Effects of three different cholecystokinin receptor antagonists on basal and stimulated insulin and glucagon secretion in mice.

Cholecystokinin (CCK) receptor antagonists may be valuable tools for investigating the physiological role of CCK in islet function. In this study, the effects of the three different CCK receptor antagonists, proglumide, CR 1409 and L-364,718, on basal and stimulated insulin and glucagon secretion were investigated in vivo in the mouse. Each of the CCK antagonists was injected intravenously, either alone or together with one of the secretagogues CCK-8 (5.3 nmol kg-1), carbachol (0.16 mumol kg-1) or glucose (2.8 mmol kg-1). At a low dose level, proglumide (28 mumol kg-1) inhibited selectively CCK-8-induced insulin and glucagon secretion. However, at a higher dose level (280 mumol kg-1), proglumide inhibited also carbachol- and glucose-induced insulin secretion. Furthermore, proglumide elevated basal plasma levels of both glucagon and glucose. CR 1409 inhibited CCK-8-induced insulin secretion at a high (21 mumol kg-1) but not at a low (0.21 mumol kg-1) dose level. In contrast, CCK-8-induced glucagon secretion was not affected by CR 1409. L-364,718 (2.4 mumol kg-1) inhibited both CCK-8-induced insulin and glucagon secretion. In contrast, L-364,718 did not affect basal plasma levels of insulin, glucagon or glucose or those levels after stimulation with carbachol or glucose. We conclude that, of these three CCK antagonists, L-364,718 is the most specific CCK receptor antagonist for studies of both insulin and glucagon secretion in the mouse.