Nitrate as Warden of Nitric Oxide Homeostasis in Mammals

Homeostasis is the self-regulating processes in cells and organisms designed to maintain stability of the internal environment while adjusting to external changes. To achieve this dynamic stability, internal conditions oscillate within tightly regulated physiological tolerance limits. In mammals, maintaining nitric oxide (NO) availability appears crucial to sustain relatively constant blood flow into all organs and tissues. We hypothesize that NO homeostasis is one of the most important vital processes for warm-blooded animals. It is impossible to conserve the stability of most other vital substances, such as O₂, CO₂, blood sugar, pH, and temperature, to name just few, without well-functioning tissue perfusion. NO in mammals is generated either from L-arginine by nitric oxide synthases (NOSs) or by the reduction of nitrate (NO₃^-) to nitrite (NO₂^-) and NO by several proteins. Here we first discuss the organization of these two NO metabolic pathways, emphasizing that both pathways "cross" and "funnel" unused NO into the overall nitrate-nitrite-NO pathway. This pathway is cyclic, which gives nitrate a unique place in metabolism and predisposes it as a reservoir for NO. Then, we discuss the role of NO homeostasis that, by maintaining organ and tissue perfusion, supports and preserves constancy of other blood-delivered substances. This "governing" role of NO makes even clearer that the existence of NO storage and precursor molecules is necessary, to avoid NO shortages in cases of the precursor's or storage molecule's temporary unavailability, to ensure uninterrupted tissue access to NO. We propose that the skeletomuscular system and skin act as nitrate reservoirs assuring NO bioavailability at various external and internal conditions.