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1 Department of Medicine and Therapeutics, Mater Misericordiae Hospital, and 2 Department of Human Anatomy and Physiology, University College Dublin, Dublin 2, Ireland
Chronic hypercapnia is commonly found in patients with
severe hypoxic lung disease and is associated with a greater elevation of pulmonary arterial pressure than that due to hypoxia alone. We
hypothesized that hypercapnia worsens hypoxic pulmonary hypertension by
augmenting pulmonary vascular remodeling and hypoxic pulmonary vasoconstriction (HPV). Rats were exposed to chronic hypoxia
[inspiratory O2 fraction
(FIO2) = 0.10],
chronic hypercapnia (inspiratory CO2 fraction = 0.10),
hypoxia-hypercapnia (FIO2 = 0.10, inspiratory CO2 fraction = 0.10), or room air. After 1 and 3 wk of exposure, muscularization of
resistance blood vessels and hypoxia-induced hematocrit elevation were
significantly inhibited in hypoxia-hypercapnia compared with hypoxia
alone (P < 0.001, ANOVA). Right
ventricular hypertrophy was reduced in hypoxia-hypercapnia compared
with hypoxia at 3 wk (P < 0.001, ANOVA). In isolated, ventilated, blood-perfused lungs, basal pulmonary
arterial pressure 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 mmHg)
but was not altered in hypoxia-hypercapnia (13.5 ± 0.9 mmHg) or
hypercapnia (11.8 ± 1.3 mmHg). HPV
(FIO2 = 0.03) was attenuated
in hypoxia, hypoxia-hypercapnia, and hypercapnia compared with control (P < 0.05, ANOVA). Addition of
N
-nitro-L-arginine
methyl ester (10
4 M), which
augmented HPV in control, hypoxia, and hypercapnia, significantly
reduced HPV in hypoxia-hypercapnia. Chronic hypoxia caused impaired
endothelium-dependent relaxation in isolated pulmonary arteries, but
coexistent hypercapnia partially protected against this effect. These
findings suggest that coexistent hypercapnia inhibits hypoxia-induced
pulmonary vascular remodeling and right ventricular hypertrophy,
reduces HPV, and protects against hypoxia-induced impairment of
endothelial function.
pulmonary hypertension; nitric oxide; endothelium; vascular resistance
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