NITRIC-OXIDE SYNTHESIS IN THE LUNG - REGULATION BY OXYGEN THROUGH A KINETIC MECHANISM

In this study, we show that oxygen regulates nitric oxide (NO) levels through effects on NO synthase (NOS) enzyme kinetics. Initially, NO sy nthesis in the static lung tvas measured in bronchiolar gases during a n expiratory breath-hold in normal individuals. NO accumulated exponen tially to a plateau, indicating balance between NO production and cons umption in the lung, Detection of NO2-, NO3-, and S-nitrosothiols in l ung epithelial lining fluids confirmed NO consumption by chemical reac tions in the lung. interestingly, alveolar gas NO (estimated from bron chiolar gases at end-expiration) tvas near zero, suggesting NO in exha led gases is not derived from circulatory/systemic sources. Dynamic NO levels during tidal breathing in different airway regions (mouth, tra chea, bronchus, and bronchiole) were similar, However, in individuals breathing varying levels of inspired oxygen, dynamic NO levels were no tably dependent on O-2 concentration in the hypoxic range (KmO2 190 mu M). Purified NOS type II enzyme activity in vitro was similarly depen dent on molecular oxygen levels (KmO2 135 mu M), revealing a means by which oxygen concentration affects NO levels in vivo. Based upon these results, we propose that NOS II if a mediator of the vascular respons e to oxygen in the lung, because its KmO2 allows generation of NO in p roportion to the inspired oxygen concentration throughout the physiolo gic range.