The role of nitric oxide in the pathogenesis of systemic and splanchnic vasodilation in cirrhotic rats before and after the onset of ascites

Background: The role of nitric oxide (NO) in the pathogenesis of splanchnic arterial vasodilation in cirrhosis has been recently debated by some experimental studies. Aims: We investigated the role of NO in the pathogenesis of the splanchnic arterial vasodilation along the course of CCl4-induced experimental cirrhosis. Methods: We analyzed the effect on mean arterial pressure (MAP), cardiac output (CO), total peripheral resistance (TPR), and resistance in the superior mesenteric artery (RSMA), before and after the administration of a unspecific NO synthase (NOS) inhibitor (N omega-nitro-L-arginine-methyl-ester, L-NAME) and a specific NOS2 inhibitor (L-N-(1-iminoethyl)-lysine, L-NIL) to cirrhotic rats with and without ascites, and to control rats. NOS2 and NOS3 protein expression was also assessed in systemic and splanchnic arteries of these animals. Results: L-NAME in cirrhotic rats markedly improved MAP, and TPR and decreased CO regardless of whether they had ascites or not. -NAME increased RSMA in cirrhotic rats, but this effect was much less intense in rats with ascites. L-NIL had an effect only on RSMA in rats with ascites, which was of a similar extent to that produced by L-NAME. Western blot experiment showed a faint overexpression of NOS3 in the mesenteric artery of cirrhotic rats with and without ascites and a clear induction of NOS2 only in the mesenteric artery of rats with ascites. Conclusions: These results indicate that NO contributes significantly to the pathogenesis of arterial splanchnic circulation in the early stages of experimental cirrhosis but has only a minor role in its maintenance after the development of ascites. Furthermore, the expression of the different NOS isoforms varies along the course of the liver disease.