Inhibition by secretin of the gastric acid responses to meals and to pentagastrin in duodenal ulcer patients

The inhibitory effects of intravenous secretion on the gastric acid responses to a meal and to pentagastrin were studied in seven duodenal ulcer patients.

A test meal of 10% peptone adjusted to pH 5·0 was introduced into the stomach and the Fordtran and Walsh method was used to measure the gastric acid output by monitoring the rate at which a solution of 0·3 M sodium bicarbonate had to be added to keep the pH of the gastric content constant at the value of 5·0. A constant dose of secretin (1 U/kg-hr) significantly depressed the serum gastrin response to a meal and produced an inhibition of acid secretion by about 70% of the control level. Secretin inhibited the acid response induced by pentagastrin by about 60% and simultaneously provoked a pancreatic bicarbonate output sufficient to neutralize about 60% of the gastric acid output to pentagastrin. We conclude that secretin is a strong inhibitor of gastric secretion in duodenal ulcer patients induced by a meal and by pentagastrin.

     

Inhibition of bombesin-stimulated gastric acid secretion by secretin, glucagon and caerulein in patients with duodenal ulcer.

The inhibitory effects of intravenous infusions of secretin, glucagon and caerulein on the gastric acid response to bombesin were studied in 8 duodenal ulcer patients. Bombesin was found to be a very potent stimulator of gastric acid secretion in patients with duodenal ulcer. There were no significant differences in acid outputs per 15-min period between bombesin infused in a dose of 0.9 microgram/kg/h and pentagastrin infusion administered in a maximal dose, at a rate of 6.0 microgram/kg/h. Secretin (1 U/kg/h), glucagon (30 microgram/kg/h) and caerulein (0.1 microgram/kg/h) produced significant decreases in gastric acid secretion evoked by bombesin given in a dose of 0.9 microgram/kg/h. Percentages of inhibition were 48.6, 45.2 and 35.5, respectively. It is supposed that secretin and glucagon given in pharmacological doses are capable of interfering with the action of gastrin released from antrum by means of bombesin on the parietal cell by noncompetitive kinetics. Caerulein administered in a pharmacological dosis, however, can inhibit the effect of gastrin released by bombesin on the parietal cells by a competitive kinetic.     

Selective inhibition of pentagastrin- and cholecystokinin-stimulated exocrine secretion by proglumide

The effectiveness and selectivity of proglumide, a putative cholecystokinin/gastrin receptor antagonist in vitro, were examined on gastric acid and pancreatic secretion in vivo. Gastric secretion was measured in conscious dogs in the basal state and during infusion of pentagastrin, histamine, or bethanechol, alone or in combination with proglumide (300 mg/kg . h). Pancreatic secretion was measured in anesthetized rats in response to cholecystokinin-octapeptide or secretin, alone or in combination with proglumide (100 mg/kg). Proglumide inhibited pentagastrin-stimulated secretion but had no effect on basal, histamine-stimulated, or bethanechol-stimulated gastric acid secretion. Inhibition of pentagastrin-stimulated secretion was of the competitive type. An apparent inhibitory constant was calculated to be 300 mg/kg . h; this dose is capable of eliciting plasma concentrations of approximately 1 mM. This estimate corresponds closely to that derived from measurements in isolated canine parietal cells. Proglumide also inhibited cholecystokinin-stimulated but not secretin-stimulated pancreatic secretion. The lack of effect of proglumide on basal, histamine-stimulated, or bethanechol-stimulated gastric acid secretion implies that background gastrin has no direct or synergistic influence on stimulation by other secretagogues. The selective effect of gastrin receptor antagonists contrasts with the effectiveness of muscarinic and histamine H2-receptor antagonists against secretion induced by all types of stimulants. Accordingly, the antisecretory potential of gastrin receptor antagonists is confined to digestive secretion when the effect of gastrin is optimal. Their potential as antitrophic agents in duodenal ulcer disease, however, has not been explored yet.     

Serum gastrin and gastric acid responses to meals at various pH levels in man

Serum gastrin and gastric acid responses to a test meal of 10% peptone were measured in six duodenal ulcer patients using intragastric titration at pH levels ranging from 5.5 to 1.0. In this way the pH profile for inhibition of serum gastrin release and gastric acid secretion was established. A peptone meal adjusted to pH 5.5 produced gastric acid similar to the maximal response to histamine. A graded decrease of pH of the peptone meal to 1.0 resulted in the progressive inhibition of the gastric acid secretion and the concomitant suppression of the serum gastrin level. Exogenous secretin given in graded doses ranging from 0.25 to 2.0 U/kg-hr caused a dose-related inhibition of gastric acid secretion and the suppression of serum gastrin level. The results of the study indicate that gastric acid secretion and the rise in serum gastrin levels in response to an experimental meal are less when the gastric contents become more acid. The mechanism may involve release of secretin from the small intestine by acid.     

Effect of somatostatin on meal-induced gastric secretion in duodenal ulcer patients

The effect of somatostatin, a growth hormone release-inhibiting hormone (GH-RIH), on basal and meal-, pentagastrin-, or histamine-stimulated gastric acid and pepsin secretion was studied in six duodenal ulcer patients. Intravenous GH-RIH infused in graded doses ranging from 0.62 to 5.0 μg/kg/hr produced a dose-related inhibition of pentagastrin-induced acid secretion reaching about 15% of control level at the dose of 5.0 μg/kg/hr. Acid inhibition was paralleled by a decrease in the pepsin output and accompanied by a dosedependent reduction in serum growth hormone and insulin levels measured by radio-immunoassay. GH-RIH used in a single dose of 2.5 μg/kg/hr produced about 85% inhibition of acid secretion induced by a meal (measured by intragastric titration) accompanied by a significant decrease in serum gastrin and insulin levels. The effect of GH-RIH on histamine-stimulated secretion was very modest and observed only after stopping the GH-RIH infusion. Thus GH-RIH suppressed acid and pepsin secretion induced by pentagastrin and a meal, and this effect was accompanied by a suppression of serum growth hormone and gastrin levels which may contribute to the inhibition of gastric secretion observed.     

Effect of secretin and jejunal acidification on gastric and pancreatic secretion in man

The inhibitory effect of intravenous secretin and intrajejunal acid infusion on basal and pentagastrin-induced gastric acid secretion as well as the stimulatory influence of both infusions on pancreatic flow rate and bicarbonate output were compared in two groups of healthy subjects.

Secretin strongly inhibited basal acid output and slightly decreased pentagastrin induced gastric secretion.

Intrajejunal acid infusion did not affect the gastric secretion but resulted in an increase in pancreatic volume flow and bicarbonate output reaching about 40% of the pancreatic response to secretin¹ infused intravenously in a dose of 2 units per kilogram per hour.

It is concluded that this provides evidence that secretin is a strong inhibitor of spontaneous gastric acid secretion and that acid in the jejunum causes the release of secretin in man.

     

The effect of 16,16-dimethyl prostaglandin E2 on meal-stimulated gastric acid secretion and serum gastrin in duodenal ulcer patients.

The effect of intragastric and intraduodenal 16,16-dimethyl prostaglandin E2 (dm PGE2) on meal-stimulated gastric acid secretion and gastrin release was studied in patients with inactive duodenal ulcer. Compared to placebo, doses of 0.75, 1.00, 1.33, and 1.77 mug per kg of dm PGE2 instilled into the stomach inhibited meal-stimulated gastric acid secretion by 61 to 94% (P less than 0.01). The 1.00, 1.33, and 1.77 mug per kg doses inhibited acid secretion significantly (P less than 0.05) more than an optimal dose of propantheline bromide. Intragastric dm PGE2 (1 mug per kg) was significantly (P less than 0.05) more effective than intraduodenal dm PGE2 (1 mug per kg) in inhibiting both gastric acid secretion and gastrin release. After 1.33 and 1.77 mug per kg, some patients experienced abdominal cramps, or diarrhea, or both, but at doses of 1.00 mug per kg or less no apparent untoward side effects were observed. It is concluded that 16,16-dm PGE2 significantly inhibits meal-stimulated gastric acid secretion and gastrin release, and may be of therapeutic value in patients with peptic ulcer provided it is free of untoward side-effects with chronic administration.     

Postprandial Pancreatic Secretion and Plasma Hormones in Dogs with Pancreatic Fistula

The responses of exocrine pancreas, plasma secretin, and gastrin to a test meal were studied in six dogs prepared with gastric and duodenal fistulas. The experiment was doubly repeated in each dog. Pancreatic juice was diverted to the exterior by direct cannulation into the major pancreatic duct. Volume, bicarbonate, and protein secretion of pancreatic juice were rapidly increased and then gradually reduced after the ingestion of the meal. Plasma secretin concentration reached a peak at 25 min after the ingestion of the meal and remained higher than the basal level for about 3 h. Plasma gastrin concentration rapidly reached a higher plateau which lasted for 40 min after the load of the test meal. A close correlation was observed between bicarbonate secretion and the increment in plasma secretin concentration and between protein secretion and the increment in plasma gastrin concentration. When pancreatic juice is diverted to the exterior, endogenously released secretin and gastrin appear to play an important role in postprandial pancreatic secretion.     

Secretin is an enterogastrone in humans

We studied in humans the effect of exogenous secretin in a physiological dose on gastric acid secretion stimulated by pentagastrin and postprandial plasma gastrin concentration. Two doses of pentagastrin, 80 and 160 pmol/kg/hr were used to stimulate gastric acid secretion. Secretin in two doses, 2.8 and 5.6 pmol/kg/hr were tried to study the response on stimulated gastric acid secretion. Intravenous secretin in a dose of 5.6 pmol/kg/hr significantly inhibited the gastric acid output stimulated by intravenous pentagastrin in a dose of 160 pmol/kg/hr, from 11.25±1.5 to 5.99±1.34 meq/hr, while lower dose of intravenous secretin (2.8 pmol/kg/hr) failed to inhibit the gastric acid output stimulated by the same dose of pentagastrin. However, the lower dose of intravenous secretin (2.8 pmol/kg/hr) inhibited the gastric acid output significantly from 8.78±1.21 to 6.37±1.62 meq/hr when gastric secretion was stimulated by the lower dose of pentagastrin (80 pmol/kg/hr). The plasma concentrations of secretin during intravenous secretin in a dose of 2.8 pmol/kg/hr was similar to postprandial plasma concentrations of secretin as previously reported. Doubling the dose of intravenous secretin resulted in almost twofold higher plasma concentrations than postprandial plasma concentrations. In addition, the low dose of secretin (2.8 pmol/kg/hr) suppressed the integrated postprandial gastrin response from 13.9±3.7 to 11.2±2.8 ng/min/ml (P=0.05) when endogenous release of secretin was blocked by intravenous cimetidine. Since the dose of pentagastrin and secretin employed in this study fell in a physiologic range, the inhibitory effect of secretin on stimulated gastric acid secretion appears to be a physiologic action in humans. Contrary to the findings in dogs, the inhibitory action of secretin on gastrin release was not statistically significant but was highly suggestive.     

Effect of gastric vagal denervation on inhibition of acid secretion by secretin

In dogs with vagally innervated gastric pouches and gastric fistulas, acid secretion was stimulated by intravenous administration of Urecholine, 0.025 and 0.1 (mg/kg)/hr; of pentagastrin, 4 (µg/kg)/hr; or by feeding a meal of liver and bone dust, 25 g/kg. Acid secretion elicited by these stimulants was significantly inhibited (P<0.05 to 0.001) by intravenous infusion of secretin, 2 (units/kg)/hr. With Urecholine, 0.1 (mg/kg)/hr, comparable inhibition resulted from endogenous duodenal acidification which was produced by closing the gastric fistula. The pouches were then vagally denervated by cutting the muscular connection, and dividing the septum between pouch and main stomach; all tests were repeated. Vagal denervation decreased the stimulatory potency of feeding and pentagastrin, but increased Urecholine-stimulated acid output. This increased sensitivity of parietal cells to a cholinomimetic stimulus after vagal denervation is an example of Cannon's law of denervation supersensitivity. Inhibition of Urecholine-stimulated secretion by duodenal acidification was not significantly modified by vagal denervation (40% inhibition before, 38% after). Percentage inhibition of acid output by secretin was slightly increased after vagal denervation when the stimulant was Urecholine (42% inhibition before, 52% after) or pentagastrin (63% inhibition before, 73% after), but these changes were not statistically significant. Vagal denervation markedly increased the degree of inhibition of food-stimulated secretion (20% inhibition before, 71% after), suggesting that secretin is primarily an antagonist of gastrin.Supported by Veterans Administration Research Funds and by USPHS Grant AM 8354.     

Abnormal pancreatic polypeptide release by secretin infusion in Zollinger-Ellison syndrome

In 28 patients with the Zollinger-Ellison syndrome (ZES), 26 studied before and two after tumor excision, and in 26 age-matched control patients with duodenal ulcer (DU), plasma pancreatic polypeptide and serum gastrin concentrations were studied before, during, and after infusion of pure secretin (3 CU/kg/hr). In 21 ZES patients, gastric acid output was simultaneously studied. Fasting pancreatic polypeptide concentrations were over 300 pmol/liter in five of 26 gastrinomas. In DU, secretin caused a nonsignificant increase in plasma pancreatic polypeptide concentration and markedly decreased gastric acid output. In ZES, however, it resulted in a marked increase of both plasma pancreatic polypeptide concentration and gastric acid output. Basal and post secretin pancreatic polypeptide concentrations showed no correlation with gastric acid output, serum gastrin levels, or the age of the subjects, in DU patients as well as in ZES. These concentrations were not different in ZES patients who had a vagotomy compared to nonvagotomized ZES patients. Furthermore, the pancreatic polypeptide response to intravenous secretin was abolished by gastrinoma excision.A portion of this work has appeared in abstract form (Gastroenterology 82:1161, 1982) and was presented at the Annual Meeting of the American Gastroenterological Association, Chicago (Illinois), on May 18, 1982.     

Stimulation of Biliary Secretion by Duodenal Acidification and Secretin

The volume and bicarbonate output of hepatic bile was observed in chronic biliary fistula dogs during intravenous infusion of varying doses of secretin or intraduodenal introduction of varying loads of acid. Secretin and acid produced a dose-related increase in bile flow and in bicarbonate output reaching a maximum at the dose of 16 units per kg per hr of secretin and 32 mEq per hr of acid. The maximal volume and bicarbonate output with secretin was about 25% higher than with acid. Closing the gastric fistula during the maximal gastric acid response to histamine or pentagastrin and thus permitting the gastric acid to pass the duodenum, resulted in the increase in bile flow and bicarbonate output comparable to that obtained with exogenous duodenal acidification.     

The role of secretin in the inhibition of gastric secretion by intraduodenal acid

The effect of intraduodenal acid on pentagastrin-stimulated gastric secretion has been investigated in 12 normal subjects and 23 patients with chronic duodenal ulceration. Plasma secretin levels were monitored during each test using a highly sensitive radioimmunoassay.Significant inhibition of gastric secretion occurred in the normal subjects and duodenal ulcer patients. A significant rise in plasma secretin was observed in both groups after intraduodenal acid though there was a complete lack of correlation between the magnitude of the secretin response and the degree of gastric inhibition. Ten subjects received intraduodenal acid and a subsequent intravenous infusion of exogenous secretin (0.125-0.25 units/kg over six minutes). Gastric inhibition occurred after the acid instillation but not after secretin infusion despite plasma secretin levels greatly in excess of those produced by intraduodenal acid.These results suggest that release of secretin by itself cannot explain the gastric inhibitory response to intraduodenal acid in man.     

Effect of low-dose exogenous secretin on pentagastrin- and meal-stimulated gastric acid secretion in humans

Intravenous infusion of secretin in a dose of 0.05 CU/kg/hr inhibited pentagastrin-stimulated (100 ng/kg/hr) acid secretion by 42% (P<0.05) abd meal-stimulated (10% peptone, pH 5.5) acid secretion by 33% (P<0.05) in 10 healthy subjects. Median serum gastrin concentration during peptone stimulation was reduced by 24% (P<0.05) during secretin infusion. Median plasma secretin concentrations were 6.0 and 5.2 pmol/liter, respectively. Since these secretin concentrations are of the same magnitude as those seen after duodenal acidification, it is concluded that secretin may participate in the physiological inhibition of gastric acid secretion.Supported by grant 12-4525, Danish Medical Research Council     

Simultaneous Changes in Pancreatic and Gastric Secretion Induced by Acute Intravenous Ethanol Infusion

The simultaneous effects of acute i.v. ethanol administration (1.3 gm./kg.) on pancreatic and gastric acid secretion was studied on dogs provided with chronic pancreatic and gastric fistulas (Thomas cannula) and subjected to a continuous i.v. injection of GIH secretin (0.5 CU./kg./hr.) and gastrin (Eurorga hog gastrin I-II, 6 gamma/kg./hr.). Acute i.v. ethanol inhibits the pancreatic secretion of protein (concentration and output) and stimulates gastric acid secretion. Experiments were repeated: 1. Superimposing an atropine infusion (1.0 mg./hr.) on the continuous hormonal perfusion. 2. After reserpine administration for 48 hours (0.10 mg./kg./24 hr.) Atropine abolished the ethanol-mediated inhibition of pancreatic protein secretion but did not prevent the alcohol-mediated gastric acid stimulation. Reserpine did not change the ethanol-mediated pancreatic inhibition. It is assumed that in nonalcoholic dogs, i.v. ethanol inhibits pancreatic secretion by an intermediate nervous mechanism and enhances gastric acid secretion by acting directly on the oxyntic cells. Reserpine induces a high plateau level of HCl secretion which obscures the ethanol-mediated excitatory influences on the oxyntic cells.     

Effect of duodenal fat on plasma levels of gastrin and secretin and on gastric acid responses to gastric and intestinal meals in dogs.

The effects of duodenal instillation of sodium oleate (10 mmoles per hr) on plasma levels of gastrin and secretin and on gastric acid secretion in response to gastric and intestinal meals were determined. Four dogs prepared with a septum between stomach and duodenum were provided with a special cannula that allowed separate access to the stomach or duodenum. Each dog received a 10% liver extract meal introduced either into the stomach (gastric phase) or into the duodenum (intestinal phase). Sodium oleate administered during the gastric phase caused approximately a 30% reduction in plasma gastrin level and a 25% inhibition of gastric acid secretion. Sodium oleate given during the intestinal phase completely abolished the plasma gastrin response and resulted in a 75% inhibition of gastric acid secretion. Plasma secretin levels were not changed during the gastric phase or the intestinal phase by instillation of sodium oleate. These results show that fat in the duodenum is a potent inhibitor of gastrin release and gastric acid secretion; the intestinal mechanism involved does not appear to affect plasma secretin concentrations.     

Effects of physiological increases of plasma noradrenaline on gastric acid secretion and gastrointestinal hormones

It is not known if the increased plasma concentration of noradrenaline in patients with chronic duodenal ulcer disease is a pathogenetic factor or not. The aim of the present study was to investigate if physiologic changes of noradrenaline would evoke any alterations in gastric acid secretion or in the plasma concentration of some gastrointestinal hormones (gastrin, secretin, PP, PYY, and GIP) known to affect gastric physiology. The results show that basal plasma noradrenaline concentration was 1.8 nM and after infusion with noradrenaline at 0.04 or 0.2 nmol/kg/min plasma levels of 2.5 and 4.4 nM were obtained. No appreciable changes could be found in basal or pentagastrin stimulated acid secretion or in any of the gastrointestinal peptides studied. If the elevated plasma noradrenaline concentration observed in duodenal ulcer patients is a pathogenetic factor; it is probable that it interferes with other variables such as blood flow, bicarbonate secretion, or prostaglandin synthesis.Grant support was from the Medical Faculty, University of Lund and the Segerfalk Foundation.     

Sequential somatostatin and gastrin releases in response to secretin in rat in vivo.

Secretin in known to inhibit gastric acid secretion. Exogenous secretin has also been shown to have a biphasic effect on acid secretion, being stimulatory then inhibitory. To explain this effect, we studied the timing of gastrin, somatostatin, and HCl releases in the gastric lumen in response to an i.v. bolus of secretin (360 pmol) or saline in conscious rats provided with a chronic double gastric fistula and having had or not antrectomy. After secretin but not saline, an immediate and transient increase in acid and gastrin secretions was first observed. After a 4 min lag, a dramatic increase in somatostatin secretion was then observed, together with a 90 percent inhibition of acid secretion and a return of gastrin release to basal level. Twenty min after secretin administration, a rebound increase in acid and gastrin outputs occurred, whereas somatostatin output returned to basal level. The secretin-induced somatostatin release was higher in rats with antrectomy than in those without antrectomy suggesting that the observed somatostatin output mostly originated from the fundus. This present study suggests that a bolus of secretin induced a gastrin release and thus could stimulate acid secretion. These pharmacological findings could provide an explanation for the so-called paradoxical secretin-induced stimulation of gastrin secretion in particular conditions.     

Atropine abolishes the potentiation effect of secretin and cholecystokinin-octapeptide on exocrine pancreatic secretion in humans

Potentiating action between secretin and cholecystokinin on exocrine pancreatic secretion of bicarbonate has been well recognized. In the present study, we studied the effect of atropine on potentiating action on pancreatic exocrine secretion stimulated by exogenous secretin in physiologic dose and cholecystokinin-octapeptide in humans. Using a dye-dilution technique and a duodenal triple-lumen tube, pancreatic secretion of both bicarbonate and trypsin was determined while gastric juice was completely aspirated. Secretin given i.v. in a dose of 2.7 pmol/kg/h, which was known to achieve a similar plasma concentration of secretin after meal in humans, and cholecystokinin-octapeptide 26.2 pmol/kg/h potentiated pancreatic secretion of bicarbonate but not the pancreatic trypsin output. Atropine given i.v. in a dose of 1 mg/h abolished the potentiation effect of the two hormones on pancreatic bicarbonate output. Since the inhibitory effect of atropine on the secretin-stimulated bicarbonate output was statistically significant, the major inhibitory effect of atropine on the potentiation of pancreatic bicarbonate secretion appears to be its effect on the action of secretin.     

Intestinal phase of gastric secretion in patients with duodenal ulcer

In 10 healthy subjects and 10 duodenal ulcer patients the intestinal phase of gastric acid secretion was studied by intraduodenal infusion of a 10% liver extract meal (pH 7) at 400 ml/h for three hours. A gastroduodenal double lumen tube with two balloons was used to block the pylorus and to prevent duodenogastric reflux. Gastric acid response to a duodenal meal of liver extract reached a peak at the end of the first hour of infusion of the extract and was then followed by a relatively well-sustained plateau. When the figure was normalised as a percentage of peak response to pentagastrin it was about 45% in healthy subjects and 63% in duodenal ulcer patients. Serum gastrin concentration increased significantly during a duodenal meal of liver extract only in duodenal ulcer patients and not in healthy subjects. The combination of the duodenal meal of liver extract with pentagastrin infusion resulted in a significantly greater increase in acid output in duodenal ulcer patients than in healthy controls. Duodenal perfusion with a liver extract meal in which the pH was gradually decreased caused a pH-dependent reduction in acid output, but not in serum gastrin, both in the duodenal ulcer patients and in healthy subjects. This study shows that the intestinal phase in man results in a potent gastric acid stimulation which is pH-dependent, greatly augmented by pentagastrin, and more vigorous in duodenal ulcer patients than in healthy controls.