Proglumide Analogues CR 1409 and CR 1392 Inhibit Cholecystokinin-Stimulated Insulin Release More Potently Than Exocrine Secretion from the Isolated Perfused Rat Pancreas

Abstract

The effects of proglumide-related cholecystokinin (CCK) receptor antagonists CR 1409 and CR 1392 on CCK-octapeptide (CCK-8)-stimulated immunoreactive insulin (IRI) release and exocrine secretion were examined simultaneously in the isolated perfused rat pancreas. The CR 1409, at concentrations of 10-100 nM, significantly inhibited CCK-8 (100 pM) stimulation on IRI release but failed to inhibit the stimulatory effect of CCK-8 on both pancreatic juice flow and protein secretion. Increasing concentrations of CR 1409 inhibited both CCK-8-stimulated IRI release and exocrine secretion. Half-maximal inhibition was observed with approximately 2 nM for IRI release and 1 microM for protein secretion. When a higher dose (1 nM) of CCK-8 was used, the inhibitory effect of 10 nM CR 1409 on CCK-8-stimulated IRI release was abolished, whereas 10 microM CR 1409 retained significant inhibitory effect. Furthermore, 1 microM carbachol-induced IRI release was not altered by the addition of 10 microM CR 1409. The CR 1392 also had an inhibitory effect on both CCK-8-stimulated IRI release and exocrine secretion. The concentration of CR 1392 that caused half-maximal inhibition of CCK-8-stimulated IRI release was 300 times lower than that of exocrine secretion. In addition, 1 microM carbachol-stimulated IRI release was not altered by 100 microM CR 1392. Thus, the inhibitory effects of CR 1409 and CR 1392 on IRI release were mediated through the interaction at the CCK receptor and were more potent than those on juice and protein secretion. This study suggests, therefore, that CCK receptors on B cells might be different from those on acinar cells in terms of their relative affinities for antagonists.