Inorganic nitrite therapy: historical perspective and future directions

Over the past several years, investigators studying nitric oxide (NO) biology and metabolism have come to learn that the one-electron oxidation product of NO, nitrite anion, serves as a unique player in modulating tissue NO bioavailability. Numerous studies have examined how this oxidized metabolite of NO can act as a salvage pathway for maintaining NO equivalents through multiple reduction mechanisms in permissive tissue environments. Moreover, it is now clear that nitrite anion production and distribution throughout the body can act in an endocrine manner to augment NO bioavailability, which is important for physiological and pathological processes. These discoveries have led to renewed hope and efforts for an effective NO-based therapeutic agent through the unique action of sodium nitrite as an NO prodrug. More recent studies also indicate that sodium nitrate may also increase plasma nitrite levels via the enterosalivary circulatory system resulting in nitrate reduction to nitrite by microorganisms found within the oral cavity. In this review, we discuss the importance of nitrite anion in several disease models along with an appraisal of sodium nitrite therapy in the clinic, potential caveats of such clinical uses, and future possibilities for nitrite-based therapies.