PROTECTIVE EFFECT OF EBSELEN ON CONSTRICTIVE HEPATIC VASCULATURE - PREVENTION OF ALCOHOL-INDUCED EFFECTS ON PORTAL PRESSURE IN PERFUSED LIVERS

The effect of an organoselenium compound, ebselen [2-phenyl-1,2-benzis oselenazol-3-(2H)-one], on ethanol-induced liver damage through pertur bation of microcirculation was investigated in perfused livers from fe d rats. Infusion of ethanol at concentrations greater than or equal to 25 mM into the portal vein increased portal pressure in a concentrati on-dependent manner. Release of lactate dehydrogenase (LDH) into the e ffluent perfusate was minimal at 30 min; thereafter LDH release began to increase gradually until the end of the experiment (60 min after th e onset of ethanol infusion) and was dependent on ethanol concentratio n. Simultaneous infusion of ebselen at a concentration of 10 or 30 mu M with ethanol reduced significantly this ethanol-induced increase in portal pressure by 50 to 75% (P < .05) and LDH release by 70% (P < .05 ). When endothelin-1 or phenylephrine was infused into the liver, port al pressure was increased, reaching maximal levels (50 +/- 17 and 46 /- 7 mm of H2O, respectively) and then decreasing gradually. Ebselen r educed the maximal increase in portal pressure induced by endothelin-l (18 +/- 2 mm of H2O) by 64% (P < .05). In addition, ebselen decreased the maximal levels of portal pressure induced by phenylephrine (8 +/- 1 mm of H2O) by 83% (P < .05). These data indicate that ebselen has a vasodilative effect on constriction of hepatic vasculature and dimini shes ethanol-induced hepatic damage by offsetting ethanol-induced incr ease in portal pressure. Thus, ebselen may prove useful for treatment of alcoholic liver injury via improvement of microcirculatory disturba nces.