New strategy for the antifibrotic therapy with oral administration of FR260330 (a selective inducible nitric oxide synthase inhibitor) in rat experimental liver cirrhosis.

Inducible nitric oxide synthase (iNOS) activity is significantly elevated in viral hepatitis, alcoholic cirrhosis, and cholestasis. However, there are few reports on the relationship between iNOS and cirrhosis. Here, we investigated the effects of a new iNOS inhibitor that has been developed for oral administration in an experimental rat liver cirrhosis model. A cirrhotic rat model was developed by long-term administration of thioacetamide injections. FR260330 is a new, rationally designed, selective iNOS inhibitor that can be administered orally. After 12 weeks of treatment with FR260330, the rats showed inhibition of progressions of cirrhosis, ascites, and splenomegaly as well as a significant reduction in the proportions of connective tissue in the liver. The expression of nitrotyrosine, which indicates the existence of peroxynitrite and nuclear factor-kappaB activation, was remarkably decreased in the FR260330 treatment group. In addition, immunohistochemical and Western blot analyses showed that the expression of transforming growth factor-beta1 was remarkably decreased in this group. The present study demonstrates that FR260330 reduces liver fibrosis by the inhibition of transforming growth factor-beta1 and retards the development of cirrhosis. This oral iNOS inhibitor will be a new strategy for the treatment of cirrhosis.