A liver-specific nitric oxide donor improves the intra-hepatic vascular response to both portal blood flow increase and methoxamine in cirrhotic rats

Background/Aims: A decreased intra-hepatic nitric oxide (NO) production participates on the pathogenesis of portal hypertension in cirrhosis. We tested the hemodynamic effects of a liver-specific NO donor (NCX-1000) derived from ursodeoxycholic acid in portal hypertensive cirrhotic rats. Methods: After a 14-day treatment with ursodeoxycholic acid or NCX-1000 by gavage, ascitic cirrhotic rats (CCl4-induced) were used in two studies: (1) in vivo mean arterial pressure (MAP), portal pressure (PP) and superior mesenteric artery (SMA) blood flow measurements before and during progressive blood volume expansion (blood infusion); and (2) in situ liver perfusion to obtain dose/response curves to methoxamine (alpha1-adrenergic agonist) and flow/pressure curves. Results: Basal heart rate, MAP, and PP were similar in both groups. During blood infusion, similar MAP and SMA flow increases were observed in both groups; however, PP increase observed in control rats was blunted in NCX-1000 treated rats (P=0.015). In liver perfusions, flow/pressure curves were similar in both groups; however, NCX-1000-treated livers showed a lower response to methoxamine (P=0.016). cGMP concentration in NCX-1000-treated livers was higher (P=0.015) than in controls. Conclusions: Treatment with a liver-specific NO donor improves the portal system adaptability to portal blood flow increase and ameliorates the intra-hepatic response to methoxamine in cirrhotic rats.