Chronic hypercapnia inhibits hypoxic pulmonary vascular remodeling

Chronic hypercapnia is commonly found in patients with severe hypoxic lung disease and is associated with a greater elevation of pulmonary arterial pr essure than that due to hypoxia alone. We hypothesized that hypercapnia wor sens hypoxic pulmonary hypertension by augmenting pulmonary vascular remode ling and hypoxic pulmonary vasoconstriction (HPV). Rats were exposed to chr onic hypoxia [inspiratory O-2 fraction (FIO2) = 0.10], chronic hypercapnia (inspiratory CO2 fraction = 0.10), hypoxia-hypercapnia (FIO2 = 0.10, inspir atory CO2 fraction = 0.10), or room air. After 1 and 3 wk of exposure, musc ularization of resistance blood Vessels and hypoxia-induced hematocrit elev ation were significantly inhibited in hypoxia-hypercapnia compared with hyp oxia alone (P < 0.001, ANOVA). Right ventricular hypertrophy was reduced in hypoxia-hypercapnia compared with hypoxia at 3 wk (P < 0.001, ANOVA). In i solated, ventilated, blood-perfused lungs, basal pulmonary arterial pressur e after 1 wk of exposure to hypoxia (20.1 +/- 1.8 mmHg) was significantly ( P < 0.01, ANOVA) elevated compared with control conditions (12.1 +/- 0.1 mm Hg) but was not altered in hypoxia-hypercapnia (13.5 +/- 0.9 mmHg) or hyper capnia (11.8 +/- 1.3 mmHg). HPV (FIO2 = 0.03) was attenuated in hypoxia, hy poxia-hypercapnia and hypercapnia compared with control (P < 0.05, ANOVA). Addition of N-omega-nitro-L-arginine methyl ester (10(-4) M), which augment ed HPV in control, hypoxia, and hypercapnia, significantly reduced HPV in h ypoxia-hypercapnia. Chronic hypoxia caused impaired endothelium-dependent r elaxation in isolated pulmonary arteries, but coexistent hypercapnia partia lly protected against this effect. These findings suggest that coexistent h ypercapnia inhibits hypoxia-induced pulmonary vascular remodeling and right ventricular hypertrophy, reduces HPV, and protects against hypoxia-induced impairment of endothelial function.