Urotensin II receptor antagonist reduces hepatic resistance and portal pressure through enhanced eNOS-dependent HSC vasodilatation in CCl4-induced cirrhotic rats.

Abstract

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 α smooth muscle actin, collagen-I (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.

• Authors: Ruoxi Zhang, Jing Chen, Diangang Liu, Yu Wang
• Journal: Frontiers of medicine (Front Med) Vol. 13 Issue 3 Pg. 398-408 (Jun 2019) ISSN: 2095-0225 [Electronic] China
• PMID: 30820806 (Publication Type: Journal Article)

Chemical References

• Quinolines
• Receptors, G-Protein-Coupled
• TIMP1 protein, rat
• Tissue Inhibitor of Metalloproteinase-1
• Uts2r protein, rat
• Urea
• Carbon Tetrachloride
• Nitric Oxide Synthase Type III
• Nos3 protein, rat
• rho-Associated Kinases
• 1-(2-(4-benzyl-4-hydroxypiperidin-1-yl)ethyl)-3-(2-methylquinolin-4-yl)urea

Topics

• Animals
• Carbon Tetrachloride
• Hemodynamics
• Hepatic Stellate Cells (drug effects)
• Liver (drug effects, metabolism)
• Liver Cirrhosis (chemically induced, drug therapy)
• Male
• Nitric Oxide Synthase Type III (metabolism)
• Portal Pressure
• Quinolines (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Receptors, G-Protein-Coupled (antagonists & inhibitors)
• Tissue Inhibitor of Metalloproteinase-1 (metabolism)
• Urea (analogs & derivatives, pharmacology)
• rho-Associated Kinases (metabolism)