CCKA receptor antagonism inhibits mechanisms underlying CCK-8-stimulated insulin release in isolated rat islets.
The influence of the cholecystokinin (CCK)A receptor antagonist, L-364,718, on beta-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. 45Ca2+ 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, Ca2+ and K+ movements stimulated by CCK-8 in isolated islets are all events mediated by CCKA 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.
Karlsson
S
S
Department of Pharmacology, Lund University, Sweden.
Ahrén
B
B
D000818:Animals; D001570:Benzodiazepinones / Q000494:pharmacology; D002132:Calcium Radioisotopes; D020109:Devazepide; D005947:Glucose / Q000494:pharmacology; D006868:Hydrolysis; D066298:In Vitro Techniques; D007294:Inositol / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D010477:Perfusion; D010716:Phosphatidylinositols / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D011949:Receptors, Cholecystokinin / Q000037:antagonists & inhibitors*; D012414:Rubidium Radioisotopes; D012844:Sincalide / Q000037:antagonists & inhibitors / Q000494:pharmacology*
D001570:Benzodiazepinones; D002132:Calcium Radioisotopes; D007328:Insulin; D010716:Phosphatidylinositols; D011949:Receptors, Cholecystokinin; D012414:Rubidium Radioisotopes; D007294:Inositol; D005947:Glucose; D020109:Devazepide; D012844:Sincalide