Ethanol-Induced Perturbation of Hepatic Microcirculation: Roles of Endothelin-1 and Nitric Oxide in Regulation of Sinusoidal Tone

Abstract

The role of microcirculation in the pathogenesis of alcoholic liver injury was investigated in isolated perfused rat liver. Upon initiation of ethanol infusion into the portal vein at concentrations ranging from 25 to100mM, portal pressure began to increase in a concentration-dependent manner and reached maximal levels in 2–5min (initial phase), followed by a gradual decrease over the period of ethanol infusion (escape phenomenon). 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 ethanolinduced hepatic vasoconstriction disturbs hepatic microcirculation, resulting in hepatic hypoxia and hepatocellular injury. Endothelin-1 antiserum significantly inhibited hepatic vasoconstriction induced by ethanol by 45–80%. 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 phenomenon and sustained the vasoconstriction. The data suggest that two endothelium-derived vasoactive factors, endothelin-1 and nitric oxide, regulate the sinusoidal tone in the presence of ethanol.