SUPRAMAXIMAL INHIBITION OF CHOLECYSTOKININ-INDUCED PANCREATIC AMYLASERELEASE INVOLVES DESENSITIZATION TO CYTOPLASMIC CA2+

Background: Cholecystokinin (CCK) is a major stimulant of pancreatic e nzyme secretion. The dose-response relationship for CCK-induced secret ion is bell-shaped, with a characteristic supramaximal inhibition. The mechanism for this inhibition has now been studied. Methods: The kine tics of amylase release and the changes of the cytoplasmic Ca2+ concen tration ([Ca2+](i)) were recorded during stimulation of guinea-pig pan creatic acinar cells with different concentrations of cholecystokinin octapeptide (CCK-8) and the Ca2+ ionophore ionomycin. Results: Individ ual cells reacted with [Ca2+](i) oscillations at 10(-11)-10(-10) M CCK -8 and with an initial peak followed by a sustained suprabasal level a t 10(-9)-10(-8) M of the agonist. The latter response was also seen in suspensions of acinar cells at all tested concentrations of CCK-8 and at 10(-6)-10(-5) M Of ionomycin. With increases of extracellular Ca2 from 0.5 to 5.0 mM there was a rise of [Ca2+](i) during exposure to 1 0(-9)-10(-8) M CCK-8 or 10(-5) M ionomycin but a paradoxical decrease at lower concentrations of CCK-8 or ionomycin. A dose-dependent increa se of amylase release was seen at CCK-8 concentrations from 10(-11) to 10(-9) M. At 10(-9)-10(-8) M CCK-EI secretion was characterized by an initial peak followed by a sustained phase. Whereas the initial peak of secretion remained unaffected by increasing CCK-8 from 10(-9) to 10 (-8) M, the sustained phase was inhibited (supramaximal inhibition). I ncreasing extracellular Ca2+ from 0.5 to 5.0 mM transiently enhanced s ecretion in response to 10(-9) M but lacked effect during supramaximal inhibition of secretion by 10(-8) M CCK-8. Conclusions: Both initial and sustained CCK-8-stimulated amylase release increase with [Ca2+](i) . However, supramaximal inhibition of secretion was not due to a decre ase of [Ca2+](i) but was characterized by desensitization to the stimu latory effect of [Ca2+](i).