Effects of YF476, a potent and selective gastrin/cholecystokinin-B receptor antagonist, on gastric acid secretion in beagle dogs with gastric fistula.

The antisecretory effects of the gastrin/cholecystokinin-B (CCK-B) receptor antagonist YF476 ((R)-1-[2,3-dihydro-2-oxo-1-pivaloylmethyl-5-(2'-pyridyl) 1H-1,4-benzodiazepin-3-yl]-3-(3-methylaminophenyl)-urea, CAS 155488-25-8) on secretagogue- and peptone-induced gastric acid secretion in beagle dogs with chronic gastric fistula were examined. Plasma gastrin concentrations were evaluated following introduction of peptone into the stomach. Intravenous administration of YF476 dose-dependently inhibited pentagastrin (1 microgram/kg/h)-induced gastric acid secretion, with an ED50 value of 0.0023 mumol/kg. In contrast, intravenous administration of YF476 (0.3 mumol/kg) did not affect histamine (15 micrograms/kg/ h)-induced gastric acid secretion. Oral administration of YF476, famotidine and omeprazole dose-dependently inhibited peptone (8%, 200 ml)-induced gastric acid secretion with ED50 values of 0.11, 0.76 and 4.28 mumol/kg, respectively. The antisecretory effect of YF476 was about 7 and 40 times more potent than that of famotidine and omeprazole, respectively. Plasma gastrin concentrations were increased by introduction of peptone. These results suggest that YF476 is an extremely potent and selective antisecretory drug and the endogenous gastrin plays an important role in peptone-induced gastric acid secretion in dogs.

Gastrin receptor antagonist YM022 prevents hypersecretion after long-term acid suppression.

Female rats were treated orally for 13 wk with YM022 (300 mumol.kg-1.day-1) and with omeprazole (400 mumol.kg-1.day-1) or famotidine (900 mumol.kg-1.day-1) with or without YM022. At 2 h after the last dose, YM022 and omeprazole markedly inhibited basal and pentagastrin-induced acid secretion. Famotidine was less potent than YM022 and omeprazole against both secretions. The degree of increase in plasma gastrin level in the three groups was parallel to the antisecretory potencies of the drugs. At 14 days after the cessation of omeprazole treatment, the secretory response to pentagastrin increased above that of the control. This hyperresponse lasted for > or = 56 days. In the famotidine-treated group, a small increase in secretory response to pentagastrin was observed but was not statistically significant. The increase in secretory response to pentagastrin was paralleled by an increase in mucosal cell mass. In contrast, YM022 not only exhibited a long-lasting inhibition of pentagastrin-induced acid secretion but also prevented the hyperresponse to pentagastrin caused by omeprazole. These results indicate that the hypergastrinemia caused by long-term administration of antisecretory drugs increases mucosal secretory response to pentagastrin through a gastrin/cholecystokinin B receptor-mediated pathway in rats.