Role of nitric oxide in hepatopulmonary syndrome in cirrhotic rats

The hepatopulmonary syndrome (HIPS) is characterized by intrapulmonary vasc ular dilatations and an increased alveolar-arterial oxygen difference (AaPo (2)). Exhaled nitric oxide (NO) concentrations are elevated, suggesting tha t pulmonary NO overproduction may be the mechanism underlying HIPS. We inve stigated whether common bile duct ligation in rats results in lung NO overp roduction and whether normalization of NO synthesis by a 6-wk course of N-G -nitro-L-arginine methyl ester (L-NAME) (5 mg (.) kg(-1) (.) d(-1)) prevent s HIPS. Untreated cirrhotic rats showed increases in AaPo(2) and in cerebra l uptake of intravenous Tc-99m-labeled albumin macroaggregates (indicating intrapulmonary vascular dilatations), with decreases in pulmonary vascular resistance and in pulmonary vasoconstriction induced by angiotensin II and hypoxia. Increases were found in exhaled NO; pulmonary total and calcium-de pendent NO synthase (NOS) activities; and pulmonary expression of inducible and, to a lesser extent, endothelial NOS. Accumulation of intravascular ma crophages accounted for the inducible NOS expression. L-NAME normalized AaP o(2), brain radioactivity, pulmonary vascular resistance, reactivity to hyp oxia and angiotensin II, exhaled NO, and NOS activities. These findings sug gest that HPS and the associated reduced response to pulmonary vasoconstric tors seen in untreated cirrhotic rats are related to increased pulmonary NO production dependent primarily on increases in the expression and activiti es of inducible NOS within pulmonary intravascular macrophages.