THE GASTRIN CHOLECYSTOKININ-B RECEPTOR ANTAGONIST L-365,260 REDUCES BASAL ACID-SECRETION AND PREVENTS GASTROINTESTINAL DAMAGE-INDUCED BY ASPIRIN, ETHANOL AND CYSTEAMINE IN THE RAT

L-365,260, a nonpeptide antagonist of gastrin/CCK-B receptors, was eva luated in receptor binding, antisecretory and gastrointestinal damage assays. L-365,260 binds potently and stereo-selectively to gastrin and CCK-B sites in guinea pig tissue. In contrast, L-365,260 binds to the isolated canine parietal cell gastrin receptor weakly, and without st ereoselectivity. In the pylorus-ligated rat, low doses of L-365,260, g iven i.v., attenuated pentagastrin-stimulated acid secretion, whereas higher doses were required to inhibit both histamine-stimulated and ba sal acid secretion. In an aspirin-induced gastric damage model, L-365, 260 was 2.4-fold less potent than the standard histamine H-2 antagoni st cimetidine in preventing gastric damage when given i.v., and was 8. 3-fold less potent than cimetidine when given p.o. Moreover, the ED50 value for L-365,260, given i.v., in prevention of aspirin-induced gast ric damage (11.5 mg/kg) agreed well with its ED50 value for inhibition of basal acid secretion (1 2.6 mg/kg). At doses as great as 1 00 mg/k g p.o., neither L-365,260 nor cimetidine had an effect on ethanol-indu ced gastric damage. L-365,260, although p.o. less bioavailable relativ e to cimetidine in the aspirin gastric damage model, was as potent as cimetidine in the prevention of cysteamine-induced duodenal ulcers in the rat. We conclude that the gastrin/CCK-B receptor antagonist L-365, 260, at doses supramaximal for the inhibition of pentagastrin-stimulat ed secretory responses in vivo, inhibits gastrointestinal damage in mo dels of peptic ulcer disease by an antisecretory mechanism of action.