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Ethanol can affect the regulation of liver hemodynamics through the release of vasoactive mediators such as nitric oxide and endothelins (ETs). The purpose of this study was to investigate the effects of ethanol on the changes in arterial and portal perfusion pressure induced by ET receptor activation. Ethanol significantly reduced portal, but not arterial perfusion pressure. ET-1 and norepinephrine (used as an ET receptor-independent vasoconstrictor) induced changes in hepatic arterial or portal inflow resistance that were not affected by ethanol treatment. However, an IRL 1620-induced increase in portal, but not arterial, inflow resistance was significantly reduced in ethanol-perfused preparations, an effect observed after either intra-arterial or intraportal administration of the agonist. These results suggest that ethanol can diminish the responsiveness of the portal vascular bed of the canine liver to ETB receptor activation.