Janina Tasler

EFFECT OF GROWTH HORMONE RELEASE-INHIBITING HORMONE ON GASTRIC SECRETION, MUCOSAL BLOOD FLOW, AND SERUM GASTRIN

In dogs with gastric fistulae and Heidenhain pouches (HP) growth hormone release-inhibiting hormone (GH-RIH) infused intravenously in a dose of 2.5 mug per kg per hr inhibited almost completely acid and pepsin responses to pentagastrin, Urecholine, and a peptone. Histamine-induced acid secretion was more resistant to the inhibition by GH-RIH, and only acid secretion evoked by the lower doses of histamine was suppressed by this peptide. The inhibition of pentagastrin-induced gastric secretion was associated with a marked reduction in mucosal blood flow. The ratio of aminopyrine concentration in the gastric juice and blood plasma was not significantly changed by GH-RIH, indicating that the reduction in mucosal blood flow was secondary to an inhibition of gastric secretion. Gastric acid and serum gastrin responses to a peptone meal adjusted to pH 5.0 and kept in the main stomach at this same pH by intragastric titration were significantly decreased by GH-RIH, indicating that the observed acid inhibition could be attributed at least in part to the suppression of gastrin release. GH-RIH inhibited acid secretion from HP stimulated by liver extract in HP. The finding that GH-RIH inhibits gastric secretion induced by exogenous stimulants as well as by the direct chemical stimulation of the HP mucosa without changing serum gastrin level suggests that the major action of GH-RIH is a direct suppression of the oxyntic glands.

Effect of growth hormone-release inhibiting hormone on hormones stimulating exocrine pancreatic secretion.

The nature and extent of growth hormone-release inhibiting hormone (GH-RIH, somatostatin)-induced inhibition of pancreatic secretion of bicarbonate and protein, an index of enzyme secretion, were studied by administration of exogenous secretin or cholecystokinin (CCK) and of a number of stimulants for endogenous release of these hormones in fasted pancreatic fistula dogs with and without an infusion of GH-RIH. The results of this study show that GH-RIH inhibits the pancreatic fluid and bicarbonate secretion induced by duodenal acidification and exogenous secretion. The kinetic analysis shows that the interaction between GH-RIH and secretin affecting pancreatic bicarbonate secretion possesses the characteristics of competitive inhibition. GH-RIH does not change the pancreatic protein response to exogenous CCK, but profoundly inhibits pancreatic response to a variety of the endogenous stimulants of CCK release, including duodenal perfusion of sodium oleate, amino acid mixture, or feeding of a peptone meal. We conclude that GH-RIH is a very potent inhibitor of the endogenous release of CCK from the intestinal mucosa and inhibits competitively the action of secretin but not CCK on the exocrine pancreatic secretion.

Effect of atropine on pancreatic responses to endogenous and exogenous cholecystokinin

The role of cholinergic innervation in endogenous release of cholecystokinin from the intestinal mucosa and in exocrine pancreatic secretion was examined by means of atropine administration in 3 chronic gastric-fistula and pancreatic-fistula dogs during pancreatic responses to various rates of intraduodenal amino acid mixture and to various doses of intravenous cholecystokinin producing equal rates of pancreatic protein secretion. Atropine infused in a dose of 100 µg/kg-hr caused a deep and prolonged decrease in pancreatic flow rate, protein and bicarbonate output, reaching a maximum of about 80% of the pre-atropine level of pancreatic secretion. The inhibition occurred regardless of the level of pancreatic response examined. Atropine also caused an inhibition of pancreatic responses to smaller doses of exogenous cholecystokinin but did not affect responses to larger doses. The maximal observed pancreatic protein secretion in response to intraduodenal administration of amino acids was about 80% of the highest response to cholecystokinin. This study suggests that the release of cholecystokinin from the intestinal mucosa might be cholinergically dependent.

Effect of Metiamide, a Histamine H2-Receptor Antagonist, on Mucosal Blood Flow and Serum Gastrin Level

In dogs with gastric fistulae and vagally denervated Heidenhain pouches, metiamide, a histamine H2-receptor antagonist, infused intravenously in a dose of 12 μmoles per kg-hr, inhibited near maximal acid responses to histamine, pentagastrin, Urecholine, or a peptone meal. Atropine sulfate (0.12 μmole per kg-hr) did not significantly affect acid output induced by histamine, but was a more effective inhibitor of acid secretion stimulated by pentagastrin, Urecholine, or a peptone meal. Serum gastrin response to a peptone meal was unchanged by metiamide but partly suppressed by atropine. The inhibitory effect of metiamide was always associated with a marked reduction in mucosal blood flow. The ratio of aminopyrine concentration in the gastric juice and blood plasma was not significantly changed by metiamide, indicating that the persistent reduction in gastric mucosal blood flow was secondary to an inhibition of gastric secretion.

Characteristics of Inhibition of Pancreatic Secretion by Glucagon

The inhibition of cholecystokinin (CCK)-induced pancreatic secretion by glucagon was studied in four dogs with chronic pancreatic fistulas and open gastric fistulas. After establishing a constant level of secretion by intravenous infusion of CCK at a constant rate (doses: 3, 6, 12 and 24 U/kg/h) glucagon was given by constant intravenous infusion for 1 h in constant doses (6, 12, 25 and 50 μg/kg/h). From the dose response curves to CCK alone and CCK plus 25 μ/kg/h glucagon, the Michaelis-Menten analysis was typical of competitive inhibition, i.e., the calculated maximal response was similar and the dose required for half maximal response was different. Glucagon also inhibited pancreatic secretion elicited by intraduodenal instillation of a solution of L-tryptophan and L -leucine. It was concluded that glucagon inhibits the CCK-stimulated pancreatic secretion in the dog and that this inhibition is competitive.

Comparison of Telenzepine, Pirenzepine and Atropine on Gastric Acid and Pepsin Secretion in Response to Histamine, Pentagastrin, Bethanechol, Sham-Feeding and Feeding

This study was designed to compare gastric antisecretory effects of telenzepine, a new antimuscarinic agent, with those of pirenzepine and atropine in dogs. None of these antimuscarinics affected gastric acid secretion induced by histamine but all of them caused a dose-dependent inhibition of acid secretion from the gastric fistula (GF) and Heidenhain pouches (HP) stimulated by pentagastrin and bethanechol, telenzepine being 5-9 times more potent than pirenzepine and equipotent with atropine. All antimuscarinics were also effective inhibitors of acid responses to sham feeding and ordinary feeding. The inhibitory effect of telenzepine and pirenzepine were not accompanied by any major alterations in plasma gastrin or somatostatin but those of atropine were related to significant increase in plasma gastrin and to significant decrease in plasma somatostatin levels, suggesting the involvement of M2 receptors in the cholinergic control of these hormones. All three antimuscarinics were effective inhibitors of pepsin secretion induced both from the GF and HP by all secretagogues used. Neither telenzepine nor pirenzepine administered in various doses affected the heart rate while atropine caused a significant increase in heart rate confirming that the former agents are selective M1 receptor antagonists. This study provides evidence that telenzepine is more potent than pirenzepine in the inhibition of gastric secretion induced by pentagastrin, bethanechol, sham-feeding and ordinary feeding and that, unlike atropine, it does not increase plasma gastrin responses to meat feeding. In fact, telenzepine and pirenzepine alike reduced plasma gastrin concentrations under these conditions. No influence of these antimuscarinics on plasma somatostatin levels was observed.

COMPARISON OF AMINO ACIDS BATHING THE OXYNTIC GLAND AREA IN THE STIMULATION OF GASTRIC SECRETION

This study was undertaken to compare the ability of L- and D-isomers of amino acids bathing the oxyntic gland area to stimulate acid secretion in conscious dogs with Heidenhain pouch (HP), gastric fistula (GF) and pancreatic fistula (PF). Acid outputs from HP were determined by an intragastric titration method when amino acid solutions were perfused into HP at various concentrations, pH values, and distention pressures. Only L-isomers of all natural amino acids were found to stimulate acid secretion, whereas D-isomers of amino acids tested were completely inert in this respect. The comparison of the secretagogue activity of amino acids shows that L-histidine among essential amino acids and glycine among nonessential amino acids exhibited the strongest stimulation of acid outputs, reaching, respectively, 52 and 40% of the maximal response to histamine. Decreasing the pH of L-histidine solution perfused into HP in sequential order from 5.0 to 1.0 resulted in a stepwise reduction of acid output, falling at pH 1.0 to about 40% of the peak response achieved at pH 5.0. Local irrigation of HP by 2% xylocaine and intravenous infusion of atropine (100 mug per kg per hr) or metiamide (2.9 mg per kg per hr) reduced but did not abolish HP response to chemical stimulation and the pH dependency of this response. We conclude that only L- and not D-isomers of amino acids bathing the oxyntic gland area stimulate acid secretion by a local, gastrin-independent mechanism sensitive to distention pressure and pH.

Effect of atropine on pancreatic responses to endogenous and exogenous secretin

The role of cholinergic innervation in endogenous release of secretin from the intestinal mucosa, and in exocrine pancreatic secretion was examined by means of atropine administration in 4 chronic gastric-fistula and pancreatic-fistula dogs during pancreatic response to various doses of synthetic secretin and to various rates of intraduodenal acid load. Atropine infused in a dose of 100µg/kg/hr caused a deep and prolonged decrease of pancreatic flow rate and bicarbonate output reaching a maximum of about 70% of the pre-atropine level of pancreatic secretion. The inhibition occurred regardless of the level of pancreatic response examined, and no significant difference between the effects of atropine on pancreatic responses to exogenous and endogenous secretin was found. Intraduodenal infusion of atropine caused significantly greater inhibition of the pancreatic response to intestinal acidification than that to exogenous secretin. This suggests that release of secretin from the intestinal mucosa might be under the cholinergic control of local nerves.

Effect of Glucagon on Food-Induced Gastrointestinal Secretions

The action of glucagon on gastrointestinal secretion has been studied in two groups of 3 dogs each. The group-A dogs were prepared with gastric fistulas, Pavlov pouches and pancreatic fistulas, while the dogs in group B possessed only gastric fistulas and biliary fistulas. Glucagon infused intravenously in a dose of 25 μg/kg-h, during a steady state of half maximal secretory response to food caused a marked inhibition of acid secretion from Pavlov pouches and bicarbonate and protein secretion from pancreatic fistula. Biliary secretion was not affected by glucagon.

Pancreatic dose response to synthetic secretin and intraduodenal acid in dogs

In 6 dogs with chronic pancreatic fistulas, dose response curves to synthetic secretin and duodenal acidification were obtained for pancreatic volume flow, bicarbonate and chloride secretion. Secretin given intravenously in doses ranging from 0.125 to 2.0µg/kg/hr, either in graded doses on the same day or in single doses given on separate days, produced almost identical response curves. Synthetic secretin produced the highest mean volume flow, 47.0 ml/30 min, and bicarbonate output, 6.31 mEq/30 min, at the dose of 2.0µg/kg/hr. Maximal response to acid infused into the duodenum in the rate from 1 to 16 mEq/hr, either in graded amounts given in 1 days test or in single amounts given on separate test days, occurred at the rate of 8 mEq/hr. The maximal pancreatic response in tests with single amounts of acid was equal to the highest response to secretin, whereas in tests with graded amounts of acid, it was about 10% lower than the highest response to secretin.