ENDOTHELIUM-DERIVED RELAXING FACTOR ACTIVITY IN RAT LUNG DURING HYPOXIC PULMONARY VASCULAR REMODELING

We have investigated the role of endothelium-derived relaxing factor in modulating hypoxic pulmonary vasoconstriction by inhibiting its synthesis with the false substrate N(G)-monomethyl-L-arginine (L-NMMA) in the isolated blood-perfused lungs of Wistar rats after chronic hypoxia (CH, fractional inspiratory 0, concentration 10%) for 15 h, 2 days, and 7 days. Lungs were perfused with blood of normal hematocrit at constant flow (18 ml/min) ventilated with 1) 95% air-5% CO2 (normoxia) and 2) 2% O2-5% CO2-93% N2 (hypoxia) and were studied in the absence and presence Of L-NMMA (30 and 300 muM) or L-arginine (L-Arg, 1 and 6 mM) in separate groups. Pulmonary arterial pressure (Ppa) rose incrementally with hypoxic exposure (all P < 0.05 vs. normoxic control group). Hypoxic pulmonary vasoconstriction (HPV) was markedly reduced after 15 h and 2 days of CH: the mean increases in Ppa (DELTAPpa) in hypoxia were 15.3, 3.5, 3.8, and 13.6 mmHg in control rats and rats exposed to 15 h (P < 0.05 vs. control and 7 days of CH), 2 days (P < 0.001 vs. control and 7 days of CH), and 7 days of CH, respectively. Ppa in control rats and rats exposed to 15 h, 2 days, and 7 days of CH were 137, 179, 184, and 166% of control, respectively, after 30 muM L-NMMA (all P < 0.05 when expressed as percent change vs. no L-NMMA). Similar augmentation in HPV was seen after 30 muM L-NMMA, with all hypoxic groups having a greater response than control groups. Hypoxic Ppa in control rats and rats exposed to 15 h, 2 days, and 7 days of CH were 96, 85 (P < 0.05 vs. control), 82 (P < 0.01 vs. control), and 91% of control after 1 MM L-Arg and 88, 77 (P < 0.05 vs. control), 56 (P < 0.001 compared with control and 7 days of CH), and 82% of control after 6 MM L-Arg. The attenuation of HPV at 15 h and 2 days of CH with partial restoration toward normal by L-NMMA suggests that the early phase of CH exposure is associated with release of endothelium-derived relaxing factor.