Nitrate and nitrite in biology, nutrition and therapeutics

Abstract

Inorganic nitrate and nitrite from endogenous or dietary sources are metabolized in vivo to nitric oxide (NO) and other bioactive nitrogen oxides. The nitrate-nitrite-NO pathway is emerging as an important mediator of blood flow regulation, cell signaling, energetics and tissue responses to hypoxia. The latest advances in our understanding of the biochemistry, physiology and therapeutics of nitrate, nitrite and NO were discussed during a recent 2-day meeting at the Nobel Forum, Karolinska Institutet in Stockholm.

Figure 1

Nitric oxide and nitrite interactions with mitochondria. In normoxic conditions NOS generates NO, which activates cGMP signaling pathways (for example, vasodilation) and directly inhibits complex IV. This allows oxygen to be diverted away from the mitochondria to other targets (such as HIF1a). This inhibition also increases ROS generation from the mitochondria, generating increased ROS to potentially mediate cell signaling and oxidative stress. In hypoxia/ischemia, NOS activity is inhibited by the lack of oxygen. Nitrite is reduced to NO by deoxygenated myoglobin (Mb), xanthine oxidoreductase (XO), enzymes of the electron transport chain (ETC) or other enzymes, and the resulting NO can inhibit respiration at complex IV to regulate oxygen gradients or mediate cardiac hibernation. During ischemia/reperfusion, nitrite inhibits complex I via S-nitrosation, which decreases ROS generation at reperfusion, leading to cytoprotection.

Figure 2

A mammalian nitrogen oxide cycle. Nitric oxide synthase (NOS) generates NO in cells to regulate a vast variety of physiological functions. The bioactivity of NO is acutely terminated by its rapid oxidation to nitrite and nitrate. In our bodies nitrate can undergo reduction to nitrite (NO₂⁻) by bacteria in the oral cavity and by xanthine oxidase and possibly other enzymes in tissues. In blood and tissues nitrite can be further metabolized to nitric oxide (NO) and other biologically active nitrogen oxides (not shown in figure). This reduction is catalyzed by various enzymatic and non-enzymatic pathways, most of which are greatly enhanced under hypoxic conditions. The reduction of nitrate and nitrite to NO completes a mammalian nitrogen oxide cycle.

Figure 3

The Nobel Forum at Karolinska Institutet, where the Third International Meeting on the Role of Nitrite in Physiology, Pathophysiology and Therapeutics was held.