THE INS AND OUTS OF BICARBONATE IN THE ALIMENTARY TRACT

Transcription

1 GASTROENTEROLOGY Copyright 1968 by The William. &: Wilkins Co. Vol. 54, No.4, Part 1 of 2 Part. Printed in U.S.A. THE INS AND OUTS OF BICARBONATE IN THE ALIMENTARY TRACT In a dog that has eaten a test meal mixed with litmus, variations in the ph of alimentary fluids should produce a blue mouth and esophagus, a red stomach, and a gradual change from pink-blue in the jejunum to blue in the ileum and colon. This editorial discusses the ph of fluids in the alimentary stream and its tributaries and the cellular mechanisms of alkaline fluid secretion. Bicarbonate is synthesized by the hydration of CO 2 in a reversible reaction that can be catalyzed by carbonic anhydrase (CA) : HOH + CO2 CA <- H 2C0 3 P (1) H+ + HCO a - Alimentary fluids are acidified by the secretion of H+ or the absorption of OHor HCOa -, and they are alkalinized by the absorption of H+ or the secretion of OHor HCOs -. Regardless of the mechanism responsible for an alkaline secretion, the concentration of HCOs- increases since, once in solution, OH - reacts with dissolved CO 2 to produce bicarbonate: OH- + CO 2 p HCO a - (2) It is likely that the base line concentration of dissolved CO 2 within the lumen of an organ is determined by the dissolved CO 2 of the adj acent cells and interstitial fluid. The concentration may be altered by ion transport, however, since OH- secretion should decrease the concentration by removing CO 2 from solution (equation 2), and HCOs - secretion should increase the CO 2 by shifting the equilibrium in equation 1 to the left. Because bicarbonate may be transported as HCOs- or its precursors and can originate in either the extracellular fluid or se- Address requests for reprints to; Kenneth A. Hubel, M.D., Gastroenterology Research Laboratory, Department of Internal Medicine, University of Iowa College of Medicine, Iowa City, Iowa creting cell, the process of s ~ c r eis t complex and defies simple description as either i o n active or passive. In the ensuing discussion, bicarbonate secretion is defined as the accumulation of bicarbonate ions in solution. The detailed review of Burgen and Emmelin neatly summarizes the factors known to influence bicarbonate secretion in the salivary glands. 1 In the ability to produce saliva with bicarbonate concentrations higher than those of plasma, the parotid and submaxillary glands differ from the sublingual which secretes bicarbonate in low concentrations. The bicarbonate concentration of human parotid saliva' rises to a peak value of about 60mM (ph 7.7) when the flow rate is one-third maximal and thereafter remains constant despite increasing rates of flow. 2 In contrast to pancreatic juice, but similar to bile during secretin-induced choleresis, salivary chloride concentration also increases with flow. Data cited by Burgen and Emmelin suggest that bicarbonate is secreted in the ducts distal to the acini. Micropuncture studies of ionic movement in the salivary ducts potentially provide the most unassailable data on the site of bicarbonate secretion, but thus far, the technique has been applied only to the study of sodium and potassium. s The concentrated acid secreted by the gastric fundus rapidly converts the bicarbonate in swallowed saliva to CO 2 which may then diffuse into the gastric mucosa or be expelled. In the dog deprived of gastrin by antrectomy and of vagal stimuli by vagotomy, the fundic mucosa secretes mucus with a mean [HCOs-] of 13 mm (ph 7.2) in response to topical acetylcholine or iodoacetamide. 4 The pyloric mucosa of the dog antrum secretes fluid with a lower [HCOs-] of 8 mm. 5 Secretions collected from pouches of proximal duodenum in which there are numerous Brunner's glands contain HCOs - in the range of 14 to 22 mm. Although no consistent rela-

2 648 EDITORIALS Vol. 54, No.4, Part 1 tionship is found between the bicarbonate concentration and secretory rate of the pouch,. the concentrations measured in juice obtained following secretory stimulation with food, crude gastrin, and Boots secretin are higher, 16 to 42 mm. 6, The ' alkalinity of intestinal fluids increases progressively from the jejunum to the ileum. The colon is similar to ileum. The degree of alkalinity varies among species, but man, dog, and rat share ph values of 6.5 to 7.0 for the jejunum and 7.5 to 8.0 for ileum and colon. Recent studies of dogs with Thiry -Vella loops show that bicarbonate is absorbed from the jejunum and accumulates in the colon at luminal concentrations of bicarbonate from o to 154 mm. In ileal loops, bicarbonate accumulates at concentrations less then 60 mm, above which absorption occurs. This same study determined for each segment of bowel "that concentration of CO 2 which, if introduced into the lumen, would remain unaltered-the equilibrium concentration./i These concentrations were 5 mm, 75 mm, imd '75 ' mm for the jejunum, ileum, and proximal colon, respectively.7 Equilibrium concep.trations have not been studied in man, * but concentrations of 5 mm and 40 mm have been reported for fluids aspirated from the jejunum and ileum. s In perfusion fluids in which chloride is the other anion, the concentrations of bicarbonate and chloride vary in complementary fashion, i.e., [HCOa-] + [CI-] = 150 rom. Although it is likely that bicarbonate is secreted by the columnar cells of the ileal and colonic epithelium, the secretory cell has not been identified with certainty. The concentration of bicarbonate in pancreatic juice rises rapidly with an increasing secretory rate and, in dog and man, is maximal at 140 to 150.roM (ph 8.2 to 8.3) when secretory rates are one-third to onehalf maximum. The curve that describes * Since the manuscript was submitted, equilibrium c.oncentrations of bicarbonate in man were found to be 5 mm in jejunum and 40 mm in ileum (Phillips, S. F., and W. H. J. Summerskill Water and electrolyte transport during maintenance of isotonicity in human jejunum and ileum. J. Lab. Clin. Med. 70: ,) the rise of bicarbonate with flow rate is approximately symmetrical around a horizontal axis with the curve that depicts the fall in chloride concentration. 9 Although the sites of secretion of bicarbonate are not known, the localization of carbonic anhydrase in the ducts 10 suggests that the ducts, rather than the acini, are responsible for secreting bicarbonate at the higher rates that require catalysis. When bile flow in the dog is augmented by intravenous infusion of bile salts, the bicarbonate and chloride concentrations decrease despite an increase in the rate of bicarbonate and chloride secretiony When bile flow is induced by secretin, however, the concentrations of both ions rise and bicarbonate may approach concentrations of 60 rom (ph 7.7 to 7.8). To explain these variations, Wheeler and Ramos proposed that the water which accompanies bile salts into the liver canaliculi (taurocholate fraction) dilutes a distal secretion (electrolyte fraction) whose rate and composition respond to secretin in a manner similar to pancreatic juice. 12 The sites of bicarbonate secretion in the liver are not known, but increasing evidence suggests that the composition of the electrolyte fraction is determined in the interlobular ducts.13 When hepatic bile is concentrated in the gall bladder, bicarbonate is absorbed and its concentration may fall below 5 mm (ph 6.3 to 6.5). Chloride absorption occurs concurrently and its concentration also decreases. 14 In the dog submaxillary gland that is secreting maximally, cellular metabolism does not produce CO 2 rapidly enough to account for the rate of HCOa- secretion, so extracellular fluid must be a source of either HCO a - or CO 2.1 Studies of the hamster ileum in vitro also suggest that extracellular fluid is a major source of the secreted bicarbonate. 15 Comparable information for bile secretion is not available. Studies of pancreatic secretion with labeled HCO a - show that extracellular fluid is an important source of COl6 despite the capacity of cellular metabolism to supply ample CO 2 at maximal rates of secretion. 17 This is particularly true for several

3 April 1968 EDITORIALS 649 minutes after secretin injection when the concentration of total CO2 in the pancreatic venous blood may be lower than that of arterial blood. The pancreatic studies suggest that CO 2 or HCOs- constantly moves between the secreting cell and extracellular fluid. Thus, bicarbonate that is synthesized in the cell and secreted into the duct inevitably contains some CO2 from extracellular fluid even when the cell is producing CO 2 in excess of that needed for bicarbonate secretion. The question is not whether the CO2 of secreted bicarbonate arises in extracellular fluid, but how much, and in what form does the CO2 cross the membrane into the cell? The effect on bicarbonate secretion of altering the acid-base balance of the blood has been studied in greatest detail in the secretin-stimulated dog pancreas. 18 Elevation in the plasma concentration of any two terms of equation 2 increases the rate (although not necessarily the concentration) of bicarbonate secretion in pancreatic juice, and a decrease in any two has the opposite effect. Thus, bicarbonate output increases in metabolic alkalosis and decreases in respiratory alkalosis and metabolic acidosis. In respiratory acidosis without an increase in plasma [HCOs-], bicarbonate output does not change. Similar changes occur in the bicarbonate output of the bile during metabolic acidosis and alkalosis. 19 The bicarbonate concentration of parotid saliva varies directly with the concentration of dissolved CO 2 in arterial blood when plasma [HCOs-] is constant and increases when plasma [HCOs-] is raised, but the data permit no assessment of the effects of either change on bicarbonate output. 1 Secretin increases the rates both of flow and bicarbonate secretion of bile and pancreatic juice in man, dog, and cat. In the anesthetized rat, however, secretin enhances pancreatic flow but has little or no effect on biliary flow. 20 The usual constancy of bicarbonate concentration for a given bile flow suggests that bicarbonate secretion is unaltered, but this has not been studied in the rat. Secretin does not affect bicarbonate secretion by the ileum of the anesthetized rat. 21 Its effect on the salivary glands is not known. Acetazolamide increases the bile flow, bicarbonate and chloride output of dogs secreting bile at basal rates and blocks response to secretin. IO 19 In animals whose flow of pancreatic juice has been augmented with secretin, acetazolamide increases the chloride output but lowers the flow rate and bicarbonate output. 19 In both instances, the bicarbonate concentration for a given flow rate is less than normai,19 By contrast, when pancreatic juice is obtained by duodenal aspiration from human subjects given secretin and acetazolamide, the bicarbonate concentration is higher than expected for a given flow rate. 22 The reasons for this are not clear but may include the effects of acetazolamide on the liver and duodenal mucosa. In the rat, acetazolamide decreases bicarbonate and chloride absorption from the jejunum and reduces the rate of bicarbonate secretion and chloride absorption by the ileum and colon.2s In Thiry-Vella loops of ileum in dogs, acetazolamide decreases chloride absorption but has little effect on bicarbonate secretion. 24 Why does acetazolamide fail to decrease bicarbonate secretion in human parotid saliva, ileal perfusion solution in the dog, and canine bile secreted at basal rates? Since the catalytic activity of carbonic anhydrase is required only for higher rates of bicarbonate production,18 it is possible that bicarbonate at those sites is totally produced by the uncatalyzed hydration of CO 2 At higher rates of secretion that occur in the pancreas and liver after secretin injection, inhibition of carbonic anhydrase results in a decrease in bicarbonate output and concentration. Janowitz and Dreiling have postulated that carbonic anhydrase inhibitors act either by reducing the rate of formation of HCO a - or by preventing the maintenance of an intracellular ph which permits optimal transport of bicarbonate. 22 Neither hypothesis would explain the increased chloride output in canine bile or the decreased absorption of chloride in the canine ileum. Such changes suggest that acetazolamide modifies chloride transport by a mechanism that does not

4 650 EDITORIALS Vol. 54, No.4, Part 1 depend on' c ~ r b oanhydrase n i c inhibition. Kinney and Code have reviewed the evidence that favors this hypothesis. 24 Additional support comes from a recent demonstration that carbonic anhydrase inhibitors can depress chloride transport in frog cornea, a tissue devoid of carbonic anhydrase. 25 Summary and Conclusions At higher flow rates, the bicarbonate concentration and alkalinity of secretions of the parotid and submaxillary glands, pancreas, and liver exceed that of plasma. The alkalinity and bicarbonate concentration of secretions of the sublingual gland, gastric mucous glands, and pylorus are lower than plasma. The bicarbonate concentration of secretions from duodenal pouches containing Brunner's glands is generally lower but may exceed that of plasma after secretory stimulation. The alkalinity of luminal fluid increases in the distal intestine and is associated with a rising bicarbonate concentration which, in the ileum and colon, exceeds that of plasma. The gall bladder absorbs bicarbonate and the resultant bile has a bicarbonate concentration and ph less than those of plasma. In tissues which secrete bicarbonate, some portion of the CO 2 in the luminal bicarbonate will always originate in the extracellular fluid regardless of the rate of cellular CO 2 production. The variable response of bicarbonate secretion to carbonic anhydrase inhibitors by different organs may be related to the rate of bicarbonate secretion or to interference with chloride transport or to both. Fragmentary data and the variations in pharmacological responses among alimentary exocrine organs preclude the formulation of a unitary hypothesis of bicarbonate secretion. Kenneth A. Hubel, M.D. Gastroenterology Research Laboratory Department of Internal Medicine University of Iowa College of Medicine Iowa City, Iowa REFERENCES L Burgen, A. S. V;, and N. G; Emmelin Physiology' )ofthe salivary glands. Edward Arnold & Co., London. 2. Thaysen, J. H., N. A. Thorn, and I. L. Schwartz Excretion of sodium, potassium, chloride and carbon dioxide in human parotid saliva. Amer. J. Physiol. 178: Young, J.A., E. Fromter, E. SchOgel, and K. F. Hahuinn A microperfusion investigation of sodium resorption and potassium secretion by the main excretory duct of the rat submaxillary gland. Pflueger Arch Ges. Physiol. 295: Hollander, F The electrolyte pattern of gastric mucinous. secretions; its implication for cystic fibrosis. Ann. N. Y. Acad. Sci. lob: Grossman, M Cited in Reference 6. The secretion of the pyloric glands of the dog, p In Symposia and special lectures, Vol. XXI. International Congress of Physiological Sciences, Buenos Aires. 6. Cooke, A. R., and M. I. Grossman Studies on the secretion and motility of Brunner's gland pouches. Gastroenterology 51: Swallow, J. H., and C. F. Code: Intestinal transmucosal fluxes of bicarbonate. Amer. J. Physiol. 212: Bucher, G. R., J. C. Flynn, and C. S. Robinson The action of the human small intestine in altering the composition of physiological saline. J. BioI. Chem. 155: Hart, W. M., and J. E. Thomas Bicarbonate and chloride of pancreatic juice secreted in response to various stimuli. Gastroenterology 4: Becker, V Histochemistry of the exocrine pancreas, p In A. V. S. de Reuck, and M. P. Cameron [eds.], Ciba Foundation Symposium on the exocrine pancreas. Little, Brown & Company, Boston. 11. Preisig, R., H. L. Cooper, and H. O. Wheeler The relationship between taurocholate secretion rate and bile production in the unanesthetized dog during cholinergic blockage and during secretin administration. J. Clin. Invest. 41: Wheeler,H. W., and O. L. Ramos Determinants of the' flow and composition of bile in the unanesthetized dog during con-

5 Apri l 1968 EDITORIALS 651 stant infusions of sodium taurocholate. J. Clin. Invest. 39: Forker, E. L Two sites of bile formation as determined by mannitol and erythritol clearance in the guinea pig. J. Clin. Invest. 46: Ravdin, I. S., C. G. Johnston, C. Riegel, and S. L. Wright, Jr VII. Studies of gallbladder function. Amer. J. Physiol. 100: Wilson, T. H. and L. Kazyak Acid-base changes across the wall of the hamster and rat intestine. Biochim. Biophys. Acta 24: Ball, E. G., H. F. Tucker, A. K. Solomon, and B. Vennesland The source of pancreatic juice bicarbonate. J. BioI. Chem. 140: 111) Still, E. U., A. L. Bennett, and V. B. Scott A study of the metabolic activity of the pancreas. Amer. J. Physiol. 106: Rawls, J. A., P. J. Wistrand, and T. H. Maren Effects of acid-base changes and carbonic anhydrase inhibition on pancreatic secretion. Amer. J. Physiol. 206: 651"'{) Pak, B. H., S. S. Hong, H. K. Pak, and S. K. Hong Effects of acetazolamide and acid-base changes on biliary and pancreatic secretion. Amer. J. Physiol. 210: Debray, C., C. Vaille, J. De La Tour, C. Roze, and M. Souchard Action des S e C f ( ~ tines du commerce sur la secretion pancreatique externe du rat. J. Physiol. (Paris) 64: Hubel, K. A Effect of secretion on bicarbonate secretion in fluid perfusing the rat ileum. Experientia 23 : Janowitz, H. D., and D. A. Dreiling In A. V. S. de Reuck, and M. P. Cameron [eds.] Ciba Foundation Symposium on the exocrine pancreas, p Little, Brown & Company, Boston. 23. Parsons, D. S The absorption of bicarbonate-saline solutions by the small intestine and colon of the white rat. Quart. J.. Exp. Physiol. 41: Kinney, V. R., and C. F. Code Canine ileal chloride absorption: effect of carbonic anhydrase inhibitor on transport. Amer. J. Physiol. 207: Kitahara, S., K. R. Fox, and C. /1... M. Hogben Depression of chloride transport by carbonic anhydrase inhibitors in the absence of carbonic anhydrase. Nature '(London) 214: