Portal hypertension is associated with increased hepatic and collateral resistance to an increased portal blood flow. Endothelin-1 (ET-1) can induce intrahepatic vasoconstriction and consequently increase portal pressure. It is unknown if ET-1 also modulates portal pressure by a direct vasoconstrictive effect on collaterals. This study investigated the collateral vascular responses to ET-1, the receptors in mediation, and the regulation of ET-1 action by nitric oxide and prostaglandin. The portal-systemic collaterals of partially portal vein—ligated rats were tested by in situ perfusion. The concentration-response curves of collaterals to graded concentrations of ET-1 (10−10-10−7 mol/L) with or without BQ-123 (ETA receptor antagonist, 2 × 10−6 mol/L), BQ-788 (ETB receptor antagonist, 10−7 mol/L) or both were recorded. In addition, the collateral responses to ET-1 with preincubation of nω-nitro-L-arginine (NNA; 100 mol/L), indomethacin (INDO; 10 mol/L), or in combination were performed. ET-1 increased the perfusion pressure of collaterals and its effect was significantly suppressed by BQ-123 alone and BQ-123 plus BQ-788, but not BQ-788 alone (P < .05). Incubation with NNA, INDO, or both significantly enhanced the response of collaterals to ET-1 (P < .05). These results show that ET-1 produces a direct vasoconstrictive effect on the collateral vessels of portal hypertensive rats. This effect is mediated by ETA, but not ETB, receptors. Both nitric oxide and prostaglandin modulate the collateral vascular response to ET-1 and may therefore participate in the development and maintenance of portal hypertension.