Nitrate–nitrite–nitric oxide (NO) pathway (Nitrate–nitrite–NO pathway)

The nitrate–nitrite–nitric oxide (NO) pathway is a physiological system that serves as a critical alternative source of NO, complementing the classical L-arginine–nitric oxide synthase (NOS) pathway (Lundberg et al., 2008, Nature Reviews Drug Discovery). It involves the ingestion of inorganic nitrate, its concentration in saliva, and its subsequent reduction to nitrite by commensal anaerobic bacteria on the tongue (Weitzberg et al., 2010, Free Radical Biology and Medicine). Once swallowed, nitrite is absorbed and further reduced to bioactive NO and other nitrogen oxides in the blood and tissues by various proteins, including deoxyhemoglobin and xanthine oxidoreductase (Gladwin et al., 2005, Nature Chemical Biology). This pathway is particularly vital during hypoxia and acidosis, conditions where the oxygen-dependent NOS enzymes are typically dysfunctional. Therapeutic modulation of this pathway, primarily through nitrate or nitrite supplementation, is being investigated for its ability to lower blood pressure, enhance exercise performance, and protect tissues from ischemia-reperfusion injury (Kapil et al., 2015, Hypertension).

Other names

Enterosalivary nitrate-nitrite-NO pathwayNitrate-nitrite-NO axisNon-enzymatic nitric oxide pathway

The pathway facilitates the generation of nitric oxide (NO) through the stepwise reduction of nitrate to nitrite by commensal oral bacteria, and the subsequent reduction of nitrite to NO by various endogenous reductases such as deoxyhemoglobin and xanthine oxidoreductase, especially under hypoxic conditions (Lundberg et al., 2008, Nature Reviews Drug Discovery).