Prolonged Administration of l-Arginine Ameliorates Chronic Pulmonary Hypertension and Pulmonary Vascular Remodeling in Rats

Abstract

Background Endothelium-dependent nitric oxide–mediated vasodilation is impaired in rats with pulmonary hypertension (PH) induced by chronic hypoxia or by monocrotaline injection. We therefore investigated whether the prolonged administration of the nitric oxide precursor l-arginine would alleviate PH in both rat models. Methods and Results Fifty-nine rats were exposed to hypobaric hypoxia (380 mm Hg, 10 days) or room air and injected intraperitoneally with l-arginine (500 mg/kg),d-arginine (500 mg/kg), or saline once daily from day −3 to day 10. An additional 38 rats injected subcutaneously with monocrotaline (60 mg/kg) or saline were treated similarly with l-arginine or saline from day −3 to day 17. At the end of the experiment, awake mean pulmonary arterial pressure was determined. The heart was dissected to weigh the right ventricle, and the lungs were obtained for vascular morphometric analysis. Hypoxic rats developed PH (30.8±0.7 versus 19.2±0.4 mm Hg in controls;P<.05) and right ventricular hypertrophy. Their pulmonary arterial wall thickness and the proportion of muscular arteries in the peripheral arteries increased.l-Arginine but not d-arginine reduced PH (24.8±0.7 mm Hg;P<.05), right ventricular hypertrophy, and pulmonary vascular disease. Monocrotaline rats developed PH (34.9±2.1 versus 18.8±1.2 mm Hg in controls;P<.05), right ventricular hypertrophy, and pulmonary vascular disease. Again,l-arginine reduced PH (24.3±1.7 mm Hg;P<.05), right ventricular hypertrophy, and pulmonary vascular disease. Conclusions We conclude that l-arginine ameliorated the changes associated with PH in rats, perhaps by modifying the endogenous nitric oxide production.