Emerging role of nitrite in human biology

Nitric oxide (NO) plays a fundamental role in maintaining normal vascular function. NO is produced by endothelial cells and diffuses both into smooth muscle causing vasodilation and into the vessel lumen where the majority of this highly potent gas is rapidly inactivated by dioxygenation reaction with oxyhemoglobin to form nitrate. Diffusional barriers for NO around the erythrocyte and along the endothelium in laminar flowing blood reduce the inactivation reaction of NO by hemoglobin, allowing sufficient NO to escape for vasodilation and also to react in plasma and tissues to form nitrite anions (NO2−) and NO-modified peptides and proteins (RX-NO). Several recent studies have highlighted the importance of the nitrite anion in human biology. These studies have shown that measurement of plasma nitrite is a sensitive index of constitutive NO synthesis, suggesting that it may be useful as a marker of endothelial function. Additionally, recent evidence suggests that nitrite represents a circulating storage pool of NO and may selectively donate NO to hypoxic vascular beds. The conversion of nitrite to NO requires a reaction with a deoxygenated heme protein, suggesting a novel function of hemoglobin as a deoxygenation-dependent nitrite reductase. This review focuses on the role of nitrite as a circulating NO donor, its potential as an index of NO synthase (NOS) activity and endothelial function, and discusses potential diagnostic and therapeutic applications.