CHAPTER 24 The Regulation of Fluid and Electrolyte Balance 425 (C) K secreted in the loop of Henle isotonic saline (0.9% NaCl) results in course for teaching renal physiology. (D) K secreted by the cortical increased Adv Physiol Education collecting duct (A) Intracellular fluid volume 1998;20:S114–S245. (E) K secreted by the inner (B) Plasma aldosterone level Giebisch G. Renal potassium transport: medullary-collecting duct (C) Plasma arginine vasopressin (AVP) Mechanisms and regulation. Am J 17.Which of the following set of values concentration Physiol 1998;274:F817–F833. would lead you to suspect that a (D) Plasma atrial natriuretic peptide Hoenderop JGJ, Willems PHGM, Bindels person has syndrome of inappropriate (ANP) concentration RJM. Toward a comprehensive molecu- secretion of ADH (SIADH)? (E) Plasma volume, but no change in lar model of active calcium reabsorp- Plasma Urine other body fluid compartments tion. Am J Physiol Osmolality Plasma Osmolality 20.The kidneys of a person with congestive 2000;278:F352–F360. (mOsm/ [Na ] (mOsm/ heart failure avidly retain Na . The best Koeppen BM, Stanton BA. Renal Physiol- kg H 2 O) (mEq/L) kg H 2 O) explanation for this is that the ogy. 3rd Ed. St. Louis: Mosby-Year (A) 300 145 100 (A) Effective arterial blood volume is Book, 2001. (B) 270 130 50 decreased Kumar R. New concepts concerning the (C) 285 140 600 (B) Extracellular fluid volume is regulation of renal phosphate excre- (D) 270 130 450 decreased tion. News Physiol Sci (E) 285 140 1,200 (C) Extracellular fluid volume is 1997;12:211–214. 18.A dehydrated hospitalized patient increased Quamme GA. Renal magnesium handling: with uncontrolled diabetes mellitus (D) Total blood volume is decreased New insights in understanding old has a plasma [K ] of 4.5 mEq/L (E) Total blood volume is increased problems. Kidney Int (normal, 3.5 to 5.0 mEq/L), a plasma 1997;52:1180–1195. [glucose] of 500 mg/dL, and an SUGGESTED READING Rose BD. Clinical Physiology of Acid-Base arterial blood pH of 7.00 (normal, Adrogue HJ, Madias NE. Hypernatremia. and Electrolyte Disorders. 4th Ed. New 7.35 to 7.45). These data suggest that N Engl J Med 2000;342:1493–1499. York:McGraw-Hill, 1994. the patient has Adrogue HJ, Madias NE. Hyponatremia. Valtin H, Schafer JA. Renal Function. 3rd (A) A decreased total body store of K N Engl J Med 2000;342:1581–1589. Ed. Boston: Little, Brown, 1995. (B) A normal total body store of K Braunwald E. Edema. In: Fauci AS, et al., Vander AJ. Renal Physiology. 5th Ed. New (C) An increased total body store of K eds. Harrison’s Principles of Internal York: McGraw-Hill, 1995. (D) Hypokalemia Medicine, 14th Ed. New York: Mc- Weiner ID, Wingo CS. Hyperkalemia: A (E) Hyperkalemia Graw-Hill, 1998;210–214. potential silent killer. J Am Soc 19.Intravenous infusion of 2.0 L of Brooks VL, Vander AJ, eds. Refresher Nephrol 1998;9:1535–1543.
CHAPTER Acid-Base Balance 25 George A. Tanner, Ph.D. 25 CHAPTER OUTLINE ■ A REVIEW OF ACID-BASE CHEMISTRY ■ RESPIRATORY REGULATION OF PH ■ PRODUCTION AND REGULATION OF HYDROGEN ■ RENAL REGULATION OF PH IONS IN THE BODY ■ REGULATION OF INTRACELLULAR PH ■ CHEMICAL REGULATION OF PH ■ DISTURBANCES OF ACID-BASE BALANCE KEY CONCEPTS 1. The body is constantly threatened by acid resulting from (mainly proteins and organic phosphates), and by meta- diet and metabolism. The stability of blood pH is main- bolic reactions. tained by the concerted action of chemical buffers, the 7. Respiratory acidosis is an abnormal process characterized lungs, and the kidneys. by an accumulation of CO 2 and a fall in arterial blood pH. 2. Numerous chemical buffers (e.g., HCO 3 /CO 2 , phosphates, The kidneys compensate by increasing the excretion of H proteins) work together to minimize pH changes in the in the urine and adding new HCO 3 to the blood, thereby, body. The concentration ratio (base/acid) of any buffer diminishing the severity of the acidemia. pair, together with the pK of the acid, automatically defines 8. Respiratory alkalosis is an abnormal process characterized the pH. by an excessive loss of CO 2 and a rise in pH. The kidneys 3. The bicarbonate/CO 2 buffer pair is effective in buffering in compensate by increasing the excretion of filtered HCO 3 , the body because its components are present in large thereby, diminishing the alkalemia. amounts and the system is open. 9. Metabolic acidosis is an abnormal process characterized 4. The respiratory system influences plasma pH by regulating by a gain of acid (other than H 2 CO 3 ) or a loss of HCO 3 . the PCO 2 by changing the level of alveolar ventilation. The Respiratory compensation is hyperventilation, and renal kidneys influence plasma pH by getting rid of acid or base compensation is an increased excretion of H bound to uri- in the urine. nary buffers (ammonia, phosphate). 5. Renal acidification involves three processes: reabsorp- 10. Metabolic alkalosis is an abnormal process characterized tion of filtered HCO 3 , excretion of titratable acid, and by a gain of strong base or HCO 3 or a loss of acid (other excretion of ammonia. New HCO 3 is added to the than H 2 CO 3 ). Respiratory compensation is hypoventilation, plasma and replenishes depleted HCO 3 when titratable and renal compensation is an increased excretion of acid (normally mainly H 2 PO 4 ) and ammonia (as NH 4 ) HCO 3 . are excreted. 11. The plasma anion gap is equal to the plasma [Na ] [Cl ] 6. The stability of intracellular pH is ensured by membrane [HCO 3 ] and is most useful in narrowing down possible transport of H and HCO 3 , by intracellular buffers causes of metabolic acidosis. very day, metabolic reactions in the body produce and that [H ] stays relatively constant both outside and inside Econsume many moles of hydrogen ions (H s). Yet, the cells. [H ] of most body fluids is very low (in the nanomolar Most of this chapter discusses the regulation of [H ] range) and is kept within narrow limits. For example, the in extracellular fluid because ECF is easier to analyze than [H ] of arterial blood is normally 35 to 45 nmol/L (pH intracellular fluid and is the fluid used in the clinical eval- 7.45 to 7.35). Normally the body maintains acid-base bal- uation of acid-base balance. In practice, systemic arterial ance; inputs and outputs of acids and bases are matched so blood is used as the reference for this purpose. Measure- 426
CHAPTER 25 Acid-Base Balance 427 ments on whole blood with a pH meter give values for strength of the solution. Note that pK a is inversely propor- the [H ] of plasma and, therefore, provide an ECF pH tional to acid strength. A strong acid has a high K a and a measurement. low pK a. A weak acid has a low K a and a high pK a. A REVIEW OF ACID-BASE CHEMISTRY pH Is Inversely Related to [H ] In this section, we briefly review some principles of acid- [H ] is often expressed in pH units. The following equa- base chemistry. We define acid, base, acid dissociation tion defines pH: constant, weak and strong acids, pK a , pH, and the Hender- son-Hasselbalch equation and explain buffering. Students pH log 10 (1/[H ]) log 10 [H ](3) who already feel comfortable with these concepts can skip where [H ] is in mol/L. Note that pH is inversely related to this section. [H ]. Each whole number on the pH scale represents a 10- fold (logarithmic) change in acidity. A solution with a pH Acids Dissociate to Release Hydrogen Ions of 5 has 10 times the [H ] of a solution with a pH of 6. in Solution An acid is a substance that can release or donate H ; a base The Henderson-Hasselbalch Equation Relates is a substance that can combine with or accept H . When pH to the Ratio of the Concentrations of an acid (generically written as HA) is added to water, it dis- Conjugate Base and Acid sociates reversibly according to the reaction, HA H A . The species A is a base because it can combine with a For a solution containing an acid and its conjugate base, we H to form HA. In other words, when an acid dissociates, can rearrange the equilibrium expression (equation 1) as it yields a free H and its conjugate (meaning “joined in a pair”) base. K a [HA] [H ] (4) [A ] The Acid Dissociation Constant K a Shows the Strength of an Acid If we take the negative logarithms of both sides, At equilibrium, the rate of dissociation of an acid to form [A ] H A , and the rate of association of H and base A –log [H ] log K a log (5) [HA] to form HA, are equal. The equilibrium constant (K a ), which is also called the ionization constant or acid dissoci- Substituting pH for log [H ] and pK a for log K a, we ation constant, is given by the expression get [H ] [A ] [A ] K a (1) pH pK a log (6) [HA] [A] The higher the acid dissociation constant, the more an This equation is known as the Henderson-Hasselbalch acid is ionized and the greater is its strength. Hydrochloric equation. It shows that the pH of a solution is determined by the pK a of the acid and the ratio of the concentration of acid (HCl) is an example of a strong acid. It has a high K a and is almost completely ionized in aqueous solutions. conjugate base to acid. Other strong acids include sulfuric acid (H 2 SO 4 ), phos- phoric acid (H 3 PO 4 ), and nitric acid (HNO 3 ). An acid with a low K a is a weak acid. For example, in a Buffers Promote the Stability of pH 5 0.1 mol solution of acetic acid (K a 1.8 10 ) in water, The stability of pH is protected by the action of buffers. A most (99%) of the acid is nonionized and little (1%) is pres- pH buffer is defined as something that minimizes the change ent as acetate and H . The acidity (concentration of free in pH produced when an acid or base is added. Note that a H ) of this solution is low. Other weak acids are lactic acid, buffer does not prevent a pH change. A chemical pH buffer is carbonic acid (H 2 CO 3 ), ammonium ion (NH 4 ), and dihy- a mixture of a weak acid and its conjugate base (or a weak drogen phosphate (H 2 PO 4 ). base and its conjugate acid). Following are examples of buffers: pK a Is a Logarithmic Expression of K a Weak Acid Conjugate Base Acid dissociation constants vary widely and often are small H 2 CO 3 HCO 3 H numbers. It is convenient to convert K a to a logarithmic (7) (carbonic acid) (bicarbonate) form, defining pK a as 2– H HPO 4 (8) H 2PO 4 (2) pK a log 10(1/K a) log 10K a (dihydrogen phosphate) (monohydrogen phosphate) In aqueous solution, each acid has a characteristic pK a, NH 4 NH 3 H which varies slightly with temperature and the ionic (9) (ammonium ion) (ammonia)
428 PART VI RENAL PHYSIOLOGY AND BODY FLUIDS Generally, the equilibrium expression for a buffer pair basic form of phosphate: H HPO 4 2– H 2PO 4 . Go- can be written in terms of the Henderson-Hasselbalch ing from left to right as strong base is added, OH com- equation: bines with H released from the acid form of the phos- 2– phate buffer: OH H 2PO 4 HPO 4 H 2O. These [conjugate base] reactions lessen the fall or rise in pH. pH pK a log (10) [acid] At the pK a of the phosphate buffer, the ratio 2– [HPO 4 ]/[H 2PO 4 ] is 1 and the titration curve is flattest 0 2– (the change in pH for a given amount of an added acid or For example, for H 2 PO 4 /HPO 4 base is at a minimum). In most cases, pH buffering is effec- 2– [HPO 4 ] tive when the solution pH is within plus or minus one pH pH 6.8 log (11) [HPO 4 ] unit of the buffer pK a. Beyond that range, the pH shift that a given amount of acid or base produces may be large, so The effectiveness of a buffer—how well it reduces pH the buffer becomes relatively ineffective. changes when an acid or base is added—depends on its concentration and its pK a . A good buffer is present in high concentrations and has a pK a close to the desired pH. PRODUCTION AND REGULATION OF Figure 25.1 shows a titration curve for the phosphate HYDROGEN IONS IN THE BODY buffer system. As a strong acid or strong base is progres- sively added to the solution (shown on the x-axis), the re- Acids are continuously produced in the body and threaten sulting pH is recorded (shown on the y-axis). Going from the normal pH of the extracellular and intracellular fluids. right to left as strong acid is added, H combines with the Physiologically speaking, acids fall into two groups: (1) H 2CO 3 (carbonic acid), and (2) all other acids (noncar- bonic; also called “nonvolatile” or “fixed” acids). The dis- tinction between these groups occurs because H 2CO 3 is in equilibrium with the volatile gas CO 2, which can leave the body via the lungs. The concentration of H 2CO 3 in arterial blood is, therefore, set by respiratory activity. By contrast, 9 2 noncarbonic acids in the body are not directly affected by HPO 4 breathing. Noncarbonic acids are buffered in the body and excreted by the kidneys. Metabolism Is a Constant Source 8 of Carbon Dioxide A normal adult produces about 300 L of CO 2 daily from metabolism. CO 2 from tissues enters the capillary blood, where it reacts with water to form H 2CO 3, which dissoci- ates instantly to yield H and HCO 3 : CO 2 H 2O pH 7 H 2CO 3 H HCO 3 . Blood pH would rapidly fall to lethal levels if the H 2CO 3 formed from CO 2 were allowed pK a 6.8 to accumulate in the body. Fortunately, H 2CO 3 produced from metabolic CO 2 is only formed transiently in the transport of CO 2 by the 6 blood and does not normally accumulate. Instead, it is con- verted to CO 2 and water in the pulmonary capillaries and the CO 2 is expired. In the lungs, the reactions reverse: H HCO 3 H 2 CO 3 H 2 O CO 2 (12) 5 As long as CO 2 is expired as fast as it is produced, arte- H 2 PO 4 rial blood CO 2 tension, H 2CO 3 concentration, and pH do not change. Amount of HCl added (mEq) Amount of NaOH added (mEq) Incomplete Carbohydrate and Fat Metabolism A titration curve for a phosphate buffer. Produces Nonvolatile Acids FIGURE 25.1 The pK a for H 2PO 4 is 6.8. A strong acid Normally, carbohydrates and fats are completely oxidized (HCl) (right to left) or strong base (NaOH) (left to right) was to CO 2 and water. If carbohydrates and fats are incompletely added and the resulting solution pH recorded (y-axis). Notice that buffering is best (i.e., the change in pH upon the addition of oxidized, nonvolatile acids are produced. Incomplete oxi- a given amount of acid or base is least) when the solution pH is dation of carbohydrates occurs when the tissues do not re- equal to the pK a of the buffer. ceive enough oxygen, as during strenuous exercise or hem-
CHAPTER 25 Acid-Base Balance 429 orrhagic or cardiogenic shock. In such states, glucose me- Food intake tabolism yields lactic acid (pK a 3.9), which dissociates into lactate and H , lowering the blood pH. Incomplete Digestion fatty acid oxidation occurs in uncontrolled diabetes melli- tus, starvation, and alcoholism and produces ketone body Absorption acids (acetoacetic and -hydroxybutyric acids). These Chemical Respiratory Renal acids have pK a values around 4 to 5. At blood pH, they Cell metabolism buffering response response mostly dissociate into their anions and H , making the of food + + blood more acidic. H H Bound by Sulfate body buffer CO 2 Phosphate Protein Metabolism Generates Strong Acids Chloride CO 2 bases The metabolism of dietary proteins is a major source of H . The oxidation of proteins and amino acids produces Extracellular New fluid strong acids such as H 2 SO 4 , HCl, and H 3 PO 4 . The oxi- [HCO ] HCO 3 - - dation of sulfur-containing amino acids (methionine, cys- 3 teine, cystine) produces H 2 SO 4 , and the oxidation of cationic amino acids (arginine, lysine, and some histidine Extracellular residues) produces HCl. H 3 PO 4 is produced by the oxi- fluid - dation of phosphorus-containing proteins and phospho- CO [HCO ] 3 esters in nucleic acids. 2 H + Excreted (combined with urinary On a Mixed Diet, Net Acid Gain Threatens pH buffer bases) A diet containing both meat and vegetables results in a net Excreted production of acids, largely from protein oxidation. To Sulfate Sulfate some extent, acid-consuming metabolic reactions balance Phosphate Phosphate H production. Food also contains basic anions, such as Chloride Chloride citrate, lactate, and acetate. When these are oxidized to CO 2 and water, H ions are consumed (or, amounting to The maintenance of normal blood pH by the same thing, HCO 3 is produced). The balance of acid- FIGURE 25.2 chemical buffers, the respiratory system, forming and acid-consuming metabolic reactions results in and the kidneys. On a mixed diet, pH is threatened by the pro- a net production of about 1 mEq H /kg body weight/day duction of strong acids (sulfuric, hydrochloric, and phosphoric) in an adult person who eats a mixed diet. Persons who are mainly as a result of protein metabolism. These strong acids are vegetarians generally have less of a dietary acid burden and buffered in the body by chemical buffer bases, such as ECF a more alkaline urine pH than nonvegetarians because most HCO 3 . The kidneys eliminate hydrogen ions (combined with fruits and vegetables contain large amounts of organic an- urinary buffers) and anions in the urine. At the same time, they ions that are metabolized to HCO 3 . The body generally add new HCO 3 to the ECF, to replace the HCO 3 consumed in buffering strong acids. The respiratory system disposes of CO 2. has to dispose of more or less nonvolatile acid, a function performed by the kidneys. Whether a particular food has an acidifying or an alka- linizing effect depends on if and how its constituents are mizes a change in pH but does not remove acid or base metabolized. Cranberry juice has an acidifying effect be- from the body. cause of its content of benzoic acid, an acid that cannot be 2) Respiratory response. The respiratory system is broken down in the body. Orange juice has an alkalinizing the second line of defense of blood pH. Normally, breath- effect, despite its acidic pH of about 3.7, because it contains ing removes CO 2 as fast as it forms. Large loads of acid citrate, which is metabolized to HCO 3 . The citric acid in stimulate breathing (respiratory compensation), which re- orange juice is converted to CO 2 and water and has only a moves CO 2 from the body and lowers the [H 2CO 3] in ar- transient effect on blood pH and no effect on urine pH. terial blood, reducing the acidic shift in blood pH. 3) Renal response. The kidneys are the third line of defense of blood pH. Although chemical buffers in the Many Buffering Mechanisms Protect and Stabilize Blood pH body can bind H and the lungs can change [H 2CO 3] of blood, the burden of removing excess H falls directly on Despite constant threats to acid-base homeostasis, a healthy the kidneys. Hydrogen ions are excreted in combination person maintains a normal blood pH. Figure 25.2 shows with urinary buffers. At the same time, the kidneys add new some of the ways in which blood pH is kept at normal lev- HCO 3 to the ECF to replace HCO 3 used to buffer els despite the daily net acid gain. The key buffering agents strong acids. The kidneys also excrete the anions (phos- are chemical buffers, along with the lungs and kidneys. phate, chloride, sulfate) that are liberated from strong 1) Chemical buffering. Chemical buffers in extra- acids. The kidneys affect blood pH more slowly than other cellular and intracellular fluids and in bone are the first buffering mechanisms in the body; full renal compensation line of defense of blood pH. Chemical buffering mini- may take 1 to 3 days.
430 PART VI RENAL PHYSIOLOGY AND BODY FLUIDS CHEMICAL REGULATION OF PH Proteins Are Excellent Buffers The body contains many conjugate acid-base pairs that act Proteins are the largest buffer pool in the body and are ex- as chemical buffers (Table 25.1). In the ECF, the main cellent buffers. Proteins can function as both acids and chemical buffer pair is HCO 3 /CO 2 . Plasma proteins and bases, so they are amphoteric. They contain many ioniz- inorganic phosphate are also ECF buffers. Cells have large able groups, which can release or bind H . Serum albumin buffer stores, particularly proteins and organic phosphate and plasma globulins are the major extracellular protein compounds. HCO 3 is present in cells, although at a lower buffers, present mainly in the blood plasma. Cells also have concentration than in ECF. Bone contains large buffer large protein stores. Recall that the buffering properties of stores, specifically phosphate and carbonate salts. hemoglobin play an important role in the transport of CO 2 and O 2 by the blood (see Chapter 21). Chemical Buffers Are the First to Defend pH The Bicarbonate/Carbon Dioxide Buffer Pair When an acid or base is added to the body, the buffers just mentioned bind or release H , minimizing the change in Is Crucial in pH Regulation pH. Buffering in ECF occurs rapidly, in minutes. Acids or For several reasons, the HCO 3 /CO 2 buffer pair is espe- bases also enter cells and bone, but this generally occurs cially important in acid-base physiology: more slowly, over hours, allowing cell buffers and bone to 1) Its components are abundant; the concentration of share in buffering. HCO 3 in plasma or ECF normally averages 24 mmol/L. Although the concentration of dissolved CO 2 is lower (1.2 mmol/L), metabolism provides a nearly limitless supply. A pK a of 6.8 Makes Phosphate a Good Buffer 2) Despite a pK of 6.10, a little far from the desired 2– plasma pH of 7.40, it is effective because the system is The pK a for phosphate, H 2 PO 4 H HPO 4 , is 6.8, close to the desired blood pH of 7.4, so phosphate is a good “open.” buffer. In the ECF, phosphate is present as inorganic phos- 3) It is controlled by the lungs and kidneys. phate. Its concentration, however, is low (about 1 mmol/L), so it plays a minor role in extracellular buffering. Forms of Carbon Dioxide. CO 2 exists in the body in sev- Phosphate is an important intracellular buffer, how- eral different forms: as gaseous CO 2 in the lung alveoli, and 2– ever, for two reasons. First, cells contain large amounts of as dissolved CO 2 , H 2 CO 3 , HCO 3 , carbonate (CO 3 ), phosphate in such organic compounds as adenosine and carbamino compounds in the body fluids. 2– triphosphate (ATP), adenosine diphosphate (ADP), and CO 3 is present at appreciable concentrations only in creatine phosphate. Although these compounds primarily rather alkaline solutions, and so we will ignore it. We will function in energy metabolism, they also act as pH also ignore any CO 2 that is bound to proteins in the car- buffers. Second, intracellular pH is generally lower than bamino form. The most important forms are gaseous CO 2 , the pH of ECF and is closer to the pK a of phosphate. (The dissolved CO 2 , H 2 CO 3 , and HCO 3 . cytosol of skeletal muscle, for example, has a pH of 6.9.) Dissolved CO 2 in Phosphate is, thus, more effective in this environment The CO 2 /H 2 CO 3 /HCO 3 Equilibria. than in one with a pH of 7.4. Bone has large phosphate pulmonary capillary blood equilibrates with gaseous CO 2 salt stores, which also help in buffering. in the lung alveoli. Consequently, the partial pressures of CO 2 (PCO 2 ) in alveolar air and systemic arterial blood are normally identical. The concentration of dissolved CO 2 ([CO 2(d) ]) is related to the PCO 2 by Henry’s law (see Chap- ter 21). The solubility coefficient for CO 2 in plasma at 37C is 0.03 mmol CO 2 /L per mm Hg PCO 2 . Therefore, TABLE 25.1 Major Chemical pH Buffers in the Body [CO 2(d) ] 0.03 PCO 2 . If PCO 2 is 40 mm Hg, then [CO 2(d) ] is 1.2 mmol/L. Buffer Reaction In aqueous solutions, CO 2(d) reacts with water to form H 2 CO 3 : CO 2(d) H 2 O H 2 CO 3 . The reaction to the Extracellular fluid right is called the hydration reaction, and the reaction to ← ← Bicarbonate/CO 2 CO 2 H 2O→ H 2CO 3 → H the left is called the dehydration reaction. These reactions HCO 3 ← Inorganic phosphate H 2PO 4 → H HPO 4 2 are slow if uncatalyzed. In many cells and tissues, such as ← Plasma proteins (Pr) HPr → H Pr the kidneys, pancreas, stomach, and red blood cells, the re- Intracellular fluid actions are catalyzed by carbonic anhydrase, a zinc-con- ← Cell proteins (e.g., HHb → H Hb taining enzyme. At equilibrium, CO 2(d) is greatly favored; hemoglobin, Hb) at body temperature, the ratio of [CO 2(d) ] to [H 2 CO 3 ] is ← Organic phosphates Organic-HPO 4 → H about 400:1. If [CO 2(d) ] is 1.2 mmol/L, then [H 2 CO 3 ] 2 organic-PO 4 equals 3 mol/L. H 2 CO 3 dissociates instantaneously into ← ← Bicarbonate/CO 2 CO 2 H 2 O→ H 2 CO 3 → H H HCO 3 . The Hender- H and HCO 3 : H 2 CO 3 HCO 3 son-Hasselbalch expression for this reaction is Bone ← Mineral phosphates H 2 PO 4 → H HPO 4 2 [HCO 3 ] ← Mineral carbonates HCO 3 → H CO 3 2 pH 3.5 log (13) [H 2CO 3]
CHAPTER 25 Acid-Base Balance 431 Note that H 2 CO 3 is a fairly strong acid (pK a 3.5). Its mmol of dissolved CO 2(d) (PCO 2 40 mm Hg). Using the low concentration in body fluids lessens its impact on acidity. special form of the Henderson-Hasselbalch equation de- scribed above, we find that the pH of the blood is 7.40: The Henderson-Hasselbalch Equation for HCO 3 /CO 2 .. Because [H 2CO 3] is so low and hard to measure and be- [HCO 3 ] cause [H 2CO 3] [CO 2(d)]/400, we can use [CO 2(d)] to pH 6.10 log 0.03 PCO 2 represent the acid in the Henderson-Hasselbalch equation: (17) [24] [HCO 3 ] 6.10 log 7.40 [1.2] pH 3.5 log [CO 2(d) ] /400 Suppose we now add 10 mmol of HCl, a strong acid. [HCO 3 ] HCO 3 is the major buffer base in the blood plasma (we 3.5 log 400 log (14) [CO 2(d)] will neglect the contributions of other buffers). From the reaction H HCO 3 H 2CO 3 H 2O CO 2, we [HCO 3 ] predict that the [HCO 3 ] will fall by 10 mmol, and that 10 6.1 log [CO 2(d)] mmol of CO 2(d) will form. If the system were closed and no CO 2 could escape, the new pH would be We can also use 0.03 PCO 2 in place of [CO 2(d)]: [24 10] pH 6.10 log 6.20 (18) [HCO3] [1.2 10] pH 6.1 log (15) 0.03 PCO 2 This is an intolerably low—indeed a fatal—pH. This form of the Henderson-Hasselbalch equation is Fortunately, however, the system is open and CO 2 can useful in understanding acid-base problems. Note that the escape via the lungs. If all of the extra CO 2 is expired and “acid” in this equation appears to be CO 2(d), but is really the [CO 2(d)] is kept at 1.2 mmol/L, the pH would be H 2CO 3 “represented” by CO 2. Therefore, this equation is [24 10] valid only if CO 2(d) and H 2CO 3 are in equilibrium with pH 6.10 log 7.17 (19) each other, which is usually (but not always) the case. [1.2] Many clinicians prefer to work with [H ] rather than pH. The following expression results if we take antiloga- Although this pH is low, it is compatible with life. rithms of the Henderson-Hasselbalch equation: Still another mechanism promotes the escape of CO 2. In the body, an acidic blood pH stimulates breathing, which [H ] 24 PCO 2 /[HCO 3 ] (16) can make the PCO 2 lower than 40 mm Hg. If PCO 2 falls to In this expression, [H ] is expressed in nmol/L, 30 mm Hg ([CO 2(d)] 0.9 mmol/L) the pH would be [HCO 3 ] in mmol/L or mEq/L, and PCO 2 in mm Hg. If PCO [24 10] is 40 mm Hg and plasma [HCO 3 ] is 24 mmol/L, [H ] is pH 6.10 log 7.29 (20) 40 nmol/L. [0.9] An “Open” Buffer System. As previously noted, the pK The system is also open at the kidneys and new HCO 3 of the HCO 3 /CO 2 system (6.10) is far from 7.40, the nor- can be added to the plasma to correct the plasma mal pH of arterial blood. From this, one might view this as [HCO 3 ]. Once the pH of the blood is normal, the stimu- a rather poor buffer pair. On the contrary, it is remarkably lus for hyperventilation disappears. effective because it operates in an open system; that is, the two buffer components can be added to or removed from Changes in Acid Production May the body at controlled rates. The HCO 3 /CO 2 system is open in several ways: Help Protect Blood pH 1) Metabolism provides an endless source of CO 2 , Another way in which blood pH may be protected is by which can replace any H 2CO 3 consumed by a base added changes in endogenous acid production (Fig. 25.4). An in- to the body. crease in blood pH caused by the addition of base to the 2) The respiratory system can change the amount of body results in increased production of lactic acid and ke- CO 2 in body fluids by hyperventilation or hypoventilation. tone body acids, which then reduces the alkaline shift in 3) The kidneys can change the amount of HCO 3 in pH. A decrease in blood pH results in decreased produc- the ECF by forming new HCO 3 when excess acid has tion of lactic acid and ketone body acids, which opposes been added to the body or excreting HCO 3 when excess the acidic shift in pH. base has been added. This scenario is especially important when the endoge- How the kidneys and respiratory system influence blood nous production of these acids is high, as occurs during stren- pH by operating on the HCO 3 /CO 2 system is described uous exercise or other conditions of circulatory inadequacy below. For now, the advantages of an open buffer system (lactic acidosis) or during ketosis as a result of uncontrolled are best explained by an example (Fig. 25.3). Suppose we diabetes, starvation, or alcoholism. These effects of pH on have 1 L of blood containing 24 mmol of HCO 3 and 1.2 endogenous acid production result from changes in enzyme
432 PART VI RENAL PHYSIOLOGY AND BODY FLUIDS Closed Open system system response response - [HCO ] 3 14 - Kidneys [HCO 3 ] Lose add new [HCO 3 - ] 24 - Add Remove CO HCO 3 24 2 10 mmol/L extra because of to blood + strong acid CO 2 [HCO ] - hyperventilation [HCO 3 - ] (excrete H ) 3 14 14 [CO 2(d) ] 11.2 ] 1.2 [CO ] 1.2 ] 1.2 [CO 2(d) 2(d) [CO 2(d) ] 0.9 [CO 2(d) pH = 7.40 pH = 6.20 pH = 7.17 pH = 7.29 pH = 7.40 Normal Normal condition condition 2 The HCO 3 /CO 2 system. This system is re- in mmol/L. See text for details. (Adapted from Pitts RF. Physiol- FIGURE 25.3 markably effective in buffering added strong ogy of the Kidney and Body Fluids. 3rd Ed. Chicago: Year acid in the body because it is open. [HCO 3 ] and [CO 2(d) ] are Book, 1974.) activities brought about by the pH changes, and they are idea is known as the isohydric principle (isohydric meaning part of a negative-feedback mechanism regulating blood pH. “same H ”). For plasma, for example, we can write 2– [HPO 4 ] All Buffers Are in Equilibrium With the Same [H ] pH 6.80 log [H 2 PO 4 ] We have discussed the various buffers separately but, in the body, they all work together. In a solution containing mul- [HCO 3 ] tiple buffers, all are in equilibrium with the same [H ]. This 6.10 log 0.03 PCO 2 Acid load Base load [proteinate ] pK protein log (21) [H-protein] Endogenous acid Systemic Systemic pH production pH If an acid or a base is added to such a complex mixture of (ketoacidosis, lactic acidosis) buffers, all buffers take part in buffering and shift from one form (base or acid) to the other. The relative importance of each buffer depends on its amount, pK, and availability. Systemic The isohydric principle underscores the fact that it is the pH concentration ratio for any buffer pair, together with its pK, that sets the pH. We can focus on the concentration ratio for Negative-feedback control of endogenous one buffer pair and all other buffers will automatically adjust FIGURE 25.4 acid production. The addition of an exoge- their ratios according to the pH and their pK values. nous acid load or increased endogenous acid production result in The rest of this chapter emphasizes the role of the a fall in pH, which, in turn, inhibits the production of ketone HCO 3 /CO 2 buffer pair in setting the blood pH. Other body acids and lactic acid. A base load, by raising pH, stimulates the endogenous production of acids. This negative-feedback buffers, however, are present and active. The HCO 3 /CO 2 mechanism attenuates changes in blood pH. (From Hood VL, system is emphasized because physiological mechanisms Tannen RL. Protection of acid-base balance by pH regulation of (lungs and kidneys) regulate pH by acting on components acid production. N Engl J Med 1998;339:819–826.) of this buffer system.
CHAPTER 25 Acid-Base Balance 433 RESPIRATORY REGULATION OF PH loss of acid or base (e.g., gastrointestinal losses) are small and can be neglected, which normally is the case. The net Reflex changes in ventilation help to defend blood pH. By loss of H in the urine can be calculated from the following changing the PCO 2 and, hence, [H 2 CO 3 ] of the blood, the equation, which shows typical values in the parentheses: respiratory system can rapidly and profoundly affect blood pH. As discussed in Chapter 22, a fall in blood pH stimu- Renal net acid excretion (70 mEq/day) lates ventilation, primarily by acting on peripheral urinary titratable acid (24 mEq/day) chemoreceptors. An elevated arterial blood PCO 2 is a pow- urinary ammonia (48 mEq/day) erful stimulus to increase ventilation; it acts on both periph- urinary HCO 3 (2 mEq/day) (22) eral and central chemoreceptors, but primarily on the latter. Urinary ammonia (as NH 4 ) ordinarily accounts for CO 2 diffuses into brain interstitial and cerebrospinal fluids, about two thirds of the excreted H , and titratable acid for where it causes a fall in pH that stimulates chemoreceptors about one third. Excretion of HCO 3 in the urine repre- in the medulla oblongata. When ventilation is stimulated, sents a loss of base from the body. Therefore, it must be the lungs blow off more CO 2 , making the blood less acidic. subtracted in the calculation of net acid excretion. If the Conversely, a rise in blood pH inhibits ventilation; the con- urine contains significant amounts of organic anions, such sequent rise in blood [H 2 CO 3 ] reduces the alkaline shift in as citrate, that potentially could have yielded HCO 3 in blood pH. Respiratory responses to disturbed blood pH be- the body, these should also be subtracted. Since the gin within minutes and are maximal in about 12 to 24 hours. amount of free H excreted is negligible, this is omitted from the equation. RENAL REGULATION OF PH Hydrogen Ions Are Added to Urine as The kidneys play a critical role in maintaining acid-base It Flows Along the Nephron balance. If there is excess acid in the body, they remove As the urine flows along the tubule, from Bowman’s capsule H , or if there is excess base, they remove HCO 3 . The on through the collecting ducts, three processes occur: fil- usual challenge is to remove excess acid. As we have tered HCO 3 is reabsorbed, titratable acid is formed, and learned, strong acids produced by metabolism are first ammonia is added to the tubular urine. All three processes buffered by body buffer bases, particularly HCO 3 . The involve H secretion (urinary acidification) by the tubular kidneys then must eliminate H in the urine and restore the epithelium. The nature and magnitude of these processes depleted HCO 3 . vary in different nephron segments. Figure 25.5 summarizes Little of the H excreted in the urine is present as free measurements of tubular fluid pH along the nephron and H . For example, if the urine has its lowest pH value shows ammonia movements in various nephron segments. (pH 4.5), [H ] is only 0.03 mEq/L. With a typical daily urine output of 1 to 2 L, the amount of acid the body must Acidification in the Proximal Convoluted Tubule. The dispose of daily (about 70 mEq) obviously is not excreted pH of the glomerular ultrafiltrate, at the beginning of the in the free form. Most of the H combines with urinary proximal tubule, is identical to that of the plasma from buffers to be excreted as titratable acid and as NH 4 . which it is derived (7.4). H ions are secreted by the prox- Titratable acid is measured from the amount of strong imal tubule epithelium into the tubule lumen; about two base (NaOH) needed to bring the urine pH back to the thirds of this is accomplished by a Na /H exchanger and pH of the blood (usually, 7.40). It represents the amount about one third by H -ATPase in the brush border mem- of H ions that are excreted, combined with urinary brane. Tubular fluid pH falls to a value of about 6.7 by the buffers such as phosphate, creatinine, and other bases. end of the proximal convoluted tubule (see Fig. 25.5). The largest component of titratable acid is normally The drop in pH is modest for two reasons: buffering of phosphate, that is, H 2 PO 4 . secreted H and the high permeability of the proximal Hydrogen ions secreted by the renal tubules also com- tubule epithelium to H . The glomerular filtrate and tubule bine with the free base NH 3 and are excreted as NH 4 . fluid contain abundant buffer bases, especially HCO 3 , Ammonia (a term that collectively includes both NH 3 and which soak up secreted H , minimizing a fall in pH. The NH 4 ) is produced by the kidney tubule cells and is se- proximal tubule epithelium is rather leaky to H , so that creted into the urine. Because the pK a for NH 4 is high any gradient from urine to blood, established by H secre- (9.0), most of the ammonia in the urine is present as NH 4 . tion, is soon limited by the diffusion of H out of the For this reason, too, NH 4 is not appreciably titrated when tubule lumen into the blood surrounding the tubules titratable acid is measured. Urinary ammonia is measured Most of the H ions secreted by the nephron are se- by a separate, often chemical, method. creted in the proximal convoluted tubule and are used to bring about the reabsorption of filtered HCO 3 . Secreted Renal Net Acid Excretion Equals the H ions are also buffered by filtered phosphate to form Sum of Urinary Titratable Acid and titratable acid. Ammonia is produced by proximal tubule cells, mainly from glutamine. It is secreted into the tubular Ammonia Minus Urinary Bicarbonate urine by the diffusion of NH 3, which then combines with a In stable acid-base balance, net acid excretion by the kid- secreted H to form NH 4 , or via the brush border mem- neys equals the net rate of H addition to the body by me- brane Na /H exchanger, which can operate in a tabolism or other processes, assuming that other routes of Na /NH 4 exchange mode.
434 PART VI RENAL PHYSIOLOGY AND BODY FLUIDS Acidification in the Distal Nephron. The distal nephron Glutamine Distal convoluted (distal convoluted tubule, connecting tubule, and collect- NH 4 + tubule Collecting ing duct) differs from the proximal portion of the nephron duct pH = 6.7 in its H transport properties. It secretes far fewer H ions, H + NH 3 and they are secreted primarily via an electrogenic H - Na + ATPase or an electroneutral H /K -ATPase. The distal nephron is also lined by “tight” epithelia, so little secreted + H + NH 3 NH 4 + H diffuses out of the tubule lumen, making steep urine-to- blood pH gradients possible (see Fig. 25.5). Final urine pH 2Cl - is typically about 6, but may be as low as 4.5. Na + NH 4 + The distal nephron usually almost completely reabsorbs pH = 7.4 Proximal + the small quantities of HCO 3 that were not reabsorbed by convoluted NH 4 more proximal nephron segments. Considerable titratable tubule H + + NH 3 Na + acid forms as the urine is acidified. Ammonia, which was re- NH 3 absorbed by the ascending limb of the Henle loop and has NH 4 + accumulated in the medullary interstitial space, diffuses as NH 4 + NH 4 + lipid-soluble NH 3 into collecting duct urine and combines H + + NH 3 with secreted H to form NH 4 . The collecting duct ep- Na + ithelium is impermeable to the lipid-insoluble NH 4 , so am- NH 3 monia is trapped in an acidic urine and excreted as NH 4 + (see Fig. 25.5). The intercalated cells of the collecting duct H + H + are involved in acid-base transport and are of two major types: an acid-secreting -intercalated cell and a bicarbon- ate-secreting -intercalated cell. The -intercalated cell has a vacuolar type of H -ATPase (the same kind as is found in NH 4 + lysosomes, endosomes, and secretory vesicles) and an H /K -ATPase (similar to that found in stomach and colon pH = 7.4 epithelial cells) in the luminal plasma membrane and a Cl /HCO 3 exchanger in the basolateral plasma membrane (Fig. 25.6). The -intercalated cell has the opposite polarity. A more acidic blood pH results in the insertion of cyto- pH ~ 6 plasmic H pumps into the luminal plasma membrane of - Acidification along the nephron. The pH of intercalated cells and enhanced H secretion. If the blood FIGURE 25.5 tubular urine decreases along the proximal con- is made alkaline, HCO 3 secretion by -intercalated cells voluted tubule, rises along the descending limb of the Henle is increased. Because the amounts of HCO 3 secreted are loop, falls along the ascending limb, and reaches its lowest values ordinarily small compared to the amounts filtered and re- in the collecting ducts. Ammonia (NH 3 NH 4 ) is chiefly absorbed, HCO 3 secretion will not be included in the re- produced in proximal tubule cells and is secreted into the tubular maining discussion. urine. NH 4 is reabsorbed in the thick ascending limb and accu- mulates in the kidney medulla. NH 3 diffuses into acidic collecting duct urine, where it is trapped as NH 4 . The Reabsorption of Filtered HCO 3 Restores Lost HCO 3 to the Blood Acidification in the Henle Loop. Along the descending HCO 3 is freely filtered at the glomerulus, about 4,320 limb of the Henle loop, the pH of tubular fluid rises (from mEq/day (180 L/day 24 mEq/L). Urinary loss of even a 6.7 to 7.4). This rise is explained by an increase in intralu- small portion of this HCO 3 would lead to acidic blood minal [HCO 3 ] caused by water reabsorption. Ammonia is and impair the body’s ability to buffer its daily load of meta- secreted along the descending limb. bolically produced H . The kidney tubules have the im- The tubular fluid is acidified by secretion of H along portant task of recovering the filtered HCO 3 and return- the ascending limb via a Na /H exchanger. Along the ing it to the blood. thin ascending limb, ammonia is passively reabsorbed. Figure 25.7 shows how HCO 3 filtration, reabsorption, Along the thick ascending limb, NH 4 is mostly actively and excretion normally vary with plasma [HCO 3 ]. This reabsorbed by the Na-K-2Cl cotransporter in the luminal type of graph should be familiar (Fig. 23.8). The y-axis of plasma membrane (NH 4 substitutes for K ). Some NH 4 the graph is unusual, however, because amounts of HCO 3 can be reabsorbed via a luminal plasma membrane K per minute are factored by the GFR. The data are expressed channel. Also, some NH 4 can be passively reabsorbed be- in this way because the maximal rate of tubular reabsorp- tween cells in this segment; the driving force is the lumen tion of HCO 3 varies with GFR. The amount of HCO 3 positive transepithelial electrical potential difference. Am- excreted in the urine per unit time is calculated as the dif- monia may undergo countercurrent multiplication in the ference between filtered and reabsorbed amounts. At low Henle loop, leading to an ammonia concentration gradient plasma concentrations of HCO 3 (below about 26 mEq/L), in the kidney medulla. The highest concentrations are at all of the filtered HCO 3 is reabsorbed. Because the plasma the tip of the papilla. [HCO 3 ] and pH were decreased by ingestion of an acid-
CHAPTER 25 Acid-Base Balance 435 Blood α-Intercalated cell Collecting duct urine - HCO 3 + ATP H Cl - ADP + P i H + - Cl ATP ADP + P i K + Blood β-Intercalated cell Collecting duct urine H + ATP H + ADP + P i ATP HCO 3 - ADP + P i - FIGURE 25.7 The filtration, reabsorption, and excretion K + Cl of HCO 3 . Decreases in plasma [HCO 3 ] - Cl were produced by ingestion of NH 4 Cl and increases were pro- duced by intravenous infusion of a solution of NaHCO 3. All the filtered HCO 3 was reabsorbed below a plasma concentration of Collecting duct intercalated cells. The - about 26 mEq/L. Above this value (“threshold”), appreciable FIGURE 25.6 intercalated cell secretes H via an electro- quantities of filtered HCO 3 were excreted in the urine. genic, vacuolar H -ATPase and electroneutral H /K -ATPase (Adapted from Pitts RF, Ayer JL, Schiess WA. The renal regula- and adds HCO 3 to the blood via a basolateral plasma mem- tion of acid-base balance in man. III. The reabsorption and excre- brane Cl /HCO 3 exchanger. The -intercalated cell, which is tion of bicarbonate. J Clin Invest 1949;28:35–44.) located in cortical collecting ducts, has the opposite polarity and secretes HCO 3 . an electrogenic cotransporter in the basolateral membrane that simultaneously transports three HCO 3 and one Na . ifying salt (NH 4 Cl), it makes good sense that the kidneys conserve filtered HCO 3 in this situation. The reabsorption of filtered HCO 3 does not result in If the plasma [HCO 3 ] is raised to high levels because of H excretion or the formation of any “new” HCO 3 . The intravenous infusion of solutions containing NaHCO 3 for secreted H is not excreted because it combines with fil- example, filtered HCO 3 exceeds the reabsorptive capacity tered HCO 3 that is, indirectly, reabsorbed. There is no of the tubules and some HCO 3 will be excreted in the urine net addition of HCO 3 to the body in this operation. It is (see Fig. 25.7). This also makes good sense. If the blood is too simply a recovery or reclamation process. alkaline, the kidneys excrete HCO 3 . This loss of base would return the pH of the blood to its normal value. Excretion of Titratable Acid and Ammonia At the cellular level (see Fig. 25.8), filtered HCO 3 is Generates New Bicarbonate not reabsorbed directly across the tubule’s luminal plasma membrane as, for example, is glucose. Instead, filtered When H is excreted as titratable acid and ammonia, new HCO 3 is reabsorbed indirectly via H secretion in the HCO 3 is formed and added to the blood. New HCO 3 following way. About 90% of the filtered HCO 3 is reab- replaces the HCO 3 used to buffer the strong acids pro- sorbed in the proximal convoluted tubule, and we will em- duced by metabolism. phasize events at this site. H is secreted into the tubule lu- The formation of new HCO 3 and the excretion of H men mainly via the Na /H exchanger in the luminal are like two sides of the same coin. This fact is apparent if we assume that H 2 CO 3 is the source of H : membrane. It combines with filtered HCO 3 to form H 2 CO 3 . Carbonic anhydrase (CA) in the luminal mem- H (urine) brane (brush border) of the proximal tubule catalyzes the z dehydration of H 2 CO 3 to CO 2 and water in the lumen. CO 2 H 2 O H 2 CO 3 x (23) The CO 2 diffuses back into the cell. Inside the cell, the hydration of CO 2 (catalyzed by in- HCO 3 (blood) tracellular CA) yields H 2 CO 3 , which instantaneously forms A loss of H in the urine is equivalent to adding new HCO 3 to the H and HCO 3 . The H is secreted into the lumen, and blood. The same is true if H is lost from the body via an- the HCO 3 ion moves into the blood surrounding the other route, such as by vomiting of acidic gastric juice. This tubules. In proximal tubule cells, this movement is favored process leads to a rise in plasma [HCO 3 ]. Conversely, a loss by the inside negative membrane potential of the cell and by of HCO 3 from the body is equivalent to adding H to the blood.
436 PART VI RENAL PHYSIOLOGY AND BODY FLUIDS the urine pH is lowered, more titratable acid can form. The supply of phosphate and other buffers is usually limited. To Peritubular Tubular Tubular excrete large amounts of acid, the kidneys must rely on in- blood epithelium urine creased ammonia excretion. Na + Ammonia Excretion. Figure 25.10 shows a cell model for Na + the excretion of ammonia. Most ammonia is synthesized in HCO 3 - HCO 3 - proximal tubule cells by deamidation and deamination of (reclaimed) H + H + HCO 3 - the amino acid glutamine: (filtered) CO 2 CO + H 2 O H 2 CO 3 NH 4 NH 4 2 CA zz H CO 3 2 2 CA Glutamine → Glutamate → -Ketoglutarate (24) Glutaminase Glutamate dehydrogenase CO 2 H O As discussed earlier, ammonia is secreted into the urine 2 by two mechanisms. As NH 3 , it diffuses into the tubular urine; as NH 4 , it substitutes for H on the Na /H ex- changer. In the lumen, NH 3 combines with secreted H to form NH 4 , which is excreted. 2 A cell model for HCO 3 reabsorption. Fil- FIGURE 25.8 For each mEq of H excreted as NH 4 , one mEq of new tered HCO 3 combines with secreted H and HCO 3 is added to the blood. The hydration of CO 2 in the is reabsorbed indirectly. Carbonic anhydrase (CA) is present in tubule cell produces H and HCO 3 , as described earlier. the cells and in the proximal tubule on the brush border. 2– Two H s are consumed when the anion -ketoglutarate is converted into CO 2 and water or into glucose in the cell. Titratable Acid Excretion. Figure 25.9 shows a cell model The new HCO 3 returns to the blood along with Na . for the formation of titratable acid. In this figure, H 2 PO 4 If excess acid is added to the body, urinary ammonia ex- is the titratable acid formed. H and HCO 3 are produced cretion is increased for two reasons. First, a more acidic in the cell from H 2 CO 3 . The secreted H combines with urine traps more ammonia (as NH 4 ) in the urine. Second, 2– the basic form of the phosphate (HPO 4 ) to form the acid renal ammonia synthesis from glutamine increases over sev- phosphate (H 2 PO 4 ). The secreted H replaces one of the Na ions accompanying the basic phosphate. The new HCO 3 generated in the cell moves into the blood, to- gether with Na . For each mEq of H excreted in the urine as titratable acid, a mEq of new HCO 3 is added to the blood. This process eliminates H in the urine, replaces Peritubular Tubular Tubular ECF HCO 3 , and restores a normal blood pH. blood epithelium urine The amount of titratable acid excreted depends on two factors: the pH of the urine and the availability of buffer. If Glutamine Na + 2 NH 4 + NH 4 + Cl - Peritubular Tubular Tubular α-Ketoglutarate 2- NH 3 NH 3 blood epithelium urine + + - Glucose or H + NH 4 Cl CO +H O H + Na + 2 2 Na + + 2 Na - 2- + HCO 3 HCO 3 - HPO 4 2Na + - - 2H (new) H + H + (filtered) HCO 3 2 HCO 3 Na + (new) CO 2 CO + H O H 2 CO 3 2 2 CA H PO Na + CO 2 2 CO + 2 H O CA 2 H CO 3 - 2 2 2 4 2 (excreted) A cell model for renal synthesis and excre- FIGURE 25.10 tion of ammonia. Ammonium ions are formed A cell model for the formation of titratable from glutamine in the cell and are secreted into the tubular urine FIGURE 25.9 acid. Titratable acid (e.g., H 2PO 4 ) is formed (top). H from H 2CO 3 (bottom) is consumed when -ketoglu- 2– when secreted H is bound to a buffer base (e.g., HPO 4 ) in the tarate is converted into glucose or CO 2 and H 2O. New HCO 3 tubular urine. For each mEq of titratable acid excreted, a mEq of is added to the peritubular capillary blood—1 mEq for each mEq new HCO 3 is added to the peritubular capillary blood. of NH 4 excreted in the urine.
CHAPTER 25 Acid-Base Balance 437 eral days. Enhanced renal ammonia synthesis and excretion 1) Hydration of CO 2 in the cells, forming H 2 CO 3 and is a lifesaving adaptation because it allows the kidneys to yielding H for secretion remove large H excesses and add more new HCO 3 to 2) Dehydration of H 2 CO 3 to H 2 O and CO 2 in the the blood. Also, the excreted NH 4 can substitute in the proximal tubule lumen, an important step in the reabsorp- urine for Na and K , diminishing the loss of these cations. tion of filtered HCO 3 With severe metabolic acidosis, ammonia excretion may If carbonic anhydrase is inhibited (usually by a drug), increase almost 10-fold. large amounts of filtered HCO 3 may escape reabsorption. This situation leads to a fall in blood pH. Several Factors Influence Renal Excretion Sodium Reabsorption. Na reabsorption is closely of Hydrogen Ions linked to H secretion. In the proximal tubule, the two ions Several factors influence the renal excretion of H , includ- are directly linked, both being transported by the Na /H ing intracellular pH, arterial blood PCO 2 , carbonic anhy- exchanger in the luminal plasma membrane. The relation is drase activity, Na reabsorption, plasma [K ], and aldos- less direct in the collecting ducts. Enhanced Na reabsorp- terone (Fig. 25.11). tion in the ducts leads to a more negative intraluminal elec- trical potential, which favors H secretion by its electro- Intracellular pH. The pH in kidney tubule cells is a key genic H -ATPase. The avid renal reabsorption of Na factor influencing the secretion and, therefore, the excretion observed in states of volume depletion is accompanied by a of H . A fall in pH (increased [H ]) enhances H secretion. parallel rise in urinary H excretion. A rise in pH (decreased [H ]) lowers H secretion. Plasma Potassium Concentration. Changes in plasma Arterial Blood PCO 2 . An increase in PCO 2 increases the [K ] influence the renal excretion of H . A fall in plasma formation of H from H 2 CO 3 , leading to enhanced renal [K ] favors the movement of K from body cells into in- H secretion and excretion—a useful compensation for any terstitial fluid (or blood plasma) and a reciprocal move- condition in which the blood contains too much H 2 CO 3 . ment of H into cells. In the kidney tubule cells, these (This will be discussed later, when we consider respiratory movements lower intracellular pH and increase H se- acidosis.) A decrease in PCO 2 results in lowered H secretion cretion. K depletion also stimulates ammonia synthesis and, consequently, less complete reabsorption of filtered by the kidneys. The result is the complete reabsorption HCO 3 and a loss of base in the urine (a useful compensa- of filtered HCO 3 and the enhanced generation of new tion for respiratory alkalosis, also discussed later). HCO 3 as more titratable acid and ammonia are ex- creted. Consequently, hypokalemia (or a decrease in body K stores) leads to increased plasma [HCO 3 ] Carbonic Anhydrase Activity. The enzyme carbonic an- hydrase catalyzes two key reactions in urinary acidification: (metabolic alkalosis). Hyperkalemia (or excess K in the body) results in the opposite changes: an increase in in- tracellular pH, decreased H secretion, incomplete reab- sorption of filtered HCO 3 , and a fall in plasma [HCO 3 ] (metabolic acidosis). Peritubular Tubular Tubular blood epithelium urine Aldosterone. Aldosterone stimulates the collecting ducts to secrete H by three actions: 1) It directly stimulates the H -ATPase in collecting Increased H + + plasma H -ATPase duct -intercalated cells. aldosterone 2) It enhances collecting duct Na reabsorption, which leads to a more negative intraluminal potential and, conse- Decreased intracellular + quently, promotes H secretion by the electrogenic H - H + H + pH Na Increased ATPase. 3) It promotes K secretion. This response leads to hy- sodium Na + reabsorption pokalemia, which increases renal H secretion. Decreased K + K + Hyperaldosteronism results in enhanced renal H ex- cretion and an alkaline blood pH; the opposite occurs with H + hypoaldosteronism. HCO 3 - HCO 3 - H + CO 2 CO + H O H CO 3 pH gradient. The secretion of H by the kidney tubules 2 2 2 Increased CA and collecting ducts is gradient-limited. The collecting Carbonic anhydrase PCO 2 ducts cannot lower the urine pH below 4.5, corresponding activity 4.5 7.4 to a urine/plasma [H ] gradient of 10 /10 or 800/1 when the plasma pH is 7.4. If more buffer base (NH 3 , 2– HPO 4 ) is available in the urine, more H can be secreted Factors leading to increased H secretion before the limiting gradient is reached. In some kidney FIGURE 25.11 by the kidney tubule epithelium. (See text tubule disorders, the secretion of H is gradient-limited for details.) (see Clinical Focus Box 25.1).
438 PART VI RENAL PHYSIOLOGY AND BODY FLUIDS CLINICAL FOCUS BOX 25.1 Renal Tubular Acidosis proximal tubule is impaired, leading to excessive losses of Renal tubular acidosis (RTA) is a group of kidney disor- HCO 3 in the urine. As a consequence, the plasma [HCO 3 ] ders characterized by chronic metabolic acidosis, a normal falls and chronic metabolic acidosis ensues. In the new plasma anion gap, and the absence of renal failure. The steady state, the tubules are able to reabsorb the filtered kidneys show inadequate H secretion by the distal HCO 3 load more completely because the filtered load is nephron, excessive excretion of HCO 3 , or reduced excre- reduced. The distal nephron is no longer overwhelmed by tion of NH 4 . HCO 3 and the urine pH is acidic. In type 2 RTA, the ad- In classic type 1 (distal) RTA, the ability of the col- ministration of an NH 4 Cl challenge results in a urine pH be- lecting ducts to lower urine pH is impaired. This condition low 5.5. This disorder may be inherited, may be associated can be caused by inadequate secretion of H (defective with several acquired conditions that result in a general- H -ATPase or H /K -ATPase) or abnormal leakiness of ized disorder of proximal tubule transport, or may result the collecting duct epithelium so that secreted H ions from the inhibition of proximal tubule carbonic anhydrase diffuse back from lumen to blood. Because the urine pH is by drugs such as acetazolamide. Treatment requires the inappropriately high, titratable acid excretion is dimin- daily administration of large amounts of alkali because ished and trapping of ammonia in the urine (as NH 4 ) is when the plasma [HCO 3 ] is raised, excessive urinary ex- decreased. Type 1 RTA may be the result of an inherited cretion of filtered HCO 3 occurs. defect, autoimmune disease, treatment with lithium or Type 4 RTA (there is no type 3 RTA) is also known as the antibiotic amphotericin B, or the result of diseases of hyperkalemic distal RTA. Collecting duct secretion of the kidney medulla. A diagnosis of this form of RTA is es- both K and H is reduced, explaining the hyperkalemia tablished by challenging the subject with a standard oral and metabolic acidosis. Hyperkalemia reduces renal am- dose of NH 4 Cl and measuring the urine pH for the next monia synthesis, resulting in reduced net acid excretion several hours. This results in a urine pH below 5.0 in and a fall in plasma [HCO 3 ]. The urine pH can go below healthy people. In subjects with type 1 RTA, however, 5.5 after an NH 4 Cl challenge because there is little ammo- urine pH will not decrease below 5.5. Treatment of type 1 nia in the urine to buffer secreted H . The underlying dis- RTA involves daily administration of modest amounts of order is a result of inadequate production of aldosterone or alkali (HCO 3 , citrate) sufficient to cover daily metabolic impaired aldosterone action. Treatment of type 4 RTA re- acid production. quires lowering the plasma [K ] to normal; if this therapy In type 2 (proximal) RTA, HCO 3 reabsorption by the is successful, alkali may not be needed. REGULATION OF INTRACELLULAR PH The intracellular and extracellular fluids are linked by ex- changes across plasma membranes of H , HCO 3 , various H + acids and bases, and CO 2 . By stabilizing ECF pH, the body helps to protect intracellular pH. If H ions were passively distributed across plasma Metabolism + membranes, intracellular pH would be lower than what is H - + seen in most body cells. In skeletal muscle cells, for exam- CO 2 CO 2 ple, we can calculate from the Nernst equation (see Chap- ter 2) and a membrane potential of 90 mV that cytosolic H + pH should be 5.9 if ECF pH is 7.4; actual measurements, however, indicate a pH of 6.9. From this discrepancy, two conclusions are clear: H ions are not at equilibrium across the plasma membrane, and the cell must use active mecha- H + nisms to extrude H . - Cells are typically threatened by acidic metabolic end- Cl HCO - + products and by the tendency for H to diffuse into the cell 3 Na down the electrical gradient (Fig. 25.12). H is extruded by Na /H exchangers, which are present in nearly all body + cells. Five different isoforms of these exchangers (desig- Na nated NHE1, NHE2, etc.), with different tissue distribu- tions, have been identified. These transporters exchange FIGURE 25.12 Cell acid-base balance. Body cells usually maintain a constant intracellular pH. The cell is one H for one Na and, therefore, function in an electri- acidified by the production of H from metabolism and the in- cally neutral fashion. Active extrusion of H keeps the in- flux of H from the ECF (favored by the inside negative plasma ternal pH within narrow limits. membrane potential). To maintain a stable intracellular pH, the The activity of the Na /H exchanger is regulated by cell must extrude hydrogen ions at a rate matching their input. intracellular pH and a variety of hormones and growth fac- Many cells also possess various HCO 3 transporters (not de- tors (Fig. 25.13). Not surprisingly, an increase in intracellu- picted), which defend against excess acid or base.
CHAPTER 25 Acid-Base Balance 439 Normal Arterial Blood Plasma TABLE 25.2 Acid-Base Values Mean Range a pH 7.40 7.35–7.45 [H ], nmol/L 40 45–35 Na /H PCO 2 , mm Hg 40 35–45 exchanger [HCO 3 ], mEq/L 24 22–26 a The range extends from 2 standard deviations below to 2 standard deviations above the mean and encompasses 95% of the healthy population. bance. Acidosis is an abnormal process that tends to pro- The plasma membrane Na /H exchanger. duce acidemia. Alkalosis is an abnormal process that tends FIGURE 25.13 This exchanger plays a key role in regulating to produce alkalemia. If there is too much or too little CO 2 , intracellular pH in most body cells and is activated by a decrease a respiratory disturbance is present. If the problem is too in cytoplasmic pH. Many hormones and growth factors, acting much or too little HCO 3 , a metabolic (or nonrespiratory) via intracellular second messengers and protein kinases, can in- disturbance of acid-base balance is present. Table 25.3 crease () or decrease () the activity of the exchange. summarizes the changes in blood pH (or [H ]), plasma [HCO 3 ], and PCO 2 that occur in each of the four simple acid-base disturbances. lar [H ] stimulates the exchanger but not only because of In considering acid-base disturbances, it is helpful to re- more substrate (H ) for the exchanger. H also stimulates call the Henderson-Hasselbalch equation for the exchanger by protonating an activator site on the cyto- HCO 3 /CO 2 : plasmic side of the exchanger, making the exchanger more effective in dealing with the threat of intracellular acidosis. [HCO 3 ] Many hormones and growth factors, via intracellular sec- pH 6.10 log (25) 0.03 PCO 2 ond messengers, activate various protein kinases that stim- ulate or inhibit the Na /H exchanger. In this way, they If the primary problem is a change in [HCO 3 ] or PCO 2 , produce changes in intracellular pH, which may lead to the pH can be brought closer to normal by changing the changes in cell activity. other member of the buffer pair in the same direction. For ex- Besides extruding H , the cell can deal with acids and ample, if PCO 2 is primarily decreased, a decrease in plasma bases in other ways. In some cells, various HCO 3 trans- [HCO 3 ] will minimize the change in pH. In various acid- porting systems (e.g., Na -dependent and Na -independ- base disturbances, the lungs adjust the blood PCO 2 and the ent Cl /HCO 3 exchangers) may be present in plasma kidneys adjust the plasma [HCO 3 ] to reduce departures membranes. These exchangers may be activated by of pH from normal; these adjustments are called compen- changes in intracellular pH. Cells have large stores of pro- sations (Table 25.4). Compensations generally do not tein and organic phosphate buffers, which can bind or re- bring about normal blood pH. lease H . Various chemical reactions in cells can also use up or release H . For example, the conversion of lactic acid to CO 2 and water to glucose effectively disposes of acid. In Respiratory Acidosis Results From an addition, various cell organelles may sequester H . For ex- Accumulation of Carbon Dioxide ample, H -ATPase in endosomes and lysosomes pumps H out of the cytosol into these organelles. In summary, Respiratory acidosis is an abnormal process characterized ion transport, buffering mechanisms, and metabolic reac- by CO 2 accumulation. The CO 2 build-up pushes the fol- tions all ensure a relatively stable intracellular pH. lowing reactions to the right: CO 2 H 2 O H 2 CO 3 H HCO 3 (26) Blood [H 2 CO 3 ] increases, leading to an increase in [H ] DISTURBANCES OF ACID-BASE BALANCE or a fall in pH. Respiratory acidosis is usually caused by a Table 25.2 lists the normal values for the pH (or [H ]), failure to expire metabolically produced CO 2 at an ade- PCO 2, and [HCO 3 ] of arterial blood plasma. A blood pH quate rate, leading to accumulation of CO 2 in the blood of less than 7.35 ([H ] 45 nmol/L) indicates acidemia. A and a fall in blood pH. This disturbance may be a result of blood pH above 7.45 ([H ] 35 nmol/L) indicates alka- a decrease in overall alveolar ventilation (hypoventilation) lemia. The range of pH values compatible with life is ap- or, as occurs commonly in lung disease, a mismatch be- proximately 6.8 to 7.8 ([H ] 160 to 16 nmol/L). tween ventilation and perfusion. Respiratory acidosis also Four simple acid-base disturbances may lead to an ab- occurs if a person breathes CO 2-enriched air. normal blood pH: respiratory acidosis, respiratory alkalo- sis, metabolic acidosis, and metabolic alkalosis. The word Chemical Buffering. In respiratory acidosis, more than “simple” indicates a single primary cause for the distur- 95% of the chemical buffering occurs within cells. The cells
440 PART VI RENAL PHYSIOLOGY AND BODY FLUIDS TABLE 25.3 Directional Changes in Arterial Blood Plasma Values in the Four Simple Acid-Base Disturbances a Arterial Plasma Disturbance pH [H ] [HCO 3 ]PCO 2 Compensatory Response Respiratory acidosis ↓↑ ↑ ⇑Kidneys increase H excretion Respiratory alkalosis ↑↓ ↓ ⇓Kidneys increase HCO 3 excretion Metabolic acidosis ↓↑ ⇓ ↓Alveolar hyperventilation; kidneys increase H excretion Metabolic alkalosis ↑↓ ⇑ ↑Alveolar hypoventilation; kidneys increase HCO 3 excretion a Heavy arrows indicate the main effect. contain many proteins and organic phosphates that can Renal Compensation. The kidneys compensate for respi- bind H . For example, hemoglobin (Hb) in red blood cells ratory acidosis by adding more H to the urine and adding combines with H from H 2 CO 3 , minimizing the increase new HCO 3 to the blood. The increased PCO 2 stimulates in free H . Recall from Chapter 21 the buffering reaction: renal H secretion, which allows the reabsorption of all fil- tered HCO 3 . Excess H is excreted as titratable acid and H 2 CO 3 HbO 2 HHb O 2 HCO 3 (27) NH 4 ; these processes add new HCO 3 to the blood, This reaction raises the plasma [HCO 3 ]. In acute respira- causing plasma [HCO 3 ] to rise. This compensation takes tory acidosis, such chemical buffering processes in the body several days to fully develop. lead to an increase in plasma [HCO 3 ] of about 1 mEq/L for With chronic respiratory acidosis, plasma [HCO 3 ] in- each 10 mm Hg increase in PCO 2 (see Table 25.4). Bicar- creases, on average, by 4 mEq/L for each 10 mm Hg rise in bonate is not a buffer for H 2 CO 3 because the reaction PCO 2 (see Table 25.4). This rise exceeds that seen with acute respiratory acidosis because of the renal addition of H 2 CO 3 HCO 3 HCO 3 H 2 CO 3 (28) HCO 3 to the blood. One would expect a person with is simply an exchange reaction and does not affect the pH. chronic respiratory acidosis and a PCO 2 of 70 mm Hg to An example illustrates how chemical buffering reduces a have an increase in plasma HCO 3 of 12 mEq/L. The fall in pH during respiratory acidosis. Suppose PCO 2 in- blood pH would be 7.33: creased from a normal value of 40 mm Hg to 70 mm Hg ([CO 2(d) ] 2.l mmol/L). If there were no body buffer bases [24 12] that could accept H from H 2 CO 3 (i.e., if there was no pH 6.10 log 7.33 (31) [2.1] measurable increase in [HCO 3 ]), the resulting pH would be 7.16: [24] pH 6.10 log 7.16 (29) TABLE 25.4 Compensatory Responses in Acid-Base [2.1] a Disturbances Respiratory acidosis In acute respiratory acidosis, a 3 mEq/L increase in Acute 1 mEq/L increase in plasma [HCO 3 ] plasma [HCO 3 ] occurs with a 30 mm Hg rise in PCO 2 (see b for each 10 mm Hg increase in PCO 2 Table 25.4). Therefore, the pH is 7.21: Chronic 4 mEq/L increase in plasma [HCO 3 ] c for each 10 mm Hg increase in PCO 2 [24 3] Respiratory alkalosis pH 6.10 log 7.21 (30) [2.1] Acute 2 mEq/L decrease in plasma [HCO 3 ] d for each 10 mm Hg decrease in PCO 2 The pH of 7.21 is closer to a normal pH because body Chronic 4 mEq/L decrease in plasma [HCO 3 ] d buffer bases (mainly intracellular buffers) such as proteins Metabolic acidosis 1.3 mm Hg decrease in PCO 2 for each for each 10 mm Hg decrease in PCO 2 and phosphates combined with H ions liberated from 1 mEq/L decrease in plasma [HCO 3 ] d H 2CO 3. Metabolic alkalosis 0.7 mm Hg increase in PCO 2 for each d 1 mEq/L increase in plasma [HCO 3 ] Respiratory Compensation. Respiratory acidosis pro- duces a rise in PCO 2 and a fall in pH and is often associated From Valtin H, Gennari FJ. Acid-Base Disorders. Basic Concepts and Clinical Management. Boston: Little, Brown, 1987. with hypoxia. These changes stimulate breathing (see a Empirically determined average changes measured in people with Chapter 22) and diminish the severity of the acidosis. In simple acid-base disorders. other words, a person would be worse off if the respiratory b This change is primarily a result of chemical buffering. c This change is primarily a result of renal compensation. system did not reflexively respond to the abnormalities in d This change is a result of respiratory compensation. blood PCO 2 , pH, and PO 2 .
CHAPTER 25 Acid-Base Balance 441 With chronic respiratory acidosis, time for renal com- chronic hyperventilation and a PCO 2 of 20 mm Hg, the pensation is allowed, so blood pH (in this example, 7.33) is blood pH is much closer to normal than is observed during acute respi- ratory acidosis (pH 7.21). [24 8] pH 6.10 log 7.53 (34) [0.6] Respiratory Alkalosis Results From an Excessive Loss of Carbon Dioxide This pH is closer to normal than the pH of 7.62 of acute respiratory alkalosis. The difference between the two situ- Respiratory alkalosis is most easily understood as the ations is largely a result of renal compensation. opposite of respiratory acidosis; it is an abnormal process causing the loss of too much CO 2 . This loss causes blood [H 2 CO 3 ] and, thus, [H ] to fall (pH rises). Metabolic Acidosis Results From a Gain of Alveolar hyperventilation causes respiratory alkalosis. Noncarbonic Acid or a Loss of Bicarbonate Metabolically produced CO 2 is flushed out of the alveo- lar spaces more rapidly than it is added by the pul- Metabolic acidosis is an abnormal process characterized monary capillary blood. This situation causes alveolar by a gain of acid (other than H 2 CO 3 ) or a loss of HCO 3 . and arterial PCO 2 to fall. Hyperventilation and respira- Either causes plasma [HCO 3 ] and pH to fall. If a strong tory alkalosis can be caused by voluntary effort, anxiety, acid is added to the body, the reactions direct stimulation of the medullary respiratory center by some abnormality (e.g., meningitis, fever, aspirin intox- H HCO 3 H 2 CO 3 H 2 O CO 2 (35) ication), or hypoxia caused by severe anemia or high al- titude. are pushed to the right. The added H consumes HCO 3 . If a lot of acid is infused rapidly, PCO 2 rises, as Chemical Buffering. As with respiratory acidosis, dur- the equation predicts. This increase occurs only tran- ing respiratory alkalosis more than 95% of chemical siently, however, because the body is an open system, buffering occurs within cells. Cell proteins and organic and the lungs expire CO 2 as it is generated. PCO 2 actually phosphates liberate H ions, which are added to the falls below normal because an acidic blood pH stimulates ECF and lower the plasma [HCO 3 ], reducing the alka- ventilation (see Fig. 25.3). line shift in pH. Many conditions can produce metabolic acidosis, in- With acute respiratory alkalosis, plasma [HCO 3 ] falls cluding renal failure, uncontrolled diabetes mellitus, lac- by about 2 mEq/L for each 10 mm Hg drop in PCO 2 (see tic acidosis, the ingestion of acidifying agents such as Table 25.4). For example, if PCO 2 drops from 40 to 20 mm NH 4 Cl, abnormal renal excretion of HCO 3 , and diar- Hg ([CO 2(d) ] 0.6 mmol/L) plasma [HCO 3 ] falls by 4 rhea. In renal failure, the kidneys cannot excrete H fast mEq/L, and the pH will be 7.62: enough to keep up with metabolic acid production and, in uncontrolled diabetes mellitus, the production of ke- [24 4] tone body acids increases. Lactic acidosis results from pH 6.10 log 7.62 (32) [0.6] tissue hypoxia. Ingested NH 4 Cl is converted into urea and a strong acid, HCl, in the liver. Diarrhea causes a If plasma [HCO 3 ] had not changed, the pH would loss of alkaline intestinal fluids. Clinical Focus Box 25.2 have been 7.70: discusses the metabolic acidosis seen in uncontrolled di- abetes mellitus. [24] pH 6.10 log 7.70 (33) [0.6] Chemical Buffering. Excess acid is chemically buffered in extracellular and intracellular fluids and bone. In metabolic Respiratory Compensation. Although hyperventilation acidosis, roughly half the buffering occurs in cells and causes respiratory alkalosis, hyperventilation also causes bone. HCO 3 is the principal buffer in the ECF. changes (a fall in PCO 2 and a rise in blood pH) that in- hibit ventilation and, therefore, limit the extent of hy- perventilation. Respiratory Compensation. The acidic blood pH stimu- lates the respiratory system to lower blood PCO 2 . This action lowers blood [H 2 CO 3 ] and tends to alkalinize the blood, Renal Compensation. The kidneys compensate for respi- ratory alkalosis by excreting HCO 3 in the urine, thereby, opposing the acidic shift in pH. Metabolic acidosis is ac- getting rid of base. A reduced PCO 2 reduces H secretion companied on average by a l.3 mm Hg fall in PCO 2 for each by the kidney tubule epithelium. As a result, some of the fil- l mEq/L drop in plasma [HCO 3 ] (see Table 25.4). Suppose, tered HCO 3 is not reabsorbed. When the urine becomes for example, the infusion of a strong acid causes the plasma more alkaline, titratable acid excretion vanishes and little [HCO 3 ] to drop from 24 to l2 mEq/L. If there was no res- piratory compensation and the PCO 2 did not change from its ammonia is excreted. The enhanced output of HCO 3 causes plasma [HCO 3 ] to fall. normal value of 40 mm Hg, the pH would be 7.10: Chronic respiratory alkalosis is accompanied by a 4 [12] mEq/L fall in plasma [HCO 3 ] for each l0 mm Hg drop in pH 6.10 log 7.10 (36) PCO 2 (see Table 25.4). For example, in a person with [1.2]
442 PART VI RENAL PHYSIOLOGY AND BODY FLUIDS CLINICAL FOCUS BOX 25.2 Metabolic Acidosis in Diabetes Mellitus lar and arterial blood PCO 2 . The consequent reduction in Diabetes mellitus is a common disorder characterized by blood [H 2 CO 3 ] acts to move the blood pH back toward nor- an insufficient secretion of insulin or insulin-resistance by mal. The labored, deep breathing that accompanies severe the major target tissues (skeletal muscle, liver, and uncontrolled diabetes is called Kussmaul’s respiration. adipocytes). A severe metabolic acidosis may develop in The kidneys compensate for metabolic acidosis by re- uncontrolled diabetes mellitus. absorbing all the filtered HCO 3 . They also increase the ex- Acidosis occurs because insulin deficiency leads to de- cretion of titratable acid, part of which is comprised of ke- creased glucose utilization, a diversion of metabolism to- tone body acids. But these acids can only be partially ward the utilization of fatty acids, and an overproduction of titrated to their acid form in the urine because the urine pH ketone body acids (acetoacetic acid and -hydroxybutyric cannot go below 4.5. Therefore, ketone body acids are ex- acids). Ketone body acids are fairly strong acids (pK a 4 to creted mostly in their anionic form; because of the re- 5); they are neutralized in the body by HCO 3 and other quirement of electroneutrality in solutions, increased uri- buffers. Increased production of these acids leads to a fall nary excretion of Na and K results. in plasma [HCO 3 ], an increase in plasma anion gap, and a An important compensation for the acidosis is in- fall in blood pH (acidemia). creased renal synthesis and excretion of ammonia. This Severe acidemia, whatever its cause, has many adverse adaptive response takes several days to fully develop, but effects on the body. It impairs myocardial contractility, re- it allows the kidneys to dispose of large amounts of H in sulting in a decrease in cardiac output. It causes arteriolar di- the form NH 4 . The NH 4 in the urine can replace Na and lation, which leads to a fall in arterial blood pressure. He- K ions, resulting in conservation of these valuable patic and renal blood flows are decreased. Reentrant cations. arrhythmias and a decreased threshold for ventricular fibril- The severe acidemia, electrolyte disturbances, and vol- lation can occur. The respiratory muscles show decreased ume depletion that accompany uncontrolled diabetes mel- strength and fatigue easily. Metabolic demands are in- litus may be fatal. Addressing the underlying cause, rather creased due, in part, to activation of the sympathetic nerv- than just treating the symptoms best achieves correction ous system, but at the same time anaerobic glycolysis and of the acid-base disturbance. Therefore, the administration ATP synthesis are reduced by acidemia. Hyperkalemia is fa- of a suitable dose of insulin is usually the key element of vored and protein catabolism is enhanced. Severe acidemia therapy. In some patients with marked acidemia (pH causes impaired brain metabolism and cell volume regula- 7.10), NaHCO 3 solutions may be infused intravenously to tion, leading to progressive obtundation and coma. speed recovery, but this does not correct the underlying An increased acidity of the blood stimulates pulmonary metabolic problem. Losses of Na , K , and water should ventilation, resulting in a compensatory lowering of alveo- be replaced. With respiratory compensation, the PCO 2 falls by 16 The Plasma Anion Gap Is Calculated From mm Hg (12 1.3) to 24 mm Hg ([CO 2(d)] 0.72 mmol/L) Na , Cl , and HCO 3 Concentrations and pH is 7.32: The anion gap is a useful concept, especially when trying to determine the possible cause of a metabolic acidosis. In any [12] pH 6.10 log 7.32 (37) body fluid, the sums of the cations and anions are equal be- [0.72] cause solutions are electrically neutral. For blood plasma, we can write This value is closer to normal than a pH of 7.10. The res- piratory response develops promptly (within minutes) and cations anions (38) is maximal after 12 to 24 hours. or [Na ] [unmeasured cations] [Cl ] Renal Compensation. The kidneys respond to metabolic [HCO 3 ] [unmeasured anions] (39) acidosis by adding more H to the urine. Since the plasma 2 2 The unmeasured cations include K , Ca , and Mg [HCO 3 ] is primarily lowered, the filtered load of HCO 3 ions and, because these are present at relatively low con- drops, and the kidneys can accomplish the complete reab- centrations (compared to Na ) and are usually fairly con- sorption of filtered HCO 3 (see Fig. 25.7). More H is ex- stant, we choose to neglect them. The unmeasured anions creted as titratable acid and NH 4 . With chronic meta- include plasma proteins, sulfate, phosphate, citrate, lactate, bolic acidosis, the kidneys make more ammonia. The and other organic anions. If we rearrange the above equa- kidneys can, therefore, add more new HCO 3 to the tion, we get blood, to replace lost HCO 3 . If the underlying cause of metabolic acidosis is corrected, then healthy kidneys can [unmeasured anions] or anion gap correct the blood pH in a few days. [Na ] [Cl ] [HCO 3 ] (40)
CHAPTER 25 Acid-Base Balance 443 In a healthy person, the anion gap falls in the range of 8 titrated in the alkaline direction. About one third of the to 14 mEq/L. For example, if plasma [Na ] is 140 mEq/L, buffering occurs in cells. [Cl ] is 105 mEq/L, and [HCO 3 ] is 24 mEq/L, the anion gap is 11 mEq/L. If an acid such as lactic acid is added to Respiratory Compensation. The respiratory compensa- plasma, the reaction lactic acid HCO 3 lactate tion for metabolic alkalosis is hypoventilation. An alkaline H 2 O CO 2 will be pushed to the right. Consequently, the plasma [HCO 3 ] will be decreased and because the [Cl ] is blood pH inhibits ventilation. Hypoventilation raises the not changed, the anion gap will be increased. The unmea- blood PCO 2 and [H 2 CO 3 ], reducing the alkaline shift in sured anion in this case is lactate. In several types of meta- pH. A l mEq/L rise in plasma [HCO 3 ] caused by meta- bolic acidosis, the low blood pH is accompanied by a high bolic alkalosis is accompanied by a 0.7 mm Hg rise in anion gap (Table 25.5). (These can be remembered from the PCO 2 (see Table 25.4). If, for example, the plasma mnemonic MULEPAKS formed from the first letters of this [HCO 3 ] rose to 40 mEq/L, what would the plasma pH list.) In other types of metabolic acidosis, the low blood pH be with and without respiratory compensation? With res- is accompanied by a normal anion gap (see Table 25.5). For piratory compensation, the PCO 2 should rise by 11.2 mm example, with diarrhea and a loss of alkaline intestinal fluid, Hg (0.7 16) to 51.2 mm Hg ([CO 2(d) ] 1.54 mmol/L). plasma [HCO 3 ] falls but plasma [Cl ] rises, and the two The pH is 7.51: changes counterbalance each other so the anion gap is un- [40] changed. Again, the chief value of the anion gap concept is pH 6.10 log 7.51 (41) that it allows a clinician to narrow down possible explana- [1.54] tions for metabolic acidosis in a patient. Without respiratory compensation, the pH would be 7.62: Metabolic Alkalosis Results From a Gain [40] of Strong Base or Bicarbonate or a Loss pH 6.10 log 7.62 (42) of Noncarbonic Acid [1.2] Metabolic alkalosis is an abnormal process characterized Respiratory compensation for metabolic alkalosis is lim- by a gain of a strong base or HCO 3 or a loss of an acid ited because hypoventilation leads to hypoxia and CO 2 re- (other than carbonic acid). Plasma [HCO 3 ] and pH rise; tention, and both increase breathing. PCO 2 rises because of respiratory compensation. These changes are opposite to those seen in metabolic acidosis (see Table 25.3). A variety of situations can produce meta- Renal Compensation. The kidneys respond to meta- bolic alkalosis, including the ingestion of antacids, vomit- bolic alkalosis by lowering the plasma [HCO 3 ]. The ing of gastric acid juice, and enhanced renal H loss (e.g., plasma [HCO 3 ] is primarily raised and more HCO 3 is as a result of hyperaldosteronism or hypokalemia). Clinical filtered than can be reabsorbed (see Fig. 25.7); in addi- Focus Box 25.3 discusses the metabolic alkalosis produced tion, HCO 3 is secreted in the collecting ducts. Both of by vomiting of gastric juice. these changes lead to increased urinary [HCO 3 ] excre- tion. If the cause of the metabolic alkalosis is corrected, Chemical Buffering. Chemical buffers in the body limit the kidneys can often restore the plasma [HCO 3 ] and the alkaline shift in blood pH by releasing H as they are pH to normal in a day or two. TABLE 25.5 High and Normal Anion Gap Metabolic Acidosis Condition Explanation High anion gap metabolicacidosis Methanol intoxication Methanol metabolized to formic acid Uremia Sulfuric, phosphoric, uric, and hippuric acids retained due to renal failure Lactic acid Lactic acid buffered by HCO 3 and accumulates as lactate Ethylene glycol intoxication Ethylene glycol metabolized to glyoxylic, glycolic, and oxalic acids p-Aldehyde intoxication p-Aldehyde metabolized to acetic and chloroacetic acids Ketoacidosis Production of -hydroxybutyric and acetoacetic acids Salicylate intoxication Impaired metabolism leads to production of lactic acid and ketone body acids; accumulation of salicylate Normal anion gap metabolic acidosis Diarrhea Loss of HCO 3 in stool; kidneys conserve Cl Renal tubular acidosis Loss of HCO 3 in urine or inadequate excretion of H ; kidneys conserve Cl Ammonium chloride ingestion NH 4 is converted to urea in liver, a process that consumes HCO 3 ; excess Cl is ingested
444 PART VI RENAL PHYSIOLOGY AND BODY FLUIDS CLINICAL FOCUS BOX 25.3 Vomiting and Metabolic Alkalosis Renal tubular Na /H exchange is stimulated by volume Vomiting of gastric acid juice results in metabolic alka- depletion because the tubules reabsorb Na more avidly losis and fluid and electrolyte disturbances. Gastric acid than usual. With more H secretion, more new HCO 3 is juice contains about 0.1 M HCl. The acid is secreted by added to the blood. The kidneys reabsorb filtered HCO 3 stomach parietal cells; these cells have an H /K -ATPase completely, even though plasma HCO 3 level is elevated, in their luminal plasma membrane and a Cl /HCO 3 ex- and maintain the metabolic alkalosis. changer in their basolateral plasma membrane. When HCl Vomiting results in K depletion because of a loss of K is secreted into the stomach lumen and lost to the outside, in the vomitus, decreased food intake and, most important there is a net gain of HCO 3 in the blood plasma and no quantitatively, enhanced renal K excretion. Extracellular change in the anion gap. The HCO 3 , in effect, replaces lost alkalosis results in a shift of K into cells (including renal plasma Cl . cells) and, thereby, promotes K secretion and excretion. Ventilation is inhibited by the alkaline blood pH, result- Elevated plasma aldosterone levels also favor K loss in ing in a rise in PCO 2 . This respiratory compensation for the the urine. metabolic alkalosis, however, is limited because hypoven- Treatment of metabolic alkalosis primarily depends on tilation leads to a rise in PCO 2 and a fall in PO 2 , both of which eliminating the cause of vomiting. Correction of the alka- stimulate breathing. losis by administering an organic acid, such as lactic acid, The logical renal compensation for metabolic alkalosis does not make sense because this acid would simply be is enhanced excretion of HCO 3 . In people with persistent converted to CO 2 and H 2 O; this approach also does not vomiting, however, the urine is sometimes acidic and renal address the Cl deficit. The ECF volume depletion and the HCO 3 reabsorption is enhanced, maintaining an elevated Cl and K deficits can be corrected by administering iso- plasma [HCO 3 ]. This situation occurs because vomiting is tonic saline and appropriate amounts of KCl. Because re- accompanied by losses of ECF and K . Fluid loss leads to a placement of Cl is a key component of therapy, this type decrease in effective arterial blood volume and engage- of metabolic alkalosis is said to be “chloride-responsive.” ment of mechanisms that reduce Na excretion, such as After Na , Cl , water, and K deficits have been replaced, decreased GFR and increased plasma renin, angiotensin, excess HCO 3 (accompanied by surplus Na ) will be ex- and aldosterone levels (see Chapter 24). Aldosterone stim- creted in the urine, and the kidneys will return blood pH ulates H secretion by collecting duct -intercalated cells. to normal. Clinical Evaluation of Acid-Base Disturbances respiratory acidosis; a low pH and low plasma [HCO 3 ] in- Requires a Comprehensive Study dicate metabolic acidosis. If alkalosis is present, it could be either respiratory or metabolic. A high blood pH and low Acid-base data should always be interpreted in the context plasma PCO 2 indicate respiratory alkalosis; a high blood pH of other information about a patient. A complete history and high plasma [HCO 3 ] indicate metabolic alkalosis. and physical examination provide important clues to possi- Whether the body is making an appropriate response for ble reasons for an acid-base disorder. a simple acid-base disorder can be judged from the values To identify an acid-base disturbance from laboratory in Table 25.4. Inappropriate values suggest that more than values, it is best to look first at the pH. A low blood pH in- one acid-base disturbance may be present. Patients may dicates acidosis; a high blood pH indicates alkalosis. If aci- have two or more of the four simple acid-base disturbances dosis is present, for example, it could be either respiratory at the same time; in which case, they have a mixed acid- or metabolic. A low blood pH and elevated PCO 2 point to base disturbance. REVIEW QUESTIONS DIRECTIONS: Each of the numbered (E) 1,000:1 (B) Thin ascending limb items or incomplete statements in this 2. An arterial blood sample taken from a (C) Thick ascending limb section is followed by answers or by patient has a pH of 7.32 ([H ] 48 (D) Distal convoluted tubule completions of the statement. Select the nmol/L) and PCO 2 of 24 mm Hg. What (E) Collecting duct ONE lettered answer or completion that is is the plasma [HCO 3 ]? 4. Most of the hydrogen ions secreted by BEST in each case. (A) 6 mEq/L the kidney tubules are (B) 12 mEq/L (A) Consumed in the reabsorption of 1. If the pK a of NH 4 is 9.0, the ratio of (C) 20 mEq/L filtered bicarbonate NH 3 to NH 4 in a urine sample with a (D) 24 mEq/L (B) Excreted in the urine as ammonium pH of 6.0 is (E) 48 mEq/L ions (A) 1:3 3. Which segment can establish the (C) Excreted in the urine as free (B) 3:1 steepest pH gradient (tubular fluid-to- hydrogen ions (C) 3:2 blood)? (D) Excreted in the urine as titratable (D) 1:1,000 (A) Proximal convoluted tubule acid (continued)
CHAPTER 25 Acid-Base Balance 445 5. The following measurements were a comatose condition. An arterial Po2 Pco2 Plasma [HCO32] made in a healthy adult: blood sample revealed a pH of 7.10, pH (mm Hg) (mm Hg) (mEq/L) PCO 2 of 20 mm Hg, and plasma (A) 7.25 95 19 8 Filtered bicarbonate 4,320 mEq/day [HCO 3 ] of 6 mEq/L. Plasma glucose (B) 7.29 55 60 28 Excreted bicarbonate 2 mEq/day and blood urea nitrogen (BUN) values (C) 7.40 95 40 24 Urinary titratable acid 30 mEq/day were normal. Plasma [Na ] was 140 (D) 7.59 95 16 15 Urinary ammonia 60 mEq/day mEq/L and [Cl ] was 105 mEq/L. (E) 7.70 95 16 19 (NH 4 ) Which of the following might explain Urine pH 5 her condition? SUGGESTED READING (A) Acute renal failure Abelow B. Understanding Acid-Base. Balti- Net acid excretion by the kidneys is more: Williams & Wilkins, 1998. (A) 28 mEq/day (B) Diarrhea as a result of food Adrogue HJ, Madias NE. Management of (B) 30 mEq/day poisoning life-threatening acid base disorders. N (C) 88 mEq/day (C) Methanol intoxication Engl J Med 1998;338:26–34, 107–111. (D) 90 mEq/day (D) Overdose with a drug that Alpern RJ, Preisig PA. Renal acid-base trans- (E) 92 mEq/day produces respiratory depression port. In: Schrier RW, Gottschalk CW, 6. If a patient with uncontrolled diabetes (E) Uncontrolled diabetes mellitus eds. Diseases of the Kidney. 6th Ed. mellitus has a daily excretion rate of 9. Which of the following arterial blood Boston: Little, Brown, 1997;189–201. 200 mEq of titratable acid and 500 values might be expected in a Bevensee MO, Alper SL, Aronson PS, mEq of NH 4 , how many mEq of new mountain climber who has been Boron WF. Control of intracellular pH. HCO 3 have the kidney tubules added residing at a high-altitude base camp In: Seldin DW, Giebisch G, eds. The to the blood? below the summit of Mt. Everest for Kidney. Physiology and Pathophysiol- (A) 0 mEq one week? Plasma ogy. 3rd Ed. Philadelphia: Lippincott (B) 200 mEq Po2 Pco2 [HCO32] Williams & Wilkins, 2000;391–442. (C) 300 mEq pH (mm Hg) (mm Hg) (mEq/L) Hood VL, Tannen RL. Protection of acid- base balance by pH regulation of acid (D) 500 mEq (A) 7.18 95 25 9 production. N Engl J Med (E) 700 mEq (B) 7.35 50 60 32 1998;339:819–826. 7. Which of the following causes (C) 7.53 40 20 16 Knepper MA, Packer R, Good DW. Am- increased tubular secretion of hydrogen (D) 7.53 95 50 40 monium transport in the kidney. Phys- ions? (E) 7.62 40 20 20 iol Rev 1989;69:179–249. 10.A 25-year-old nurse is brought to the (A) A decrease in arterial PCO 2 Lowenstein J. Acid and basics: A guide to un- (B) Adrenal cortical insufficiency emergency department shortly before derstanding acid-base disorders. New (C) Administration of a carbonic midnight. Although somewhat drowsy, York: Oxford University Press, 1993. anhydrase inhibitor she was able to relate that she had Rose BD. Clinical Physiology of Acid-Base (D) An increase in intracellular pH attempted to kill herself by swallowing and Electrolyte Disorders. 4th Ed. New (E) An increase in tubular sodium the contents of a bottle of aspirin York: McGraw-Hill, 1994. reabsorption tablets a few hours before. Which of Valtin H, Gennari FJ. Acid-Base Disorders. 8. A homeless woman was found on a hot the following set of arterial blood Basic Concepts and Clinical Manage- summer night lying on a park bench in values is expected? ment. Boston: Little, Brown, 1987. CASE STUDIES FOR PART IV • • • CASE STUDY FOR CHAPTER 23 microscopy, but effacement of podocyte foot processes and loss of filtration slits is seen with the electron micro- Nephrotic Syndrome scope. No immune deposits or complement are seen af- A 6-year-old boy is brought to the pediatrician by his ter immunostaining. The biopsy indicates minimal mother because of a puffy face and lethargy. A few change glomerulopathy. The podocyte cell surface and weeks before, he had an upper respiratory tract infec- glomerular basement membrane show reduced staining tion, probably caused by a virus. Body temperature is with a cationic dye. 36.8C; blood pressure, 95/65; and heart rate, 90 Questions beats/min. Puffiness around the eyes, abdominal 1. What features in this case would cause suspicion of swelling, and pitting edema in the legs are observed. A nephrotic syndrome? urine sample (dipstick) is negative for glucose but re- 2. What is the explanation for the proteinuria? veals 3 protein. Microscopic examination of the urine 3. Why does the abnormally high rate of urinary protein excre- reveals no cellular elements or casts. Plasma [Na ] is tion underestimate the rate of renal protein loss? 140 mEq/L; BUN, 10 mg/dL; [glucose], 100 mg/dL; creati- 4. What is the endogenous creatinine clearance, and is it nor- nine, 0.8 mg/dL; serum albumin, 2.3 g/dL (normal, 3.0 to mal? (The boy’s body surface area is 0.86 m .) 2 4.5 g/dL); and cholesterol, 330 mg/dL. A 24-hour urine 5. What is the explanation for the edema? sample has a volume of 1.10 L and contains 10 mEq/L Na , 60 mg/dL creatinine, and 0.8 g/dL protein. Answers to Case Study Questions for Chapter 23 The child is treated with the corticosteroid prednisone, 1. The child has the classical feature of nephrotic syndrome: and the edema and proteinuria disappear in 2 weeks. heavy proteinuria (8.8 g/day), hypoalbuminemia (3 g/dL), Puffiness and proteinuria recur 4 months later, and a re- generalized edema, and hyperlipidemia (plasma cholesterol nal biopsy is performed. Glomeruli are normal by light 330 mg/dL).
446 PART VI RENAL PHYSIOLOGY AND BODY FLUIDS 2. Proteinuria is a consequence of an abnormally high perme- mm Hg. She is transferred to a general hospital and, dur- ability of the glomerular filtration barrier to the normal ing transfer, has three grand mal seizures and arrives in plasma proteins. This condition might be a result of an in- a semiconscious, uncooperative state. A blood sample creased size of “holes” or pores in the basement membrane reveals a plasma [Na ] of 103 mEq/L. Urine osmolality is and filtration slit diaphragms. The decreased staining with a 362 mOsm/kg H 2 O and urine [Na ] is 57 mEq/L. She is cationic dye, however, suggests that there was a loss of given an intravenous infusion of hypertonic saline (1.8% fixed negative charges from the filtration barrier. Recall that NaCl) and placed on water restriction. Several days after serum albumin bears a net negative charge at physiological she had improved, bronchoscopy is performed. pH values, and that negative charges associated with the Questions glomerular filtration barrier impede filtration of this plasma 1. What is the likely cause of the severe hyponatremia? protein. 2. How much of an increase in plasma [Na ] would an infu- 3. Proteins that have leaked across the glomerular filtration sion of 1 L of 1.8% NaCl (308 mEq Na /L) produce? Assume barrier are not only excreted in the urine but are reabsorbed that her total body water is 25 L (50% of her body weight). by proximal tubules. The endocytosed proteins are digested Why is the total body water used as the volume of distribu- in lysosomes to amino acids, which are returned to the cir- tion of Na , even though the administered Na is limited to culation. Both increased renal catabolism by tubule cells the ECF compartment? and increased excretion of serum albumin in the urine con- 3. Why is the brain so profoundly affected by hypoosmolality? tribute to the hypoalbuminemia. The liver, which synthe- Why should the hypertonic saline be administered slowly? sizes serum albumin, cannot keep up with the renal losses. 4. Why was the bronchoscopy performed? 4. The endogenous creatinine (CR) clearance (an estimate of GFR) equals (U CR V)/P CR (60 1.10)/0.8 82 L/day. Nor- Answers to Case Study Questions for Chapter 24 2 malized to a standard body surface area of 1.73 m , C CR is 1. The problem started with ingestion of excessive amounts of 2 166 L/day 1.73 m , which falls within the normal range water. Compulsive water drinking is a common problem in 2 (150 to 210 L/day 1.73 m ). Note that the permeability of psychotic patients. The increased water intake, combined the glomerular filtration barrier to macromolecules (plasma with an impaired ability to dilute the urine (note the inap- proteins) was abnormally high, but permeability to fluid propriately high urine osmolality), led to severe hypona- was not increased. In some patients, a loss of filtration slits tremia and water intoxication. may be significant and may lead to a reduced fluid perme- 2. Addition of 1 L of 308 mEq Na /L to 25 L produces an in- ability and GFR. crease in plasma [Na ] of 12 mEq/L. The total body water is 5. The edema is a result of altered capillary Starling forces and used in this calculation because when hypertonic NaCl is renal retention of salt and water. The decline in plasma added to the ECF, it causes the movement of water out of [protein] lowers the plasma colloid osmotic pressure, favor- the cell compartment, diluting the extracellular Na . ing fluid movement out of the capillaries into the interstitial 3. Because the brain is enclosed in a nondistensible cranium, compartment. The edema is particularly noticeable in the when water moves into brain cells and causes them to soft skin around the eyes (periorbital edema). The abdomi- swell, intracranial pressure can rise to very high values. nal distension (in the absence of organ enlargement) sug- This can damage nervous tissue directly or indirectly by im- gests ascites (an abnormal accumulation of fluid in the ab- pairing cerebral blood flow. The neurological symptoms dominal cavity). The kidneys avidly conserve Na (note the seen in this patient (headache, semiconsciousness, grand low urine [Na ]) despite an expanded ECF volume. Al- mal seizures) are consequences of brain swelling. The in- though the exact reasons for renal Na retention are contro- creased blood pressure and cool and pale skin may be a versial, a decrease in the effective arterial blood volume consequence of sympathetic nervous system discharge re- may be an important stimulus (see Chapter 24). This leads sulting from increased intracranial pressure. Too rapid to activation of the renin-angiotensin-aldosterone system restoration of a normal plasma [Na ] can produce serious and stimulation of the sympathetic nervous system, both of damage to the brain (central pontine myelinolysis). which favor renal Na conservation. In addition, distal seg- 4. The physicians wanted to exclude the presence of a bron- ments of the nephron reabsorb more Na than usual be- chogenic tumor, which is the most common cause of cause of an intrinsic change in the kidneys. SIADH. No abnormality was detected. Today, a computed tomography (CT) scan would be performed first. Reference Orth SR, Ritz E. The nephrotic syndrome. N Engl J Med References 1998;338:1202–1211 Grainger DN. Rapid development of hyponatremic seizures in a psychotic patient. Psychol Med 1992;22:513–517. CASE STUDY FOR CHAPTER 24 Goldman MB, Luchins DJ, Robertson GL Mechanisms of al- tered water metabolism in psychotic patients with polydipsia Water Intoxication and hyponatremia. N Engl J Med 1988;318:397–403. A 60-year-old woman with a long history of mental ill- ness was institutionalized after a violent argument with CASE STUDY FOR CHAPTER 25 her son. She experiences visual and auditory hallucina- tions and, on one occasion, ran naked through the ward Lactic Acidosis and Hemorrhagic Shock screaming. She refuses to eat anything since admission, During a violent argument over money, a 30-year-old but maintains a good fluid intake. On the fifth hospital man was stabbed in the stomach. The assailant escaped, day, she complains of a slight headache and nausea and but friends were able to rush the victim by car to the has three episodes of vomiting. Later in the day, she is county hospital. The patient is unconscious, with a blood found on the floor in a semiconscious state, confused pressure (mm Hg) of 55/35 and heart rate of 165 and disoriented. She is pale and had cool extremities. beats/minute. Breathing is rapid and shallow. The sub- Her pulse rate is 70/min and blood pressure is 150/100 ject is pale, with cool, clammy skin. On admission, about
CHAPTER 25 Acid-Base Balance 447 an hour after the stabbing, an arterial blood sample is tilation is stimulated by the low blood pH, sensed by the pe- taken, and the following data were reported: ripheral chemoreceptors. Patient Normal Range 3. The anion gap is [Na ] [Cl ] [HCO 3 ] 140 103 Glucose 125 mg/dL 70–110 mg/dL (3.9–6.1 mmol/L) 4 33 mEq/L, which is abnormally high. Considering the (fasting values) history and physical findings, the high anion gap is most Na 140 mEq/L 136–145 mEq/L likely caused by inadequate tissue perfusion, with resultant K 4.8 mEq/L 3.5–5.0 mEq/L anaerobic metabolism and production of lactic acid. The lac- Cl 103 mEq/L 95–105 mEq/L tic acid is buffered by HCO 3 and lactate accumulates as the HCO 3 4 mEq/L 22–26 mEq/L unmeasured anion. Note that tissue hypoxia can occur if BUN 23 mg/dL 7–18 mg/dL blood flow is diminished, even when arterial PO 2 is normal. (1.2–3.0 mmol/L urea nitrogen) 4. The low hematocrit is a result of absorption of interstitial Creatinine 1.1 mg/dL 0.6–1.2 mg/dL fluid by capillaries, consequent to the hemorrhage, low arte- (53–106 mol/L) rial blood pressure, and low capillary hydrostatic pressure. pH 7.08 7.35–7.45 5. In response to the blood loss and low blood pressure, kid- PaCO 2 14 35–45 mm Hg ney blood flow and GFR would be drastically reduced. The PaO 2 97 mm Hg 75–105 mm Hg sympathetic nervous system, combined with increased Hematocrit 35% 41–53% plasma levels of AVP and angiotensin II, would produce in- Questions tense renal vasoconstriction. The hydrostatic pressure in the 1. What type of acid-base disturbance is present? glomeruli would be so low that practically no plasma would 2. What is the reason for the low PaCO 2 ? be filtered and little urine (oliguria) or no urine (anuria) 3. Calculate the plasma anion gap and explain why it is high. would be excreted. Because of the short duration of renal 4. Why is the hematocrit low? shutdown, plasma [creatinine] is still in the normal range; 5. Discuss the status of kidney function. the elevated BUN is probably mainly a result of bleeding 6. What is the most appropriate treatment for the acid-base into the gastrointestinal tract, digestion of blood proteins, disturbance? and increased urea production. Answers to Case Study Questions for Chapter 25 6. Control of bleeding and administration of whole blood (or 1. The subject has a metabolic acidosis, with an abnormally isotonic saline solutions and packed red blood cells) would low arterial blood pH and plasma [HCO 3 ]. help restore the circulation. With improved tissue perfusion, 2. The low PaCO 2 is a result of respiratory compensation. Ven- the lactate will be oxidized to HCO 3 .
PART VII Gastrointestinal Physiology CHAPTER Neurogastroenterology 26 and Gastrointestinal 26 Motility Jackie D. Wood, Ph.D. CHAPTER OUTLINE ■ THE MUSCULATURE OF THE DIGESTIVE TRACT ■ BASIC PATTERNS OF GI MOTILITY ■ CONTROL OF DIGESTIVE FUNCTIONS BY THE ■ MOTILITY IN THE ESOPHAGUS NERVOUS SYSTEM ■ GASTRIC MOTILITY ■ SYNAPTIC TRANSMISSION ■ MOTILITY IN THE SMALL INTESTINE ■ ENTERIC MOTOR NEURONS ■ MOTILITY IN THE LARGE INTESTINE KEY CONCEPTS 1. The musculature of the digestive tract is mainly smooth and presynaptic facilitation are key synaptic events in the muscle. ENS. 2. Electrical slow waves and action potentials are the main 10. Enteric motor neurons may be excitatory or inhibitory to forms of electrical activity in the gastrointestinal muscula- the musculature. ture. 11. Enteric inhibitory motor neurons to the intestinal circular 3. Gastrointestinal smooth muscles have properties of a func- muscle are continuously active and transiently inactivated tional electrical syncytium. to permit muscle contraction. 4. A hierarchy of neural integrative centers in the central 12. Enteric inhibitory motor neurons to the musculature of nervous system (CNS) and peripheral nervous system sphincters are inactive and transiently activated for timed (PNS) determines moment-to-moment behavior of the di- opening and the passage of luminal contents. gestive tract. 13. A polysynaptic reflex circuit determines the behavior of the 5. The digestive tract is innervated by the sympathetic, intestinal musculature during peristaltic propulsion. parasympathetic, and enteric divisions of the autonomic 14. Physiological ileus is the normal absence of contractile ac- nervous system (ANS). tivity in the intestinal musculature. 6. Vagus nerves transmit afferent sensory information to the 15. Peristalsis and relaxation of the lower esophageal sphinc- brain and parasympathetic autonomic efferent signals to ter are the main motility events in the esophagus. the digestive tract. 16. The gastric reservoir and antral pump have different motor 7. Splanchnic nerves transmit sensory information to the behavior. spinal cord and sympathetic autonomic efferent signals to 17. Vago-vagal reflexes are important in the control of gastric the digestive tract. motor functions. 8. The enteric nervous system (ENS) functions as a minibrain 18. Feedback signals from the duodenum determine the rate in the gut. of gastric emptying. 9. Fast and slow excitatory postsynaptic potentials, slow in- 19. The migrating motor complex is the small intestinal motil- hibitory postsynaptic potentials, presynaptic inhibition, ity pattern of the interdigestive state. (continued) 449
450 PART VII GASTROINTESTINAL PHYSIOLOGY 20. Mixing movements are the small intestinal motility pattern 23. Motor functions of the large intestine are specialized for of the digestive state. storage and dehydration of feces. 21. Intestinal power propulsion is a protective response to 24. The physiology of the rectosigmoid region, anal canal, and harmful agents. pelvic floor musculature is important in maintaining fecal 22. Cramping abdominal pain may be associated with intes- continence. tinal power propulsion. his chapter presents concepts and principles of neuro- suited to differing digestive states (e.g., fasting and pro- Tgastroenterology in relation to motor functions of the cessing of a meal) as well as abnormal patterns such as oc- specialized organs and muscle groups of the digestive tract. cur during vomiting. Neurogastroenterology is a subspecialty of clinical gas- troenterology and digestive science. As such, it encom- passes the investigative sciences dealing with functions, THE MUSCULATURE OF THE DIGESTIVE TRACT malfunctions, and malformations in the brain and spinal cord and the sympathetic, parasympathetic, and enteric di- The smooth muscles of the digestive tract are generally or- visions of the autonomic innervation of the digestive tract. ganized in distinct layers. Two important muscle layers for Somatic motor systems are included insofar as pharyngeal motility in the lower esophagus and small and large intes- phases of swallowing and pelvic floor involvement in defe- tine are the longitudinal and circular layers (Fig. 26.1). The cation and continence are concerned. The basic physiology two layers form the intestinal muscularis externa. The of smooth muscles, as it relates to enteric neural control of stomach has an additional obliquely oriented muscle layer. motor movements, is a part of neurogastroenterology. Psy- chological and psychiatric aspects of gastrointestinal disor- ders are significant components of the neurogastroentero- The Structure and Function of Circular logical domain, especially in relation to projections of and Longitudinal Muscles Differ discomfort and pain to the digestive tract. The circular muscle layer is thicker than the longitudinal Gastrointestinal (GI) motility refers to wall movement layer and more powerful in exerting contractile forces on or lack thereof in the digestive tract. The integrated func- the contents of the lumen. The long axis of the muscle tion of multiple tissues and types of cells is necessary for fibers of circular muscle is oriented in the circumferential generation of the various patterns of motility found in the direction. Consequently, contraction reduces the diameter organs of the digestive tract. Digestive motor movements of the lumen of an intestinal segment and increases its involve the application of forces of muscle contraction to length. Because the long axis of the muscle fibers is oriented material that may be present in the mouth, pharynx, esoph- in the longitudinal direction, contraction of the longitudi- agus, stomach, gallbladder, or small and large intestines. nal muscle coat shortens the segment of intestine where it The musculature is striated in the mouth, pharynx, upper occurs and expands the lumen. esophagus, and pelvic floor and in visceral-type smooth muscle elsewhere. Specialized pacemaker cells, called in- terstitial cells of Cajal, are associated with the smooth mus- culature. The nervous system, with its different kinds of neurons and glial cells, organizes muscular activity into Longitudinal muscle functional patterns of wall behavior. Functions of the nerv- Myenteric ganglion ous system are influenced by chemical signals released from enterochromaffin cells, enteroendocrine cells, and cells as- Interganglionic fiber tract sociated with the enteric immune system (e.g., mast cells Circular and polymorphonuclear leukocytes). muscle Motility in the various organs of the digestive tract is or- ganized to fulfill the specialized function of the individual organ. Esophageal motility, for example, differs from gas- tric motility, and gastric motility differs from small intes- tinal motility. The motility in the different organs reflects coordinated contractions and relaxations of the smooth muscle. Contractions are organized to produce the propul- 200 µm sive forces that move the contents along the tract, triturate large particles to smaller particles, mix ingested foodstuff Submucosal with digestive enzymes, and bring nutrients into contact Mucosa ganglion with the mucosa for efficient absorption. Relaxation of spontaneous tone in the smooth muscle allows sphincters FIGURE 26.1 Structural relationship of the intestinal mus- culature and the enteric nervous system. to open and ingested material to be accommodated in Ganglia and interganglionic fiber tracts form the myenteric reservoirs of the stomach and large intestine. The enteric plexus between the longitudinal and the circular muscle layer and nervous system (ENS), together with its input from the form the submucosal plexus between the mucosa and circular CNS, organizes motility into patterns of efficient behavior muscle layer.
CHAPTER 26 Neurogastroenterology and Gastrointestinal Motility 451 Both longitudinal and circular muscle layers are innervated transmit electrical current from muscle fiber to muscle by motor neurons of the ENS. The longitudinal muscle layer fiber. Ionic connectivity, without cytoplasmic continuity is innervated mainly by excitatory motor neurons; the circu- from fiber to fiber, accounts for the electrical syncytial lar muscle layer by both excitatory and inhibitory motor neu- properties of smooth muscle, which confers electrical be- rons. Nonneural pacemaker cells and excitatory motor neu- havior analogous to that of cardiac muscle (see Chapter rons activate contraction of the circular muscle, and 13). Electrical activity and associated contractions spread excitatory motor neurons are the main triggers for contrac- from a point of initiation (e.g., the pacemaker region) in tion of the longitudinal muscle. More gap junctions between three dimensions throughout the bulk of the muscle. The adjacent muscle fibers are found in the circular layer than in distance and the direction of electrical activity spread are the longitudinal muscle layer. Calcium influx from outside the controlled by the ENS. A failure of nervous control can lead muscle cells is important for excitation-contraction coupling to disordered motility that includes spasm and associated in longitudinal muscle fibers. Intracellular release from inter- abdominal pain. nal stores is more important for excitation-contraction cou- pling in the muscle fibers of the circular layer. Slow Waves and Action Potentials Are Forms of Electrical Activity in GI Muscles Smooth Muscles Are Classified as Unitary Electrical slow waves are omnipresent and responsible for or Multiunit Types triggering action potentials in some regions, whereas in Smooth muscles are classified based on their behavioral other regions (e.g., the gastric antrum and large intestinal properties and associations with nerves (see Chapter 9). circular muscle) they represent the only form of electrical Muscles of the stomach and intestine behave like unitary activity (Fig. 26.2). They are always present in the small in- type smooth muscle. These muscles contract sponta- testine where they decrease in frequency along a gradient neously in the absence of neural or endocrine influence and from the duodenum to the ileum. In the gastric antrum, the contract in response to stretch. There are no structured terms slow wave and action potential are used interchangeably neuromuscular junctions, and neurotransmitters travel over for the same electrical event. When action potentials are as- extended diffusion distances to influence relatively large sociated with electrical slow waves, they occur during the numbers of muscle fibers. The smooth muscle of the esoph- plateau phase of the slow wave (see Fig. 26.2). agus and gallbladder is more like the multiunit type. These Action potentials in GI smooth muscle are mediated by muscles do not contract spontaneously in the absence of changes in calcium and potassium conductances. The de- nervous input and do not contract in response to stretch. polarization phase of the action potential is produced by an Activation to contract is by nervous input to relatively all-or-nothing increase in calcium conductance, with the small groups of muscle fibers. inward calcium current carried by L-type calcium channels. The opening of potassium channels as the calcium channels are closing at or near the peak of the action potential ac- Electromechanical and Pharmacomechanical counts for the repolarization phase. The L-type calcium Coupling Trigger Contractions in GI Muscles channels in GI smooth muscle are essentially the same as those found in cardiac and vascular smooth muscle. There- GI smooth muscle differs from skeletal muscle in having fore, disordered GI motility may be a adverse effect of two mechanisms that initiate the processes leading to con- treating of cardiovascular disease with drugs that block L- tractile shortening and development of tension. In both type calcium channels. skeletal muscle and GI smooth muscle, depolarization of the membrane electrical potential leads to the opening of voltage-gated calcium channels, followed by the elevation of cytosolic calcium, which, in turn, activates the contrac- tile proteins. This mechanism is called electromechanical 2 coupling. Smooth muscles have an additional mechanism in which the binding of a ligand to its receptor on the mus- 3 cle membrane leads to the opening of calcium channels and the elevation of cytosolic calcium without any change in 1 4 the membrane electrical potential. This mechanism is called pharmacomechanical coupling. The ligands may be 0 0 chemical substances released as signals from nerves (neuro- crine), from nonneural cells in close proximity to the mus- Electrical slow waves. In GI muscles, slow cle (paracrine), or from endocrine cells as hormones deliv- FIGURE 26.2 waves occur in four phases determined by ered to the muscle by the blood. specific ionic mechanisms. Phase 0: Resting membrane poten- tial; outward potassium current. Phase 1, the rising phase (up- stroke depolarization), activates voltage-gated calcium chan- GI and Esophageal Smooth Muscles Have nels and voltage-gated potassium channels. Phase 3, the plateau Properties of a Functional Electrical Syncytium phase, balances inward calcium current and outward potassium current. Phase 4, the falling phase (repolarization), inactivates Smooth muscle fibers are connected to their neighbors by voltage-gated calcium channels and activates calcium-gated gap junctions, which are permeable to ions and, thereby, potassium channels.
452 PART VII GASTROINTESTINAL PHYSIOLOGY -30 (Fig. 26.5). The ICCs are interconnected into networks by Stomach mV gap junctions that impart the properties of a functional electrical syncytium to the network. Gap junctions also elec- -70 trically connect the ICCs to the circular muscle. Electrical -22 current flows from the ICC network across the gap junctions Small mV to depolarize the membrane potential of the circular muscle intestine fibers to the threshold for action potential discharge. -62 Pacemaker networks of ICCs are located surrounding the small intestinal circular muscle at the border with the -41 longitudinal muscle (myenteric border) and at its border Colon mV with the submucosa. Slow waves generated by the ICC net- work at the submucosal border spread passively across gap -81 junctions into the bulk of circular muscle, and those at the myenteric border spread passively into both longitudinal 30 sec and circular muscle. Muscle fibers of the circular muscle are Electrical slow-wave frequencies. Slow interconnected by gap junctions that transmit the slow- FIGURE 26.3 waves with similar waveforms occur at different wave electrical current from fiber to fiber throughout the frequencies in the stomach, small intestine, and colon. bulk of the muscle. Electrical Slow-Wave Frequencies in the Stomach, Small CONTROL OF DIGESTIVE FUNCTIONS Intestine, and Colon. Electrical slow waves with essen- BY THE NERVOUS SYSTEM tially the same waveform occur at different frequencies in the gastric antrum and small and large intestinal circular The innervation of the digestive tract controls muscle con- muscle when recorded with intracellular electrodes (Fig. traction, secretion, and absorption across the mucosal lin- 26.3). Slow waves occur at 3/min in the antrum, as high as ing and blood flow inside the walls of the esophagus, stom- 18/min in the duodenum, and 6 to 10/min in the colon. The ach, intestines, and gallbladder. Depending on the kind of maximum contractile frequency of the muscle does not ex- neurotransmitter released, the neurons can activate or in- ceed the frequency of the slow waves, but it may occur at a hibit muscle contraction. The secretion of water, elec- lower frequency because all slow waves may not trigger trolytes, and mucus into the lumen and absorption from the contractions. The nervous system determines the nature of lumen are determined by the innervation. The amount of the contractile response during each slow wave in the inte- blood flow within the wall and the distribution of flow be- grated functional state of the whole organ. tween the muscle layers and mucosa are also controlled by nervous activity. Sensory nerves transmit information on the state of the Electrical Slow Waves Without Action Potentials in the Small Intestine. As a general rule, slow waves in the small gut to the brain for processing. Sensory transmission and intestinal circular muscle trigger action potentials and ac- central processing account for sensations that are localized tion potentials trigger contractions. Slow waves are om- to the digestive tract. These include sensations of discom- nipresent in virtually all mammalian species and may or fort (such as upper abdominal fullness), abdominal pain, may not be accompanied by action potentials. Contrac- and chest pain (heartburn). Neural interactions include the tions do not occur in the absence of action potentials. The sensory inflow of information from the gut to the brain and electrical slow waves in Figure 26.4 were recorded with an outflow from the brain to the gut. Outflow may originate in extracellular electrode attached to the serosal surface of the higher processing centers of the brain (the frontal cortex) intestine. This method records from many circular muscle and account for the projection of an individual’s emotional fibers. Shallow contractions appearing in the absence of ac- state (psychogenic stress) to the gut. This kind of brain-gut tion potentials on the slow waves reflect the responses of a interaction underlies the symptoms of diarrhea and lower few of the total population of muscle fibers under the elec- abdominal discomfort often reported by students anticipat- trode (Fig. 26.4A). In this case, the action potential currents ing an examination. from the small number of fibers are too small to be detected by the surface electrode. With this method of recording, A Hierarchy of Neural Integrative Centers the size of an action potential appears larger when larger Determines the Moment-to-Moment Motor numbers of the total population of muscle fibers are depo- Behavior of the Digestive Tract larized to action potential threshold by each slow wave. The amplitude of phasic contractions associated with each The sympathetic, parasympathetic, and enteric nervous electrical slow wave increases in direct relation to the num- systems make up the divisions of the ANS that innervate ber of muscle fibers recruited to firing threshold by each the digestive tract. Figure 26.6 illustrates how neural con- slow-wave cycle (Fig. 26.4B). trol of the gut is hierarchical with five basic levels of inte- grative organization. Level 1 is the ENS, which behaves Electrical Slow Waves and Interstitial Cells of Cajal. Inter- like a minibrain in the gut. Level 2 consists of the preverte- stitial cells of Cajal (ICCs) are the generators of electrical bral ganglia of the sympathetic nervous system. Levels 3, 4, slow waves in the stomach and small and large intestine and 5 are within the CNS. Sympathetic and parasympa-
CHAPTER 26 Neurogastroenterology and Gastrointestinal Motility 453 Small intestine 10 g Contraction 10 sec Slow waves 1.2 mV Electrical FIGURE 26.4 A slow waves in the small intestine. A, No action potentials appear at the crests of the slow waves, and Small the muscle contractions associ- intestine Contraction 10 g ated with each slow wave are small. B, Muscle action poten- tials appear as sharp upward- downward deflections at the 10 sec crests of the slow waves. Large- amplitude muscle contractions are associated with each slow B Slow waves 1.2 mV wave when action potentials are present. Electrical slow waves Action potentials trigger action potentials, and action potentials trigger con- tractions. thetic signals to the digestive tract originate at levels 3 and gestive tract consists of interconnections between the 4 (central sympathetic and parasympathetic centers) in the brain, the spinal cord, and the ENS. medulla oblongata and represent the final common path- ways for the outflow of information from the brain to the gut. Level 5 includes higher brain centers that provide in- Autonomic Parasympathetic Neurons Project to put for integrative functions at levels 3 and 4. the Gut From the Medulla Oblongata and Sacral Autonomic signals to the gut are carried from the brain Spinal Cord and spinal cord by sympathetic and parasympathetic nerv- ous pathways that represent the extrinsic component of in- The origins of parasympathetic nerves to the gut are lo- nervation. Neurons of the enteric division form the local in- cated in both the brainstem and sacral region of the spinal tramural control networks that make up the intrinsic cord (Fig. 26.7). Projections to the digestive tract from component of the autonomic innervation. The parasympa- these regions of the CNS are preganglionic efferents. Neu- thetic and sympathetic subdivisions are identified by the positions of the ganglia containing the cell bodies of the postganglionic neurons and by the point of outflow from 5 the CNS. Comprehensive autonomic innervation of the di- Higher brain centers 4 3 Central parasympathetic Central sympathetic centers centers ICC network 2 Prevertebral sympathetic ganglia 1 GI muscle Enteric nervous system Interstitial cells of Cajal. ICCs form net- FIGURE 26.5 works that contact the GI musculature. Gastrointestinal, esophageal, and biliary tract Electrical slow waves originate in the networks of ICCs. ICCs are musculature and mucosa the generators (pacemaker sites) of the slow waves. Gap junctions connect the ICCs to the circular muscle. Ionic current flows FIGURE 26.6 A hierarchy of neural integrative centers. across the gap junctions to depolarize the membrane potential of Five levels of neural organization determine the the circular muscle fibers to the threshold for the discharge of ac- moment-to-moment motor behavior of the digestive tract. (See tion potentials. text for details.)
454 PART VII GASTROINTESTINAL PHYSIOLOGY Motility Area postrema Medulla Esophagus oblongata (+/-) Fourth ventricle Dorsal motor Solitary tract nucleus Stomach Nucleus tractus (+/-) solitarius (+) Small intestine (+) (+) Sacral Nucleus Right vagus nerve Colon Pelvic spinal ambiguus nerves cord Dorsal vagal complex of medulla oblon- (+) FIGURE 26.8 gata. Parasympathetic innervation. Signals from FIGURE 26.7 parasympathetic centers in the CNS are trans- mitted to the enteric nervous system by the vagus and pelvic Vago-Vagal Reflex Circuits Consist of Sensory nerves. These signals may result in contraction () or relaxation () of the digestive tract musculature. Afferents, Second-Order Interneurons, and Efferent Neurons A reflex circuit known as the vago-vagal reflex underlies moment-to-moment adjustments required for optimal di- ronal cell bodies in the dorsal motor nucleus in the medulla gestive function in the upper digestive tract (see Clinical oblongata project in the vagus nerves, and those in the Focus Box 26.1). The afferent side of the reflex arc consists sacral region of the spinal cord project in the pelvic nerves of vagal afferent neurons connected with a variety of sen- to the large intestine. Efferent fibers in the pelvic nerves sory receptors specialized for the detection and signaling of make synaptic contact with neurons in ganglia located on mechanical parameters, such as muscle tension and mucosal the serosal surface of the colon and in ganglia of the ENS brushing, or luminal chemical parameters, including glu- deeper within the large intestinal wall. Efferent vagal fibers cose concentration, osmolality, and pH. Cell bodies of the synapse with neurons of the ENS in the esophagus, stom- vagal afferents are in the nodose ganglia. The afferent neu- ach, small intestine, and colon, as well as in the gallbladder rons are synaptically connected with neurons in the dorsal and pancreas. motor nucleus of the vagus and in the nucleus of the tractus Efferent vagal nerves transmit signals to the enteric inner- solitarius. The nucleus of the tractus solitarius, which lies vation of the GI musculature to control digestive processes directly above the dorsal motor nucleus of the vagus (see both in anticipation of food intake and following a meal. This Fig. 26.8), makes synaptic connections with the neuronal involves the stimulation and inhibition of contractile behav- pool in the vagal motor nucleus. A synaptic meshwork ior in the stomach as a result of activation of the enteric cir- formed by processes from neurons in both nuclei tightly cuits that control excitatory or inhibitory motor neurons, re- links the two into an integrative center. The dorsal vagal spectively. Parasympathetic efferents to the small and large neurons are second- or third-order neurons representing intestinal musculature are predominantly stimulatory as a re- the efferent arm of the reflex circuit. They are the final sult of their input to the enteric microcircuits that control the common pathways out of the brain to the enteric circuits activity of excitatory motor neurons. innervating the effector systems. The dorsal vagal complex consists of the dorsal motor Efferent vagal fibers form synapses with neurons in the nucleus of the vagus, nucleus tractus solitarius, area ENS to activate circuits that ultimately drive the outflow of postrema, and nucleus ambiguus; it is the central vagal in- signals in motor neurons to the effector systems. When the tegrative center (Fig. 26.8). This center in the brain is more effector system is the musculature, its innervation consists directly involved in the control of the specialized digestive of both inhibitory and excitatory motor neurons that par- functions of the esophagus, stomach, and the functional ticipate in reciprocal control. If the effector systems are cluster of duodenum, gallbladder, and pancreas than the gastric glands or digestive glands, the secretomotor neu- distal small intestine and large intestine. The circuits in the rons are excitatory and stimulate secretory behavior. dorsal vagal complex and their interactions with higher The circuits for CNS control of the upper GI tract are centers are responsible for the rapid and more precise con- organized much like those dedicated to the control of trol required for adjustments to rapidly changing condi- skeletal muscle movements (see Chapter 5), where funda- tions in the upper digestive tract during anticipation, in- mental reflex circuits are located in the spinal cord. Inputs gestion, and digestion of meals of varied composition. to the spinal reflex circuits from higher order integrative
CHAPTER 26 Neurogastroenterology and Gastrointestinal Motility 455 CLINICAL FOCUS BOX 26.1 Delayed Emptying and Rapid Emptying: Disorders of Gas- tric Motility Disorders of gastric motility can be divided into the broad categories of delayed and rapid emptying. The generalized Abdominal Early satiety symptoms of both disorders overlap (Fig. 26.A). cramping Feeling of fullness Delayed gastric emptying is common in diabetes melli- Epigastric pain Diarrhea tus and may be related to disorders of the vagus nerves, as Belching Nausea Vasomotor changes Vomiting part of a spectrum of autonomic neuropathy. Surgical Heartburn Pallor vagotomy results in a rapid emptying of liquids and a de- Anorexia Rapid pulse layed emptying of solids. As mentioned earlier, vagotomy Weight loss Perspiration Syncope impairs adaptive relaxation and results in increased con- tractile tone in the reservoir (see Fig. 26.29). Increased pressure in the gastric reservoir more forcefully presses liquids into the antral pump. Paralysis with a loss of Delayed Rapid propulsive motility in the antrum occurs after a vagotomy. gastric emptying gastric emptying The result is gastroparesis, which can account for the de- Symptoms of disordered gastric empty- layed emptying of solids after a vagotomy. When selective FIGURE 26.A ing. Some of the symptoms of delayed vagotomy is performed as a treatment for peptic ulcer dis- and rapid gastric emptying overlap. ease, the pylorus is enlarged surgically (pyloroplasty) to compensate for postvagotomy gastroparesis. Delayed gastric emptying with no demonstrable un- absence of inhibitory motor neurons and the failure of derlying condition is common. Up to 80% of patients the circular muscles to relax account for the obstructive with anorexia nervosa have delayed gastric emptying of stenosis. solids. Another such condition is idiopathic gastric Rapid gastric emptying often occurs in patients who stasis, in which no evidence of an underlying condition have had both vagotomy and gastric antrectomy for the can be found. Motility-stimulating drugs (e.g., cisapride) treatment of peptic ulcer disease. These individuals have are used successfully in treating these patients. In chil- rapid emptying of solids and liquids. The pathological ef- dren, hypertrophic pyloric stenosis impedes gastric fects are referred to as the dumping syndrome, which re- emptying. This is a thickening of the muscles of the py- sults from the “dumping” of large osmotic loads into the loric canal associated with a loss of enteric neurons. The proximal small intestine. centers in the brain (motor cortex and basal ganglia) com- Sympathetic input generally functions to shunt blood plete the neural organization of skeletal muscle motor con- from the splanchnic to the systemic circulation during ex- trol. Memory, the processing of incoming information ercise and stressful environmental change, coinciding with from outside the body, and the integration of propriocep- the suppression of digestive functions, including motility tive information are ongoing functions of higher brain cen- and secretion. The release of norepinephrine (NE) from ters responsible for the logical organization of outflow to sympathetic postganglionic neurons is the principal media- the skeletal muscles by way of the basic spinal reflex circuit. tor of these effects. NE acts directly on sphincteric muscles The basic connections of the vago-vagal reflex circuit are to increase tension and keep the sphincter closed. Presy- like somatic motor reflexes, in that they are “fine-tuned” naptic inhibitory action of NE at synapses in the control from moment to moment by input from higher integrative circuitry of the ENS is primarily responsible for inactiva- centers in the brain. tion of motility. Suppression of synaptic transmission by the sympathetic nerves occurs at both fast and slow excitatory synapses in the Autonomic Sympathetic Neurons Project to neural networks of the ENS. This inactivates the neural cir- the Gut From Thoracic and Upper Lumbar cuits that generate intestinal motor behavior. Activation of Segments of the Spinal Cord the sympathetic inputs allows only continuous discharge of inhibitory motor neurons to the nonsphincteric muscles. Sympathetic innervation to the gut is located in thoracic and lumbar regions of the spinal cord (Fig. 26.9). The nerve The overall effect is a state of paralysis of intestinal motility cell bodies are in the intermediolateral columns. Efferent in conjunction with reduced intestinal blood flow. When sympathetic fibers leave the spinal cord in the ventral roots this state occurs transiently, it is called physiological ileus to make their first synaptic connections with neurons in and, when it persists abnormally, is called paralytic ileus. prevertebral sympathetic ganglia located in the abdomen. The prevertebral ganglia are the celiac, superior mesen- Splanchnic Nerves Transmit Sensory Information teric, and inferior mesenteric ganglia. Cell bodies in the to the Spinal Cord and Efferent Sympathetic prevertebral ganglia project to the digestive tract where Signals to the Digestive Tract they synapse with neurons of the ENS in addition to inner- vating the blood vessels, mucosa, and specialized regions of The splanchnic nerves are mixed nerves that contain both the musculature. sympathetic efferent and sensory afferent fibers. Sensory
456 PART VII GASTROINTESTINAL PHYSIOLOGY Medulla oblongata Superior cervical ganglion 1 Thoracolumbar region 2 3 Prevertebral sympathetic ganglia 1: Celiac 2: Superior mesenteric Sympathetic innerva- FIGURE 26.9 3: Inferior mesenteric tion. nerves course side by side with the sympathetic fibers; nev- at the effector sites have evolved as an organized array of ertheless, they are not part of the sympathetic nervous sys- different kinds of neurons interconnected by chemical tem. The term sympathetic afferent, which is sometimes synapses. Function in the circuits is determined by the gen- used, is incorrect. eration of action potentials within single neurons and Sensory afferent fibers in the splanchnic nerves have chemical transmission of information at the synapses. their cell bodies in dorsal root spinal ganglia. They transmit The enteric microcircuits in the various specialized re- information from the GI tract and gallbladder to the CNS gions of the digestive tract are wired with large numbers of for processing. These fibers transmit a steady stream of in- neurons and synaptic sites where information processing formation to the local processing circuits in the ENS, to pre- occurs. Multisite computation generates output behavior vertebral sympathetic ganglia, and to the CNS. The gut has from the integrated circuits that could not be predicted mechanoreceptors, chemoreceptors, and thermoreceptors. from properties of their individual neurons and synapses. Mechanoreceptors sense mechanical events in the mucosa, As in the brain and spinal cord, emergence of complex be- musculature, serosal surface, and mesentery. They supply haviors is a fundamental property of the neural networks of both the ENS and the CNS with information on stretch-re- the ENS. lated tension and muscle length in the wall and on the The processing of sensory signals is one of the major movement of luminal contents as they brush the mucosal functions of the neural networks of the ENS. Sensory sig- surface. Mesenteric mechanoreceptors code for gross move- nals are generated by sensory nerve endings and coded in ments of the organ. Chemoreceptors generate information the form of action potentials. The code may represent the on the concentration of nutrients, osmolality, and pH in the status of an effector system (such as tension in a muscle), or luminal contents. Recordings of sensory information exiting it may signal a change in an environmental parameter, such the gut in afferent fibers reveal that most receptors are mul- as luminal pH. Sensory signals are computed by the neural timodal, in that they respond to both mechanical and chem- networks to generate output signals that initiate homeosta- ical stimuli. The presence in the GI tract of pain receptors tic adjustments in the behavior of the effector system. (nociceptors) equivalent to C fibers and A-delta fibers else- The cell bodies of the neurons that make up the neural where in the body is likely, but not unequivocally con- networks are clustered in ganglia that are interconnected firmed, except for the gallbladder. The sensitivity of by fiber tracts to form a plexus. The structure, function, and splanchnic afferents, including nociceptors, may be elevated neurochemistry of the ganglia differ from other ANS gan- when inflammation is present in intestine or gallbladder. glia. Unlike autonomic ganglia elsewhere in the body, where they function mainly as relay-distribution centers for signals transmitted from the brain and spinal cord, enteric The Enteric Division of the ANS Functions as a ganglia are interconnected to form a nervous system with Minibrain in the Gut mechanisms for the integration and processing of informa- tion like those found in the CNS. This is why the ENS is The ENS is a minibrain located close to the effector sys- tems it controls. Effector systems of the digestive tract are sometimes referred to as the “minibrain-in-the-gut.” the musculature, secretory glands, and blood vessels. Rather than crowding the vast numbers of neurons required Myenteric and Submucous Plexuses for controlling digestive functions into the cranium as part Are Parts of the ENS of the cephalic brain and relying on signal transmission over long and unreliable pathways, the integrative micro- The ENS consists of ganglia, primary interganglionic fiber circuits are located at the site of the effectors. The circuits tracts, and secondary and tertiary fiber projections to the
CHAPTER 26 Neurogastroenterology and Gastrointestinal Motility 457 effector systems (i.e., musculature, glands, and blood ves- rations less than 50 msec and slow synaptic potentials last- sels). These structural components of the ENS are inter- ing several seconds can be recorded in cell bodies of enteric laced to form a plexus. Two ganglionated plexuses are the ganglion cells. These synaptic events may be excitatory most obvious constituents of the ENS (see Fig. 26.1). The postsynaptic potentials (EPSPs) or inhibitory postsynaptic myenteric plexus, also known as Auerbach’s plexus, is lo- potentials (IPSPs). They can be evoked by experimental cated between the longitudinal and circular muscle layers stimulation of presynaptic axons, or they may occur spon- of most of the digestive tract. The submucous plexus, also taneously. Presynaptic inhibitory and facilitatory events known as Meissner’s plexus, is situated in the submucosal can involve axoaxonal, paracrine, or endocrine forms of region between the circular muscle and mucosa. The sub- transmission, and they occur at both fast and slow synaptic mucous plexus is most prominent as a ganglionated net- connections. work in the small and large intestines. It does not exist as a Figure 26.11 shows three kinds of synaptic events that ganglionated plexus in the esophagus and is sparse in the occur in enteric neurons. The synaptic potentials in this il- submucosal space of the stomach. lustration were evoked by placing fine stimulating elec- Motor innervation of the intestinal crypts and villi orig- trodes on interganglionic fiber tracts of the myenteric or inates in the submucous plexus. Neurons in submucosal submucous plexus and applying electrical shocks to stimu- ganglia send fibers to the myenteric plexus and also receive late presynaptic axons and release the neurotransmitter at synaptic input from axons projecting from the myenteric the synapse. plexus. The interconnections link the two networks into a functionally integrated nervous system. Enteric Slow EPSPs Have Specific Properties Mediated by Metabotropic Receptors Sensory Neurons, Interneurons, and Motor The slow EPSP in Figure 26.11 was evoked by repetitive Neurons Form the Microcircuits of the ENS shocks (5 Hz) applied to the fiber tract for 5 seconds. The heuristic model for the ENS is the same as that for the Slowly activating depolarization of the membrane poten- brain and spinal cord (Fig. 26.10). In fact, the ENS has as tial with a time course lasting longer than 2 minutes after many neurons as the spinal cord. Like the CNS, sensory neu- termination of the stimulus is apparent. Repetitive dis- rons, interneurons, and motor neurons in the ENS are con- charge of action potentials reflects enhanced neuronal ex- nected synaptically for the flow of information from sensory citability during the EPSP. The record shows hyperpolariz- neurons to interneuronal integrative networks to motor neu- ing after-potentials associated with the first four spikes of rons to effector systems. The ENS organizes and coordinates the train. As the slow EPSP develops, the hyperpolarizing the activity of each effector system into meaningful behavior after-potentials are suppressed and can be seen to recover of the integrated organ. Bidirectional communication occurs at the end of the spike train as the EPSP subsides. Suppres- between the central and enteric nervous systems. sion of the after-potentials is part of the mechanism of slow synaptic excitation that permits the neuron to convert from low to high states of excitability. Slow EPSPs are mediated by multiple chemical messen- SYNAPTIC TRANSMISSION gers acting at a variety of different metabotropic receptors. Multiple kinds of synaptic transmission occur in the micro- Different kinds of receptors, each of which mediates slow circuits of the ENS. Both fast synaptic potentials with du- synaptic-like responses, are found in varied combinations Central nervous system Enteric nervous system Effector systems Interneurons Muscle Sensory Reflexes Motor neurons Secretory epithelium Enteric nervous Program library neurons Blood vessels FIGURE 26.10 Information processing system. Sensory neurons, interneurons, and motor neu- rons are synaptically interconnected to form the microcircuits of the ENS. As Gut behavior in the CNS, information flows from Motility pattern sensory neurons to interneuronal inte- Secretory pattern grative networks to motor neurons to Circulatory pattern effector systems.
458 PART VII GASTROINTESTINAL PHYSIOLOGY A Slow EPSP On Off Afterhyperpolarization Stimulus 40 mV 20 sec B Fast EPSPs C Slow IPSP Action potential Stimulus artifact Stimulus EPSPs artifact 10 mV 10 mV 10 msec 0.5 sec Synaptic events in enteric neurons. Slow EP- reflects enhanced neuronal excitability. B, The fast EPSPs were FIGURE 26.11 SPs, fast EPSPs, and slow IPSPs all occur in en- also evoked by single electrical shocks applied to the axon that teric neurons. A, The slow EPSP was evoked by repetitive electri- synapsed with the recorded neuron. Two fast EPSPs were evoked cal stimulation of the synaptic input to the neuron. Slowly by successive stimuli and are shown as superimposed records. activating membrane depolarization of the membrane potential Only one of the EPSPs reached the threshold for the discharge of continues for almost 2 minutes after termination of the stimulus. an action potential. C, The slow IPSP was evoked by the stimula- During the slow EPSP, repetitive discharge of action potentials tion of an inhibitory input to the neuron. on each individual neuron. A common mode of signal trans- tatory motor neurons to the intestinal musculature or the duction involves receptor activation of adenylyl cyclase mucosa results in prolonged contraction of the muscle or and second messenger function of cAMP, which links sev- prolonged secretion from the crypts. The occurrence of eral different chemical messages to the behavior of a com- slow EPSPs in inhibitory motor neurons to the musculature mon set of ionic channels responsible for generation of the results in prolonged inhibition of contraction. This re- slow EPSP responses. Serotonin, substance P, and acetyl- sponse is observed as a decrease in contractile tension. choline (ACh) are examples of enteric neurotransmitters that evoke slow EPSPs. Paracrine mediators released from nonneural cells in the gut also evoke slow EPSP-like re- Enteric Fast EPSPs Have Specific Properties sponses when released in the vicinity of the ENS. Hista- Mediated by Inotropic Receptors mine, for example, is released from mast cells during hy- Fast EPSPs (see Fig. 26.11B) are transient depolarizations of persensitivity reactions to antigens and acts at the membrane potential that have durations of less than 50 histamine H 2 -receptor subtype to evoke slow EPSP-like re- msec. They occur in the enteric neural networks through- sponses in enteric neurons. Subpopulations of enteric neu- out the digestive tract. Most fast EPSPs are mediated by rons in specialized regions of the gut (e.g., the upper duo- ACh acting at inotropic nicotinic receptors. Ionotropic re- denum) have receptors for hormones, such as gastrin and ceptors are those coupled directly to ion channels. Fast EP- cholecystokinin, that also evoke slow EPSP-like responses. SPs function in the rapid transfer and transformation of neurally coded information between the elements of the enteric microcircuits. They are “bytes” of information in the Slow EPSPs Are a Mechanism for information-processing operations of the logic circuits. Prolonged Neural Excitation or Inhibition of GI Effector Systems Enteric Slow IPSPs Have Specific Properties The long-lasting discharge of spikes during the slow EPSP Mediated by Multiple Chemical Receptors drives the release of neurotransmitter from the neuron’s axon for the duration of the spike discharge. This may re- The slow IPSP of Figure 26.11 was evoked by stimulation of sult in either prolonged excitation or inhibition at neuronal an interganglionic fiber tract in the submucous plexus. This synapses and neuroeffector junctions in the gut wall. hyperpolarizing synaptic potential will suppress excitability Contractile responses within the musculature and secre- (decrease the probability of spike discharge), compared with tory responses within the mucosal epithelium are slow enhanced excitability during the slow EPSP. events that span time courses of several seconds from start Several different chemical messenger substances that to completion. The train-like discharge of spikes during may be peptidergic, purinergic, or cholinergic produce slow EPSPs is the neural correlate of long-lasting responses slow IPSP-like effects. Enkephalins, dynorphin, and mor- of the gut effectors during physiological stimuli. Figure phine are all slow IPSP mimetics. This action is limited to 26.12 illustrates how the occurrence of slow EPSPs in exci- subpopulations of neurons. Opiate receptors of the sub-
CHAPTER 26 Neurogastroenterology and Gastrointestinal Motility 459 at sympathetic inhibitory synapses in the neural networks of the submucous plexus and at excitatory neuromuscular junctions. It is a specialized form of neurocrine transmis- Slow EPSP sion whereby neurotransmitter released from an axon acts at receptors on a second axon to prevent the release of neu- Muscles rotransmitter from the second axon. Presynaptic inhibition, resulting from actions of paracrine or endocrine mediators Contractile tension motor neuron mechanism for modulating synaptic transmission. on receptors at presynaptic release sites, is an alternative Excitatory Presynaptic inhibition in the ENS is mediated by multi- ple substances and their receptors, with variable combina- chemical messenger substances may be peptidergic, amin- Inhibitory tions of the receptors involved at each release site. The motor neuron ergic, or cholinergic. NE acts at presynaptic 2 -adrenergic Short-circuit current 0 420 EPSPs, and cholinergic transmission at neuromuscular junc- receptors to suppress fast EPSPs at nicotinic synapses, slow Mucosal epithelium tions. Serotonin suppresses both fast and slow EPSPs in the myenteric plexus. Opiates or opioid peptides suppress some fast EPSPs in the intestinal myenteric plexus. Excitatory 81216 ACh acts at muscarinic presynaptic receptors to sup- motor neuron Time (sec) press fast EPSPs in the myenteric plexus. This is a form of The functional significance of slow EPSPs. autoinhibition where ACh released at synapses with nico- FIGURE 26.12 Slow EPSPs in excitatory motor neurons to the tinic postsynaptic receptors feeds back onto presynaptic muscles or mucosal epithelium result in prolonged muscle con- traction or mucosal crypt secretion. Stimulation of secretion in experiments is seen as an increase in ion movement (short-circuit current). Slow IPSPs in inhibitory motor neurons to the muscles result in prolonged inhibition of contractile activity, which is ob- served as decreased contractile tension. type predominate on myenteric neurons in the small intes- tine; the receptors on neurons of the intestinal submucous plexus belong to the -opiate receptor subtype. The effects of opiates and opioid peptides are blocked by the antago- nist naloxone. Addiction to morphine may be seen in en- teric neurons, and withdrawal is observed as high-fre- quency spike discharge upon the addition of naloxone during chronic morphine exposure. NE acts at 2 -adrenergic receptors to mimic slow IPSPs. This action occurs primarily in neurons of the submucous plexus that are involved in controlling mucosal secretion. The stimulation of sympathetic nerves evokes slow IPSPs that are blocked by 2 -adrenergic receptor antagonists in submucosal neurons. Slow IPSPs in submucosal neurons is a mechanism by which the sympathetic innervation sup- presses intestinal secretion during physical exercise when blood is shunted from the splanchnic to systemic circulation. Galanin is a 29-amino acid polypeptide that simulates slow synaptic inhibition when applied to any of the neu- rons of the myenteric plexus. The application of adenosine, ATP, or other purinergic analogs also mimics slow IPSPs. The inhibitory action of adenosine is at adenosine 1 re- ceptors. Inhibitory actions of adenosine 1 agonists result Presynaptic inhibition. Presynaptic inhibitory from the suppression of the enzyme adenylyl cyclase and FIGURE 26.13 receptors are found on axons at neurotransmit- the reduction in intraneuronal cAMP. ter release sites for both slow and fast EPSPs. Different neuro- transmitters act through the presynaptic inhibitory receptors to suppress axonal release of the transmitters for slow and fast EP- Presynaptic Inhibitory Receptors Are Found at SPs. Presynaptic autoreceptors are involved in a special form of Enteric Synapses and Neuromuscular Junctions presynaptic inhibition whereby the transmitter for slow or fast EPSPs accumulates at the synapse and acts on the autoreceptor to Presynaptic inhibition (Fig. 26.13) is an important function suppress further release of the neurotransmitter. (), excitatory at fast nicotinic synapses, at slow excitatory synapses, and receptor; (), inhibitory receptor.
460 PART VII GASTROINTESTINAL PHYSIOLOGY CLINICAL FOCUS BOX 26.2 Chronic Intestinal Pseudoobstruction sence of inhibitory nervous control of the muscles, which Intestinal pseudoobstruction is characterized by symp- are self-excitable when released from the braking action of toms of intestinal obstruction in the absence of a mechan- enteric inhibitory motor neurons. ical obstruction. The mechanisms for controlling orderly Paralytic ileus, another form of pseudoobstruction, propulsive motility fail while the intestinal lumen is free is characterized by prolonged motor inhibition. The elec- from obstruction. This syndrome may result from abnor- trical slow waves are normal, but muscular action poten- malities of the muscles or ENS. Its general symptoms of tials and contractions are absent. Prolonged ileus com- colicky abdominal pain, nausea and vomiting, and abdom- monly occurs after abdominal surgery. The ileus results inal distension simulate mechanical obstruction. from suppression of the synaptic circuits that organize Pseudoobstruction may be associated with degenera- propulsive motility in the intestine. A probable mecha- tive changes in the ENS. Failure of propulsive motility re- nism is presynaptic inhibition and the closure of synaptic flects the loss of the neural networks that program and gates (see Fig. 26.22). control the organized motility patterns of the intestine. Continuous discharge of the inhibitory motor neurons This disorder can occur in varying lengths of intestine or in accompanies suppression of the motor circuits. This activ- the entire length of the small intestine. Contractile behav- ity of the inhibitory motor neurons prevents the circular ior of the circular muscle is hyperactive but disorganized in muscle from responding to electrical slow waves, which the denervated segments. This behavior reflects the ab- are undisturbed in ileus. muscarinic receptors to suppress ACh release in negative- ical mediators at neurotransmitter release sites on enteric feedback fashion (see Fig. 26.13). Histamine acts at hista- axons (Fig. 26.14). The phenomenon is known to occur mine H 3 presynaptic receptors to suppress fast EPSPs. at fast excitatory synapses in the myenteric plexus of the Presynaptic inhibition mediated by paracrine or endocrine small intestine and gastric antrum and at noradrenergic release of mediators is significant in pathophysiological inhibitory synapses in the submucous plexus. It is also an states, such as inflammation. The release of histamine from action of cholecystokinin in the ENS of the gallbladder. intestinal mast cells in response to sensitizing allergens is an Presynaptic facilitation is evident as an increase in ampli- important example of paracrine-mediated presynaptic sup- tude of fast EPSPs at nicotinic synapses and reflects an pression in the enteric neural networks. enhanced ACh release from axonal release sites. At nora- Presynaptic inhibition operates normally as a mechanism drenergic inhibitory synapses in the submucous plexus, it for selective shutdown or deenergizing of a microcircuit (see involves the elevation of cAMP in the postganglionic Clinical Focus Box 26.2). Preventing transmission among sympathetic fiber and appears as an enhancement of the the neural elements of a circuit inactivates the circuit. For slow IPSPs evoked by the stimulation of sympathetic example, a major component of shutdown of gut function postganglionic fibers. by the sympathetic nervous system involves the presynaptic Therapeutic agents that improve motility in the GI tract inhibitory action of NE at fast nicotinic synapses. are known as prokinetic drugs. Presynaptic facilitation is the mechanism of action of some prokinetic drugs. Such drugs act to facilitate nicotinic transmission at the fast ex- Presynaptic Facilitation Enhances the citatory synapses in the enteric neural networks that con- Synaptic Release of Neurotransmitters trol propulsive motor function. In both the stomach and the and Increases the Amplitude of EPSPs intestine, increases in EPSP amplitudes and rates of rise de- crease the probability of transmission failure at the Presynaptic facilitation refers to an enhancement of synapses, thereby increasing the speed of information synaptic transmission resulting from the actions of chem- transfer. This mechanism “energizes” the network circuits Control EPSP Presynaptic receptors (facilitative) Stimulus artifact Neurotransmitter Enhanced EPSP 20 mV (e.g., ACh) 10 msec FIGURE 26.14 Presynaptic facilitation. Postsynaptic Action potential Presynaptic facilitation en- receptors threshold hances release of ACh and in- (nicotinic) creases the amplitude of fast EP- SPs at a nicotinic synapse.
CHAPTER 26 Neurogastroenterology and Gastrointestinal Motility 461 and enhances propulsive motility (i.e., gastric emptying Inhibitory motor neurons Excitatory motor neurons and intestinal transit). ENTERIC MOTOR NEURONS EJP IJP Substance P Motor neurons innervate the muscles of the digestive tract VIP NO ACh and, like spinal motor neurons, are the final pathways for (–) (–) (+) (+) signal transmission from the integrative microcircuits of the minibrain-in-the-gut (see Figs. 26.10 and 26. 15). The mo- Muscle Muscle tor neuron pool of the ENS consists of excitatory and in- hibitory neurons. FIGURE 26.15 Enteric motor neurons. Motor neurons are fi- nal pathways from the ENS to the GI muscula- The neuromuscular junction is the site where neuro- ture. The motor neuron pool of the ENS consists of both excita- transmitters released from axons of motor neurons act on tory and inhibitory neurons. Release of VIP or NO from muscle fibers. Neuromuscular junctions in the digestive inhibitory motor neurons evokes IJPs. Release of ACh or sub- tract are simpler structures than the motor endplates of stance P from excitatory motor neurons evokes EJPs. VIP, vasoac- skeletal muscle (see Chapter 8). Most motor axons in the tive intestinal peptide; NO, nitric oxide; IJP, inhibitory junction digestive tract do not release neurotransmitter from termi- potential; EJP, excitatory junction potential. nals as such; instead, release is from varicosities that occur along the axons. The neurotransmitter is released from the varicosities all along the axon during propagation of the ac- tion potential. Once released, the neurotransmitter diffuses over relatively long distances before reaching the muscle mine release from mast cells during allergic responses, can and/or interstitial cells of Cajal. This structural organiza- lead to neurogenic secretory diarrhea. Suppression of ex- tion is an adaptation for the simultaneous application of a citability, for example, by morphine or other opiates, can chemical neurotransmitter to a large number of muscle lead to constipation. fibers from a small number of motor axons. Inhibitory Motor Neurons Suppress Excitatory Motor Neurons Evoke Muscle Muscle Contraction Contraction and Secretion in the Intestinal Crypts of Lieberkühn Inhibitory neurotransmitters released from inhibitory mo- tor neurons activate receptors on the muscle plasma mem- Excitatory motor neurons release neurotransmitters that branes to produce inhibitory junction potentials (IJPs) (see evoke contraction and increased tension in the GI muscles. Fig. 26.15). IJPs are hyperpolarizing potentials that move ACh and substance P are the principal excitatory neuro- the membrane potential away from the threshold for the transmitters released from enteric motor neurons to the discharge of action potentials and, thereby, reduce the ex- musculature. citability of the muscle fiber. Hyperpolarization during IJPs Two mechanisms of excitation-contraction coupling are prevents depolarization to the action potential threshold involved in the neural initiation of muscle contraction in by the electrical slow waves and suppresses propagation of the GI tract. Transmitters from excitatory motor axons may action potentials among neighboring muscle fibers within trigger muscle contraction by depolarizing the muscle the electrical syncytium. membrane to the threshold for the discharge of action po- Early evidence suggested a purine nucleotide, possibly tentials or by the direct release of calcium from intracellu- ATP, as the inhibitory transmitter released by enteric in- lar stores. Neurally evoked depolarizations of the muscle hibitory motor neurons. Consequently, the term purinergic membrane potential are called excitatory junction poten- neuron temporarily became synonymous with enteric in- tials (EJPs) (see Fig. 26.15). Direct release of calcium by the hibitory motor neuron. The evidence for ATP as the in- neurotransmitter fits the definition of pharmacomechanical hibitory transmitter is now combined with evidence for va- coupling. In this case, occupation of receptors on the mus- soactive intestinal peptide (VIP), pituitary adenylyl cle plasma membrane by the neurotransmitter leads to the cyclase–activating peptide, and nitric oxide (NO) as in- release of intracellular calcium, with calcium-triggered con- hibitory transmitters. Enteric inhibitory motor neurons traction independent of any changes in membrane electri- with VIP and/or NO synthase innervate the circular muscle cal activity. of the stomach, intestines, gallbladder and the various Cell bodies of the excitatory motor neurons are present sphincters. Cell bodies of inhibitory motor neurons are in the myenteric plexus. In the small and large intestines, present in the myenteric plexus. In the stomach and small they project in the aboral direction to innervate the circu- and large intestines, they project in the aboral direction to lar muscle. innervate the circular muscle. Secretomotor neurons excite secretion of H 2 O, elec- The longitudinal muscle layer of the small intestine does trolytes, and mucus from the crypts of Lieberkühn. ACh not appear to have inhibitory motor innervation. In con- and VIP are the principal excitatory neurotransmitters. The trast to the circular muscle, where inhibitory neural control cell bodies of secretomotor neurons are in the submucosal is essential, enteric neural control of the longitudinal mus- plexus. Excitation of these neurons, for example, by hista- cle during peristalsis may be exclusively excitatory.
462 PART VII GASTROINTESTINAL PHYSIOLOGY Inhibitory Motor Neurons Control the tetrodotoxin in the small intestine. This response coincides Myogenic Intestinal Musculature with a progressive increase in baseline tension. Tetrodotoxin is an effective pharmacological tool for The need for inhibitory neural control is determined by the demonstrating ongoing inhibition because it selectively specialized physiology of the musculature. As mentioned blocks neural activity without affecting the muscle. This ac- earlier, the intestinal musculature behaves like a self-ex- tion is a result of a selective blockade of sodium channels in citable electrical syncytium as a result of cell-to-cell com- neurons. The rising phase of the muscle action potentials is munication across gap junctions and the presence of a pace- caused by an inward calcium current that is unaffected by maker system. Action potentials triggered anywhere in the tetrodotoxin. muscle will spread from muscle fiber to muscle fiber in three As a general rule, any treatment or condition that re- dimensions throughout the syncytium, which can be the en- moves or inactivates inhibitory motor neurons results in tire length of the bowel. Action potentials trigger contrac- tonic contracture and continuous, uncoordinated contrac- tions as they spread. A nonneural pacemaker system of elec- tile activity of the circular musculature. Several circum- trical slow waves (i.e., interstitial cells of Cajal) accounts for stances that remove the inhibitory neurons are associated the self-excitable characteristic of the electrical syncytium. with conversion from a hypoirritable condition of the cir- In the integrated system, the electrical slow waves are an ex- cular muscle to a hyperirritable state. These include the ap- trinsic factor to which the circular muscle responds. plication of local anesthetics, hypoxia from restricted Why does the circular muscle fail to respond with action blood flow to an intestinal segment, an autoimmune attack potentials and contractions to all slow-wave cycles? Why on enteric neurons, congenital absence in Hirschsprung’s don’t action potentials and contractions spread in the syn- disease, treatment with opiate drugs, and inhibition of NO cytium throughout the entire length of intestine each time synthase (see Clinical Focus Boxes 26.3 and 26.4). they occur? Answers to these questions lie in the functional significance of enteric inhibitory motor neurons. Inhibitory Motor Neurons and the Strength of Contrac- tions Evoked by Electrical Slow Waves. The strength of Inhibitory Motor Neurons to the Circular Muscle. Figure circular muscle contraction evoked by each slow-wave cy- 26.16A shows the spontaneous discharge of action poten- cle is a function of the number of inhibitory motor neurons tials occurring in bursts, as recorded extracellularly from a in an active state. The circular muscle in an intestinal seg- neuron in the myenteric plexus of the small intestine. This ment can respond to the electrical slow waves only when kind of continuous discharge of action potentials by subsets the inhibitory motor neurons are inactivated by inhibitory of intestinal inhibitory motor neurons occurs in all mam- synaptic input from other neurons in the control circuits. mals. The result is continuous inhibition of myogenic ac- This means that inhibitory neurons determine when the tivity because, in intestinal segments where neuronal dis- constantly running slow waves initiate a contraction, as charge in the myenteric plexus is prevalent, muscle action well as the strength of the contraction that is initiated by potentials and associated contractile activity are absent or each slow-wave cycle. The strength of each contraction is occur only at reduced levels with each electrical slow wave. determined by the proportion of muscle fibers in the pop- The continuous release of the inhibitory neurotransmitters ulation that can respond during a given slow-wave cycle, VIP and NO can be detected in intestinal preparations in which, in turn, is determined by the proportion exposed to this case. When the inhibitory neuronal discharge is inhibitory transmitters released by motor neurons. With blocked experimentally with tetrodotoxin, every cycle of maximum inhibition, no contractions can occur in response the electrical slow wave triggers an intense discharge of ac- to a slow wave (see Fig.26.4A); contractions of maximum tion potentials. Figure 26.16B shows how phasic contrac- strength occur after all inhibition is removed and all of the tions, occurring at slow-wave frequency, progressively in- muscle fibers in a segment are activated by each slow-wave crease to maximal amplitude during a blockade of cycle (see Fig. 26.4B). Contractions between the two ex- inhibitory neural activity after the application of tremes are graded in strength according to the number of A Neural 1 sec discharge Tetrodotoxin 10 sec B Muscle contraction Ongoing Neural discharge discharge blocked by tetrodotoxin Inhibitory motor neurons. Ongoing firing with tetrodotoxin, every cycle of the electrical slow wave trig- FIGURE 26.16 of a subpopulation of inhibitory motor neu- gers discharge of action potentials and large-amplitude con- rons to the intestinal circular muscle prevents electrical slow tractions. A, Electrical record of ongoing burst-like firing. B, waves from triggering the action potentials that trigger con- Record of muscle contractile activity before and after applica- tractions. When the inhibitory neural discharge is blocked tion of tetrodotoxin.
CHAPTER 26 Neurogastroenterology and Gastrointestinal Motility 463 CLINICAL FOCUS BOX 26.3 Hirschsprung’s Disease and Incontinence: Motor Disor- can be factors in the pathophysiology of incontinence. ders of the Large Intestine and Anorectum Sensory malfunction renders the patient unaware of the Hirschsprung’s disease is a developmental disorder filling of the rectum and stimulation of the anorectum, in that is present at birth but may not be diagnosed until which case he or she does not perceive the need for vol- later childhood. It is characterized by defecation difficulty untary control over the muscular mechanisms of conti- or failure. The disease is often called congenital mega- nence. This condition is tested clinically by distending an colon, because the proximal colon may become grossly intrarectal balloon. The healthy subject will perceive the enlarged with impacted feces, or congenital agan- distension with an instilled volume of 15 mL or less, glionosis, because the ganglia of the ENS fail to develop whereas the sensory-deprived patient either will not report in the terminal region of the large intestine. Mutations in any sensation at all or will require much larger volumes RET or endothelin genes account for the disease in some before becoming aware of the distension. patients. Incompetence of the internal anal sphincter is usually Enteric neurons may be absent in the rectosigmoid re- related to a surgical or mechanical factor or perianal dis- gion only, in the descending colon, or in the entire colon. ease, such as prolapsing hemorrhoids. Disorders of the The aganglionic region appears constricted as a result of neuromuscular mechanisms of the external sphincter and continuous contractile activity of the circular muscle, pelvic floor muscles may also result from surgical or me- whereas the normally innervated intestine proximal to the chanical trauma, such as during childbirth. aganglionic segment is distended with feces. Physiological deficiencies of the skeletal motor mech- The constricted terminal segment of the large intestine anisms can be a significant factor in the common occur- in Hirschsprung’s disease presents a functional obstruc- rence of incontinence in older adults. Whereas the rest- tion to the forward passage of fecal material. Constriction ing tone of the internal anal sphincter does not seem to and narrowing of the lumen of the segment reflects un- decrease with age, the strength of contraction of the ex- controlled myogenic contractile activity in the absence of ternal anal sphincter does weaken. Moreover, the stri- inhibitory motor neurons ated muscles of the external anal sphincter and pelvic Incontinence is an inappropriate leakage of feces and floor lose contractile strength with age. This condition flatus to a degree that it disables the patient by disrupting occurs in parallel with a deterioration of nervous func- routine daily activities. As discussed earlier, the mecha- tion, reflected by decreased conduction velocity in fibers nisms for maintaining continence involve the coordinated of the pelvic nerves. Clinical examination with intra-anal interactions of several different components. Conse- manometry reveals a decreased ability of the patient quently, sensory malfunction, incompetence of the inter- with disordered voluntary muscle function to increase in- nal anal sphincter, or disorders of neuromuscular mecha- tra-anal pressure when asked to “squeeze” the intra-anal nisms of the external sphincter and pelvic floor muscles catheter. inhibitory motor neurons that are inactivated by the ENS tracting segment by controlling the distance of spread of minibrain during each slow wave. action potentials within the three-dimensional electrical geometry of the muscular syncytium (Fig. 26.17). This oc- Control by Inhibitory Motor Neurons of the Length of In- curs coincidently with control of contractile strength. Con- testine Occupied by a Contraction and the Direction of tractions can only occur in segments where ongoing inhi- Propagation of Contractions. The state of activity of in- bition has been inactivated, while it is prevented in hibitory motor neurons determines the length of a con- adjacent segments where the inhibitory innervation is ac- CLINICAL FOCUS BOX 26.4 Dysphagia, Diffuse Spasm, and Achalasia: Motor Disor- In achalasia of the lower esophageal sphincter, the ders of the Esophagus sphincter fails to relax normally during a swallow. As a re- Failure of peristalsis in the esophageal body or failure of the sult, the ingested material does not enter the stomach and lower esophageal sphincter to relax will result in dysphagia accumulates in the body of the esophagus. This leads to or difficulty in swallowing. Some people show abnormally megaesophagus, in which distension and gross enlarge- high pressure waves as peristalsis propagates past the ment of the esophagus are evident. In advanced untreated recording ports on manometric catheters. This condition, cases of achalasia, peristalsis does not occur in response called nutcracker esophagus, is sometimes associated to a swallow. with chest pain that may be experienced as angina-like pain. Achalasia is a disorder of inhibitory motor neurons in In diffuse spasm, organized propagation of the peri- the lower esophageal sphincter. The number of neurons staltic behavioral complex fails to occur after a swallow. In- in the lower esophageal sphincter is reduced, and the lev- stead, the act of swallowing results in simultaneous con- els of the inhibitory neurotransmitter VIP and the enzyme tractions all along the smooth muscle esophagus. On NO synthase are diminished. This degenerative disease manometric tracings, this response is observed as a syn- results in a loss of the inhibitory mechanisms for relaxing chronous rise in intraluminal pressure at each of the the sphincter with appropriate timing for a successful recording sensors. swallow.
464 PART VII GASTROINTESTINAL PHYSIOLOGY Direction of propagation Oral Aboral Activity status of inhibitory motor Contractile state neurons Activity Activity status status Lack of contraction Active (physiological ileus) Inactive Active Propagating Contraction contraction Contraction Inactive Active Contraction Inactive Physiological Lack of contraction Active ileus (physiological ileus) Inhibitory control of the direction of prop- FIGURE 26.18 Inhibitory control of the intestinal muscula- agation of contractions. Contractions propa- FIGURE 26.17 gate into intestinal segments where inhibitory motor neurons are ture. Myogenic contraction occurs in segments of intestine where inhibitory motor neurons are inactive. Physio- inactivated. Sequential inactivation in the oral direction permits logical ileus occurs in segments of intestine where the inhibitory oral propagation of contractions. Sequential inactivation in the neurons are actively firing. aboral direction permits aboral propagation. tive. The oral and aboral boundaries of a contracted seg- vomiting, the integrative microcircuits of the ENS inacti- ment reflect the transition zone from inactive to active in- vate inhibitory motor neurons in a reverse sequence, allow- hibitory motor neurons. This is the mechanism by which ing small intestinal propulsion to travel in the oral direction the ENS generates short contractile segments during the and propel the contents toward the stomach (see Clinical digestive (mixing) pattern of small intestinal motility and Focus Box 26.5). longer contractile segments during propulsive motor pat- terns, such as “power propulsion” that travels over extended The Inhibitory Innervation of GI Sphincters Is distances along the intestine. Transiently Activated for Timed Opening As a result of the functional syncytial properties of the musculature, inhibitory motor neurons are necessary for and the Passage of Luminal Contents control of the direction in which contractions travel along The circular muscle of sphincters remains tonically con- the intestine. The directional sequence in which inhibitory tracted to occlude the lumen and prevent the passage of motor neurons are inactivated determines whether contrac- contents between adjacent compartments, such as between tions propagate in the oral or aboral direction (Fig. 26.18). stomach and esophagus. Inhibitory motor neurons are nor- Normally, the neurons are inactivated sequentially in the mally inactive in the sphincters and are switched on with aboral direction, resulting in contractile activity that prop- timing appropriate to coordinate the opening of the sphinc- agates and moves the intraluminal contents distally. During ter with physiological events in adjacent regions CLINICAL FOCUS BOX 26.5 Emesis tents into the stomach. At the same time, the longitudinal During emesis (vomiting), powerful propulsive peristalsis muscle of the esophagus and the gastroesophageal junc- starts in the midjejunum and travels to the stomach. As a tion dilates. The overall result is the formation of a funnel- result, the small intestinal contents are propelled rapidly like cavity that allows the free flow of gastric contents into and continuously toward the stomach. As the propulsive the esophagus as intra-abdominal pressure is increased by complex advances, the gastroduodenal junction and the contraction of the diaphragm and abdominal muscles dur- stomach wall relax, allowing passage of the intestinal con- ing retching.
CHAPTER 26 Neurogastroenterology and Gastrointestinal Motility 465 Inhibitory motor neurons Lower esophageal Lower esophageal sphincter sphincter (closed) (open) Inactive Active Pylorus Pylorus (closed) (open) Inhibitory motor neurons In- FIGURE 26.19 hi- bitory control of sphincters. GI sphinc- ters are closed when their inhibitory innerva- Internal anal Inactive Active Internal anal sphincter sphincter tion is inactive. The (closed) (open) sphincters are opened by active firing of the in- hibitory motor neurons. (Fig. 26.19). When this occurs, the inhibitory neurotrans- Peristalsis Is a Stereotyped Propulsive mitter relaxes the ongoing muscle contraction in the sphinc- Motor Reflex teric muscle and prevents excitation and contraction in the adjacent muscle from spreading into and closing the Peristalsis is the organized propulsion of material over vari- sphincter. able distances within the intestinal lumen. The muscle lay- ers of the intestine behave in a stereotypical pattern during peristaltic propulsion (Fig. 26.20). This pattern is deter- mined by the integrated circuits of the ENS. During peri- BASIC PATTERNS OF GI MOTILITY stalsis, the longitudinal muscle layer in the segment ahead Motility in the digestive tract accounts for the propulsion, of the advancing intraluminal contents contracts while the mixing, and reservoir functions necessary for the orderly circular muscle layer simultaneously relaxes. The intestinal processing of ingested food and the elimination of waste tube behaves like a cylinder with constant surface area. The products. Propulsion is the controlled movement of in- shortening of the longitudinal axis of the cylinder is ac- gested foods, liquids, GI secretions, and sloughed cells companied by a widening of the cross-sectional diameter. from the mucosa through the digestive tract. It moves the The simultaneous shortening of the longitudinal muscle food from the stomach into the small intestine and along and relaxation of the circular muscle results in expansion of the small intestine, with appropriate timing for efficient di- the lumen, which prepares a receiving segment for the for- gestion and absorption. Propulsive forces move undigested ward-moving intraluminal contents during peristalsis. material into the large intestine and eliminate waste The second component of stereotyped peristaltic be- through defecation. Trituration, the crushing and grinding havior is contraction of the circular muscle in the segment of ingested food by the stomach, decreases particle size, in- behind the advancing intraluminal contents. The longitudi- creasing the surface area for action by digestive enzymes in the small intestine. Mixing movements blend pancreatic, biliary, and intestinal secretions with nutrients in the small Relaxation of Contraction of intestine and bring products of digestion into contact with longitudinal muscle; longitudinal muscle; the absorptive surfaces of the mucosa. Reservoir functions contraction of circular muscle inhibition of circular muscle are performed by the stomach and colon. The body of the stomach stores ingested food and exerts steady mechanical forces that are important determinants of gastric emptying. The colon holds material during the time required for the Direction of absorption of excess water and stores the residual material propulsion until defecation is convenient. Each of the specialized organs along the digestive tract exhibits a variety of motility patterns. These patterns differ Propulsive depending on factors such as time after a meal, awake or segment sleeping state, and the presence of disease. Motor patterns Receiving segment that accomplish propulsion in the esophagus and small and Peristaltic propulsion. Peristaltic propulsion in- FIGURE 26.20 large intestines are derived from a basic peristaltic reflex volves formation of a propulsive and a receiving circuit in the ENS. segment, mediated by reflex control of the intestinal musculature.
466 PART VII GASTROINTESTINAL PHYSIOLOGY nal muscle layer in this segment relaxes simultaneously with The basic circuit for peristalsis is repeated serially along contraction of the circular muscle, resulting in the conver- the intestine (Fig. 26.21). Synaptic gates connect the sion of this region to a propulsive segment that propels the blocks of basic circuitry and provide a mechanism for con- luminal contents ahead, into the receiving segment. Intesti- trolling the distance over which the peristaltic behavioral nal segments ahead of the advancing front become receiv- complex travels. When the gates are opened, neural signals ing segments and then propulsive segments in succession as pass between successive blocks of the basic circuit, result- the peristaltic complex of propulsive and receiving seg- ing in propagation of the peristaltic event over extended ments travels along the intestine. distances. Long-distance propulsion is prevented when all gates are closed (see Clinical Focus Box 26.1). Presynaptic mechanisms are involved in gating the A Polysynaptic Reflex Circuit transfer of signals between sequentially positioned blocks Determines Peristalsis of peristaltic reflex circuitry. Synapses between the neu- rons that carry excitatory signals to the next block of cir- The peristaltic reflex (i.e., the formation of propulsive and receiving segments) can be triggered experimentally by dis- cuitry function as gating points for controlling the dis- tending the intestinal wall or by “brushing” the mucosa. In- tance over which peristaltic propulsion travels (Fig. 26.22). volvement of the reflex in the neural organization of peri- Messenger substances that act presynaptically to inhibit staltic propulsion is similar to the reflexive behavior the release of transmitter at the excitatory synapses close mediated by the CNS for somatic movements of skeletal the gates to the transfer of information, determining the muscles. Reflex circuits with fixed connections in the spinal distance of propagation. Drugs that facilitate the release of cord automatically reproduce a stereotypical pattern of be- neurotransmitters at the excitatory synapses (e.g., cis- havior each time the circuit is activated (e.g., the myotatic apride) have therapeutic application by increasing the reflex; see Chapter 5). Connections for the reflex remain, ir- probability of information transfer at the synaptic gates, respective of the destruction of adjacent regions of the enhancing propulsive motility. spinal cord. The peristaltic reflex circuit is similar, but the basic circuit is repeated along and around the intestine. Just Peristaltic Propulsion in the Upper Small Intestine During as the monosynaptic reflex circuit of the spinal cord is the Vomiting. The enteric neural circuits can be programmed terminal circuit for the production of almost all skeletal to produce peristaltic propulsion in either direction along muscle movements (see Chapter 5), the same basic peri- the intestine. If forward passage of the intraluminal con- staltic circuitry underlies all patterns of propulsive motility. tents is impeded in the large intestine, reverse peristalsis Blocks of the same basic circuit are connected in series along propels the bolus over a variable distance away from the the length of the intestine and repeated in parallel around obstructed segment. Retroperistalsis then stops and for- the circumference. The basic peristaltic circuit consists of ward peristalsis moves the bolus again in the direction of synaptic connections between sensory neurons, interneu- the obstruction. During the act of vomiting, retroperistalsis rons, and motor neurons. Distances over which peristaltic occurs in the small intestine. In this case, as well as in the propulsion travels are determined by the number of blocks obstructed intestine, the coordinated muscle behavior of recruited in sequence along the bowel. Synaptic gates be- peristalsis is the same except that it is organized by the tween blocks of the basic circuit determine whether or not nervous system to travel in the oral direction (see Clinical recruitment occurs for the next circuit in the sequence. Focus Box 26.5). Gates open; Gates closed; long-distance long-distance propulsion can occur propulsion cannot occur Operation of synaptic gates between FIGURE 26.21 basic blocks of peristaltic circuitry. Opening the gates between successive blocks of the basic Basic circuit results in extended propagation of the propulsive peristaltic neural circuit event. Long-distance propulsion is prevented when all gates are closed.
CHAPTER 26 Neurogastroenterology and Gastrointestinal Motility 467 Sphincters Prevent the Reflux Presynaptic inhibitory of Luminal Contents Peristaltic receptor Interneuron Peristaltic reflex reflex Smooth muscle sphincters are found at the gastroe- circuit circuit sophageal junction, gastroduodenal junction, opening of Synaptic gate the bile duct, ileocolonic junction, and termination of the large intestine in the anus. They consist of rings of smooth muscle that remain in a continuous state of contraction. Propagated propulsion The effect of the tonic contractile state is to occlude the lu- men in a region that separates two specialized compart- ments. With the exception of the internal anal sphincter, sphincters function to prevent the backward movement of intraluminal contents. Gating synapses uninhibited: synaptic gates open The lower esophageal sphincter prevents the reflux of gastric acid into the esophagus. Incompetence results in chronic exposure of the esophageal mucosa to acid, which No propagated propulsion can lead to heartburn and dysplastic changes that may be- come cancerous. The gastroduodenal sphincter or pyloric sphincter prevents the excessive reflux of duodenal con- Gating synapses inhibited: synaptic gates closed tents into the stomach. Incompetence of this sphincter can result in the reflux of bile acids from the duodenum. Bile Control of the distance and direction of FIGURE 26.22 peristaltic propulsion. Synaptic gates deter- acids are damaging to the protective barrier in the gastric mine distance and direction of propagation of propulsive motility. mucosa; prolonged exposure can lead to gastric ulcers. Presynaptic inhibitory receptors determine the open and closed The sphincter of Oddi surrounds the opening of the states of the gates. When the gating synapses are uninhibited bile duct as it enters the duodenum. It acts to prevent the (i.e., no presynaptic inhibition), propagation proceeds in the di- reflux of intestinal contents into the ducts leading from rection in which the gates are open. The gates are closed by acti- the liver, gallbladder, and pancreas. Failure of this sphinc- vation of presynaptic inhibitory receptors. ter to open leads to distension, which is associated with the biliary tract pain that is felt in the right upper abdom- inal quadrant. The ileocolonic sphincter prevents the reflux of colonic contents into the ileum. Incompetence can allow the entry Ileus Reflects the Operation of a of bacteria into the ileum from the colon, which may result Program in the ENS in bacterial overgrowth. Bacterial counts are normally low in the small intestine. The internal anal sphincter prevents Physiological ileus is the absence of motility in the small the uncontrolled movement of intraluminal contents and large intestine. It is a fundamental behavioral state of through the anus. the intestine in which quiescence of motor function is neu- The ongoing contractile tone in the smooth muscle rally programmed. The state of physiological ileus disap- sphincters is generated by myogenic mechanisms. The pears after ablation (removal) of the ENS. When enteric contractile state is an inherent property of the muscle and neural functions are destroyed by pathological processes, independent of the nervous system. Transient relaxation of disorganized and nonpropulsive contractile behavior oc- the sphincter to permit the forward passage of material is curs continuously because of the myogenic electrical prop- accomplished by activation of inhibitory motor neurons erties (see Clinical Focus Box 26.2). (see Fig. 26.19). Achalasia is a pathological state in which Quiescence of the intestinal circular muscle is be- smooth muscle sphincters fail to relax. Loss of the ENS and lieved to reflect the operation of a neural program in its complement of inhibitory motor neurons in the sphinc- which all the gates within and between basic peristaltic ters can underlie achalasia (see Clinical Focus Box 26.4). circuits are held shut (see Fig. 26.22). In this state, the in- hibitory motor neurons remain in a continuously active state and responsiveness of the circular muscle to the MOTILITY IN THE ESOPHAGUS electrical slow waves is suppressed. This normal condi- tion, physiological ileus, is in effect for varying periods of The esophagus is a conduit for the transport of food from time in different intestinal regions, depending on such the pharynx to the stomach. Transport is accomplished by factors as the time after a meal. peristalsis, with propulsive and receiving segments pro- The normal state of motor quiescence becomes patho- duced by neurally organized contractile behavior of the logical when the gates for the particular motor patterns are longitudinal and circular muscle layers. rendered inoperative for abnormally long periods. In this The esophagus is divided into three functionally distinct state of paralytic ileus, the basic circuits are locked in an in- regions: the upper esophageal sphincter, the esophageal operable state while unremitting activity of the inhibitory body, and the lower esophageal sphincter. Motor behavior motor neurons suppresses myogenic activity (see Clinical of the esophagus involves striated muscle in the upper Focus Box 26.1). esophagus and smooth muscle in the lower esophagus.
468 PART VII GASTROINTESTINAL PHYSIOLOGY Peristalsis and Relaxation of the Lower esophageal sphincter relaxes. This is recorded as a fall in Esophageal Sphincter Are the Main Motility pressure in the sphincter that lasts throughout the swallow Events in the Esophagus and until the esophagus empties its contents into the stom- ach. Signals for relaxation of the lower esophageal sphinc- Esophageal peristalsis may occur as primary peristalsis or ter are transmitted by the vagus nerves. The pressure-sens- secondary peristalsis. Primary peristalsis is initiated by the ing ports along the catheter assembly show transient voluntary act of swallowing, irrespective of the presence of increases in pressure as the segment with the sensing port food in the mouth. Secondary peristalsis occurs when the becomes the propulsive segment of the peristaltic pattern primary peristaltic event fails to clear the bolus from the as it passes on its way to the stomach. body of the esophagus. It is initiated by activation of mechanoreceptors and can be evoked experimentally by distending a balloon in the esophagus. When not involved in the act of swallowing, the muscles GASTRIC MOTILITY of the esophageal body are relaxed and the lower The functional regions of the stomach do not correspond esophageal sphincter is tonically contracted. In contrast to to the anatomic regions. The anatomic regions are the fun- the intestine, the relaxed state of the esophageal body is dus, corpus (body), antrum, and pylorus (Fig. 26.24). not produced by the ongoing activity of inhibitory motor Functionally, the stomach is divided into a proximal reser- neurons. Excitability of the muscle is low and there are no voir and distal antral pump on the basis of distinct differ- electrical slow waves to trigger contractions. The activa- ences in motility between the two regions. The reservoir tion of excitatory motor neurons rather than myogenic consists of the fundus and approximately one third of the mechanisms accounts for the coordinated contractions of corpus; the antral pump includes the caudal two thirds of the esophagus during a swallow. the corpus, the antrum, and the pylorus. Differences in motility between the reservoir and antral pump reflect adaptations for different functions. The mus- Manometric Catheters Monitor Esophageal cles of the proximal stomach are adapted for maintaining Motility and Diagnose Disordered Motility continuous contractile tone (tonic contraction) and do not Esophageal motor disorders are diagnosed clinically with contract phasically. By contrast, the muscles of the antral manometric catheters, multiple small catheters fused into a pump contract phasically. The spread of phasic contrac- single assembly with pressure sensors positioned at various tions in the region of the antral pump propels the gastric levels (see Clinical Focus Box 26.4). They are placed into contents toward the gastroduodenal junction. Strong the esophagus via the nasal cavity. Manometric catheters propulsive waves of this nature do not occur in the proxi- record a distinctive pattern of motor behavior following a mal stomach. swallow (Fig. 26.23). At the onset of the swallow, the lower Motor Behavior of the Antral Pump Is Swallow Initiated by a Dominant Pacemaker Gastric action potentials determine the duration and strength of the phasic contractions of the antral pump and are initiated by a dominant pacemaker located in the cor- Anatomic regions Functional motor regions Fundus Lower Reservoir esophageal Pylorus (tonic contractions) Corpus sphincter 100 mm Hg (body) 5 sec Antrum Manometric recordings of pressure events FIGURE 26.23 Antral pump in the esophageal body and lower (phasic contractions) esophageal sphincter following a swallow. The propulsive segment of the peristaltic behavioral complex produces a positive FIGURE 26.24 The stomach: three anatomic and two func- pressure wave at each recording site in succession as it travels tional regions. The reservoir is specialized for down the esophagus. Pressure falls in the lower esophageal receiving and storing a meal. The musculature in the region of the sphincter shortly after the onset of the swallow, and the sphincter antral pump exhibits phasic contractions that function in the mix- remains relaxed until the propulsive complex has transported the ing and trituration of the gastric contents. No distinctly identifi- swallowed material into the stomach. able boundary exists between the reservoir and antral pump.
CHAPTER 26 Neurogastroenterology and Gastrointestinal Motility 469 pus distal to the midregion. Once started at the pacemaker pump. A leading contraction, with a relatively constant am- site, the action potentials propagate rapidly around the gas- plitude, is associated with the rising phase of the action po- tric circumference and trigger a ring-like contraction. The tential, and a trailing contraction, of variable amplitude, is action potentials and associated ring-like contraction then associated with the plateau phase (Fig. 26.25). Gastric action travel more slowly toward the gastroduodenal junction. potentials are generated continuously by the pacemaker, but Electrical syncytial properties of the gastric musculature they do not trigger a trailing contraction when the plateau account for the propagation of the action potentials from phase is reduced below threshold voltage. Trailing contrac- the pacemaker site to the gastroduodenal junction. The tions appear when the plateau phase is above threshold. pacemaker region in humans generates action potentials They increase in strength in direct relation to increases in the and associated antral contractions at a frequency of 3/min. amplitude of the plateau potential above threshold. The gastric action potential lasts about 5 seconds and has a The leading contractions produced by the rising phase rising phase (depolarization), a plateau phase, and a falling of the gastric action potential have negligible amplitude as phase (repolarization) (see Fig. 26.2). they propagate to the pylorus. As the rising phase reaches the terminal antrum and spreads into the pylorus, contrac- tion of the pyloric muscle closes the orifice between the The Gastric Action Potential Triggers stomach and duodenum. The trailing contraction follows Two Kinds of Contractions the leading contraction by a few seconds. As the trailing The gastric action potential is responsible for two compo- contraction approaches the closed pylorus, the gastric con- nents of the propulsive contractile behavior in the antral tents are forced into an antral compartment of ever-de- creasing volume and progressively increasing pressure. This results in jet-like retropulsion through the orifice formed by the trailing contraction (Fig. 26.26). Trituration and reduction in particle size occur as the material is Gastric action potential forcibly retropelled through the advancing orifice and back Trailing and contractile cycle Gastric contraction start in midcorpus into the gastric reservoir to await the next propulsive cycle. contractile Leading Repetition at 3 cycles/min reduces particle size to the 1- to cycle contraction 7-mm range that is necessary before a particle can be emp- tied into the duodenum during the digestive phase of gas- tric motility. Plateau phase Gastric Rapid action Enteric Neurons Determine the Minute-to-Minute upstroke potential Strength of the Trailing Antral Contraction The action potentials of the distal stomach are myogenic Gastric action potential (i.e., an inherent property of the muscle) and occur in the and contractile cyle absence of any neurotransmitters or other chemical mes- propagate to antrum sengers. The myogenic characteristics of the action poten- tial are modulated by motor neurons in the gastric ENS. Neurotransmitters primarily affect the amplitude of the plateau phase of the action potential and, thereby, control the strength of the contractile event triggered by the plateau phase. Neurotransmitters, such as ACh from exci- tatory motor neurons, increase the amplitude of the plateau Gastric action potential and contractile cycle arrive at pylorus; pylorus is closed by Onset of terminal Complete terminal leading contraction; antral contraction antral contraction second cycle starts in midcorpus Pylorus Pylorus closing closed Contractile cycle of the antral pump. The FIGURE 26.25 rising phase of the gastric action potential ac- counts for the leading contraction that propagates toward the py- lorus during one contractile cycle. The plateau phase accounts for FIGURE 26.26 Gastric retropulsion. Jet-like retropulsion the trailing contraction of the cycle. (Modified from Szurszewski through the orifice of the antral contraction JH. Electrical basis for gastrointestinal motility. In: Johnson LR, triturates solid particles in the stomach. The force for retropulsion Christensen J, Jackson M, et al., eds. Physiology of the Gastroin- is increased pressure in the terminal antrum as the trailing antral testinal Tract. 2nd Ed. New York: Raven, 1987;383–422.) contraction approaches the closed pylorus.
470 PART VII GASTROINTESTINAL PHYSIOLOGY phase and of the contraction initiated by the plateau. In- hibitory neurotransmitters, such as NE and VIP, decrease the amplitude of the plateau and the strength of the associ- ated contraction. The magnitude of the effects of neurotransmitters in- creases with increasing concentration of the transmitter Tonic Reservoir substance at the gastric musculature. Higher frequencies contraction of action potential discharged by motor neurons release Decrease Relaxation greater amounts of neurotransmitter. In this way, motor in volume Increase neurons determine, through the actions of their neuro- Antral in volume transmitters on the plateau phase, whether the trailing pump contraction of the propulsive complex of the distal stom- ach occurs. With sufficient release of transmitter, the plateau exceeds the threshold for contraction. Beyond threshold, the strength of contraction is determined by FIGURE 26.27 Muscular tone in the gastric reservoir. Tonic contraction of the musculature decreases the amount of neurotransmitter released and present at re- the volume and exerts pressure on the contents. Tonic relaxation ceptors on the muscles. of the musculature expands the volume of the gastric reservoir. The action potentials in the terminal antrum and pylorus Neural mechanisms of feedback control determine intramural differ somewhat in configuration from those in the more contractile tone in the reservoir. proximal regions. The principal difference is the occur- rence of spike potentials on the plateau phase (see Fig. 26.25), which trigger short-duration phasic contractions superimposed on the phasic contraction associated with Three Kinds of Relaxation Occur in the the plateau. These may contribute to the sphincteric func- Gastric Reservoir tion of the pylorus in preventing a reflux of duodenal con- Neurally mediated decreases in tonic contracture of the tents back into the stomach. musculature are responsible for relaxation in the gastric reservoir (i.e., increased volume). Three kinds of relaxation are recognized. Receptive relaxation is initiated by the act Neural Control of Muscular Tone Determines of swallowing. It is a reflex triggered by stimulation of Minute-to-Minute Volume and Pressure in the mechanoreceptors in the pharynx followed by transmission Gastric Reservoir over afferents to the dorsal vagal complex and activation of The gastric reservoir has two primary functions. One is to efferent vagal fibers to inhibitory motor neurons in the gas- accommodate the arrival of a meal, without a significant in- tric ENS. Adaptive relaxation is triggered by distension of crease in intragastric pressure and distension of the gastric the gastric reservoir. It is a vago-vagal reflex triggered by wall. Failure of this mechanism can lead to the uncomfort- stretch receptors in the gastric wall, transmission over vagal able sensations of bloating, epigastric pain, and nausea. The afferents to the dorsal vagal complex, and efferent vagal second function is to maintain a constant compressive force on the contents of the reservoir. This pushes the contents into motor activity of 3 cycles/min for the antral pump. Brain Drugs that relax the musculature of the gastric reservoir (medulla) neutralize this function and suppress gastric emptying. The musculature of the gastric reservoir is innervated by Vagal efferents both excitatory and inhibitory motor neurons of the ENS. Vagal afferents The motor neurons are controlled by the efferent vagus Enteric nervous system nerves and intramural microcircuits of the ENS. They func- tion to adjust the volume and pressure of the reservoir to Gastric stretch Interneuronal circuits the amount of solid and/or liquid present while maintaining receptors constant compressive forces on the contents. Continuous Inhibitory adjustments in the volume and pressure within the reservoir motor neurons are required during both the ingestion and the emptying of a meal. Increased activity of excitatory motor neurons, in coor- Muscle dination with decreased activity of inhibitory motor neu- relaxation rons, results in increased contractile tone in the reservoir, a decrease in its volume, and an increase in intraluminal pres- FIGURE 26.28 Adaptive relaxation in the gastric reservoir. Adaptive relaxation is a vago-vagal reflex in sure (Fig. 26.27). Increased activity of inhibitory motor which information from gastric stretch receptors is the afferent neurons in coordination with decreased activity of excita- component and outflow from the medullary region of the brain is tory motor neurons results in decreased contractile tone in the efferent component. Vagal efferents transmit to the ENS, the reservoir, expansion of its volume, and a decrease in in- which controls the activity of inhibitory motor neurons that re- traluminal pressure. laxes contractile tone in the reservoir.
CHAPTER 26 Neurogastroenterology and Gastrointestinal Motility 471 25 tying of isotonic noncaloric liquids (e.g., H 2 O) is propor- tional to the initial volume in the reservoir. The larger the Intragastric pressure (cm H 2 O) 15 XX Discomfort than solids. If an experimental meal consisting of solid par- initial volume, the more rapid the emptying. 20 Postvagotomy With a mixed meal in the stomach, liquids empty faster Normal ticles of various sizes suspended in water is instilled in the stomach, emptying of the particles lags behind emptying of 10 XX the liquid (Fig. 26.30). With digestible particles (e.g., stud- Fullness ies with isotopically labeled chunks of liver), the lag phase pump to reduce the particle size. If the particles are plastic spheres of various sizes, the smallest spheres are emptied 0 5 is the time required for the grinding action of the antral 0 100 200 300 400 500 600 first; however, spheres up to 7 mm in diameter empty at a slow but steady rate when digestible food is in the stomach. Gastric volume (mL) The selective emptying of smaller particles first is referred Loss of adaptive relaxation following a to as the sieving action of the distal stomach. Inert spheres FIGURE 26.29 vagotomy. A loss of adaptive relaxation in the larger than 7 mm in diameter are not emptied while food is gastric reservoir is associated with a lowered threshold for sensa- in the stomach; they empty at the start of the first migrat- tions of fullness and epigastric pain. ing motor complex as the digestive tract enters the interdi- gestive state. Osmolality, acidity, and caloric content of the gastric chyme are major determinants of the rate of gastric empty- fibers to inhibitory motor neurons in the gastric ENS (Fig. ing. Hypotonic and hypertonic liquids empty more slowly 26.28). Feedback relaxation is triggered by the presence of than isotonic liquids. The rate of gastric emptying de- nutrients in the small intestine. It can involve both local re- creases as the acidity of the gastric contents increases. flex connections between receptors in the small intestine Meals with a high caloric content empty from the stomach and the gastric ENS or hormones that are released from en- at a slower rate than meals with a low caloric content. The docrine cells in the small intestine and transported by the mechanisms of control of gastric emptying keep the rate of blood to signal the gastric ENS. delivery of calories to the small intestine within a narrow Adaptive relaxation is lost in patients who have under- range, regardless of whether the calories are presented as gone a vagotomy as a treatment for gastric acid disease carbohydrate, protein, fat, or a mixture. Of all of these, fat (e.g., peptic ulcer). Following a vagotomy, increased tone is emptied the most slowly, or stated conversely, fat is the in the musculature of the reservoir decreases the wall com- most potent inhibitor of gastric emptying. Part of the inhi- pliance, which, in turn, affects the responses of gastric bition of gastric emptying by fats may involve the release of stretch receptors to distension of the reservoir. Pressure- the hormone cholecystokinin, which itself is a potent in- volume curves before and after a vagotomy reflect the de- hibitor of gastric emptying. crease in compliance of the gastric wall (Fig. 26.29). The The intraluminal milieu of the small intestine is ex- loss of adaptive relaxation after a vagotomy is associated tremely different from that of the stomach (see Chapter with a lowered threshold for sensations of fullness and pain. This response is explained by increased stimulation of the gastric mechanoreceptors that sense distension of the gas- tric wall. These effects of vagotomy may explain disordered Lag phase Emptying phase gastric sensations in diseases with a component of vagus 100 nerve pathology (e.g., autonomic neuropathy of diabetes mellitus) (see Clinical Focus Box 26.1). Solid meal The Rate of Gastric Emptying Is Determined by the Kind of Meal and Conditions in Meal remaining in stomach (%) 50 the Duodenum Semisolid meal In addition to storage in the reservoir and mixing and Liquid meal grinding by the antral pump, an important function of gas- tric motility is the orderly delivery of the gastric chyme to the duodenum at a rate that does not overload the digestive 0 0 20 40 60 80 100 and absorptive functions of the small intestine (see Clinical Focus Box 26.1). The rate of gastric emptying is adjusted by Time after meal (min) neural control mechanisms to compensate for variations in Gastric emptying. The rate of gastric emptying the volume, composition, and physical state of the gastric FIGURE 26.30 varies with the composition of the meal. Solid contents. meals empty more slowly than semisolid or liquid meals. The emp- The volume of liquid in the stomach is one of the im- tying of a solid meal is preceded by a lag phase, the time required portant determinants of gastric emptying. The rate of emp- for particles to be reduced to sufficient size for emptying.
472 PART VII GASTROINTESTINAL PHYSIOLOGY 27). Undiluted stomach contents have a composition that • Phase I: a silent period having no contractile activity; is poorly tolerated by the duodenum. Mechanisms of con- corresponds to physiological ileus trol of gastric emptying automatically adjust the delivery of • Phase II: irregularly occurring contractions gastric chyme to an optimal rate for the small intestine. • Phase III: regularly occurring contractions This guards against overloading the small intestinal mech- Phase I returns after phase III, and the cycle is repeated anisms for the neutralization of acid, dilution to iso-osmo- (Fig. 26.33). With multiple sensors positioned along the in- lality, and enzymatic digestion of the foodstuff (see Clini- testine, slow propagation of the phase II and phase III ac- cal Focus Box 26.1). tivity down the intestine becomes evident. At a given time, the MMC occupies a limited length of intestine called the activity front, which has an upper and MOTILITY IN THE SMALL INTESTINE a lower boundary. The activity front slowly advances (mi- grates) along the intestine at a rate that progressively slows The time required for transit of experimentally labeled as it approaches the ileum. Peristaltic propulsion of luminal meals from the stomach to the small intestine to the large contents in the aboral direction occurs between the oral intestine is measured in hours (Fig. 26.31). Transit time in and aboral boundaries of the activity front. The frequency the stomach is most rapid of the three compartments; tran- of the peristaltic waves within the activity front is the same sit in the large intestine is the slowest. Three fundamental as the frequency of electrical slow waves in that intestinal patterns of motility that influence the transit of material segment. Each peristaltic wave consists of propulsive and through the small intestine are the interdigestive pattern, receiving segments, as described earlier (see Fig. 26.20). the digestive pattern, and power propulsion. Each pattern Successive peristaltic waves start, on average, slightly far- is programmed by the small intestinal ENS. ther in the aboral direction and propagate, on average, slightly beyond the boundary where the previous one The Migrating Motor Complex Is the stopped. Thus, the entire activity front slowly migrates Small Intestinal Motility Pattern of the down the intestine, sweeping the lumen clean as it goes. Interdigestive State Phases II and III are commonly used descriptive terms of minimal value for understanding the MMC. Contractile ac- The small intestine is in the digestive state when nutrients tivity described as phase II or phase III occurs because of are present and the digestive processes are ongoing. It con- the irregularity of the arrival of peristaltic waves at the ab- verts to the interdigestive state when the digestion and ab- oral boundary of the activity front. On average, each con- sorption of nutrients are complete, 2 to 3 hours after a meal. secutive peristaltic wave within the activity front propa- The pattern of motility in the interdigestive state is called gates farther in the aboral direction than the previous wave. the migrating motor complex (MMC). The MMC can be Nevertheless, at the lower boundary of the activity front, detected by placing pressure sensors in the lumen of the in- some waves terminate early and others travel farther (see testine or attaching electrodes to the intestinal surface (Fig. Fig. 26.32). Therefore, as the lower boundary of the front 26.32). Sensors in the stomach show the MMC starting as passes the recording point, only the waves that reach the large-amplitude contractions at 3/min in the distal stomach. sensor are recorded, giving the appearance of irregular con- Elevated contraction of the lower esophageal sphincter co- tractions. As propagation continues and the midpoint of incides with the onset of the MMC in the stomach. Activ- the activity front reaches the recording point, the propul- ity in the stomach appears to migrate into the duodenum sive segment of every peristaltic wave is detected. Because and on through the small intestine to the ileum. the peristaltic waves occur with the same rhythmicity as the At a single recording site in the small intestine, the electrical slow waves, the contractions can be described as MMC consists of three consecutive phases: being “regular.” The regular contractions that are seen Stomach Duodenum Large intestine 100 100 100 75 75 75 Content (%) 50 50 50 Solid meal 25 25 25 Liquid meal GI transit times. The FIGURE 26.31 time during which 0 components of solid and liquid meals 0 246 0 2468 0 246810 enter and leave the stomach, duodenum, Time after ingestion of meal (hr) and large intestine is measured in hours.
CHAPTER 26 Neurogastroenterology and Gastrointestinal Motility 473 Pressure recording port on catheter MMC activity front 0 5 10 15 20 25 Time (min) Migrating motor complex in the small intes- small intestine to the ileum. Repetitive peristaltic propulsion oc- FIGURE 26.32 tine. The MMC consists of an activity front curs within the activity front. that starts in the gastric antrum and slowly migrates through the when the central region of the front passes a single record- The MMC is organized by the microcircuits in the ENS. ing site last for 8 to 15 minutes. This time is shortest in the It continues in the small intestine after a vagotomy or sym- duodenum and progressively increases as the MMC mi- pathectomy but stops when it reaches a region of the intes- grates toward the ileum. tine where the ENS has been interrupted. Presumably, The MMC is seen in most mammals, including humans, command signals to the enteric neural circuits are necessary in conscious states and during sleep. It starts in the antrum for initiating the MMC, but whether the commands are of the stomach as an increase in the strength of the regu- neural, hormonal, or both is unknown. Although levels of larly occurring antral contractile complexes and accom- the hormone motilin increase in the blood at the onset of plishes the emptying of indigestible particles (e.g., pills and the MMC, it is unclear whether motilin is the trigger or is capsules) greater than 7 mm. In humans, 80 to 120 minutes released as a consequence of its occurrence. are required for the activity front of the MMC to travel from the antrum to the ileum. As one activity front termi- nates in the ileum, another begins in the antrum. In hu- Adaptive Significance of the MMC. Gallbladder contrac- mans, the time between cycles is longer during the day than tion and delivery of bile to the duodenum is coordinated at night. The activity front travels at about 3 to 6 cm/min in with the onset of the MMC in the intraduodenal region. the duodenum and progressively slows to about 1 to 2 After entering the duodenum, the activity front of the cm/min in the ileum. It is important not to confuse the MMC propels the bile to the terminal ileum, where it is re- speed of travel of the activity front of the MMC with that absorbed into the hepatic portal circulation. This mecha- of the electrical slow waves, action potentials, and peri- nism minimizes the accumulation of concentrated bile in staltic waves within the activity front. Slow waves with as- the gallbladder and increases the movement of bile acids in sociated action potentials and associated contractions of the enterohepatic circulation during the interdigestive state circular muscle travel about 10 times faster. (see Chapter 27). Cycling of the MMC continues until it is ended by the The adaptive significance of the MMC appears also to ingestion of food. A sufficient nutrient load terminates the be a mechanism for clearing indigestible debris from the in- MMC simultaneously at all levels of the intestine. Termi- testinal lumen during the fasting state. Large indigestible nation requires the physical presence of a meal in the upper particles are emptied from the stomach only during the in- digestive tract; intravenous feeding does not end the fasting terdigestive state. pattern. The speed with which the MMC is terminated at Bacterial overgrowth in the small intestine is associated all levels of the intestine suggests a neural or hormonal with an absence of the MMC. This condition suggests that mechanism. Gastrin and cholecystokinin, both of which the MMC may play a housekeeper role in preventing the are released during a meal, terminate the MMC in the overgrowth of microorganisms that might occur in the stomach and upper small intestine but not in the ileum, small intestine if the contents were allowed to stagnate in when injected intravenously. the lumen.
474 PART VII GASTROINTESTINAL PHYSIOLOGY (physiological ileus) Activity Start Phase I front Antrum Phase II Phase III Peristalsis Stop Duodenum Upper boundary Jejunum Activity front Lower boundary Ileum 6 0 1235 4 Time (hr) The three phases of the MMC. (See text for details.) FIGURE 26.33 Mixing Movements Characterize the pulse transmission in the nerves result in an interruption Digestive State of the pattern of mixing movements. When the vagus nerves are blocked during the digestive state, MMCs A mixing pattern of motility replaces the MMC when the reappear in the intestine but not in the stomach. With small intestine is in the digestive state following ingestion warming of the nerves and release of the neural blockade, of a meal. The mixing movements are sometimes called the mixing motility pattern returns. segmenting movements or segmentation, as a result of their appearance on X-ray films of the small intestine. Peri- staltic contractions, which propagate for only short dis- tances, account for the segmentation appearance. Circular muscle contractions in short propulsive segments are sepa- rated on either end by relaxed receiving segments (Fig. 26.34). Each propulsive segment jets the chyme in both directions into the relaxed receiving segments where stirring and mixing occur. This happens continuously at closely spaced sites along the entire length of the small in- testine. The intervals of time between mixing contractions are the same as for electrical slow waves or are multiples of the shortest slow-wave interval in the particular region of intestine. A higher frequency of electrical slow waves and associated contractions in more proximal regions and the peristaltic nature of the mixing movements result in a net aboral propulsion of the luminal contents over time. The Role of the Vagus Nerves and ENS. The mixing pattern of small intestinal motility is programmed by the ENS. Signals transmitted by vagal efferent nerves to the ENS interrupt the MMC and initiate mixing motility dur- ing ingestion of a meal. After the vagus nerves are cut, a larger quantity of ingested food is necessary to interrupt FIGURE 26.34 Mixing movements. The segmentation pat- tern of motility is characteristic of the digestive the interdigestive motor pattern, and interruption of the state. Propulsive segments separated by receiving segments occur MMCs is often incomplete. Evidence of vagal commands randomly at many sites along the small intestine. Mixing of the for the mixing pattern has been obtained in animals with luminal contents occurs in the receiving segments. Receiving seg- cooling cuffs placed surgically around each vagus nerve. ments convert to propulsive segments, while propulsive segments During the digestive state, cooling and blockade of im- become receiving segments.
CHAPTER 26 Neurogastroenterology and Gastrointestinal Motility 475 Power Propulsion Is a Defensive Response Splenic Against Harmful Agents Hepatic flexure flexure Transverse Power propulsion involves strong, long-lasting contrac- colon tions of the circular muscle that propagate for extended dis- tances along the small and large intestines. The giant mi- grating contractions are considerably stronger than the phasic contractions during the MMC or mixing pattern. Descending Giant migrating contractions last 18 to 20 seconds and span colon several cycles of the electrical slow waves. They are a com- Ascending colon ponent of a highly efficient propulsive mechanism that rap- Tenia coli idly strips the lumen clean as it travels at about 1 cm/sec Ileum Haustra over long lengths of intestine. Intestinal power propulsion differs from peristaltic propulsion during the MMC and mixing movements, in that circular contractions in the propulsive segment are Cecum stronger and more open gates permit propagation over Appendix longer reaches of intestine. The circular muscle contrac- Rectum Sigmoid colon tions are not time-locked to the electrical slow waves and probably reflect strong activation of the muscle by excita- tory motor neurons. Anal sphincter Power propulsion occurs in the retrograde direction dur- ing emesis in the small intestine and in the orthograde di- FIGURE 26.35 Anatomy of the large intestine. The main rection in response to noxious stimulation in both the small anatomic regions of the large intestine are the and the large intestines. Abdominal cramping sensations ascending colon, transverse colon, descending colon, sigmoid and, sometimes, diarrhea are associated with this motor be- colon, and rectum. The hepatic flexure is the boundary between the ascending and the transverse colon; the splenic flexure is the havior. Application of irritants to the mucosa, the introduc- boundary between the transverse and the descending colon. The tion of luminal parasites, enterotoxins from pathogenic bac- sigmoid colon is so defined by its shape. The rectum is the most teria, allergic reactions, and exposure to ionizing radiation distal region. The cecum is the blind ending of the colon at the all trigger the propulsive response. This suggests that power ileocecal junction. The appendix is an evolutionary vestige. Inter- propulsion is a defensive adaptation for the rapid clearance nal and external anal sphincters close the terminus of the large in- of undesirable contents from the intestinal lumen. It may testine. The longitudinal muscle layer is restricted to bundles of also accomplish mass movement of intraluminal material in fibers called tenia coli. normal states, especially in the large intestine. pressure. Chemoreceptors and mechanoreceptors in the ce- cum and ascending colon provide feedback information for controlling delivery from the ileum, analogous to the feed- MOTILITY IN THE LARGE INTESTINE back control of gastric emptying from the small intestine. In the large intestine, contractile activity occurs almost Dwell-time of material in the ascending colon is found continuously. Whereas the contents of the small intestine to be short when studied with gamma scintigraphic imag- move through sequentially with no mixing of individual ing of radiolabeled markers. When radiolabeled chyme is meals, the large bowel contains a mixture of the remnants instilled into the human cecum, half of the instilled volume of several meals ingested over 3 to 4 days. The arrival of empties, on average, in 87 minutes. This period is long in undigested residue from the ileum does not predict the time comparison with an equivalent length of small intestine, of its elimination in the stool. but it is short in comparison with the transverse colon. It The large intestine is subdivided into functionally dis- suggests that the ascending colon is not the primary site for tinct regions corresponding approximately to the ascend- the large intestinal functions of storage, mixing, and re- ing colon, transverse colon, descending colon, rectosig- moval of water from the feces. moid region, and internal anal sphincter (Fig. 26.35). The The motor pattern of the ascending colon consists of or- transit of small radiopaque markers through the large intes- thograde or retrograde peristaltic propulsion. The signifi- tine occurs, on average, in 36 to 48 hours. cance of backward propulsion in this region is uncertain; it may be a mechanism for temporary retention of the chyme in the ascending colon. Forward propulsion in this region is The Ascending Colon Is Specialized for probably controlled by feedback signals on the fullness of Processing Chyme Delivered From the the transverse colon. Terminal Ileum Power propulsion in the terminal length of ileum may de- The Transverse Colon Is Specialized for the liver relatively large volumes of chyme into the ascending Storage and Dehydration of Feces colon, especially in the digestive state. Neuromuscular mechanisms analogous to adaptive relaxation in the stom- Radioscintigraphy shows that the labeled material is moved ach permit filling without large increases in intraluminal relatively quickly into the transverse colon (Fig. 26.36),
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