Evaluation of Three Novel Cholecystokinin‐B/Gastrin Receptor Antagonists: A Study of their Effects on Rat Stomach Enterochromaffin‐Like Cell Activity

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Abstract
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 μmol kg−1hr−1, respectively; the corresponding ID50values were 0.002, 0.008, and 0.01 μmol kg−1hr−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.

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