CCK A receptor antagonism inhibits mechanisms underlying CCK-8-stimulated insulin release in isolated rat islets

Abstract

The influence of the cholecystokinin (CCK) A receptor antagonist, L-364,718, on β-cell activation was examined in isolated perifused prelabelled rat islets. Insulin secretion and 3H efflux from myo-[2- 3H]inositol-prelabelled islets (reflecting phosphoinositide hydrolysis) stimulated by CCK-8 (100 nM) were both inhibited by L-364,718, partially at 1 nM and totally at 10 nM. 45Ca 2+ efflux from prelabelled islets was markedly stimulated by CCK-8. This stimulation was inhibited equally by 1 and 10 nM L-364,718. CCK-8 stimulated the 86Rb + efflux (reflecting K + movements) from prelabelled islets, which probably reflects an indirect effect of CCK-8 due to opening of Ca 2+-activated K + channels. This 86Rb + efflux was inhibited by L-364,718 at 10 nM but not affected by L-364,718 at 1 nM. It is concluded that insulin secretion, phosphoinositide hydrolysis, Ca 2+ and K + movements stimulated by CCK-8 in isolated islets are all events mediated by CCK A receptors. The L-364,718-induced inhibition of phosphoinositide hydrolysis was most closely correlated to the inhibition of insulin secretion. This suggests that induction of cellular events activated through stimulation of phosphoinositide hydrolysis is a major mechanism underlying CCK-8-stimulated insulin secretion.