Ethanol inhibits CCK-induced enzyme secretion by affecting calcium-pump activity in isolated rat pancreatic acini

The aim of this study was to clarify the effect of ethanol on stimulus-secretion coupling in pancreatic exocrine secretion. We investigated the effects of 600 mM ethanol on cholecystokinin octapeptide (CCK-8)-stimulated amylase release, cytosolic free Ca2+ concentration ([Ca2+]i) and Ca2+ fluxes using in vitro isolated rat pancreatic acini. Ethanol, given alone, stimulated both the initial and the sustained phases of amylase release. On the other hand, ethanol inhibited only the sustained phase of amylase release stimulated by CCK-8. Ethanol also inhibited amylase release in response to fluoride, a direct activator of guanine nucleotide-binding protein, suggesting that ethanol affects intracellular signal transduction molecules. Ethanol had no influences on the initial rise but increased the sustained rise in [Ca2+]i stimulated by CCK-8 and inhibited CCK-8-stimulated Ca2+ outflux without affecting Ca2+ influx. 8-Bromoguanosine 3':5'-cyclic monophosphate, a membrane-permeable analogue of cGMP regulating membrane Ca(2+)-pump activity in various cells, completely reversed the ethanol-induced inhibition of amylase release and Ca2+ outflux in response to CCK-8 as well as fluoride. Given that Ca2+ plays a critical role in stimulus-secretion coupling in pancreatic exocrine secretion, our results indicate that 600 mM ethanol inhibits CCK-8-stimulated amylase release by inhibiting Ca(2+)-pump activity on the plasma membrane.