Background: One of the early events leading to alcoholic pancreatitis seems to be the effect of ethanol on stimulus-secretion coupling. This study examines ethanol-induced modifications of filamentous actin (F-actin) content and localization in acini, the resulting alpha-amylase secretion and the role of protein kinase C (PKC) activity in these processes.
Methods: Freshly isolated acini were treated with different concentrations of ethanol or cholecystokinin octapeptide (CCK-8) for different periods. F-actin was localized by confocal laser scanning microscopy; its quantity was determined fluorometrically, and the alpha-amylase secretion was measured.
Results: Ethanol caused F-actin reorganization resembling the effects of supramaximal CCK-8 stimulation and of direct PKC activation by phorbol-12-myristate-13-acetate. The polyphasic time course of the F-actin content also resembled that under supramaximal CCK-8 stimulation and was counteracted by inhibition of PKC. The PKC inhibitor bisindolylmaleimide I did not increase the ethanol- induced alpha-amylase secretion, but the suboptimally CCK-8-stimulated secretion via high-affinity receptors.
Conclusion: Ethanol, like supramaximal CCK-8 concentrations, inhibits acinar secretion by reorganization of the actin cytoskeleton via PKC activation. This effect is suggested to be mediated by low-affinity CCK-A receptors. Together with the ethanol-induced stimulation of early steps of stimulus-secretion coupling, this may be a pancreas-damaging mechanism resembling that in experimental hyperstimulation pancreatitis.
Copyright 2004 S. Karger AG, Basel and IAP