Although hypertensive lungs of chronically hypoxic rats express increased levels of nitric oxide (NO) synthases (NOSs) and produce increased amounts of NO-containing compounds (NO_x) during normoxic ventilation, the level of NO production during hypoxic exposure is unclear. Because hypoxia inhibits NO synthesis in normotensive lungs, we investigated whether hypoxic ventilation inhibited NO synthesis in isolated hypertensive lungs and chronically hypoxic rats. Measurement of perfusate NO_x concentration in hypertensive lungs from male rats exposed to 4 wk of hypobaric hypoxia showed that basal NO_x production was reduced during hypoxic (0% O₂) vs. normoxic (21% O₂) ventilation. Similarly, plasma NO_x concentration was lower in chronically hypoxic rats breathing 10% O₂ than in those breathing 21% O₂. Hypoxic inhibition of lung NO_x production was not prevented by supplementary L-arginine or tetrahydrobiopterin and was not mimicked by inhibition of Ca²⁺ influx. However, it was mimicked by inhibition of constitutive NOS with N^G-monomethyl-L-arginine and chelation of intracellular Ca²⁺. The endothelin type B-receptor antagonist BQ-788 prevented the increases in NO_x production associated with normoxic ventilation in both isolated hypertensive lungs and intact chronically hypoxic rats. These results suggest that a reduced supply of the cosubstrate molecular O₂ to NOS counteracts an endothelin type B receptor-mediated stimulation of NO synthesis in hypertensive rat lungs. Thus, despite increased NOS protein in the lungs and pulmonary arteries of chronically hypoxic rats, direct hypoxic inhibition of NO production may contribute to the development of pulmonary hypertension.

nitric oxide; endothelin type B; pulmonary hypertension; nitric oxide synthase; nitric oxide-containing compounds; endothelin-1

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