ETHANOL-INDUCED MODIFICATION OF SOMATOSTATIN-RESPONSIVE ADENYLYL-CYCLASE IN RAT EXOCRINE PANCREAS

Male rats were given 10% (w/v) ethanol in drinking fluid during the fi rst 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 wer e then allowed the withdrawal of ethanol for a period of 2 weeks or 7 weeks. No significant differences were seen for the basal and forskoli n (FK)-stimulated adenylate cyclase (AC) enzyme activities in the panc reatic 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 ra t pancreatic acinar membranes. The ability of the stable GTP analogue 5'-guanylylimidodiphosphate (Gpp[NH]p) to inhibit FK-stimulated AC act ivity was also decreased in pancreatic acinar membranes from ethanol-t reated rats. Gpp[NH]p was a much less potent inhibitor of SS binding i n the pancreatic acinar membranes from chronic ethanol-treated animals than in those from controls, suggesting a change of G(i). A significa nt reduction in the number of I-125-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 ef fect on the parameters cited above persisted. At week 7 of withdrawal, these parameters reached the level of water controls. Ethanol adminis tration did not affect either the number or the affinity of secretin r eceptors as compared to control values which suggests that the change in SS binding is not a non-specific effect. Neither chronic ethanol co nsumption nor withdrawal affected somatostatin-like immunoreactivity ( SSLI). These results suggest that the attenuated inhibition of AC by S S in pancreatic acinar membranes from ethanol-treated rats and ethanol withdrawal (2 weeks) rats may be caused by decreases in both G(i) act ivity 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 a nd in SS-mediated inhibition of AC. Since SS has been suggested to be an inhibitor of basal and cholecystokinin (CCK)- and/or secretin-stimu lated 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 sec retion described after chronic ethanol consumption.