143 Tropic hormones, 623 Tropomyosin, 83 Troponin, 80, 83, 94 TnC, 83 TnI, 83 TnT, 83 Trousseau’s sign, 648 Trypsin, 517, 588 Trypsin inhibitors, 517 Trypsinogen, 517, 588 Tryptophan hydroxylase, 64 T score, 652 TSH receptor, 733 t-SNARE syntaxin, 65 T-tubule, 86, 94 T-type calcium channels, 55 D-Tubocurare, 70 Tubular maximum (Tm), 418, 426 Tubular osmolality, 447f Tubular potassium transport, 465t Tubular transport mechanisms limits on rate Tm and gradient-limited systems, 426–427 paracellular route, 424 proximal tubule reabsorption, 423–426 transcellular and paracellular reabsorption, 424f transcellular route, 424 Tubuloglomerular feedback, 456 Tubulovesicles, 509, 512 Tufted cells, 159 Tumor necrosis factor, 731 Turbulent flow, 257, 322 T wave, 215f, 216, 226, 236, 237, 239, 241, 242, 248, 360 Twitch, 88 Two-point discrimination test, 117 Tympanic membrane, 147 Tympanic reflex, 152 Type A intercalated cells, 475 Type B intercalated cells, 476 Type diabetes mellitus, 394, 587 Type diabetes mellitus, 292, 406 Type I alveolar cells, 310 Type II alveolar epithelial cells, 307 Tyrosine hydroxylase (TH), 63, 665 Tyrosine kinases, 629 Tyrosine-tyrosine, 502 U UDP glucuronyl transferase (UGT), 576 Ulcerative, 538 Ulcerative colitis, 534 Unacclimatized person, 736 Uncal herniation, 171 Uncompensated respiratory alkalosis, 361, 384 Unidirectional efflux, 27 Unidirectional influx, 27 Uniporters (UT family) transports, 434 Unloading oxygen, at tissues, 366 Upper endoscopy, 556 Upper esophageal sphincter, 544 Upper motor neuron lesion, 130 Upper motor neurons, 168 Urate, 432–433 Urea, 433–435, 445–447 Urea cycle, 578, 579, 580f See also KrebsHenseleit cycle Urea disposition, 579–580 Ureases, 579 Uremia, 434, 653 Ureter, 399f, 400, 403, 414, 435, 444, 447 Urethra, 399f, 684 Uric acid, 208, 398, 405, 432, 435 Urinary system anatomy, 399 in female, 399f Urobilinogens, 539, 577 Urobilins, 577 Urolithiasis, 653 Ursodeoxycholic acid, 566 Uterine contractility, 708 Utricle, 147, 149f, 150, 154, 155f V Vagal communication, 503 Vagovagal reflexes, 510, 529 Vagus nerves, 60, 162, 178, 216, 323, 390, 503, 509, 545, 547, 552f Valsalva maneuver, 299 Valve abnormalities, common, 246 Vanilloid receptor, 45 VR1 for, 45 Vanillylmandelic acid (VMA), 665 Variable obstructions, 326 Varicocele, 692 Vasa recta, 409, 445 Vascular bed, 753 stiffening (see Arteriosclerosis) Vascular control mechanisms, 269 in specific organs, 269 cerebral blood flow, 271–272 coronary blood flow, 269–270 skeletal muscle blood flow, 270–271 Vascular function, basic, 255 arteries and veins, elastic properties, 259 blood flow velocities, peripheral, 256–258 blood volumes, peripheral, 258 and flow in networks of vessels, 255–256 resistance, 255–256 vascular resistances, peripheral, 258 Vascular pressure effect of gravity on, 296f responses to changes in body position, 296–297 785 Vascular smooth muscle, 263–264 Vascular tone, 264 Vasculature, 206–207, 257, 267, 336, 404, 445, 451, 563, 619 blood vessels, control of, 207 Vas deferens, 683 Vasoactive intestinal polypeptide (VIP), 64, 265, 501, 503, 521, 529, 547, 630 Vasopressin, 64, 268, 302 Vasovagal syncope, 210, 289 Venoconstriction, 268 Venous admixture, 355 Venous capacitance, 747 Venous function curve, 278 Venous return, 277, 747f Venous tone control of, 268–269 Ventilation–perfusion mismatch, 355 Ventilation-perfusion ratio, 748 matching, 737 mismatching, 754 Ventilation–perfusion ratio line, 355 Ventilation-perfusion ratio matching, 737 Ventilation-perfusion relationships and ratios, 353–356 alveolar–arterial oxygen difference, 355–356 increased, causes of, 356t mismatched, testing for, 355 physiologic dead space, 355 physiologic shunts, 355 shunt equation, 355 regional differences in lung, 356–357 distribution, 357f ventilation–perfusion ratios, 353–355 high and low, consequences of, 353–355 Ventral anterior/lateral nuclei, 108 Ventral cochlear nuclei, 153 Ventral posterior lateral (VPL), 108 nucleus, 118 Ventral posteromedial, 108 nucleus, 162 Ventral respiratory groups (VRG), 386 Ventricular abnormalities, 242–244 Ventricular arrhythmias, 243f Ventricular depolarization, 238, 239 and generation of QRS complex, 239f Ventricular fibrillation, 243 Ventricular gallop rhythm, 226 Ventricular repolarization, 239 and T wave, 239f Ventricular systole, 225 Ventricular tachycardia, 243 Ventrolateral spinothalamic tract, 119–120 Verapamil, 273 Vermis, 174, 175 Vertigo, 156, 552 Vesicles, 10, 60 Vestibular movements, 144 Vestibular schwannoma, 162 Vestibular system, 154 Deiters’ nucleus, 154 vestibular apparatus, 154 vestibular nuclei, 154 Vestibulo-ocular reflex, 155 Vestibulospinal tracts, 167 Vibratory sensibility, 120 Vibrio cholerae, 533 Vibrissae, 308 Villus structures, 493 VIP See Vasoactive intestinal polypeptide (VIP) Virilization, 657 786 INDEX Visceral senses, 159 Visual acuity, 134 Visual agnosia, 121 Visual evoked potential test, 112 Visual field exam, 144 Visual pathways, 139–141, 140f optic pathways, effect of lesions in, 142 macular sparing, 142 primary visual cortex, 141–142 Vital capacity (VC), 325, 332, 334 Vitamin A, 139 Vitamin B12, 507 Vitamin D toxicity, 650 Vitamins, 590 homeostasis, 590 vitamin A, retinoic acid, 594 vitamin B12, 507, 591 deficiencies, 120 gastrointestinal absorption, 591f vitamin C, 590 (See also Ascorbic acid) vitamin D, 486, 643 abnormal levels, 650 active form, 398 analogs, 653 calciferol, 594 cellular effects of, 650 1,25-(OH)2D; calcitriol, 487 insufficiency, 755 metabolism and physiologic effects at, 649f production, regulation, 398 synthesis and activation, 649–650 vitamin E, tocopherol, 594 vitamin K, 594 Vmax, 88, 96, 96f Voltage-activated L-type CaV channels, 54 Voltage clamping, 49–51 circuit for squid giant axon, 49 Voltage-dependent Ca2+ channels, 673 Voltage-dependent K channels (KV), 49 topology of monomer, 19f Voltage-dependent Na (NaV) channels, 19, 48 Voltage-gated channels, 213, 485 Voltage-sensitive Ca2+ channels (CaV), 19 Voltage-sensitive channels, 11 voltage-sensitive Ca2+ channels (CaV), 11, 19 voltage-sensitive Na channels (NaV), 11, 19 role of, 47–49 Voltage-sensitive Na channels (NaV), 11, 19 role of, 47–49 Voluntary movement, 167, 168f, 169 Voluntary muscle, 80, 85 Vomiting, 156, 279, 379, 394, 474, 489, 551–552, 563 neural pathways, 552f v-SNARE synaptobrevin, 65 V-type H+ pump, 23, 60 W Wallerian degeneration, 66, 111 Warfarin, 262 Wasting syndrome, 718 Water balance concept, regulation, 397–398 diuresis, 444 excretion, regulation, 458 ADH secretion, baroreceptor control, 459–460 ADH secretion, osmoreceptor control, 459 goals, 449 mechanism, 459f, 460f plasma volume pathway, 457f thirst and salt appetite, 460–461 gain and loss, normal routes, 439t insensible loss, 439 obligatory water loss, 440 reabsorption, 439–440 pathways for, 440f Water-soluble vitamins, 429 assimilation, 590–591 vitamin B12 (cobalamin), 591 vitamin C, 590 digestion and absorption, 583 Weak acid, 375 Weber and Schwabach tests, 154 Wernicke’s area, 195 White rami communicans, 178 Willebrand factor, 208 Wirsung’s duct, 518 Withdrawal reflex, 116 Wolff-Chaikoff effect, 636 Working memory, 192–194 Work of breathing, 329, 748 X Xenobiotics, 560 Z Zones of the lung, 346–348 Zone-specific, adrenal steroid hormone synthetic pathway, 657f Z score, 652 Zymogen granules, 518 ... McGraw-Hill Medical, 20 07 alkalosis Similarly, an alkalemia could represent more than one cause of alkalosis, an alkalosis with some compensation, or even an alkalosis and a separate underlying acidosis.)... arterial Po2 was 55 mm Hg, the arterial Pco2 was 32 mm Hg, the arterial pH was 7. 52, and the bicarbonate was 25 mEq/L, indicating hypoxemia and uncompensated respiratory alkalosis Asthma is an episodic... INTERPRETATION OF ARTERIAL BLOOD GASES Samples of arterial blood are usually analyzed clinically to determine the “arterial blood gases”: the arterial Po2, Pco2, and pH The plasma bicarbonate can then