Protective effect of gabexate mesilate (FOY) against pancreatic injuries induced by ethanol in rats.

Abstract

Four-hour intravenous ethanol infusion at two doses of 0.5 and 1.0 g/kg.hr caused mild, but significant, rises in serum amylase and pancreatic water content as well as pancreatic histological changes such as interstitial edema in rats. These doses of ethanol also caused an impaired pancreatic adenylate energy charge levels and increased pancreatic mitochondrial fragility. The dose of 0.2 g/kg.hr caused only marginal changes in these parameters. Moreover, gabexate mesilate (FOY) at the dose of 20 mg/kg.hr inhibited almost completely all these pancreatic injuries induced by ethanol, exerting significant protective effects. These results suggest that impaired pancreatic energy metabolism and increased mitochondrial fragility seem to play an important role in the pathogenesis of ethanol-induced pancreatic injuries, and that some unknown protease activity, which can be inhibited by FOY, also seems to play an important role. Finally, FOY seems to be useful in protecting the exocrine pancreas in the alcoholic patients. Excessive intake of ethanol often precedes the development of both acute and chronic pancreatitis, and pancreatitis occurs more commonly in alcoholics than in the general population. Thus, alcohol has been reported to be one etiological factor in the pathogenesis of human pancreatitis. However, little is known about the mechanism whereby alcohol induces pancreatic acinar cell injuries. Moreover, there have been few reports regarding the effect of ethanol on pancreatic adenylate energy metabolism. Recently, we have reported the important role of subcellular organellar fragility in the triggering of pancreatic injuries in other models of pancreatitis such as secretagogue-induced and pancreatic duct obstruction. In this study, we evaluated the effect of ethanol administration at various doses on the exocrine pancreas from several parameters including pancreatic adenylate energy charge levels and subcellular organellar fragility as well as the protective effect of a synthetic protease inhibitor, gabexate mesilate (FOY) [ethyl-4-(6-guanidino hexanyloxy benzoate) methanesulfonate; M.W. 417 daltons].