NO2− Oxyhemoglobin NO2− Oxidation Ceruloplasmin oxygen Bacterial nitrate reductases Neuroglobin Deoxyhemoglobin/myoglobin Xanthine oxidoreductase (XOR) Respiratory chain enzymes Plant-based nitrite reductase Aldehyde oxidase Carbonic anhydrase Protons Vitamin C, polyphenols Diet NO3− NO NOS Evidence-Based Complementary and Alternative Medicine 3 Figure 1: A schematic presentation of a mammalian nitric oxide (NO) cycle. NO is generated by nitric oxide synthases (NOS) in most cells of the body and participates in regulation of numerous physiologic functions. The bioactivity of nitric oxide is partly regulated by its rapid oxidation to nitrite (NO2–) or, in the presence of oxyhemoglobin, to nitrate (NO3–). Nitrate is the predominant nitric oxide oxidation product in the circulation. In our bodies, nitrate can undergo reduction to nitrite, and this process is strongly dependent on oral commensal bacteria. In blood and tissues, nitrite can be further reduced to nitric oxide and other bioactive nitrogen oxides. There are several enzymatic and nonenzymatic routes that can catalyze this reduction, most of which are greatly enhanced under hypoxic conditions. This mammalian nitrogen cycle can be fueled by the diet because vegetables contain high amounts of inorganic nitrate. to protect from tissue injury and restore NO homeostasis in eNOS /− mice [13, 14]. Orally administered nitrite also attenuates cardiac allograft rejection in rats [15]. Nitrate is the primary anion present in green leafy vegetables and has been hypothesized to account for some of the health bene- ﬁts of vegetables [16]. There are a number of published studies to support this hypothesis via its reduction to nitrite [17, 18]. The nitrate-nitrite-nitric oxide pathway is boosted by dietary intake of nitrate. Dietary nitrate supplementation has been shown to reduce diastolic blood pressure [19], inhi- bit platelet aggregation, and protect the heart from ischemia- reperfusion injury [20]. This pathway may also explain the eﬀects of certain ethnic diets. Dietary nitrate in Japanese food was shown to lower blood pressure in healthy volunteers [21]. It is well established that diets rich in fruit and vege- tables (e.g., the Mediterranean diet) protect against develop- ment of cardiovascular disease [22–24] and these data may provide evidence as to why. The ﬁrst metabolic activation step for this pathway re- quires commensal bacteria to reduce nitrate to nitrite [25]. There are a number of endogenous systems in mammals capable of reducing nitrite to NO although most are very in- eﬃcient and inhibited by oxygen [26]. For this system to pro- ceed, there must be enough substrate for reduction and the necessary bacteria and reductive machinery to reduce nitrate all the way down to NO. Dietary and enzymatic sources of nitrate are a potentially large source of nitrite and ultimately NO in the human body. The nitrite converted from nitrate by oral bacteria disproportionates with formation of NO after entering the acidic environment of the stomach, helping to reduce gastrointestinal tract infection, increase mucous barrier thickness and increase gastric blood ﬂow [27]. In addition to the simple protonation of nitrite in the stoma- ch, there are several enzymatic pathways for conversion of systemic nitrite to NO and other bioactive nitrogen species. Hemoglobin, myoglobin, neuroglobin, xanthine oxidoredu- ctase, aldehyde oxidase, carbonic anhydrase, and mitochon- drial enzymes have all been identiﬁed with having a role in nitrite bioactivation [28] (Figure 1). However, all of these pathways are grossly ineﬃcient along the physiological oxy- gen gradient with oxygen being a potent inhibitor of nitrite reduction [26, 29]. Therefore, for this system to generate enough bioactive NO, there must be suﬃcient nitrate and nitrite available for this ineﬃcient reduction. A consequence of endothelial dysfunction is reduced blood and tissue levels of nitrite available for reduction [14, 30], further comprising this alternative NO pathway. Since most of the TCMs are herbal extracts, we initially thought they may be good sources of nitrite and nitrate. Also antioxidants and polyphenols have been shown to eﬀectively reduce nitrite to NO [31]. This combination of nitrite, nitrate and polyphenols could pro- vide then a system for repleting NO homeostasis. We recently tested and conﬁrmed this hypothesis [32] and ﬁnd that select herbal extracts contain high amounts of nitrate and also the capacity to reduce nitrite to NO. If our current paradigm is true, then restoration of NO homeostasis may be a primary target for treating and preventing CVD. A short review of this paradigm follows.