Regulation of pulmonary circulation by alveolar oxygen tension via airway nitric oxide

The effects of airway (AH) and vascular hypoxia (VH) on the production of nitric oxide (NO;V˙no) were tested in isolated buffer-perfused (BFL) and blood-perfused rabbit lungs (BLL). To produce AH and/or VH, the lung was ventilated with 1% O₂ gas, and/or the perfusate was deoxygenated by a membrane oxygenator located on the inlet limb to the pulmonary artery. We measured exhaled NO (V˙no), accumulation of perfusate NOx, and pulmonary arterial pressure (Ppa) during AH (inspired O₂ fraction = 0.01) and/or VH (venous $P{O}_2$ = 26 Torr). In BFL, a pure AH without VH caused decreases inV˙no and NOx accumulation with a rise in Ppa. However, neitherV˙no, NOx accumulation, nor Ppa changed during VH. Similarly, in BLL, only AH reduced V˙no, although NOx accumulation was not measurable because of Hb. When alveolar $P{O}_2$ was gradually reduced from 152 to 0 Torr for 20 min, AH reducedV˙nocurvilinearly from 73.9 ± 8 to 25.6 ± 8 nl/min in BFL and from 26.0 ± 2 to 5.2 ± 1 nl/min in BLL. This plot was analogous to that of a substrate-velocity curve for an enzyme obeying Michaelis-Menten kinetics. The apparent Michaelis-Menten constant for O₂ was calculated to be 23.2 μM for BLL and 24.1 μM for BFL. These results indicate that theV˙no in the airway epithelia is dependent on the level of inspired O₂ fraction, leading to the tentative conclusion that epithelial NO synthase is O₂ sensitive over the physiological range of alveolar $P{O}_2$ and controls pulmonary circulation.