Endothelium-derived Relaxing Factor Inhibits Hypoxic Pulmonary Vasoconstriction in Rats

The hypothesis that endothelium-derived relaxing factor (EDRF) modulates hypoxic pulmonary vasoconstriction (HPV) was tested in isolated, blood-perfused rat lungs ventilated with gas mixtures of 21% O2-5% CO2-74% N2 (normoxia) or of 3% O2-5% CO2-92% N2 (hypoxia); 30 µM NG-monomethyl-l-arginine (l-NMMA), an inhibitor of EDRF production, caused a reduction in the endothelium-dependent relaxant response to acetylcholine (ACh) from 62 ± 7, 88 ± 4, and 100 ± 4% to 26 ± 8, 49 ± 12, and 75 ± 7% at ACh concentrations of 1, 10, and 100 µM, respectively (p < 0.05 at all concentrations), indicating that l-NMMA acts via the inhibition of EDRF production. l-NMMA induced a concentration-related augmentation in HPV of 20 ± 5, 32 ± 8, and 34 ± 8% at concentrations of 30, 300, and 1,000 µM (p < 0.05, compared with a vehicle control group at all concentrations). The pressor response to a dose of anglotensin II (A-II), which produced the same increase in pulmonary artery pressure as that induced by hypoxia, was also significantly augmented (2 ± 0.6%), but to a lesser extent. The augmentation of HPV by 30 µM l-NMMA was completely reversed by 1 mM l-arginine (a precursor of EDRF), but not by d-arginine (an isomer of l-arginine). One and 6 mM l-arginine, but not 6 mM d-arginine caused a significant inhibition of HPV by 20 ± 2 and 47 ± 12% (p< 0.05, compared with the vehicle control group) and a small but not significant reduction in A-II-mediated contraction. We conclude that endothelium-derived relaxing factor modulates HPV and that the modulating action of EDRF on pulmonary blood pressure may be more relevant to HPV than to A-II-induced contraction. The ability of l-arginine to reduce HPV suggests that the formation of EDRF during hypoxemia may be limited by the availability of its precursor.