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Recent studies have characterized a rebound pulmonary vasoconstriction with abrupt withdrawal of inhaled nitric oxide (NO) during therapy for pulmonary hypertension. Although it has been suggested that inhaled NO may down-regulate basal NO production, the exact mechanism of this rebound pulmonary hypertension remains unclear. The objectives of these studies were to determine the effect of NO exposure on endothelial NOS (eNOS) gene expression and enzyme activity. The addition of NO donors had no effect on eNOS mRNA or protein levels, in cultured pulmonary arterial endothelial cells, but did produce a significant decrease in enzyme activity. Although NO treatment induced protein kinase C (PKC) dependent eNOS phosphorylation, blockade of PKC activity did not protect against the effects of NO. Superoxide levels were elevated in the presence of NO-donors and when the xanthine oxidase inhibitor, allopurinol, or the superoxide scavenger, 4,5-dihydroxy-1-benzene-disulphonic acid, were co-incubated with NO donors, the inhibitory effects on eNOS activity could be partially alleviated. This suggests that NO stimulates xanthine oxidase causing an increase in cellular superoxide generation. It is known that the reaction between NO and superoxide produces peroxynitrite which can cause the nitrosylation of proteins and subsequent inactivation. To further evaluate the potential effect of peroxynitrite on eNOS activity we purified eNOS protein using a yeast expression system. The presence of peroxynitrite was found to significantly reduce the activity of the purified eNOS protein. These data suggest that peroxynitrite reacts with the eNOS protein resulting in enzyme inactivation. This may explain, at least in part, how NO causes NOS inhibition in vivo, and may delineate the mechanism of rebound pulmonary hypertension following withdrawal of inhaled NO.

Nitric Oxide Exposure Inhibits Endothelial NOS Activity But Not Gene Expression: A Role For Superoxide And Peroxynitrite • 1937