Figure 1.
Nitric oxide pathways via nitric oxide synthase (NOS) and nitrate reduction. This figure depicts the two pathways for the formation of nitric oxide (NO) and the areas within the body (designated in purple type) where the essential metabolic reactions occur. Arrows provide direction of substrate movement or chemical reactions. NO is produced continuously by NOS by catalyzing the five electron oxidation of the guanidino nitrogen of L-arginine. L-citrulline is a product of this reaction and can be converted back to L-arginine in the urea cycle. NO generated from the NOS system can be supported by the reduction of dietary nitrate to nitrite and then to NO. The majority of nitrate entering the body is initially cleared by the kidneys while the remainder is taken up from the circulation by the salivary glands and concentrated. This concentrated nitrate is then reduced in the mouth by commensal bacteria to nitrite and swallowed. A portion of the nitrite entering the digestive system is converted to NO by acidic reduction, which is enhanced by vitamin C and polyphenols. However, the majority of the nitrite is absorbed into the circulatory system, where it is reduced to NO by deoxyhemoglobin or reductase enzymes or enters tissues of the body, where it is reduced by deoxymyoglobin, xanthine oxidase, the electron transport chain, etc. NO can be converted back to nitrite and nitrate via oxidation by ceruloplasmin and oxyhemoglobin.
Figure 2.
Nitric oxide (NO) from nitrate reduction supports NO requirements when nitric oxide synthase (NOS) activity is low. Damage to the endothelium (red structure) can uncouple eNOS (green bar) and limit NO availability. This can result in inadequate regulation of platelet function (blue), leukocyte adhesion and migration (light gray), and vasculature smooth muscle cell proliferation (dark gray) and lead to the development of neointimal hyperplasia. However, the nitrate-nitrite-NO pathway can supplement the NO produced from eNOS and help to effectively regulate (inhibit, red lines) platelet aggregation and adhesion, leukocyte adhesion, and transendothelial migration and chemotaxis, control inflammation, and inhibit smooth muscle cell proliferation and migration. Without the nitratenitrite-NO pathway to supplement the NOS system, the probability of developing atherosclerosis and other cardiovascular diseases would likely be increased dramatically. This underscores the importance of consuming a diet sufficient in inorganic nitrate.