Ethanol–Induced Vasoconstriction Causes Focal Hepatocellular Injury in the Isolated Perfused Rat Liver

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Abstract
: The role of microcirculation in the pathogenesis of alcoholic liver injury was investigated in isolated perfused livers from fed rats. Infusion of ethanol into the portal vein at concentrations ranging from 25 to 200 mmol/L increased portal pressure, which is an indicator of hepatic vasoconstriction, in a concentration–dependent fashion. Portal pressure started to rise immediately on initiation of ethanol load and remained at higher than basal levels throughout the period of ethanol infusion. Release of lactate dehydrogenase, an indicator of cell injury, into the effluent perfusate began to increase after 20 to 30 min of ethanol infusion and continued to increase until the end of the experiment (60 min after the initiation of ethanol infusion). The lactate dehydrogenase level in the effluent perfusate at 60 min was dependent on the ethanol concentration (0 mmol/L, 8 ± 3 IU/L; 25 mmol/L, 22 ± 3 IU/L; 50 mmol/L, 51 ± 11 IU/L; 100 mmol/L, 60 ± 7 IU/L; 200 mmol/L, 120 ± 7 IU/L). Simultaneous infusion of sodium nitroprusside (100 μmol/L), a known vasodilator, inhibited significantly the ethanol–induced increases in portal pressure and lactate dehydrogenase release by abolishing hepatic vasoconstriction. In histological examinations focal hepatocellular necrosis, evidenced by trypan blue staining of cell nuclei, was detected predominantly in midzonal and pericentral areas of the liver lobule after 60 min of ethanol infusion. Change in portal pressure during 60 min of ethanol infusion correlated significantly with levels of lactate dehydrogenase after ethanol infusion (r = 0.82; p < 0.001). These data indicate that ethanol in the portal blood at concentrations higher than 25 mmol/L causes focal hepatocellular necrosis, at least in part because of hepatic vasoconstriction. Therefore this ethanol–induced microcirculatory disturbance might be involved in the pathogenesis of alcoholic liver disease. (HEPATOLOGY 1992;16:1007-1013.)