Cirrhosis of liver leads to portal hypertension and the development of portal-systemic collaterals. 10 The increased hepatic and collateral resistances to an increased portal blood flow maintain portal hypertension. 11 Recently, a possible role of endothelins in the pathophysiology of portal hypertension has been suggested. ET-1 was found to induce hepatic vasoconstriction and subsequently increase portal venous resistance. 4,12 In addition, ET-1 could stimulate contraction of hepatic stellate cells to increase intrahepatic resistance. 13 In vitro experiments also showed that ET-1 produced contraction of rat portal vein. 14 Furthermore, the mesenteric expressions of ET A and ET B receptors and ET-1-induced vasoconstriction were significantly enhanced in partially portal veinligated (PVL) rats. 5 Recently, it has been shown that bosentan, a nonselective endothelin receptor antagonist, significantly reduced the portal pressure of portal hypertensive rats. 15 However, it is not clear if ET-1 could modulate portal pressure by a direct constrictive effect on the collateral vessels of portal hypertensive rats.The aims of this study were to investigate the vascular activity and the receptor-mediated effects of ET-1 on the portalsystemic collaterals of portal hypertensive rats. The regulation of nitric oxide (NO) and prostaglandin on the effects of ET-1 was also evaluated. MATERIALS AND METHODSMale Sprague-Dawley rats weighing 280 to 300 g at the time of surgery were used for experiments. The rats were housed in a plastic cage and allowed free access to food and water. All rats were fasted for 12 hours before operation. In all experiments, the investigators adhered to the American Physiological Society Guiding Principles for the Care and Use of Laboratory Animals.A prehepatic portal hypertensive animal model was created as previously reported. 16 Anesthesia was performed with ketamine HCl (100 mg/kg body weight, intramuscularly). In brief, the portal vein was isolated and a 3-0 silk ligature was tied around both the portal vein and an adjacent 20-gauge blunt-tipped needle. The needle was then removed and the vein allowed to reexpand. A second loose ligature was left around the portal vein with 2 endings of the ligature placed on each side in the abdominal cavity. The abdomen was then closed and the animal was allowed to recover. Perfusion studies were performed in overnight-fasted rats 10 to 13 days after the operation, at which time an extensive collateralization of the portal system was fully established. 17 The body weights of rats were measured on the day of perfusion studies.Abbreviations: ET-1, endothelin-1; PVL, portal vein-ligated; NO, nitric oxide; NNA, n -nitro-L-arginine; INDO, indomethacin.From the Divisions of