Am. J. Respir. Crit. Care Med., Volume 164, Number 5, September 2001, 879-885

Role of Nitric Oxide in Hepatopulmonary Syndrome in Cirrhotic Rats

HILARIO NUNES, DIDIER LEBREC, MICHEL MAZMANIAN, FRÉDÉRIQUE CAPRON, JÖRG HELLER, KHALID A. TAZI, ERIC ZERBIB, ELISABETH DULMET, RICHARD MOREAU, A. TUAN DINH-XUAN, GERALD SIMONNEAU, and PHILIPPE HERVÉ

Surgical Research Laboratory-UPRES (EA-2705), Marie Lannelongue Surgical Center, Paris South University, Paris, France; and Hôpital Beaujon, Clichy, France

The hepatopulmonary syndrome (HPS) is characterized by intrapulmonary vascular dilatations and an increased alveolar-arterial oxygen difference (AaPO₂). Exhaled nitric oxide (NO) concentrations are elevated, suggesting that pulmonary NO overproduction may be the mechanism underlying HPS. We investigated whether common bile duct ligation in rats results in lung NO overproduction and whether normalization of NO synthesis by a 6-wk course of N^G-nitro-L-arginine methyl ester (L-NAME) (5 mg · kg¹ · d¹) prevents HPS. Untreated cirrhotic rats showed increases in AaPO₂ and in cerebral uptake of intravenous ^99mTc-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-dependent NO synthase (NOS) activities; and pulmonary expression of inducible and, to a lesser extent, endothelial NOS. Accumulation of intravascular macrophages accounted for the inducible NOS expression. L-NAME normalized AaPO₂, brain radioactivity, pulmonary vascular resistance, reactivity to hypoxia and angiotensin II, exhaled NO, and NOS activities. These findings suggest that HPS and the associated reduced response to pulmonary vasoconstrictors seen in untreated cirrhotic rats are related to increased pulmonary NO production dependent primarily on increases in the expression and activities of inducible NOS within pulmonary intravascular macrophages.

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