Cyclosporine A Inhibits Protein-Kinase-C-Mediated Amylase Release from Isolated Rat Pancreatic Acini

Abstract

The present study was performed to characterize a direct influence of cyclosporine A (CsA) on exocrine pancreatic enzyme secretion. CsA inhibited dose-dependently amylase release from isolated rat pancreatic acini in response to carbachol or cholecystokinin octapeptide (CCK-8). A significant reduction in amylase release by 17% was observed at 0.2 μmol/l CsA (p < 0.001) when compared to controls. At 0.2 mmol/l, CsA reduced amylase release in response to both secretagogues by maximally 45%, whereas basal secretion was not affected. CsA had no influence on CCK-8-stimulated increase in intracellular Ca²⁺ concentrations or amylase release in response to the Ca²⁺ ionophore A 23187. In contrast, the dose-response curve for amylase secretion induced by the phorbol ester phorbolmyristate-13-acetate was shifted to the right without a reduction of the maximal secretory response. Unexpectedly, vasoactive-intestinal-polypeptide- and secretin-stimulated acinar secretion was not diminished by CsA. In isolated pancreatic lobules exposed to 0.1 mmol/l CsA, amylase release stimulated by cerulein or veratridine was reduced by 26.7 ± 2 or 28.3 ± 4%, respectively. CsA had no influence on the displacement of ¹²⁵I-Bolton-Hunter-labeled CCK-8 from acinar CCK receptors. The ultrastructure of cellular organelles in isolated lobules was not altered after incubation with 0.1 mmol/l CsA for 60 min. Our data suggest that CsA interferes with proteinkinase-C-mediated signal transduction in isolated rat pancreatic acini, without affecting cAMP-dependent signalling.

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“…Augments synthesis of ACh (Esqui¢no et al, 1997), and also interferes with protein kinase C-mediated signal transduction from mAChR (Hoecker et al, 1994).…”