Harnessing the Nitrate–Nitrite–Nitric Oxide Pathway for Therapy of Heart Failure With Preserved Ejection Fraction

D ow nloaded from DOI: 10.1161/CIRCULATIONAHA.114.014149 2 Nitrate accumulates in the plasma from oral intake of foods rich in nitrate, such as green leafy vegetables and root plants like beet root, or from the intravascular oxidation of NO, produced by the NO synthase enzymes, to nitrate by oxyhemoglobin. Nitrate is then concentrated in the saliva and reacts with oral commensal bacteria which contain nitrate reductase enzymes.1 Humans do not possess nitrate reductase enzymes so require these bacteria for conversion of nitrate to nitrite. Nitrite is then swallowed and systemically absorbed where it can be further reduced via one-electron transfer reactions with hemoglobin, myoglobin, neuroglobin and molybopterrin-containing enzymes (such as xanthine oxidase, aldehyde oxidase and mARC).2-7 This is now referred to as the nitrate-nitrite-NO pathway and involves a series of oxygen-independent and NO synthase independent single electron transfer reactions (Figure 1A)