Increased serum urotensin Ⅱ (UⅡ) levels in human cirrhotic populations have been recently shown,but the long-term effects of UⅡ receptor antagonist on the cirrhosis have not been investigated.To investigate the therapeutic effects of urotensin Ⅱ receptor (UT) antagonist palosuran on rats with carbon tetrachloride (CCl4)-induced cirrhosis,the hepatic and systemic hemodynamics,liver fibrosis,the metalloproteinase-13 (MMP-13)/tissue inhibitor of metalloproteinase-1 (TIMP-1) ratio,hepatic Rho-kinase activity,and the endothelial nitric oxide synthase (eNOS) activity are measured in CCl4-cirrhotic rats treated with palosuran or vehicle for 4 weeks.Primary hepatic stellate cells (HSCs) are used to investigate the changes in UⅡ/UT expression and the in vitro effect of palosuran.Compared with the vehicle-treated cirrhotic rats,treatment with palosuran can reduce the portal pressure (PP),decrease the risk of liver fibrosis and the level of a smooth muscle actin,collagen-Ⅰ (COL-Ⅰ),and transforming growth factor β expression.However,treatment with palosuran can increase MMP-13/TIMP-1,p-vasodilator-stimulated phosphoprotein (p-VASP),and p-eNOS expression.Moreover,in vitro UⅡ/UT mRNA expression increases during HSC activation.MMP-13/TIMP-1,COL-Ⅰ,and p-VASP are inhibited after palosuran treatment.Our data indicate that long-term administration of palosuran can decrease PP in cirrhosis,which results from decreased hepatic fibrosis and enhanced eNOS-dependent HSC vasodilatation.