Neoangiogenesis and nitric oxide is increased in hepatic arteries of decompensated but not compensated CCl4-cirrhotic rats, a process that can be blocked by Sorafenib

Hepatic arteries in cirrhosis show neoangiogenesis and vasodilatation, the latter mainly as a consequence of increased nitric oxide (Zipprich et al.JHep;49: 739). It remains unclear, when these pathological changes occur during the natural history of cirrhosis, i.e. in compensated or decompensated cirrhosis, and if the multikinase-inhibitor Sorafenib has an inhibitory effect. The aim of the study was to investigate 1)the differences of nitric oxide production in different stages of cirrhosis and 2)the influence of long-time treatment with Sorafenib on the hepatic artery in CCl4-cirrhotic rats. Methods: Cirrhosis was induced by CCl4 administration for 8 (compensated cirrhosis [CC]) and 12 weeks (decompensated cirrhosis [DC]) in the presence or absence of Sorafenib (5mg/kg bw per day). Bivascular liver perfusions were performed. Dose-response curves to the alpha1-receptor agonist methoxamine were obtained in the absence or presence of the nitric oxide synthetase inhibitor L-NMMA (10–4 M). Results: Basal perfusion pressure was significantly lower in DC (p<0.05) compared with Sorafenib-treated DC. In contrast, basal perfusion pressure was similar in CC and Sorafenib-treated CC suggesting, that an increase of neangiogenesis is only typical for DC. Dose-response curves to methoxamine, too, were significantly different in DC (p=0.019 vs. control) compared with Sorafenib-treated DC (n.s. vs. control), while CC and Sorafenib-treated CC did not show any difference. The presence of L-NMMA corrected the response in DC to a level of Sorafenib-treated DC. Therefore, nitric oxide production is increased in DC but not in CC and can be decreased by long-time Sorafenib treatment. Conclusion: Neoangiogenesis and increased nitric oxide production of the hepatic artery appear to be associated with advanced liver disease and decompensated cirrhosis. Treatment with Sorafenib might be a new therapeutic strategy to reduce neoangiogenesis and nitric oxide production of the hepatic artery.