Novel CCK analogues and bombesin: a detailed analysis between phosphoinositide breakdown and high-dose inhibition of pancreatic enzyme secretion in three rodent species

Abstract

Cholecystokinin octapeptide (26-33) (CCK-8) stimulates pancreatic amylase secretion in a biphasic manner. Amylase secretion is stimulated in a dose-dependent manner up to a maximal level, but reduced secretion is observed at supramaximal concentrations. The downward portion of the dose-response curve has been referred to as "high-dose" inhibition. Recent studies with CCK-8 and Boc-Tyr(SO3H)-Nle-Gyl-Trp-Nle-Asp-2-phenylethylester (JMV-180) using rat acini have suggested that activation of the low-affinity CCK receptor leads to enhanced phosphoinositide (PI) breakdown, which in turn is responsible for high-dose inhibition of enzyme release. However, the secretory effect of JMV-180 varied considerably between rat and mouse. To explore further the relationship between PI breakdown and high-dose inhibition, we compared the effects of JMV-180 as well as the novel cholecystokinin tetrapeptide (30-33) Trp-Met-Asp-Phe-NH2 analogs A-70874 and A-57282, using rat, mouse and guinea pig pancreatic acini. The maximal secretory activity of CCK-8 was lowest (approximately 10% of total cellular amylase) in mouse, as compared with guinea pig and rat (approximately 15-20% of total amylase). The efficacies of A-70874, A-57282 and JMV-180 for stimulation of PI breakdown, relative to CCK-8, were 100, 100 and 45%, respectively, in mouse; 95, 70 and 20%, respectively, in rat and 75, 40 and 0%, respectively, in guinea pig.(ABSTRACT TRUNCATED AT 250 WORDS)