Hypoxia inhibits increased ETB receptor-mediated NO synthesis in hypertensive rat lungs

Although hypertensive lungs of chronically hypoxic rats express increased l evels of nitric oxide (NO) synthases (NOSs) and produce increased amounts o f NO-containing compounds (NOx) during normoxic ventilation, the level of N O production during hypoxic exposure is unclear. Because hypoxia inhibits N O synthesis in normotensive lungs, we investigated whether hypoxic ventilat ion inhibited NO synthesis in isolated hypertensive lungs and chronically h ypoxic rats. Measurement of perfusate NOx concentration in hypertensive lun gs from male rats exposed to 4 wk of hypobaric hypoxia showed that basal NO x production was reduced during hypoxic (0% O-2) vs. normoxic (21% O-2)vent ilation. Similarly, plasma NOx concentration was lower in chronically hypox ic rats breathing 10% O-2 than in those breathing 21% O-2. Hypoxic inhibiti on of lung NOx production was not prevented by supplementary L-arginine or tetrahydrobiopterin and was not mimicked by inhibition of Ca2+ influx. Howe ver, it was mimicked by inhibition of constitutive NOS with N-G-monomethyl- L-arpinine and chelation of intracellular Ca2+. The endothelin type B-recep tor antagonist BQ-788 prevented the increases in NOx production associated with normoxic ventilation in both isolated hypertensive lungs and intact ch ronically hypoxic rats. These results suggest that a reduced supply of the cosubstrate molecular O-2 to NOS counteracts an endothelin type B receptor- mediated stimulation of NO synthesis in hypertensive rat lungs. Thus, despi te 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.