Significant Inhibition Of Acid Secretion Research Articles

Structure and Function of Rat Parietal Cells during Treatment with Omeprazole, SCH 28080, SCH 32651, or Ranitidine

For 2 weeks four groups of adult female rats were given daily peroral doses of 400 mumols/kg of one of the following inhibitors of gastric acid secretion: omeprazole, SCH 28080, SCH 32651, or ranitidine; additional control rats were given vehicle only. Six rats in each group were killed 2 h after the last dose and another six in each group at 48 h. Samples of the gastric corpus wall were processed for light and electron microscopy. The maximal reduction of stimulated acid secretion in parallel gastric fistula rats was 100%, 90%, 40%, and 85%, respectively. Forty-eight hours after the last dose only SCH 28080 produced significant inhibition of acid secretion. 'Vacuolation' of parietal cells was occasionally observed in paraffin sections. Such 'vacuoles', which were not found in plastic sections, probably represent dilated secretory canaliculi. A small number of lucid parietal cells--presumably in the process of desquamation--were seen in all groups of rats; their proportion was significantly higher 2 h after the last dose of ranitidine, SCH 28080, or SCH 32651 than in the controls. Forty-eight hours after the last dose the proportion of such degenerating parietal cells was about the same in all groups.

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 gastric 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.

Action of FPL 52694 on gastric acid secretion in the healthy human stomach.

In a double blind crossover experiment in 16 healthy male volunteers, the effects of oral FPL 52694 and a matching placebo upon pentagastrin stimulated gastric acid secretion, gastric mucosal histamine content, and gastric mucosal mast cell count were compared. There was a significant increase in acid secretion, and a fall in tissue histamine and the mast cell count after treatment with the placebo. All these changes were inhibited by FPL 52694, and there was a significant difference between the effects of this compound and the placebo in all three parameters. It is concluded that FPL 52694 caused significant inhibition of acid secretion, and that the likely mechanism of action is by stabilisation of mast cells and inhibition of histamine release.

Effect of transdermally administered hyoscine methobromide on nocturnal acid secretion in patients with duodenal ulcer.

Use of anticholinergic drugs in treatment of duodenal ulcers is limited by the side effects of widespread parasympathetic blockade evoked by usual therapeutic doses. A study was conducted into the effectiveness of transdermal delivery of hyoscine methobromide using a new system which releases the drug into the circulation at a controlled rate. In six patients whose duodenal ulcer had healed secretion of acid was measured over two nights, the first on placebo and the second on hyoscine methobromide. All patients responded to the active drug and showed a significant inhibition of acid secretion. Four subjects complained of a dry mouth after overnight treatment with hyoscine methobromide; no other side effects were reported. Transdermal delivery of anticholinergic drugs may be useful in maintenance treatment of duodenal ulcers and further clinical tests are indicated.

Effect of vagotomy on gastric acid secretion in the rat

The effects of pentagastrin, histamine or feeding on gastric acid secretion were studied in conscious rats with total gastric by-pass, achieved by transection of the cardia and pylorus, followed by an oesophago-duodenostomy. After closure of the cardia, the by-passed stomach was connected to the small intestine through a Roux-en-Y loop. A chronic gastric fistula was fitted into the rumen. Basal acid output was low in chronically vagotomized rats, being 6% of that in the innervated animals. A clear-cut stimulation was observed after both pentagastrin and histamine in innervated as well as denervated rats, although the maximal acid output in the denervated group was less than 10% of that in the innervated group. In previous studies on acid secretion in vagotomized rats with chronic gastric fistulas, neither basal nor stimulated acid secretion could be detected. Apparently, by-passing the stomach eliminates sources of error associated with the conventional gastric fistula technique (for instance, neutralization of acid gastric juice by swallowed saliva or regurgitated duodenal juice). Nonetheless, the greatly reduced acid output following vagotomy indicates that normal basal as well as normal stimulated acid secretion is dependent upon an intact vagus. Pentagastrin- and histamine-stimulated acid secretion was blocked by atropine and cimetidine in both the innervated and denervated rats. Feeding caused a significant inhibition of acid secretion in the by-passed, innervated stomach. In the denervated stomach feeding was without effect. The mechanism behind the postprandial inhibition of acid secretion in the innervated stomach is obscure. Direct vagal inhibition as well as humoral substances, liberated by vagal stimulation or by the presence of food in the intestine, may be responsible.

Effects of arachidonic acid on rat gastric acid secretion in response to different secretogogues; inhibition of these effects by indomethacin.

1 The effects of the prostaglandin precursor, arachidonic acid, and the non-steroidal anti-inflammatory drug, indomethacin, on gastric acid secretion were studied in the rat, in vivo and in vitro. Gastric mucosal blood flow was also measured in vivo. 2 Arachidonate produced significant inhibition of acid secretion stimulated by pentagastrin or histamine. It did not significantly affect dibutyryl cyclic adenosine 3',5'-monophosphate (db cyclic AMP)-induced acid secretion. 3 Inhibition of acid secretion by arachidonate was accompanied by a rise in the ratio of mucosal blood flow to acid secretion. 4 Indomethacin did not significantly alter histamine- or pentagastrin-induced acid secretion. 5 In the presence of indomethacin, the inhibitory effect of arachidonate was significantly reduced. 6 These results provide evidence that the rat gastric mucosa is capable of synthesizing, from exogenous precursor, products of cyclo-oxygenase which inhibit gastric acid secretion.

The effect of hexamethonium on gastric acid secretion in the conscious rat

Evidence against a role for histamine in pentagastrin-stimulated acid secretion has been obtained previously using hexamethonium in gastric fistula rats. This possibility has been re-examined in conscious rats provided with gastric fistulae or Heidenhain pouches. Hexamethonium (20 mg/kg s.c.) inhibited basal acid secretion and acid secretion stimulated by histamine and pentagastrin in gastric fistula rats. The same dose of hexamethonium failed to produce a significant inhibition of acid secretion stimulated by bethanechol, pentagastrin or histamine in the presence of a low dose of bethanechol in Heidenhain pouch rats. These results provide no evidence to oppose the view that pentagastrin-stimulated acid secretion in the rat is mediated at least in part through the mobilization of gastric mucosal histamine. The inhibition of secretagogue induced acid secretion in the gastric fistula rat is mainly the result of a reduction in the basal acid output.

Inhibition of Gastric Acid Secretion in Man by Exogenous and Endogenous Pancreatic Glucagon

The interaction of intravenously infused glucagon and pentagastrin on gastric acid secretion was studied in 5 healthy subjects. First a step dose-response study with pentagastrin in doses of 0.01, 0.1,1.0, and 10.0 mug per kg-hr was performed. The dose required for one-half maximal response (D50) was 130 ng per kg-hr. With this dose of pentagastrin as background stimulation a step dose-response study with glucagon in doses of 0.5, 2.0, 8.0, and 16.0 mug per kg-hr was performed. The dose of glucagon required for one-half maximal inhibition was 1.64 mug per kg-hr. In a third experiment the dose-response study with pentagastrin was repeated on a background infusion of glucagon in the dose found to be D50. A significant inhibition of acid secretion was found on all dose levels. The inhibition followed noncompetitive kinetics. Plasma concentrations of pancreatic glucagon in 4 of the 5 subjects in this experiment were comparable concentrations seen after a protein meal. Intravenous infusion of l-arginine on a background stimulation of acid secretion with synthetic human gastrin I in a dose of 250 ng per kg-hr was performed in 7 healthy subjects. Arginine increased serum glucagon concentration to levels seen after a meal and resulted in a significant inhibition of acid secretion. The results favor the hypothesis that pancreatic glucagon may participate in the physiological inhibition of gastric acid secretion.

Gastric Secretory Inhibition by Two 16-Methylated Analogs of Prostaglandin E2 Given Intragastrically to Patients with Duodenal Ulcer Disease

The effects of two methylated analogs of prostaglandin E2 (PGE2), namely 16,16-dimethyl PGE2 and its methyl ester, on gastric acid and pepsin secretion have been studied in 5 ulcer patients. Both analogs produced significant inhibition of acid secretion in a dose-dependent fashion, but the effect was less pronounced than the inhibition found in a group of healthy volunteers, and it was necessary to give 140 mug of each analog to reach about the ED50. The mean values of pepsin output and pepsin concentration were decreased following administration of PGE2, but the individual results varied.

The effect of bile on the gastric secretory responses of vagally denervated canine fundic pouches.

The gastric secretory responses of vagally denervated canine fundic pouches stimulated by a meat meal have been defined following preliminary exposure of the pouches to ox bile at various pH levels. Generally, exposure of the pouches to bile caused reduced outputs of H+ and increased outputs of Na+ which were unassociated with significant changes in secretory volumes or in outputs of Cl−. These changes were compatible with increased exchange-diffusion unaccompanied by significant inhibition of acid secretion. The changes were most pronounced when the bile was administered at pH 2. These studies support the concept that biliary reflux is harmful to the stomach. Furthermore, they indicate that bile is more injurious to the gastric mucosa at low pH levels.