Resveratrol improves intrahepatic endothelial dysfunction and reduces hepatic fibrosis and portal pressure in cirrhotic rats

Background & Aims: Resveratrol, a polyphenol found in a variety of fruits, exerts a wide range of beneficial effects on the endothelium, regulates multiple vasoactive substances and decreases oxidative stress, factors involved in the pathophysiology of portal hypertension. Our study aimed at evaluating the effects of resveratrol on hepatic and systemic hemodynamics, hepatic endothelial dysfunction, and hepatic fibrosis in CCl4 cirrhotic rats. Methods: Resveratrol (10 and 20 mg/kg/day) or its vehicle was administered to cirrhotic rats for two weeks and hepatic and systemic hemodynamics were measured. Moreover, we evaluated endothelial function by dose-relaxation curves to acetylcholine, hepatic NO bioavailability and TXA(2) production. We also evaluated liver fibrosis by Sirius Red staining of liver sections, collagen-1, NF kappa B, TGF beta mRNA expression, and desmin and alpha-smooth muscle actin (alpha-SMA) protein expression, as a surrogate of hepatic stellate cell activation. Results: Resveratrol administration significantly decreased portal pressure compared to vehicle (12.1 +/- 0.9 vs. 14.3 +/- 2.2 mmHg; p <0.05) without significant changes in systemic hemodynamics. Reduction in portal pressure was associated with an improved vasodilatory response to acetylcholine, with decreased TXA(2) production, increased endothelial NO, and with a significant reduction in liver fibrosis. The decrease in hepatic fibrosis was associated with a reduced collagen-1, TGF beta, NF kappa B mRNA expression and desmin and alpha-SMA protein expression. Conclusions: Resveratrol administration reduces portal pressure, hepatic stellate cell activation and liver fibrosis, and improves hepatic endothelial dysfunction in cirrhotic rats, suggesting it may be a useful dietary supplement in the treatment of portal hypertension in patients with cirrhosis. (c) 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.