The compartmentalization model of nitrate homeostasis: Role of the salivary glands, skeletal muscle, and liver

Nitric oxide (NO) is a small, bioactive molecule with diverse physiological functions. It is generated both enzymatically by NO synthases (NOS) and non-enzymatically through the nitrate-nitrite-NO reduction pathway. Recent studies have renewed interest in nitrate-based regulation of NO, highlighting a compartmentalization model of nitrate homeostasis. In this model, excess NO is rapidly oxidized to nitrite, which is then oxidized to nitrate, a more stable species that limits oxidative damage. Nitrate is differentially distributed across tissues, allowing both storage and rapid mobilization to maintain NO availability. Human and animal studies show that nitrate concentrations in skeletal muscle, plasma, and liver are approximately 100, 35, and 10 nmol/g, respectively, corresponding to a skeletal muscle-to-plasma-to-liver ratio of ~3:1:0.3. The large skeletal muscle reservoir and its higher muscle-to-plasma gradient support the release of nitrate into the circulation when needed. In contrast, the liver-to-plasma ratio < 1 suggests active hepatic uptake of circulating nitrate. Together, these findings support a compartmentalized system in which nitrate storage and flux contribute to whole-body NO homeostasis. Understanding this model may have implications for exercise physiology, metabolic regulation, and liver pathophysiology – all conditions in which NO biology plays a critical role.