Portal hypertension (PHT) is characterized by increased portal pressure caused in part by a reduction in mesenteric vascular resistance. The aim of this study was to evaluate the role of endothelin (ET) and specific ET receptors in maintaining the vasculopathy of PHT. PHT was created in Sprague-Dawley rats by a partial portal vein ligation. Control animals were sham-operated. ET receptor expression was determined in the superior mesenteric artery of sham and PHT rats by in situ autoradiography, radioligand binding analysis, and reverse-transcription polymerase chain reactions (RT-PCR). The pressor response to ET-1 was determined in vitro using isolated vascular rings and in vivo by measuring mean arterial pressure, splanchnic blood flow, and portal venous pressure following treatment with ET and selective ET receptor antagonists. The pressor response to ET in vitro was significantly enhanced in PHT concomitant with increased ET-A and ET-B receptor expression. There was a significant increase in the peak pressor response to ET (10 μg/kg intravenously) in portal hypertensive rats without any significant change in plasma ET-1 levels. There was no significant difference in the peak splanchnic blood flow or portal venous pressure response following ET-A receptor blockade with JKC-301 infusion (200 μg/kg intravenously). In contrast, ET-B receptor blockade with IRL-1038 (200 μg/kg intravenously) preferentially decreased splanchnic blood flow and portal venous pressure in portal hypertensive rats. These data suggest that enhanced ET-B receptor expression in portal hypertensive vessels contributes to the maintenance of elevated portal pressure in these animals.