The influence of morphine on acid secretion by the isolated rat gastric mucosa

The influence of morphine on acid secretion by the isolated gastric mucosa was studied in adult rats. A wide range of morphine concentrations (1 X 10(-4) to 1.6 X 10(-3) M) was found to have no effect on basal acid output, or on acid secretion maximally stimulated by bethanechol or histamine. It is suggested that the opiate receptors in the rat gastric mucosa, if there are any, are not involved in modulating acid secretion.     

Luminal Nalpha-methyl histamine stimulates gastric acid secretion in duodenal ulcer patients via releasing gastrin

Nalpha-methyl histamine is an unusual histamine metabolite which is produced in the stomach infected by Helicobacter pylori and which was shown in animals to stimulate gastric acid secretion and to release gastrin in vitro isolated G-cells, but no information is available regarding its influence on gastric secretion and gastrin release in duodenal ulcer patients before and after H. pylori eradication. In this study, we compared the effects of intragastric administration of single or graded doses of Nalpha-methyl histamine on gastric acid secretion and plasma gastrin levels in 16 male duodenal ulcer patients (aging from 35 to 48 years and weighing 65-82 kg) before and after the eradication of H. pylori. Furthermore, the gastric luminal histamine and gastrin contents were determined before and after H. pylori eradication. In H. pylori-infected duodenal ulcer patients, the intragastric application of Nalpha-methyl histamine failed to affect gastric acid secretion or plasma gastrin levels. Following eradication of H. pylori, gastric luminal histamine and gastrin, and both basal gastric acid secretion and plasma gastrin levels, were significantly reduced. Nalpha-methyl histamine given intragastrically in graded doses to such H. pylori-eradicated duodenal ulcer patients was found to increase dose-dependently gastric acid output reaching at a dose of 5 mg, about 80% of histamine maximum induced by i.v. infusion of 25 microg/kg h of histamine dihydrochloride. We conclude that Nalpha-methyl histamine is a potent luminally active stimulant of gastrin release and gastric acid secretion in H. pylori-eradicated patients when luminal histamine is low but is not effective in H. pylori infected patients when luminal histamine is enhanced, possibly due to desensitization of gastrin (G-cells) and acid-producing (parietal) cells by Nalpha-methyl histamine produced excessively in H. pylori-infected stomach.     

Effects of indomethacin, piroxicam and selected prostanoids on gastric acid secretion by the rat isolated gastric mucosa

The effects of the cyclo-oxygenase inhibitors indomethacin and piroxicam have been investigated on histamine- and dibutyryl cyclic AMP-induced acid secretion in the rat isolated gastric mucosa. The relative potencies of a number of prostanoids as inhibitors of histamine-induced acid secretion were determined in an attempt to classify the prostaglandin receptor mediating this response. Indomethacin (8 X 10(-9) - 2.7 X 10(-6) M) and piroxicam (3 X 10(-6) M) potentiated the secretory responses elicited by histamine. This effect might be due to inhibition of the biosynthesis of antisecretory prostanoids. Indomethacin (2.7 X 10(-6) M) and piroxicam (3 X 10(-6) M) also potentiated the secretory response to dibutyryl cyclic AMP, but since prostaglandin E2 (PGE2, 10(-5) M) did not inhibit this secretory response, the mechanism of the potentiation may differ from that of histamine. The potency of the thromboxane mimetic U-46619 as an inhibitor of histamine-induced acid secretion was markedly reduced in the presence of indomethacin, suggesting that U-46619 may release endogenous antisecretory prostanoids. In the presence of indomethacin (2.7 X 10(-6) M) all the prostanoids tested produced concentration-related inhibitions of histamine-induced gastric acid secretion. PGE-analogues were the most potent compounds, the rank order of potency being 16, 16 dimethyl PGE2 greater than PGE2 greater than PGF2 alpha greater than U-46619 greater than PGD2 greater than PGI2. This order of potency is very similar to that obtained in smooth muscle preparations containing 'EP' receptors, suggesting that this receptor type also mediates inhibition of histamine-induced acid secretion in the rat.     

Analysis of the actions of cimetidine and metiamide on gastric acid secretion in the isolated guinea pig gastric mucosa

Summary Cumulative dose-response curves for histamine were determined on acid secretion from the isolated guinea pig gastric mucosa. Two H₂-receptor antagonists—metiamide and cimetidine—behaved like competitive antagonists to histamine on gastric acid secretion in vitro. The isolated guinea pig gastric mucosa seems to be a suitable in vitro model for analysing the action of compounds on receptors involved in acid secretion.     

Effects of alkyl analogs of histamine and metiamide on gastric acid secretion.

Histamine and metiamide analogs with alkyl, methyl, ethyl or isopropyl groups on the imidazole ring in position 5, not previously tested on an in vivo preparation, were studied for their effects on gastric acid secretion in cats with gastric fistulas. Our findings confirmed that the methyl group appears to be optimal for an effect on gastric acid secretion as regards both agonism and antagonism. Ethyl substitution apparently did not change the pharmacological activity of histamine but modified the inhibitory effect of metiamide from competitive to non-competitive kinetics. Isopropyl analogs were inactive on gastric secretion under our experimental conditions.     

Centrally applied histamine increases gastric acid secretion in rats

Summary Administration of 10–100 g of histamine into the lateral cerebral ventricle of anaesthetized rats stimulated gastric acid secretion in a dose-dependent manner, while subcutaneous (s. c.) injections of the same doses produced clearly less pronounced increases in the acid output. In vagotomized rats only a marginal response to histamine given into the lateral ventricle was observed. When injected into the third cerebral ventricle the doses of histamine needed for the stimulation of gastric acid secretion were 1–10 g, the effect being totally abolished by vagotomy. The results indicate that histamine is capable of stimulating gastric acid secretion by a central, vagal-dependent mechanism.Send offprint requests to J. Puurunen at the above address     

Cadmium inhibits acid secretion in stimulated frog gastric mucosa

Cadmium, a toxic environmental pollutant, affects the function of different organs such as lungs, liver and kidney. Less is known about its toxic effects on the gastric mucosa. The aim of this study was to investigate the mechanisms by which cadmium impacts on the physiology of gastric mucosa. To this end, intact amphibian mucosae were mounted in Ussing chambers and the rate of acid secretion, short circuit current (I_sc), transepithelial potential (V_t) and resistance (R_t) were recorded in the continuous presence of cadmium. Addition of cadmium (20 µM to 1 mM) on the serosal but not luminal side of the mucosae resulted in inhibition of acid secretion and increase in NPPB-sensitive, chloride-dependent short circuit current. Remarkably, cadmium exerted its effects only on histamine-stimulated tissues. Experiments with TPEN, a cell-permeant chelator for heavy metals, showed that cadmium acts from the intracellular side of the acid secreting cells. Furthermore, cadmium-induced inhibition of acid secretion and increase in I_sc cannot be explained by an action on: 1) H₂ histamine receptor, 2) Ca²⁺ signalling 3) adenylyl cyclase or 4) carbonic anhydrase. Conversely, cadmium was ineffective in the presence of the H⁺/K⁺-ATPase blocker omeprazole suggesting that the two compounds likely act on the same target. Our findings suggest that cadmium affects the functionality of histamine-stimulated gastric mucosa by inhibiting the H⁺/K⁺-ATPase from the intracellular side. These data shed new light on the toxic effect of this dangerous environmental pollutant and may result in new avenues for therapeutic intervention in acute and chronic intoxication.     

Spizofurone, a new anti-ulcer agent, increases alkaline secretion in isolated bullfrog duodenal mucosa

The effect of spizofurone, a new anti-ulcer agent, on alkaline secretion was studied in an isolated sheet of bullfrog (10(-4)-10(-3) M) as well as prostaglandin E2 (PGE2, 10(-8)-10(-5) M) added to the nutrient solution increased alkaline secretion, transmucosal potential difference (PD) and short-circuit current (Isc), in a concentration-dependent manner. The maximum increases in alkaline secretion stimulated by spizofurone and PGE2 were much the same. Spizofurone also showed this effect when added to the secretory solution while PGE2 did not. Treatment with indomethacin partly but significantly inhibited the effect of spizofurone, but did not affect that of PGE2. These results indicate that the increase in alkaline secretion in bullfrog duodenal mucosa seen in the presence of spizofurone is mediated, at least in part, by stimulation of endogenous PGs synthesis.     

硝酸钇对大鼠胃粘膜和胃酸分泌的影响

本文研究硝酸钇对饥饿大鼠和幽门结扎大鼠的胃粘膜和胃酸分泌的影响。硝酸钇ig对饥饿大鼠的胃粘膜有严重损伤,但硝酸钇ip对幽门结扎大鼠胃粘膜的损伤却有预防作用。硝酸钇在8～32mg/kg范围内,无论是ig还是ip对胃酸分泌均有抑制作用,且呈明显的剂量效应关系,但4mg/kg对胃酸分泌影响不大。硝酸钇ig可减少胃壁结合粘液的分泌,ip途径则无影响。     

Effect of amodiaquine on gastric histamine methyltransferase and on histamine-stimulated gastric secretion.

1 Amodiaquine was found to be a potent inhibitor in vitro of gastric histamine methyltransferase from human and canine corpus and from pig antrum. The ID50 for the enzyme, purified from pig antrum mucosa by ultracentrifugation and chromatography on DEAE-cellulose, was 2.5 muM. 2 In six dogs with Heidenhanin pouches the maximum secretory response to histamine (40 mug/kg i.m.) was augmented by i.m. injection of amodiaquine. The augmentation depended on the dose of amodiaquine, the optimum effect (40% increase in volume of gastric juice, 80% in acid output) being achieved with 2 mg/kg. The maximum secretory response to betazole was also enhanced by amodiaquine. 3 It was suggested that amodiaquine may enhance the histamine and betazole stimulated gastric secretion by an inhibition of gastric histamine methyltransferase in vivo.     

Effects of calcium on acid secretion from the rat isolated gastric mucosa during stimulation with histamine, pentagastrin, methacholine and dibutyryl cyclic adenosine-3'',5''-monophosphate.

1. An isolated gastric mucosal preparation from immature rats is described. The mucosal surface was superfused and acid secretion was recorded continuously by monitoring H+ -ion concentration. 2. Repeated stimulation with submaximal concentrations of histamine or dibutyryl cyclic adenosine 3',5'-monophosphate (db cyclic AMP) produced consistent responses. Secretion induced by pentagastrin and methacholine demonstrated varying degrees of tachyphylaxis. All responses were readily reversed on washing out the secretagogue. 3. Reduction of Ca2+ from 3.6 mM increased responses to histamine, pentagastrin and methacholine while increase of Ca2+ to 7.2 mM decreased responses. Db cyclic AMP-induced secretion was not influenced by external Ca2+. 4. When Mg2+ was raised from 1.2 mM responses to histamine and pentagastrin increased. Replacement of Ca2+ with Mg2+ produced a transient increase followed by a decrease in responses. 5. The similarity of the effects of Ca2+ on pentagastrin, methacholine and histamine indicates that neither pentagastrin nor methacholine act via Ca2+ -dependent histamine release.     

Fade and tachyphylaxis of gastric acid secretory response to pentagastrin in rat isolated gastric mucosa.

1. Gastric acid secretory responses to pentagastrin were characterized in the rat isolated gastric mucosa. In particular, the mechanisms underlying fade, declining response upon continued stimulation, and tachyphylaxis, progressively reduced responses upon repeated stimulation, were investigated. 2. Pentagastrin, 10(-9)-10(-7) M, resulted in concentration-related increases in acid secretion, with a mean maximum of 2.65 mumol cm-2 h-1 in response to pentagastrin, 10(-7) M. Higher concentrations of pentagastrin produced sub-maximal secretory rates; we define this as auto-inhibition. The responses to all concentrations of pentagastrin demonstrated fade. The rate of fade was correlated with the maximum acid secretory rate, declining at about 36% of the peak over the first 16 min. 3. The PO2, PCO2, [HCO3-], pH, [glucose], [lactate], [Na+] and [K+] did not decline during the fade of the acid secretory response to pentagastrin, 10(-7) M. Addition of a second aliquot of pentagastrin was not able to reverse fade, but these tissues were responsive to histamine. Replacement of the serosal solution, before addition of a second aliquot of pentagastrin, increased the acid response from 3% to 24% of the first response. 4. Serosal solution from donor tissues, allowed to respond to pentagastrin and then the acid secretion to fade, was able to stimulate secretion in fresh recipient tissues, although at lower rates. 5. Acid secretory responses to a second dose of pentagastrin were not significantly different, whether the tissues were previously unstimulated, or stimulated with pentagastrin washed out after attaining its peak secretory response (after 10-20 min). The second response was significantly reduced if the first response was allowed to fade with the pentagastrin in contact for 100 min; i.e. fade significantly influenced the extent of tachyphylaxis. 6. Proglumide, 10(-2) M, a gastrin receptor antagonist, and omeprazole, 10(-5) M, an inhibitor of the gastric (H+ + K+)-ATPase, both inhibited pentagastrin-stimulated acid secretion to similar extents. The second response to pentagastrin after pentagastrin alone, or pentagastrin plus omeprazole were both reduced compared to responses after no stimulation or omeprazole alone, respectively. After pentagastrin plus proglumide, the second response to pentagastrin was not lower than after proglumide alone. Proglumide, but not omeprazole, therefore, prevented pentagastrin tachyphylaxis. 7. It is concluded that gastrin fade and tachyphylaxis are related phenomena. Part of the fade may be due to release of an inhibitor(s). The major proportion of tachyphylaxis is a result of specific interaction of gastrin with its receptors.     

Effects of SCH 32651 on resting and stimulated acid secretion in guinea-pig isolated fundic mucosa.

Effects of SCH 32651, a novel antisecretory and cytoprotective agent, on resting and stimulated acid secretion by the guinea-pig isolated fundic mucosa were studied. SCH 32651 inhibited resting acid secretion in proportion to concentrations in serosal solution (0.1-10 microM), the IC50 being 4.4 microM. Cimetidine and atropine at concentrations up to 100 microM were inactive. Serosal application of SCH 32651 inhibited acid secretory responses to histamine (10 microM), methacholine (1 microM) or dibutyryl cyclic AMP (0.5 mM) plus theophylline (1 mM) in a concentration-dependent manner. The IC50S against histamine, methacholine and db cyclic AMP plus theophylline were 4.2 microM, 0.71 microM and 2.9 microM, respectively. In contrast, atropine and cimetidine each at 100 microM, a concentration that entirely abolished responses to methacholine and histamine, respectively, did not affect acid responses to db cyclic AMP plus theophylline. The inhibitory effects of SCH 32651 on resting and histamine-stimulated acid secretion were readily reversible upon washing. SCH 32651 0.1 mM in the mucosal solution also greatly suppressed the resting and stimulated acid secretion. In the presence of histamine treatment, SCH 32651 concomitantly caused a marked rise in K+ entry into the mucosal solution in parallel to a decline in the appearance of H+ in the same solution. The various events demonstrated by SCH 32651 in the present study are shared by omeprazole, a potent antisecretory agent working through inhibition of gastric H+/K+-ATPase. We conclude that SCH 32651 as a potent antisecretory agent seems to act directly on the parietal cell, near or at the site of H+/K+-ATPase which is a final step in the acid secretory process triggered by various stimuli.