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 two-day meeting at the Nobel Forum, Karolinska Institutet in Stockholm.

Mammalian tissues produce nitric oxide (NO) to modify proteins at heme and sulfhydryl sites, thereby regulating vital cell functions. The majority of NO produced is widely assumed to be neutralized into supposedly inert oxidation products including nitrite (NO2(-)). Here we show that nitrite, also ubiquitous in dietary sources, is remarkably efficient at modifying the same protein sites, and that physiological nitrite concentrations account for the basal levels of these modifications in vivo. We further find that nitrite readily affects cyclic GMP production, cytochrome P450 activities, and heat shock protein 70 and heme oxygenase-1 expression in a variety of tissues. These cellular activities of nitrite, combined with its stability and abundance in vivo, suggest that this anion has a distinct and important signaling role in mammalian biology, perhaps by serving as an endocrine messenger and synchronizing agent. Thus, nitrite homeostasis may be of great importance to NO biology.

The plasma level of NOx, i.e., the sum of NO2 ؊ and NO3 ؊ , is frequently used to assess NO bioavailability in vivo. However, little is known about the kinetics of NO conversion to these metabolites under physiological conditions. Moreover, plasma nitrite recently has been proposed to represent a delivery source for intravascular NO. We therefore sought to investigate in humans whether changes in NO x concentration are a reliable marker for endothelial NO production and whether physiological concentrations of nitrite are vasoactive. NO 2 ؊ and NO3 ؊ concentrations were measured in blood sampled from the antecubital vein and brachial artery of 24 healthy volunteers. No significant arterial-venous gradient was observed for either NO 2 ؊ or NO3 ؊ . Endothelial NO synthase (eNOS) stimulation with acetylcholine (1-10 g͞min) dose-dependently augmented venous NO 2 ؊ levels by maximally 71%. This effect was paralleled by an almost 4-fold increase in forearm blood flow (FBF), whereas an equieffective dose of papaverine produced no change in venous NO 2 ؊ . Intraarterial infusion of NO2 ؊ had no effect on FBF. NOS inhibition (N G -monomethyl-L-arginine; 4 -12 mol͞min) dosedependently reduced basal NO 2؊ and FBF and blunted acetylcholine-induced vasodilation and NO release by more than 80% and 90%, respectively. In contrast, venous NO3 ؊ and total NOx remained unchanged as did systemic arterial NO 2 ؊ and NO3 ؊ levels during all these interventions. FBF and NO release showed a positive association (r ‫؍‬ 0.85; P < 0.001). These results contradict the current paradigm that plasma NO 3 ؊ and͞or total NOx are generally useful markers of endogenous NO production and demonstrate that only NO2 ؊ reflects acute changes in regional eNOS activity. Our results further demonstrate that physiological levels of nitrite are vasodilator-inactive.endothelium ͉ blood flow ͉ red blood cells ͉ endothelial dysfunction

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