Nitric Oxide Production from Nitrite Occurs Primarily in Tissues Not in the Blood

Reaction of the semiquinone radical with oxygen leads to superoxide production at complex III.

“Although in most cases this semiquinone is rapidly oxidized, its reaction with oxygen leads to superoxide production at this site (567, 678).”

Reports for the maximum rate of NO production by NOS vary from 1 nM/s to 70 μM/s.

“Unfortunately, the reports for the maximum rate of NO production by NOS vary from 1 nM/s to 70 μM/s [39–41].”

Other studies have reported negligible XOR in blood.

“Other studies have reported negligible XOR in blood [39].”

Tissue generation from nitrite was found to increase greatly as the pH was reduced from 7 to 6 and approached 1 nM/s.

“Tissue generation from nitrite was found to increase greatly as the pH was reduced from 7 to 6 and approached 1 nM/s [39].”

Levels of XOR vary by tissue and have been reported to be about 7g/g tissue in the heart and 80 g/g tissue in the liver but these levels can increase dramatically along with levels of NADPH in ischemia.

“Levels of XOR vary by tissue and have been reported to be about 7g/g tissue in the heart and 80 g/g tissue in the liver but these levels can increase dramatically along with levels of NADPH in ischemia [39].”

Use of an AO inhibitor raloxifene substantially reduced NO production from rat liver and heart tissue in the presence of nitrite.

“Use of an AO inhibitor raloxifene substantially reduced NO production from rat liver and heart tissue in the presence of nitrite [39].”

NO generation from nitrite was directly measured when AO was present along with NADH.

“In addition, NO generation from nitrite was directly measured when AO was present along with NADH [39].”

Li and coworkers found that NO production rates are much higher from tissue, including rat aorta, than from blood.

“Li and coworkers found that NO production rates are much higher from tissue, including rat aorta, than from blood [39].”

Several studies have emphasized the importance of XOR in mediating nitrite-dependent increases in blood flow either due to XOR in the blood vessels or erythrocytic XOR.

“Several studies have emphasized the importance of XOR in mediating nitrite-dependent increases in blood flow either due to XOR in the blood vessels [39, 88] or erythrocytic XOR [25, 88].”

Nitrite-mediated cytoprotection is mediated by NO production from the molybdenum-containing enzyme XOR and to some extent SO.

“Numerous studies have suggested that nitrite-mediated cytoprotection is mediated by NO production from the molybdenum containing enzyme XOR [8, 39, 86, 118, 127] and to some extent SO [39] as well.”

Between about 60% and 80% of NO generation from 100 μM nitrite is abrogated when inhibitors of XOR and AO are administered.

“They subsequently found that between about 60% to 80% of NO generation from 100 μM nitrite is abrogated when inhibitors of XOR and AO are administered [39].”

Dietary NO3− supplementation elevates nitric oxide bioavailability via reduction of exogenous NO3− to nitrite by commensal anaerobic bacteria in the oral cavity, followed by one-electron reduction of NO2− to NO catalyzed by various NO2− reductases in tissue and blood.

“Dietary NO3− supplementation has been observed to elevate nitric oxide (NO) bioavailability via the reduction of exogenous NO3− to nitrite (NO2−) by commensal anaerobic bacteria in the oral cavity [79], followed by the one-electron reduction of NO2− to NO (and other nitrogen intermediates) catalyzed by various NO2− reductases [80,81,82,83,84] in the tissue and blood.”