NCX-1000, a NO-releasing derivative of ursodeoxycholic acid, selectively delivers NO to the liver and protects against development of portal hypertension

Portal hypertension resulting from increased intrahepatic resistance is a c ommon complication of chronic liver diseases and a leading cause of death i n patients with liver cirrhosis, a scarring process of the liver that inclu des components of both increased fibrogenesis and wound contraction. A redu ced production of nitric oxide (NO) resulting from an impaired enzymatic fu nction of endothelial NO synthase and an increased contraction of hepatic s tellate cells (HSCs) have been demonstrated to contribute to high intrahepa tic resistance in the cirrhotic liver. 2-(Acetyloxy) benzoic acid 3-(nitroo xymethyl) phenyl ester (NCX-1000) is a chemical entity obtained by adding a n NO-releasing moiety to ursodeoxycholic acid (UDCA), a compound that is se lectively metabolized by hepatocytes. In this study we have examined the ef fect of NCX-1000 and UDCA on liver fibrosis and portal hypertension induced by i.p. injection of carbon tetrachloride in rats. Our results demonstrate d that although both treatments reduced liver collagen deposition, NCX-1000 , but not UDCA, prevented ascite formation and reduced intrahepatic resista nce in carbon tetrachloride-treated rats as measured by assessing portal pe rfusion pressure. In contrast to UDCA, NCX-1000 inhibited HSC contraction a nd exerted a relaxing effect similar to the NO donor S-nitroso-N-acetylpeni cillamine. HSCs were able to metabolize NCX-1000 and release nitrite/nitrat e in cell supernatants. In aggregate these data indicate that NCX-1000, rel easing NO into the liver microcirculation, may provide a novel therapy for the treatment of patients with portal hypertension.