Ethanol-induced modification of somatostatin-responsive adenylyl cyclase in rat exocrine pancreas

Abstract

Male rats were given 10% (w/v) ethanol in drinking fluid during the first week, 15% (w/v) during the second week, 20% (w/v) during the third, and 25% (w/v) during the fourth week, at the end of which they were kept on 25% (w/v) ethanol drinking water for 3 weeks. Some animals were then allowed the withdrawal of ethanol for a period of 2 weeks or 7 weeks. No significant differences were seen for the basal and forskolin (FK_-stimulated adenylate cyclase (AC) enzyme activities in the pancreatic acinar membranes of ethanol-treated and ethanol withdrawal rats as compared to the control group. Chronic ethanol ingestion resulted in an attenuation of somatostatin(SS)-inhibited FK-stimulated AC in rat pancreatic acinar membranes. The ability of the stable GTP analogue 5′-guanylylimidodiphosphate (Gpp[NH]p) to inhibit FK-stimulated AC activity was also decreased in pancreatic acinar membranes from ethanol-treated rats. Gpp[NH]p was a much less potent inhibitor of SS binding in the pancreatic acinar membranes from chronic ethanol-treated animals than in those from controls, suggesting a change of G 1. A significant reduction in the number of 125I-Tyr 11-SS receptors was observed after ethanol ingestion, when compared with control values. Two weeks after the replacement of the ethanol solution by water, the ethanol effect on the parameters cited above persisted. At week 7 of withdrawal, these parameters reached the level of water controls. Ethanol administration did not affect either the number or the affinity of secretin receptors as compared to control values which suggests that the change in SS binding is not a non-specific effect. Neither chronic ethanol consumption nor withdrawal affected somatostatin-like immunoreactivity (SSLI). These results suggest that the attenuated inhibition of AC by SS in pancreatic acinar membranes from ethanol-treated rats and ethanol withdrawal (2 weeks) rats may be caused by decreases in both G i activity and in the number of SS receptors. Alternatively, an uncoupling of SS receptors from G i and/or a decrease in the level of functional G i may result in both a decrease in apparent B max for SS binding and in SS-mediated inhibition of AC. Since SS has been suggested to be an inhibitor of basal and cholecystokinin (CCK)- and/or secretin-stimulated exocrine pancreatic secretion, it is tempting to speculate that the impairment of the SS receptor/effector system seen in the present study can participate in the increase of basal pancreatic exocrine secretion described after chronic ethanol consumption.