Inhibition of Pentagastrin-induced Gastric Acid Secretion in Man by Glucagon Given Intravenously

The effect of 2 mg of glucagon given intravenously on the pentagastrininduced gastric acid secretion was studied in 8 patients with peptic ulcer disease. On the maximal acid output produced by pentagastrin glucagon induced a moderate but significant depression of the secretion. When a submaximal pentagastrin infusion of 0.0025 μg/kg/min was given, glucagon induced approximately a 50 % decrease of the gastric acid output. Glucagon inhibits the basal as well as the pentagastrin-stimulated gastric acid secretion, but not the secretion in response to a maximal dose of histamine.     

Effect of Somatostatin on Gastrointestinal Secretions and Peptic Ulcer Production in Cats

In conscious cats with chronic gastric and pancreatic fistulas, the effect of somatostatin (GH-RIH) on gastric and pancreatic secretion and peptic ulcer formation was examined. GH-RIH infused intravenously in graded doses (range: 0.62 to 5.0 μg/kg-hr) inhibited dose-dependently gastric acid response to pentagastrin but failed to affect acid response to histamine. GH-RIH caused a marked inhibition of pepsin secretion induced by both pentagastrin and histamine and decreased pancreatic bicarbonate but not protein response to exogenous secretin or intraduodenal acid. It effectively prevented the formation of duodenal ulcers produced by prolonged administration of both pentagastrin or histamine.     

Effect of somatostatin on gastrointestinal secretions and peptic ulcer production in cats.

In conscious cats with chronic gastric and pancreatic fisulas, the effect of somatostatin (GH-RIH) on gastric and pancreatic secretion and peptic ulcer formation was examined. GH-RIH infused intravenously in graded doses (range: 0.62 to 5.0 microng/kg-hr) inhibited dose-dependently gastric acid response to pentagastrin but failed to affect acid response to histamine. GH-RIH caused a marked inhibition of pepsin secretion induced by both pentagastrin and histamine and decreased pancreatic bicarbonate but not protein response to exogenous secretin or intraduodenal acid. It effectively prevented the formation of duodenal ulcers produced by prolonged administration of both pentagastrin or histamine.     

Effect of endogenous pancreatic glucagon on gastric acid secretion in patients with duodenal ulcer before and after parietal cell vagotomy.

The effect of endogenous pancreatic glucagon on submaximal pentagastrin stimulated gastric acid secretion was studied by infusion of 1-arginine in patients with duodenal ulcer before and after parietal cell vagotomy without drainage (PCV). Preoperatively infusion of 1-arginine resulted in a marked inhibition of acid secretion, whereas no effect was found postoperatively. Plasma glucagon concentrations were identical pre- and postoperatively, fasting as well as during arginine infusion. Serum gastrin concentration rose after PCV but not unaffected by arginine infusion both pre- and postoperatively. The study demonstrates that intact vagal innervation of the fundic glands is a condition of inhibition of pentagastrin induced acid secretion by pancreatic glucagon released by infusion of 1-arginine.     

Effect of calcitonin on gastric and pancreatic secretion and peptic ulcer formation in cats

In conscious cats with chronic gastric fistula and the diversion of bile and pancreatic juice to the jejunum, calcitonin (5 U/kg-hr) caused a marked inhibition of near maximal gastric acid response to pentagastrin and to histamine. In cats with chronic pancreatic fistula, calcitonin inhibited near maximal pancreatic response to exogenous secretin, caerulein, and duodenal acidification. Calcitonin prevented the formation of duodenal ulcers in cats infused with pentagastrin and histamine, for 36 hours. The antiulcer action of calcitonin can be attributed mainly to its inhibitory action on gastric acid secretion.     

Effect of enkephalin and naloxone on gastric acid and serum gastrin and pancreatic polypeptide concentrations in humans.

The effects of a synthetic enkephalin analogue with prolonged opioid activity, D-ala-2-enkephalin (ala-enk) and naloxone given alone or in combination, on vagally, pentagastrin- and histamine-induced gastric secretion and plasma hormonal responses to vagal stimulation have been studied in healthy subjects. D-ala-2-enkephalin reduced basal gastric acid and pepsin secretion, and caused a dose-dependent inhibition of gastric secretory responses to modified sham-feeding and pentagastrin but not to histamine. It increased serum gastrin concentration and suppressed plasma pancreatic polypeptide response to modified sham-feeding. Naloxone alone at lower dose levels did not affect gastric secretion and plasma hormonal concentrations but at higher doses it reduced both basal and modified sham-feeding-induced secretion. When combined with ala-enk it reversed in part gastric secretory and plasma hormonal changes induced by this peptide during modified sham-feeding and pentagastrin stimulation. These results indicate that (1) stable enkaphalin analogue inhibits basal and vagally or pentagastrin-induced gastric secretion, and affects plasma hormonal response to vagal stimulation, at least in part, via activation of opioid receptors and (2) endogenous opioid substances may be involved in the stimulation of gastric secretion in man.     

Effect of intestinal hormones on pentagastrin- and histamine-evoked gastric acid secretion and duodenal ulcerations in cats

In conscious cats with gastric fistulae and the diversion of bile and pancreatic juice to jejunum, secretin (1 unit/kg-hr), cholecystokinin (CCK) (4 units/kg-hr), and duodenal acidification (1 mEq HCl/hr) caused a marked inhibition of half maximal gastric acid response to pentagastrin (8 μg/kg-hr) but did not alter the response to histamine (160 μg/kg-hr). Secretin, CCK, and jejunal acidification prevented the formation of duodenal ulcerations in conscious cats infused with pentagastrin or histamine for 36 hours. The antiulcer action of the intestinal hormones can be attributed to their inhibitory effect on gastric acid secretion and to the stimulation of pancreatic juice and bile secretion resulting in the increased neutralization of gastric acid in the duodenum.     

The Effect of Glucagon on the Exocrine Pancreas

Glucagon can depress normal animal and human pancreatic exocrine secretions and modify experimentally-induced pancreatitis in animals. It has yet to be demonstrated that glucagon has any efficacy in the treatment of the diseased pancreas in man. Glucagon might act on the exocrine pancreas by 1. reducing pancreatic blood flow, 2. decreasing gastric secretion, 3. lowering serum calcium levels by the release of calcitonin, 4. acting to inhibit the secretin mechanism, 5. causing a hyperglycemia and 6. degranulating pancreatic acinar cells. While a reduction in pancreatic blood flow, an inhibition of the secretin mechanism and a hyperglycemia seemed to have been ruled out as possible mechanisms of action, there is too little available data to effectively speculate on the mechanism(s) of action of glucagon on the exocrine pancreas.     

Effect of pentagastrin and caerulein on intragastric pressure in the dog.

When gastric acid was not neutralized, doses of pentagastrin as small as 1 mug kg-1 hr-1 decreased intragastric pressure in dogs. When gastric acid was neutralized the smallest effective dose of pentagastrin was 8 mug kg-1 hr-1 which is 16 times the D50 for acid secretion. Thus the decrease in intragastric pressure by small doses of pentagastrin is mediated at least in part by acid secretion. Even with gastric neutralization, a dose of caerulein as small as 63 ng kg-1 hr-1, which is the D50 for pancreatic protein secretion, decreased intragastric pressure. These findings support the view that inhibition of gastric pressure occurs with physiological doses of the cholecystokinin-like peptide caerulein but only with pharmacological doses of pentagastrin.     

Effects of omeprazole, a substituted benzimidazole, on gastrointestinal secretions, serum gastrin, and gastric mucosal blood flow in dogs

In dogs with gastric fistulas and vagally denervated Heidenhain pouches, omeprazole, a benzimidazole derivative infused intravenously or given intraduodenally, dose-dependently inhibited gastric acid secretion, which had been induced by histamine, pentagastrin, or urecholine. It also suppressed gastric acid response to physiologic stimulants such as sham-feeding and gastric peptone meal without affecting serum gastrin level. The inhibition of histamine-induced acid secretion was accompanied by a parallel reduction in the mucosal blood flow, but no significant alteration in the ratio (R) value, indicating that omeprazole primarily affected gastric acid secretion but did not limit gastric mucosal microcirculation. Omeprazole, infused into the Heidenhain pouch, caused a dose-dependent inhibition of the Heidenhain pouch response to intravenous histamine without any significant change in the acid response of the main stomach and plasma concentrations of the drug. This indicates that omeprazole may exhibit local inhibitory action on the oxyntic glands. Omeprazole did not affect gastric mucosal integrity or the rate of alkaline secretion from the gastroduodenal mucosa or the pancreas stimulated by duodenal acidification or secretin.     

Regulation of glucagon secretion at low glucose concentrations: evidence for adenosine triphosphate-sensitive potassium channel involvement

Glucagon is a potent counterregulatory hormone that opposes the action of insulin in controlling glycemia. The cellular mechanisms by which pancreatic alpha-cell glucagon secretion occurs in response to hypoglycemia are poorly known. SUR1/K(IR)6.2-type ATP-sensitive K(+) (K(ATP)) channels have been implicated in the glucagon counterregulatory response at central and peripheral levels, but their role is not well understood. In this study, we examined hypoglycemia-induced glucagon secretion in vitro in isolated islets and in vivo using Sur1KO mice lacking neuroendocrine-type K(ATP) channels and paired wild-type (WT) controls. Sur1KO mice fed ad libitum have normal glucagon levels and mobilize hepatic glycogen in response to exogenous glucagon but exhibit a blunted glucagon response to insulin-induced hypoglycemia. Glucagon release from Sur1KO and WT islets is increased at 2.8 mmol/liter glucose and suppressed by increasing glucose concentrations. WT islets increase glucagon secretion approximately 20-fold when challenged with 0.1 mmol/liter glucose vs. approximately 2.7-fold for Sur1KO islets. Glucagon release requires Ca(2+) and is inhibited by nifedipine. Consistent with a regulatory interaction between K(ATP) channels and intra-islet zinc-insulin, WT islets exhibit an inverse correlation between beta-cell secretion and glucagon release. Glibenclamide stimulated insulin secretion and reduced glucagon release in WT islets but was without effect on secretion from Sur1KO islets. The results indicate that loss of alpha-cell K(ATP) channels uncouples glucagon release from inhibition by beta-cells and reveals a role for K(ATP) channels in the regulation of glucagon release by low glucose.     

Pancreatic polypeptide and vagal stimulation of gastric and pancreatic secretion in dogs

In four dogs provided with pancreatic, gastric, and esophageal fistulae, the effects of bovine pancreatic polypeptide (BPP) infused at a physiological dose level (240 pmol per kg/hr) on gastric and pancreatic responses to sham-feeding were studied. The maximal gastric and pancreatic secretion was produced by pentagastrin and secretin, and OP-CCK infusion, respectively, with or without additions of BBP. Exogenous BPP did not change gastric acid and pepsin outputs stimulated by pentagastrin or sham-feeding, but significantly inhibited basal and maximally stimulated pancreatic protein secretion. The peak pancreatic protein, but not bicarbonate response to sham-feeding was reduced by about 31% by BPP. This reduction by BPP amounted to about 57% when the pancreas was stimulated maximally by OP-CCK. It is concluded the PP released by cephalic-vagal excitation does not affect gastric secretion, but inhibits pancreatic protein secretion, and thus might contribute to the lower pancreatic response to sham-feeding as compared with that produced by exogenous stimulants such as secretin and OP-CCK.     

Inhibition of gastric acid secretion in humans by glucagon during euglycemia,hyperglycemia, and hypoglycemia

The effect of intravenous infusion of glucagon in a dose of 85 pmol/kg/hr on submaximal pentagastrin-stimulated gastric acid secretion was studied in eight healthy volunteers. The study was repeated four times in each subject. By a glucose-insulin clamp technique blood glucose levels were kept constant during the studies at 5.0 mmol/liter (euglycemic clamp), 2.5 mmol/liter (hypoglycemic clamp), or 7.0 mmol/liter (hyperglycemic clamp) on three different days. Glucose and insulin were not infused during one control day study. During glucagon infusion, plasma glucagon levels increased but the level reached was lower during the hyperglycemic condition when compared to euglycemic and hypoglycemic conditions. Glucagon infusion inhibited gastric acid secretion during hyper- and euglycemic conditions but not during hypoglycemic conditions. Hyperglycemia caused a modest but significant inhibition of acid secretion. Serum gastrin concentrations were unaltered during glucagon infusion regardless of the level of blood glucose. The present observations indicate that the inhibitory effect of glucagon is independent of the glucagon-induced hyperglycemia, but the effect is lost when blood glucose is below a certain limit, suggesting that blood glucose may have a modulating effect on gastric acid secretion.This study was supported by the Danish Hospital Foundation for Medical Research. Region of Copenhagen, The Faroe Islands and Greenland.     

Quantitation of somatostatin inhibition of insulin-stimulated gastric acid and pepsin secretion in the cat.

Somatostatin inhibition of gastric acid and pepsin secretion stimulated by insulin-hypoglycaemia was quantified in six conscious cats prepared with cannulated gastric fistulae. Somatostatin 0.5-5 microgram kg-1h-1 produced a dose dependent reduction of both acid and pepsin secretions stimulated by insulin 0.2 u kg-1h-1. The doses of somatostatin which produced 50% inhibition of pepsin and acid secretions (ID50) were not significantly different (0.70 +/- 0.16 and 0.93 +/- 0.11 microgram kg-1h-1 respectively). The slope of the calculated correlation line relating % inhibition of pepsin and % inhibition of acid is within experimental error of unity indicating equality of action of somatostatin on insulin-stimulated acid and pepsin secretion. The results indicate that somatostatin is a more potent inhibitor of insulin 0.2 u kg-1h-1 stimulated acid secretion than pentagastrin 8 microgram kg-1h-1 stimulated acid secretion, but is a more potent inhibitor of pentagastrin--than insulin--stimulated pepsin secretion. As insulin stimulates less acid and more pepsin secretion than pentagastrin, the differences in sensitivities to somatostatin of these secretions produced by the two stimulants is thought to be a result of the different absolute amounts of secretion produced by the stimulants.     

Effect of caerulein on histamine and pentagastrin-induced gastric secretion in man

In 6 human subjects caerulein, a decapeptide isolated from frog skins, slightly stimulated gastric acid secretion when given alone. This peptide, added in a dose of 0.1µg/kg/hr to intravenous infusion of pentagastrin in a dose of 2.0µg/kg/hr, produced about 50% inhibition of near maximal gastric acid secretion. In 8 human subjects, however, it evidently increased gastric acid response to histamine diphosphate infused intravenously in a dose of 40 µg/kg/hr. The hypothesis of hormonal interaction was applied to explain the inhibitory and stimulatory effect of caerulein on pentagastrin and histamine-induced gastric acid secretion in man.The authors wish to thank Professor Bruno Camerino, Farmitalia. Milano, Italy, for his generous supply of natural caerulein.     

Effect of pentagastrin on parietal cell ultrastructure in glucagon-pretreated subjects

The effect on parietal cells of glucagon given prior to pentagastrin is unknown. Fifteen healthy volunteers were studied during constant intravenous infusion of pentagastrin (2g/kg body weight/hr) and during pentagastrin infusion initiated 20 min after intravenous injection of 2 mg glucagon. Three types of studies were performed: Gastric mucosal biopsies were obtained with a Quinton instrument. Electron micrographs of 320 parietal cells were analyzed by the Loud quantitative method, and intragastric pH (pH probe), or gastric potential difference (PD) were recorded continuously. Pentagastrin infusion produced a significant increase in canalicular and simultaneous reduction of tubulovesicular membrane area of parietal cells. Glucagon pretreatment did not inhibit canalicular and tubulovesicular membrane reaction to pentagastrin; unexpectedly this reaction was significantly greater when compared to that after pentagastrin alone. Initiation of pentagastrin infusion in subjects pretreated with glucagon produced a greater absolute value drop in gastric PD (23±2mV) and an earlier drop in intragastric pH (3 min) than in subjects receiving pentagastrin infusion alone (13±1mV and 10min, respectively). In conclusion, at the doses studied, glucagon pretreatment increases parietal cell canalicular reaction to pentagastrin.This work was supported in part by the Medical Research Service of the Veterans Administration.     

Gastric acid response to pentagastrin and gastrin-releasing peptide in conscious cats

The mammalian counterpart to bombesin, gastrin-releasing peptide (GRP), is considered to stimulate gastric acid secretion by release of endogenous gastrin. The present study was carried out to examine if GRP has a stimulatory action on acid secretion in addition to that produced by released gastrin. In 4 gastric fistula (GF) and Heidenhain pouch (HP) cats, 160 pmol X kg-1 X h-1 i.v. GRP produced a GF and HP acid response that amounted to 22 and 13%, respectively, of the maximal acid response to pentagastrin, with no rise in serum gastrin concentration. GRP significantly increased the maximal acid response to pentagastrin in the GF but not in the HP. These results suggest that GRP stimulates acid secretion in cats also by an action not related to the release of gastrin. This action is greater in the presence of vagal innervation.     

Pancreatic glucagon response to an ordinary meal.

Glucagon concentrations in the portal and peripheral venous blood were measured in 3 patients after an ordinary meal. A brief increase in glucagon concentration was found in the portal blood but not in the peripheral blood. As the glucose concentrations rose, the glucagon levels fell. The secretion of pancreatic glucagon therefore seems to depend largely on the blood glucose level.     

Glucagon inhibition of secretin and combined secretin and cholecystokinin stimulated pancreatic exocrine secretion in health and disease

The effect of glucagon infusion on secretin and combined secretin and cholecystokinin stimulated exocrine pancreatic secretion was studied in normal subjects and in patients after acute and with chronic pancreatic disease. Glucagon inhibited pancreatic protein secretion and had no inhibitory effect on volume or bicarbonate secretion.     

Clinical significance of glucagon provocation test in the diagnosis of hypergastrinemia

Glucagon provocation test was performed in the patients with hypergastrinemia and hyperchlorhydria to investigate its diagnostic value. A paradoxical response of plasma gastrin level in the patients with the Zollinger-Ellison syndrome and a marked decrease of plasma gastrin level in the patients with gastric ulcer, duodenal ulcer, excluded gastric antrum, multiple endocrine adenomatosis, pernicious anemia and chronic renal failure were demonstrated by glucagon infusion. Glucagon provocation test, therefore, was considered to be of great value in the diagnosis of the Zollinger-Ellison syndrome, particularly, in the case of an excluded gastric antrum in which secretin provocation test caused the false positive result because of a marked increase of pancreatic secretion. Glucagon provocation test in combination with secretin provocation test, therefore, is at present the most preferable diagnostic procedure for detecting the Zollinger-Ellison syndrome.U