L-365,260, a Potent CCK-B/Gastrin Receptor Antagonist, Suppresses Gastric Acid Secretion Induced by Histamine and Bethanechol as Well as Pentagastrin in Rats.

Abstract

ABSTRACT-We evaluated the effects of a potent cholecystokinin (CCK)-B/gastrin receptor antagonist, L-365,260 (3R(+)-N-(2,3-dihydro-l-methyl-2-oxo-5-phenyl-lH 1,4-benzodiazepin-3-yl)-N'-(3-methylphenyl)urea); a selective CCK-A receptor antago nist, devazepide (L-364,718); and cimetidine on gastric acid secretion induced by pen tagastrin, histamine and bethanechol in anesthetized rats. We also evaluated the effects of L-365,260 and cimetidine on acid secretion in pylorus-ligated rats. In travenous administration of L-365,260, L-364,718 and cimetidine dose-dependently re duced acid secretion induced by pentagastrin (20 nmol/kg/hr), with ED50 values of 0.63, 19.1 and 2.5 pmol/kg, respectively. Of interest was the finding that L-365,260, like cimetidine, dose-dependently inhibited acid secretion induced by histamine (100 umol/kg/hr) and bethanechol (5 ,umol/kg/hr) with ED50 values of 5.9 and 4.3 ,umol/kg, respectively. L-364,718, even at 30,umol/kg, i.v., had only a slight effect on histamine or bethanechol-induced acid secretion. Gastric acid secretion was sup pressed by treatment with L-365,260 (3-100 pmol/kg, i.v.) and cimetidine (11.9 396.4 ,u mol/kg, i.v.) in pylorus-ligated rats, with ED50 values of 13.3 and 96.9 ,umol/kg, respectively. These results indicate that L-365,260 suppresses acid secretion induced by histamine and bethanechol in rats and that the gastrin receptor plays an important role in acid secretion in pylorus-ligated rats.Gastrin plays an important role in the gas tric phase of acid secretion in animals (1) and humans (2). There is a good correlation be tween the serum gastrin concentration and the amount of gastric acid secretion during feeding (2, 3). However, few studies have examined the role of gastrin in basal and histamine or cholinomimetic-induced gastric acid secretion, as no potent and selective gastrin receptor antagonists have been developed. Proglumide, which has been reported to be a gastrin recep tor antagonist, inhibits basal (4) and acetyl choline-induced gastric acid secretion (5). However, it is unclear whether endogenous gastrin participates in gastric acid secretion in duced by histamine or cholinomimetics or whether it plays an important role in basal acid secretion, since the gastrin receptor an tagonistic activity of proglumide is very weak and shows low selectivity.

L‐365,260 inhibits in vitro acid secretion by interacting with a PKA pathway

“…L Lotti & Chang (1989) failed to demonstrate that L-365,260 inhibits basal acid secretion in vivo in mice, our results are in accordance with some reports (Hirst et al, 1991;Nishida et al, 1992;Pendley et al, 1993) showing that L-365,260 is able to inhibit in vivo basal acid secretion in the rat. These results suggested that one site of action of L-365,260 in¯uencing acid secretion was located between the second(s) messenger(s) system and the proton pump.…”

“…It has been mentioned that in the rat in vivo, low doses of L-365,260 inhibited pentagastrin-stimulated secretion (Hirst et al, 1991), whereas higher doses inhibited basal-, histamineand carbachol-stimulated secretion (Hirst et al, 1991;Nishida et al, 1992;Pendley et al, 1993). In order to provide a better understanding of the role of L-365,260 in acid secretion in vitro, we decided to investigate further its antisecretory mechanism in isolated rabbit gastric glands.…”

Influence of L-365,260, a CCK-B/Gastrin Receptor Antagonist, on Tetragastrin- Stimulated Mucin Metabolism in Rat Gastric Mucosa

“…These agents have been demonstrated to inhibit gastric acid secretion [22,23]. Although L-365,260 and YM022 have been reported to potently prevent the experimental acute gastroduodenal lesions in rats [24,25], little is investigated into the CCK-B/gastrin receptor antagonist function in the mechanism of the gastric mucosal defense.…”

Comparative Evaluation of the Role of Endogenous Gastrin in Basal Acid Secretion in Conscious Rats Provided with Chronic Fistula and Pylorus Ligation

“…On the contrary, we and Pendley et al reported that i.v. injection of this drug inhibited acid secretion in these rats (4,5). However, L-365,260 also inhibits histamine or cholinomimetic-stimulated acid secretion, whereas other gastrin antagonists do not affect this secretion (6)(7)(8)(9).…”