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 synthesis in the static lung tvas measured in bronchiolar gases during an expiratory breath-hold in normal individuals. NO accumulated exponentially to a plateau, indicating balance between NO production and consumption in the lung, Detection of NO2-, NO3-, and S-nitrosothiols in lung epithelial lining fluids confirmed NO consumption by chemical reactions in the lung. interestingly, alveolar gas NO (estimated from bronchiolar gases at end-expiration) tvas near zero, suggesting NO in exhaled gases is not derived from circulatory/systemic sources. Dynamic NO levels during tidal breathing in different airway regions (mouth, trachea, bronchus, and bronchiole) were similar, However, in individuals breathing varying levels of inspired oxygen, dynamic NO levels were notably dependent on O-2 concentration in the hypoxic range (KmO2 190 mu M). Purified NOS type II enzyme activity in vitro was similarly dependent 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 response to oxygen in the lung, because its KmO2 allows generation of NO in proportion to the inspired oxygen concentration throughout the physiologic range.