Changes in the hepatic artery perfusion during the development of cirrhosis and the effects of an anti-angiogenic multikinase inhibitor

Hepatic arteries (HA) of cirrhotic livers show neoangiogenesis and vasodilatation, the latter mainly as a consequence of increased nitric oxide (Zipprich et al. JHep;49:739). Both mechanisms lead complementary to a greater influence of the HA on sinusoidal pressure in cirrhosis. It remains however unclear, when these pathological changes occur during the development of cirrhosis and if an anti-angiogenic multikinase-inhibitor treatment has an inhibitory effect.

Aims of the study:

1) the differences of nitric oxide production in different stages of cirrhosis and

2) the influence of long-time and short-time treatment with the anti-angiogenic multikinase inhibitor Sorafenib on the HA in cirrhosis.

Methods: Cirrhosis was induced by CCl4 administration for 8 weeks (early cirrhosis) and 12 weeks (late cirrhosis) in the presence or absence of Sorafenib (5mg/kg bw per day). Sorafenib was given for entire time of development of cirrhosis (i.e. 8 and 12 weeks; long-time treatment) and after cirrhosis was established (i.e. from 8 to 12 weeks; short-time treatment). Bivascular liver perfusions were performed. Dose-response curves to the alpha1-receptor agonist methoxamine of the HA were obtained in the absence or presence of the nitric oxide synthetase inhibitor L-NMMA (10–4M).

Results: HA perfusion pressure was significantly lower in cirrhosis (8 and 12 weeks) compared to normal (p<0.05) and long-time Sorafenib-treated cirrhosis (p<0.05). Short-time Sorafenib treatment increased HA perfusion pressure. Dose-response curves to methoxamine were significantly lower in cirrhosis compared with normal (p<0.05). Long- and short-time treatment with Sorafenib increased the dose-response to methoxamin to a level of normal. Presence of L-NMMA increased the response in cirrhosis only in early cirrhosis to a level of normal. L-NMMA did not change the response to methoxamine of normal, long- and short-time Sorafenib-treated rats.

Conclusion: Hepatic artery vasodilatation is present in early cirrhosis due to increased production of nitric oxide. Neoangiogenesis of the hepatic artery appear to be associated with advanced cirrhosis. Anti-angiogenic treatment might be a new therapeutic strategy to reduce neoangiogenesis and nitric oxide production of the hepatic artery.