EFFECT OF SECRETIN AND CHOLECYSTOKININ ON THE TRANSPORT OF ELECTROLYTE AND WATER IN HUMAN JEJUNUM

Transcription

1 GASTROENTEROLOGY Copyright 1973 by The Williams & Wilkins Co. Vol. 64, No.1 Printed in U.S.A. EFFECT OF SECRETIN AND CHOLECYSTOKININ ON THE TRANSPORT OF ELECTROLYTE AND WATER IN HUMAN JEJUNUM MORDEKHAI MORITZ, M.D., GARY FINKELSTEIN, HOOSHANG MESHKINPOUR, M.D., JERALD FINGERUT, M.D., AND STANLEY H. LORBER, M.D. Department of Gastroenterology, Temple University School of Medicine, Philadelphia, Pennsylvania The effect of natural porcine secretin and cholecystokinin on the transport of electrolytes and water in human jejunum was studied in eight normal volunteers utilizing a triple lumen tube technique of perfusion. These hormones were observed to inhibit significantly (P < 0.05) the absorption of water, sodium, potassium, and chloride. A graded response was observed with both hormones-2 U per kg per hr produced significantly (P < 0.05) more fluid accumulation than 1 U per kg per hr. The effects of the hormones on the above parameters were qualitatively and quantitatively similar in doses employed. Studies of the effects of secretin and cholecystokinin (CCK) on the transport of water and electrolytes in the intestine have been limited. Cooke and Grossman 1 observed that Boots secretin induced secretion of Brunner's glands in the dog but that Vitrum secretin had no such effect. However, the administration of large doses of pure natural porcine secretin or synthetic secretin produced a secretory response of these glands in dogs or cats. 2 Similar results were reported by Love et al. 3 A highly purified preparation of CCK was reported to be a less effective stimulant of Brunner's glands. 4 Gardner et al. 5 employing an everted gut sac preparation of the hamster, observed that Vitrum secretin and CCK produced inhibition of the net transfer of sodium, chloride, and fluid across the small intestine. Hubel 6 however, observed no significant change in electrolyte movement in rat ileum in vivo during the administration of Boot's secre- Received June 9, Accepted August 10, Address requests for reprints to: Dr. Mordekhai Moritz, Temple University School of Medicine, Health Sciences Center, 3401 N. Broad Street, Philadelphia, Pennsylvania The authors wish to acknowledge the clerical assistance of Miss Norma E. Register. 76 tin. A similar observation was reported on dog 7 and human 8 jejunum in vivo using the more potent secretin preparation of Jorpes. In a recent study, both secretin and CCK were observed to increase net secretion of water, sodium, and chloride in human jejunum in vivo. 9, 10 In this study, the effect of natural porcine secretin and CCK on electrolyte and water transport was evaluated in the jejunum of normal man. Materials and Methods Studies were performed on eight volunteers who were free of gastrointestinal disease. The study group consisted of four males and four females whose ages ranged from 22 to 36 years. Perfusion experiments were performed using a triple lumen tube 11 arranged so that the middle and distal tube openings were 10 and 40 cm, respectively, from the proximal opening. Each lumen had an internal diameter of 1.4 mm. After an overnight fast, the tube was introduced and positioned under fluoroscopic observation so that the opening of the proximal lumen was 10 to 15 cm distal to the ligament of Trietz in order to prevent reflux of the marker into the stomach. '2 The test solution employed was infused at a rate of 10 ml per min through the proximal opening employing a peristaltic pump (Harvard Apparatus Co., Dover, Mass.). Samples from the middle opening were ob-

2 January 1973 SECRETIN AND CCK IN INTESTINAL ABSORPTION 77 tained by continuous aspiration at a rate of 1.0 ml per min using a peristaltic pump (Scientific Industries, Inc., Springfield, Mass.). Samples from the distal opening were collected by siphonage. The test solution contained (mm): Na, 145; K, 2.6; Mg, 0.6; Ca, 2.2; CI, 135; HC0 3, 12; PO" 2.6. The solution was isotonic (296 millios moles per kg) and contained glucose 5.6 mm and polyethylene glycol (mol wt 4000: polyethylene glycol Baker Chemical Co., Phillipsberg, N. J.) 5 g per liter as a nonabsorbable marker. Secretin and CCK were purchased from the Gastrointestinal Hormone Research Unit, Karolinska Institutet, Stockholm, Sweden (batch no and 27121, respectively). The hormones were dissolved in saline for administration. The intestine was perfused continuously with the test solution throughout the study. A 1-hr period was allowed initially for equilibration. The study was divided into five periods. During the 1st or control hr, normal saline was administered intravenously at a rate of 9 ml per hr (Harvard Apparatus Co.). This was followed sequentially by an intravenous infusion of secretin 1 and 2 U per kg per hr, each for 1 hr; 40 min of normal saline and CCK 1 and 2 U per kg per hr, each for 40 min. With the exception of the equilibration period, luminal samples were obtained throughout the study at 20-min intervals. Analytical Methods The concentration of polyethylene glycol was analyzed by the turbimetric method of Hyden 13 as modified by Malawer and Powell." Concentrations of sodium and potassium were measured by a flame photometer (Model IL 143, Instrumentation Laboratory Inc., Lexington, Mass.), and the concentration of chloride was measured by amperometric titration (Chlor-O Counter, Fisk Assoc., Inc., Uxbridge, Mass.). Net water and ion transport was calculated as the difference in the amount of solute and water (flow rate times concentration) entering and leaving the study segment, i.e., between the middle and distal openings. Statistical analysis was done by analysis of variance because of the experimental design. For this analysis, the 20-min samples of each study period were pooled. The analysis of variance was done on volume and ion fluxes comparing the pooled data of each and of both doses of secretin and CCK with the normal saline control period. Results Control. In 7 of 8 control subjects (27 samples) there was net absorption of water, sodium chloride, and a small net secretion of potassium (fig. 1, table 1). In 1 subject, a small secretion of water, sodium, and chloride and slight absorption of potassium occurred. Secretin. The administration of secretin in a dose of 1 U per kg per hr (n = 8, 27 samples) resulted in a significant decrease in net water absorption [(P < 0.05) fig. 1, table 1]. This was associated with net secretion of chloride, an increased net secretion of pvtassium and a small secretion of sodium. Increasing the dose of secretin to 2 U per kg per hr (n = 5, 14 samples) resulted in a significantly greater net secretion of water (P < 0.05) but there was no significant change in the net secretion of sodium, chloride, and potassium. CCK. The administration of CCK in a dose of 1 U per kg per hr (n = 5, 16, samples) produced net secretion of water, sodium, chloride, and potassium (fig. 1, table 1). An additional increase in net secretion of water, sodium, chloride, and potassium was observed employing CCK at a dose of 2 U per kg per hr (n = 4, 11 samples). The pooled net fluxes of water, sodium, and chloride for each dose period were significantly different (P < 0.05) from those of the control period. CCK in a dose of 2 U per kg per hr apparently had a greater effect than - 60 FIG. 1. Mean net water transport in human jejunum during constant intravenous infusion of normal saline (N.S.). secretin (SEC.), and cholecystokinin (CCK).

3 78 MORITZ ET AL. Vol. 64, No.1 TABLE 1. Mean ± 1 SEM H 2 0 and ionic fluxes in normal human jejunum in response to intravenous infusion of normal saline (NS), secretin (SEC), and cholecystokinin (CCK)" Intravenous infusion No. of H 2 O Na K Cl patients mllhr meqlhr NS ± ± ± ± 2.57 SEC 1 U/kg/hr ± ± ± ± 6.21 SEC 2 U/kg/hr ± ± ± ± 2.50 CCK 1 U/kg/hr ± ± ± ± 0.32 CCK 2 U/kg/hr ± ± ± ± 9.74 " Positive values indicate absorption from lumen, negative values secretion into lumen. secretin administered at the same dose (table 1), but the difference was not statistically significant (P = 0.05). Discussion This study demonstrates that both secretin and CCK inhibit net absorption of water, sodium, potassium, and chloride in normal human jejunum. These observations confirm previous reports that secretin and CCK decrease transport of these substances across the intestinal epithelium in viv but are in disagreement with another in vivo observation 8 in which no demonstrable effect on the net absorption of water and electrolytes was observed in response to the intravenous administration of J orpes secretin in a dose of 1 U per kg per hr. The mechanism by which these hormones induce their effect is not indicated in this study. Previous reports have shown that secretin and CCK inhibit selectively the unidirectional flux of sodium from lumen to blood in vitro 5 and that CCK had a similar effect in normal human jejunum in vivo. 9 Although it appears that net water accumulation is due primarily to the inhibition of sodium absorption, the presence of a concomitant water secretion resulting from stimulation of chloride secretion should be considered also. It has been suggested that such a secretory pump is mediated through cyclic adenosine monophosphate (AMP) Secretin has been observed to increase the intracellular concentration of cyclic AMP in isolated fat cells of the rau 9 ; cyclic AMP and theophylline augment enzyme secretion by the pancreas ; since CCK stimulates enzyme secretion by the pancreas, these data suggest that cyclic AMP may be induced by CCK. At this time, however, the effect of these hormones on cyclic AMP is inconclusive. The net chloride accumulation (table 1) observed in our study are consistent with the inhibition of absorption of sodium noted above. The possible contribution of a chloride secretory pump will have to be determined by employing isotopes. The influence of intestinal motility and transit time on fluxes must be considered because of the effects of these hormones on motor function. Secretin inhibits 22 ' 25 and CCK stimulates motor activity in the gastrointestinal tract of man and animals. Although it is conceivable that rapid transit can interfere with fluid absorption, as is true in clinical conditions manifested by diarrhea, absorption of various substances in hypermotility states may be either decreased or increased. 30 Recently, it has been shown 9 that the administration of CCK to man will decrease both intestinal transit time and absorption of water, sodium, and chloride; it was suggested that the increase in motor activity per se was responsible for the alteration of normal absorption. Conflicting observations on the influence of hypomotility states have been reported also. Anticholinergic drugs, which increase transit time, were reported to result in either a decrease or increase 33 in absorption of water and sodium from human small intestine. Previous studies employing secretin had failed to demonstrate alterations in the absorption of water and electrolyte 6 ' 8 in spite of its established effect on motor activity. Our data indicate that

4 January 1973 SECRETIN AND CCK IN INTESTINAL ABSORPTION 79 secretin alters the normal absorption of water and electrolytes. The fact that secretin and CCK had similar qualitative and quantitative effects in spite of their different effects on motor activity suggests that the influence of secretin on water and electrolyte absorption is probably not related to its action on intestinal motor activity. Finally, the effect of bile acids on the absorption of water should be mentioned. In hamster jejunum, in vivo dihydroxy bile acids either inhibit water absorption or stimulate water secretion depending upon their concentration in the perfusion test solution. 34 Thus, the stimulation of bile acids secretion by secretin and CCK 35 and the emptying of the gallbladder by CCK could have resulted in an increased entry of bile acids into the study segment causing more inhibition of water absorption or perhaps net water secretion. The relevance of these data to clinical conditions remains to be determined. It is possible that these hormones contribute to the production of diarrhea in the Zollinger Ellison syndrome and in the non-fj-cell non-gastrin producing adenoma of the pancreas. In the former, the excessive elaboration of gastrin induces a hypersecretion of gastric acid which upon entrance into the duedenum stimulates the release of secretin and CCK. These in turn could then inhibit the normal absorption of water and solute from the lumen. The latter syndrome is characterized by a decrease or an absence of gastric acid secretion, normal duodenal ph, severe watery diarrhea, hypopotassemia, and metabolic alkalosis. Secretin has been postulated to be the hormone elaborated by this tumor. Thus, a high output of secretin by this tumor could lead to the production of diarrhea both by stimulating the excessive secretion of pancreatic and biliary fluids as well as by the impedance of normal absorption of water and electrolyte from the intestinal lumen. REFERENCES 1. Cooke AR, Grossman MI: Studies on the secretion and motility of Brunner's glands pouches. Gastroenterology 51: , Stening GF, Grossman MI: Hormonal control of Brunner's glands. Gastroenterology 56: , Love JW, Walder AI, Bingham C: Effect of pure and synthetic secretin on Brunner's gland secretion in dogs. Nature 219: , Vagne M, Grossman MI: Cholecystokinetic potency of gastrointestinal hormones and related peptides. Am J Physiol 215: , Gardner JD, Peskin GW, Cerda JJ, et al: Alterations of in-vitro fluid and electrolyte absorption by gastrointestinal hormones. Am J Surg 113:57-64, Hubel KA: Effect of secretin on bicarbonate secretion in fluid perfusing the rat ileum. Experientia 23: , Bynum TE, Jacobson ED, Johnson LR: Gastrin inhibition of intestinal absorption in dogs. Gastroenterology 61: , Modigliani R, Huet PM, Rambaud JC, et al: Effect of secretin upon movements of water and electrolytes across the small intestine in man. Rev Eur Etud Clin BioI 16: , Matuchansky C, Huet PM, Mary JY, et al: Effects of cholecystokinin and metoclopramide on jejunal movements of water and electrolytes and on transit time of luminal fluid in man. Eur J Clin Invest 2: , Mekhjian H, King D, Sanzenbacher L, et al: Glucagon (Gl) and secretin (Se) inhibit water and electrolyte transport in the human jejunum (abstr). Gastroenterology 62:782, Cooper H, Levitan R, Fordtran JS, et al: A method for studying absorption of water and solute from the human small intestine. Gastroenterology 50:1-7, Soergel KH: Intestinal perfusion studies: values, pitfalls, and limitations. Gastroenterology 61 : , Hyden S: A turbimetrjc method for the determination of higher polyethylene glycols in biological materials. K Lantbruks-Hogskol Ann 22: , Malawer SJ, Powell DW: An improved turbimetric analysis of polyethylene glycol utilizing an emulsifier. Gastroenterology 53: , Field M, Fromm D, Wallace CK, et al: Stimulation of active chloride secretion in small intestine by cholera exotoxin. J Clin Invest 48:24a, Al-Awaqti Q, Cameron JL, Field M, et al: Response of human ileal mucosa to choleragen and theophylline. J Clin Invest 49:2a, Kimberg DV, Field M, Johnson J, et al: Stimulation of intestinal mucosal adenyl cyclase by cholera exotoxin and prostaglandins. J Clin Invest 50: , Field M: Intestinal secretion: effect of cyclic AMP and its role in cholera. N Engl J Med 284: , 1971

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