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) over dot 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% O-2 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) over dot NO), accumulation of perfusate NOx, and pulmonary arterial pressure (Ppa) during AH (inspired O-2 fraction = 0.01) and/or VH (venous PO2 = 26 Torr). In BFL, a pure AH without VH caused decreases in (V) over dot NO and NOx accumulation with a rise in Ppa. However, neither (V) over dot NO, NOx accumulation, nor Ppa changed during VH. Similarly, in BLL, only AH reduced (V) over dot NO, although NOx accumulation was not measurable because of Hb. When alveolar PO2 as gradually reduced from 152 to 0 Torr for 20 min, AH reduced (V) over dot NO curvilinearly 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 O-2 was calculated to be 23.2 mu M for BLL and 24.1 mu M for BFL. These results indicate that the (V) over dot NO in the airway epithelia is dependent on the level of inspired O-2 fraction, leading to the tentative conclusion that epithelial NO synthase is O-2 sensitive over the physiological range of alveolar PO2 and controls pulmonary circulation.