Portal hypertension resulting from increased intrahepatic resistance is a common complication of chronic
liver diseases and a leading cause of death in patients with
liver cirrhosis, a
scarring process of the liver that includes components of both increased fibrogenesis and
wound contraction. A reduced production of
nitric oxide (NO) resulting from an impaired enzymatic function of endothelial
NO synthase and an increased contraction of hepatic stellate cells (HSCs) have been demonstrated to contribute to high intrahepatic resistance in the cirrhotic liver. 2-(Acetyloxy)
benzoic acid 3-(nitrooxymethyl) phenyl
ester (NCX-1000) is a chemical entity obtained by adding an NO-releasing moiety to
ursodeoxycholic acid (UDCA), a compound that is selectively metabolized by hepatocytes. In this study we have examined the effect of
NCX-1000 and UDCA on
liver fibrosis and
portal hypertension induced by i.p. injection of
carbon tetrachloride in rats. Our results demonstrated that although both treatments reduced liver
collagen deposition,
NCX-1000, but not UDCA, prevented ascite formation and reduced intrahepatic resistance in
carbon tetrachloride-treated rats as measured by assessing portal perfusion pressure. In contrast to UDCA,
NCX-1000 inhibited HSC contraction and exerted a relaxing effect similar to the NO donor
S-nitroso-N-acetylpenicillamine. HSCs were able to metabolize
NCX-1000 and release
nitrite/
nitrate in cell supernatants. In aggregate these data indicate that
NCX-1000, releasing NO into the liver microcirculation, may provide a novel
therapy for the treatment of patients with
portal hypertension.