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

Abstract

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

Two weeks of watermelon juice supplementation improves nitric oxide bioavailability but not endurance exercise performance in humans

“…There is evidence to suggest that the plasma [nitrite] sensitively reflects endothelial nitric oxide synthase activity [32] and that L-citrulline supplementation can increase nitric oxide synthase activation [20] and nitric oxide biomarkers [19,21]. [nitrite]) were increased after 4 weeks supplementation with watermelon pomace in Zucker diabetic fatty rats [31], but the current study is the first, to our knowledge, to suggest that watermelon juice supplementation can increase nitric oxide production through nitric oxide synthase in humans.…”

“…Consequently, watermelon juice ingestion has been reported to increase plasma L-citrulline [29] and L-arginine [29,30], and may also increase nitric oxide biomarkers [31]. We recently reported that seven days of supplementation with 6 g Lcitrulline·day -1 tended to, but did not significantly, increase plasma [nitrite] [22], a sensitive marker of nitric oxide synthase activity [32]. It has been suggested that concurrently supplementing with L-citrulline and glutathione is more effective at increasing plasma nitric oxide markers than L-citrulline alone [33].…”

The chemistry of cell signaling by reactive oxygen and nitrogen species and 4-hydroxynonenal

“…Furchgott and Bhadrakom in 1953 used supraphysiological concentrations of acidified nitrite to relax precontracted aortic strips (148). The idea that nitrite is an in vivo regulator of vascular tone was challenged years later when it was reported that physiological concentrations of nitrite are insufficient to regulate vascular tone (149). However, nitrite is now thought to serve as a source of · NO under pathophysiological conditions such as hypoxia and ischemia where NOS derived · NO is unavailable.…”

Low-amplitude pulses to the circulation through periodic acceleration induces endothelial-dependent vasodilatation

“…Instead, serum nitrite, a metabolite, is measured as a qualitative marker of NO release. The same increased values of serum nitrite in the nanomole range that occur with increased shear stress during flow-mediated dilation or aerobic exercise do not produce immediate vasodilatation when infused into the circulation at such concentrations in humans (30,44,47). Therefore, in this investigation, we relied on the vasodilator properties of NO to assess effectiveness of pG z .…”