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

Abstract

Gastrin stimulates rat stomach enterochromaffin-like (ECL) cells via activation of cholecystokinin-Blgastrin 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-nediated response. YF476, JB93182 and AG041R antagonized the gastrin-evoked histidine decarboxylase activation in a dose-dependent manner. YF476, JB93182 and AGO41 R induced maximal inhibition at 0.03, 0.1 and 0.1 pmol kg-' hr-I, respectively; the corresponding IDso values were 0.002, 0.008, and 0.01 pmol kg-' hr-'. YF476 was selected for further analysis. It produced a rightward shift of the gastrin doseresponse 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.

Cholecystokinin and Gastrin Receptors

“…This effect involves activation of CCK1R, as evidenced by studies with antagonists in rats and humans (131,154,437,459,591). Reduction of gastric emptying by a specific CCK1R agonist is also consistent with a CCK1R-mediated mechanism (80).…”

“…In several rat studies, treatment with CCK2R antagonists caused changes in ECL cell activity, indicating the presence of the receptor on these cells (131,195). Binding and functional studies demonstrated that both CCK1R and CCK2R are present on guinea pig chief cells (91, 389).…”

Cholecystokinin-B/gastrin receptors enhance wound healing in the rat gastric mucosa

“…As a control, we also assessed the drug effects on plasma gastrin levels and on cell proliferation in the normal oxyntic mucosa (10,11). Omeprazole and YF-476 caused approximately a sevenfold increase in plasma gastrin levels and a slight, but significant, increase in cell proliferation of the oxyntic mucosa.…”

Lansoprazole Induces Mucosal Protection through Gastrin Receptor-Dependent Up-Regulation of Cyclooxygenase-2 in Rats

“…AG-041R, a potent and specific gastrin receptor antagonist (Ding et al, 1997;Chiba et al, 1998;Fukui et al, 1998;Hakanson et al, 1999), was a gift from Chugai Pharmaceutical Co., Ltd. (Tokyo, Japan). NS-398, a specific inhibitor of COX-2 (Futaki et al, 1993a,b;Masferrer et al, 1994;Tsuji et al, 1996), was purchased from Cayman Chemicals (Ann Arbor, MI).…”

“…The functionally defined receptors for gastrin include cholecystokinin A receptor, which is discriminating for sulfated CCK 8 ; gastrin/cholecystokinin B (CCKB) receptor, which binds gastrin 17 sulfated and nonsulfated CCK 8 with nearly equal affinities; cholecystokinin C, which is a low-affinity gastrin binding protein; and novel, high-affinity receptors selective for amidated gastrin, processing intermediates of gastrin, or both (Yassin, 1999). We also examined the influences of a gastrin/CCKb receptor antagonist (Ding et al, 1997;Chiba et al, 1998;Fukui et al, 1998;Hakanson et al, 1999) on gastric mucosal expression of cyclooxygenase and gastric mucosal protection.…”