Nitric oxide metabolites (NOx)

Nitric oxide metabolites (NOx), primarily inorganic nitrate and nitrite, are molecules traditionally viewed as the inactive oxidative end-products of nitric oxide (NO) signaling. However, recent evidence has redefined them as crucial storage pools and precursors that can be recycled back into bioactive NO via the nitrate-nitrite-NO pathway, especially during hypoxia or acidic conditions where oxygen-dependent nitric oxide synthases (NOS) are impaired [1, 2, 10]. This pathway is essential for regulating systemic blood flow, blood pressure, and mitochondrial respiration [1, 10]. Clinically, NOx levels serve as vital biomarkers for monitoring endothelial function and systemic NO bioavailability in patients with cardiovascular and chronic kidney diseases [3, 15, 18]. Therapeutically, these metabolites are targeted through the administration of nitrate and nitrite donors or through dietary interventions aimed at enhancing the nitrate-nitrite-NO axis. Sodium nitrite, for instance, is utilized as a pharmaceutical agent in the treatment of cyanide poisoning and is under investigation for its potential to limit ischemia-reperfusion injury and manage pulmonary hypertension [1, 5, 6]. However, targeting this pathway requires careful management to avoid safety concerns such as methemoglobinemia and profound systemic hypotension [16, 21]. Furthermore, high concentrations of these metabolites in the presence of reactive oxygen species can lead to the formation of peroxynitrite, a potent oxidant implicated in cellular damage and neurodegeneration [12, 19].

Other names

Nitrate (NO3-)Nitrite (NO2-)NOxTotal nitric oxideReactive nitrogen species (RNS)Nitrogen oxides

Reduction to nitric oxide (NO) followed by activation of soluble guanylate cyclase (sGC); direct protein S-nitrosylation; regulation of mitochondrial respiration via complex IV inhibition.