Urotensin Ⅱ receptor antagonist reduces hepatic resistance and portal pressure through enhanced eNOS-dependent HSC vasodilatation in CCI4-induced cirrhotic rats

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 (CCI4)- 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 CCI4-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-l (COL-I),and transforming growth factor β expression.However,treatment with palosuran can increase MMP-13/TIMP-1,pvasodilator- 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.