Plasma nitrite rather than nitrate reflects regional endothelial nitric oxide synthase activity but lacks intrinsic vasodilator action

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 k inetics of NO conversion to these metabolites under physiological condition s. Moreover, plasma nitrite recently has been proposed to represent a deliv ery source for intravascular NO. We therefore sought to investigate in huma ns whether changes in NO. concentration are a reliable marker for endotheli al NO production and whether physiological concentrations of nitrite are va soactive. NO2- and NO3- concentrations were measured in blood sampled from the antecubital vein and brachial artery of 24 healthy volunteers. No signi ficant arterial-venous gradient was observed for either NO2- or NO3-. Endot helial NO synthase (eNOS) stimulation with acetylcholine (1-10 mug/min) dos e-dependently augmented venous NO2- levels by maximally 71 %. This effect w as paralleled by an almost 4-fold increase in forearm blood flow (FBF), whe reas an equieffective dose of papaverine produced no change in venous NO2- Intraarterial infusion of NO2- had no effect on FBF. NOS inhibition (N-G-mo nomethyl-L-arginine; 4-12 mu mol/min) dose-dependently reduced basal NO2- a nd FBF and blunted acetylcholine-induced vasodilation and NO release by mor e than 80% and 90%, respectively. In contrast, venous NO3- and total NOx re mained unchanged as did systemic arterial NO2- and NO3- levels during all t hese interventions. FBF and NO release showed a positive association (r = 0 .85; P < 0.001). These results contradict the current paradigm that plasma NO3- and/or total NOx are generally useful markers of endogenous NO product ion and demonstrate that only NO2- reflects acute changes in regional eNOS activity. Our results further demonstrate that physiological levels of nitr ite are vasodilator-in active.