Novel CCK analogues and bombesin: a detailed analysis between phosphoinositide breakdown and high-dose inhibition of pancreatic enzyme secretion in three rodent species.
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)
Bianchi
B R
BR
Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, Illinois.
Miller
T R
TR
Witte
D G
DG
Lin
C W
CW
D000681:Amylases / Q000378:metabolism*; D000818:Animals; D001839:Bombesin / Q000494:pharmacology*; D002766:Cholecystokinin / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D010179:Pancreas / Q000187:drug effects*; D010716:Phosphatidylinositols / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012844:Sincalide / Q000031:analogs & derivatives / Q000494:pharmacology; D013045:Species Specificity; D013758:Tetragastrin / Q000031:analogs & derivatives / Q000494:pharmacology
D010716:Phosphatidylinositols; D013758:Tetragastrin; C058451:JMV 180; C067892:A 70874; D002766:Cholecystokinin; D000681:Amylases; D012844:Sincalide; D001839:Bombesin