Evaluation of three novel cholecystokinin-B/gastrin receptor antagonists: a study of their effects on rat stomach enterochromaffin-like cell activity.

Gastrin stimulates rat stomach enterochromaffin-like (ECL) cells via activation of cholecystokinin-B/gastrin receptors. The stimulation is manifested in the activation of the histamine-forming enzyme histidine decarboxylase and in the secretion of histamine and pancreastatin, a chromogranin A-derived peptide. We have examined the short-term effects of three novel cholecystokinin-B/gastrin receptor antagonists (YF476, JB93182 and AG041R) on the ECL cells in intact fasted rats. The drugs and/or gastrin were infused intravenously for 3 hr and the oxyntic mucosal histidine decarboxylase activity and the serum pancreastatin concentration were measured. We also studied the effects of the three drugs on gastric emptying in mice, a cholecystokinin-A receptor-mediated response. YF476, JB93182 and AG041R antagonized the gastrin-evoked histidine decarboxylase activation in a dose-dependent manner. YF476, JB93182 and AG041R induced maximal inhibition at 0.03, 0.1 and 0.1 mumol kg-1 hr-1, respectively; the corresponding ID50 values were 0.002, 0.008, and 0.01 mumol kg-1 hr-1. YF476 was selected for further analysis. It produced a rightward shift of the gastrin dose-response curve, consistent with competitive inhibition. Moreover, it antagonized the omeprazole-evoked histidine decarboxylase activation and the gastrin- and omeprazole-induced rise in the circulating pancreastatin concentration. None of the three drugs tested inhibited gastric emptying or prevented the cholecystokinin-8s-induced inhibition of gastric emptying at the doses tested. The results show that YF476, JB93182 and AG041R are potent and selective cholecystokinin-B/ gastrin receptor antagonists, and that YF476 is 4-5 times more potent than JB93182 and AG041R.