Although structural changes are most important to determine vascular resistance in portal hypertension, vasoactive mediators also contribute to its regulation. Hepatic stellate cells (HSCs) are assumed to play a role in modulating intrahepatic vascular resistance based on their residence in the space of Disse and capacity to contract. Because sphingosine 1-phosphate (S1P) has been shown to stimulate HSC contractility, we wondered if S1P could regulate portal pressure. S1P at 0.5-5 muM increased portal pressure in isolated rat perfused liver. This effect was abrogated in the presence of a binding antagonist for S1P(2), JTE-013. Perfusion of isolated rat liver with 5 muM S1P increased Rho activity in the liver, and co-perfusion with JTE-013 cancelled S1P-induced Rho activation. Because S1P is present in human plasma at approximately 0.2 muM, S1P might readily regulate portal vascular tone in physiological and pathological status. The antagonist for S1P(2) merits consideration for treatment of portal hypertension. (C) 2004 Elsevier Inc. All rights reserved.