Nitric oxide production in the hypoxic lung

Nitric oxide (NO) is a potent vasodilator and inhibitor of vascular remodel ing. Reduced NO production has been implicated in the pathophysiology of pu lmonary hypertension, with endothelial NO synthase (NOS) knockout mice show ing an increased risk for pulmonary hypertension. Because molecular oxygen (O-2) is an essential substrate for NO synthesis by the NOSs and biochemica l studies using purified NOS isoforms have estimated the Michaelis-Menten c onstant values for O-2 to be in the physiological range, it has been sugges ted that O-2 substrate limitation may limit NO production in various pathop hysiological conditions including hypoxia. This review summarizes numerous studies of the effects of acute and chronic hypoxia on NO production in the lungs of humans and animals as well as in cultured vascular cells. In addi tion, the effects of hypoxia on NOS expression and posttranslational regula tion of NOS activity by other proteins are also discussed. Most studies fou nd that hypoxia limits NO synthesis even when NOS expression is increased.