Alcoholic liver injury predominates in the pericentral region, in which oxygen tension is physiologically lowest. The enhanced injurious effect of ethanol at this site is postulated to be due to hypoxia, resulting from an enhanced oxygen demand of hepatocytes for the oxidative metabolism of ethanol. Moreover, we found that ethanol at higher concentrations induces hypoxia in the liver by causing microcirculatory disturbance. Upon initiation of ethanol infusion into the portal vein of isolated perfused rat liver at concentrations ranging from 25 to 100 mM, portal pressure began to increase in a concentration-dependent manner and reached maximal levels in 2-5 min (initial phase), followed by a gradual decrease over the period of ethanol infusion (escape phase). Sodium nitroprusside, a known vasodilator, diminished the ethanol-induced increase in portal pressure, increased oxygen consumption leading to inhibition of the reduction of the respiratory cytochromes of the liver, and diminished liver injury. The data indicate that the ethanol-induced hepatic vasoconstriction disturbs hepatic microcirculation, leading to hepatic hypoxia and hepatocellular injury. Endothelin-1 antiserum inhibited significantly hepatic vasoconstriction induced by ethanol. Cessation of infusion of endothelin-1 antiserum was followed by a subsequent increase in portal pressure. On the other hand, when a nitric oxide synthesis inhibitor, NG-monomethyl-L-arginine (L-NMMA), was infused into the portal vein simultaneously with ethanol, the initial phase of the response of portal pressure to ethanol was not altered and the peak values of portal pressure remained unchanged. However, following the peak increase in portal pressure, the rate of decrease was less than in the absence of L-NMMA. Thus, L-NMMA diminished the escape phase the sustained the vasoconstriction. Based on the current results, we propose that the sinusoidal tone in the presence of ethanol is regulated predominantly by the actions of the two endothelium-derived vasoactive factors, endothelin-1 and nitric oxide.