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Role of Endogenous Secretin in Acid-Induced Inhibition of Human Gastric Function

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Role of Endogenous Secretin in Acid-Induced Inhibition of Human Gastric Function Role of endogenous secretin in acid-induced inhibition of human gastric function. J H Kleibeuker, … , V E Maxwell, J H Walsh J Clin Invest. 1984;73(2):526-532. https://doi.org/10.1172/JCI111239. Research Article The role of secretin in the inhibition of gastric acid secretion that occurs during acidification of the gastric lumen was studied in nine healthy men. Gastric acid secretion was stimulated by 500-ml meals of 8% peptone solution, and the pH of the stomach was maintained at 5.5, 2.5, or 2.0 by intragastric titration. The increase in plasma secretin was measured, after extraction, by a new secretin radioimmunoassay. After determining the intravenous dose of secretin required to reproduce plasma secretin concentrations achieved during pH 2.5 and 2.0 meals, similar doses were given during administration of a pH 5.5 peptone meal. The doses of secretin led to plasma secretin concentrations that averaged 3.4 pM, not different from the 3.2 and 3.9 pM concentrations achieved during acidified meals. However, exogenous secretin infusion failed to inhibit acid secretion or gastrin response to peptone, although significant inhibitions occurred in both during peptone meals given at pH 2.5 or 2.0. When secretin infusions were given at fivefold higher rates, plasma gastrin responses again failed to demonstrate significant inhibition. Gastric emptying was inhibited significantly by both acidified peptone meals but only slightly (P = 0.053) during exogenous infusion of physiologic secretin doses. The decrease in acid secretion could be explained by decreased gastrin release, but neither of these findings could be explained by circulating secretin concentrations. These […] Find the latest version: https://jci.me/111239/pdf Role of Endogenous Secretin in Acid-induced Inhibition of Human Gastric Function J. H. Kloibeuker, V. E. Eysselein, V. E. Maxwell, and J. H. Walsh Center for Ulcer Research and Education, Veterans Administration Wadsworth Hospital Center, Los Angeles California 90073; University of California, Los Angeles, California 90024 A bstract. The role of secretin in the inhibition Introduction of gastric acid secretion that occurs during acidification of the gastric lumen was studied in nine healthy men. Secretin is released by endocrine cells in the mucosa of the Gastric acid secretion was stimulated by 500-ml meals duodenum and upper jejunum when the intraduodenal pH falls of 8% peptone solution, and the pH of the stomach was below 3 to 4 (1-3). The amount of secretin released probably is dependent on the total amount of titratable acid delivered to maintained at 5.5, 2.5, or 2.0 by intragastric titration. the duodenum. It is now generally accepted that secretin is a The increase in plasma secretin was measured, after ex- physiologic stimulant of pancreatic water and bicarbonate se- traction, by a new secretin radioimmunoassay. After de- cretion (4, 5). Whether it has any other function has not yet termining the intravenous dose of secretin required to been established. Exogenous secretin in supraphysiologic doses reproduce plasma secretin concentrations achieved during inhibits acid secretion and gastrin release, basally as well as in pH 2.5 and 2.0 meals, similar doses were given during response to a variety of stimuli (6-10). administration of a pH 5.5 peptone meal. The doses of Recent studies in the dog (1 1, 12) indicate that secretin is secretin led to plasma secretin concentrations that av- a physiologic inhibitor ofgastric acid secretion and gastrin release. eraged 3.4 pM, not different from the 3.2 and 3.9 pM So far, this has not been reported in man. A recent study (13) concentrations achieved during acidified meals. However, showed that secretin in low doses inhibits the gastric emptying exogenous secretin infusion failed to inhibit acid secretion of liquid meals in humans. We have found that inhibition of peptone-stimulated acid secretion at low intragastric pH was or gastrin response to peptone, although significant in- due entirely to inhibition of gastrin release (14). hibitions occurred in both during peptone meals given We used a newly developed radioimmunoassay for secretin at pH 2.5 or 2.0. When secretin infusions were given at to study whether circulating secretin is a mediator of this acid- fivefold higher rates, plasma gastrin responses again failed induced inhibition of gastrin release and acid secretion. In ad- to demonstrate significant inhibition. Gastric emptying dition, we studied the gastric emptying rate. was inhibited significantly by both acidified peptone meals but only slightly (P = 0.053) during exogenous infusion of physiologic secretin doses. The decrease in acid secre- Methods tion could be explained by decreased gastrin release, but Nine healthy male subjects (mean age 38 yr, range 20-69 yr) without neither ofthese findings could be explained by circulating previous gastric or duodenal disorders were studied. All gave written secretin concentrations. These results cast strong doubt informed consent. The study was approved by the Human Studies Com- on a physiological role of secretin in inhibition of acid mittee at Veterans Administration Wadsworth Center. After an overnight secretion in man. fast a nasogastric tube (AN 10, Andersen Samplers Inc., Atlanta GA) was passed into the stomach. The position of the tube was checked by a water-recovery (15) test and, if necessary, by fluoroscopy. After complete Address reprint request to Dr. John H. Walsh, Veterans Administration emptying ofthe stomach by aspiration, 500 ml ofa liquid meal, containing Wadsworth/CURE, Veterans Administration Wadsworth Hospital Cen- 8% peptone (wt/vol) (Bacto Peptone, Difco Laboratories, Inc., Detroit, ter, Bldg. 115, Room 217, Los Angeles, CA 90073. MI), was instilled intragastrically and acid secretion was measured during Received for publication 23 August 1983 and in revised form 24 I h by automated intragastric titration (16). During the test the volume October 1983. of the intragastric contents was measured at 5, 15, 30, 45, and 60 min, using the dye-dilution technique (17). Phenol red was used as marker. The Journal of Clinical Investigation, Inc. Its concentration was measured spectrophotometrically at pH 1 1, at a Volume 73, February 1984, 526-532 wavelength of 560 nm (Model DU, Beckman Instruments, Inc., Fullerton, 526 J. H. Kleibeuker, V. E. Eysselein, V. E. Maxwell, and J. H. Walsh CA). The duodenal acid load during meals at low pH was calculated containing 0.425% sodium chloride (wt/vol) and 2% Plasmanate (human according to Gross et al. ( 18). Titratable acid of the gastric contents was plasma protein fraction, Cutter Laboratories, Inc., Emeryville, CA). The measured by titration to pH 7. flow rate was I ml/min, and 2-ml fractions were collected. From the Before and during tests blood samples were taken through a needle first peak the fractions with the highest radioactivity were pooled, and, in the antecubital vein for measurement of plasma gastrin and secretin for further purification, applied to a SP-Sephadex C-25 column, 20 concentrations. Samples were collected in standard EDTA-containing X I cm, eluted with the same buffer as the first column, but with a tubes (10.5 mg/tube) to which 200 Ml Trasylol (aprotinin), 10,000 KIU/ concentration gradient from 0.05 to 0.1 M in 0.85% NaCl over 12 h, ml (Bayer AG, Bayerwerk, FRG) per 5 ml blood was added. Samples at a flow rate of 0.2 ml/min. Fractions of 2 ml were collected. From were refrigerated immediately after collection, centrifuged within 30 the second high peak the fractions with the highest radioactivity, con- min, and the plasma was stored at -20'C until radioimmunoassays taining the purified label, were pooled and after addition of0.5% Trasylol, were performed. 10,000 KIU/ml, (vol/vol), divided in 250-Ml portions, which were stored For secretin infusion pure natural porcine secretin (manufactured at -20'C until use. Each portion was used for only one assay. Fractions by Kabi Vitrum AB, Stockholm, Sweden) dissolved in 0.15 M NaCl, preceding and following the labeled antigen containing peak were assayed containing 0.25% human serum albumin (wt/vol), was used. The infusion to identify unlabeled secretin. was administered through a needle in the other arm. A small portion The specific activity of the label was determined by comparing the of each infusion solution was stored at -20'C for measurement of the displacement of a known amount of labeled antigen by doubling amounts secretin concentration. The biologic activity of the secretin was tested of the same label and known amounts of standard secretin. by infusing increasing doses intravenously in a dog with a chronic pan- The immunoreactivity was determined by comparing serial dilution creatic fistula after an overnight fast, and measuring pancreatic secretion curves of the labeled secretin and standard secretin, and by determining in respect to volume and bicarbonate contents. Gastrin plasma con- the binding of label to an excess amount of antibody (titer 1:5,000). To centrations were measured with a specific radioimmunoassay as pre- each assay tube 2,000 cpm of label in 200 Ml were added. Counting time viously described (19), using antibody 161 1. was I min. Secretin plasma levels were measured with a newly developed ra- Standard secretin. Squibb synthetic secretin was used as standard. dioimmunoassay. The dry powder was dissolved in the assay buffer to a concentration of Antibody. Secretin antibodies were raised in rabbits, using synthetic I nmol/ml. 250-Ml portions of this solution were stored at -20'C, each secretin (E. R. Squibb & Sons, Princeton, NJ) as antigen. The secretin portion to be used for only one assay. was conjugated to bovine serum albumin with carbodiimide as described Assay conditions. The incubation volume was I ml. The assay buffer earlier (19). The conjugation product was emulsified with complete was 0.05 M ammonium acetate (J.
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