Plasma nitrite rather than nitrate reflects regional endothelial nitric oxide synthase activity but lacks intrinsic vasodilator action
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The plasma level of NO x , i.e., the sum of NO 2 − and NO 3 − , 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 NO 3 − 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 NO 3 − . Endothelial NO synthase (eNOS) stimulation with acetylcholine (1–10 μg/min) 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 NO 2 − had no effect on FBF. NOS inhibition (N G -monomethyl- l -arginine; 4–12 μmol/min) dose-dependently reduced basal NO 2 − and FBF and blunted acetylcholine-induced vasodilation and NO release by more than 80% and 90%, respectively. In contrast, venous NO 3 − and total NO x remained unchanged as did systemic arterial NO 2 − and NO 3 − 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 − and/or total NO x are generally useful markers of endogenous NO production and demonstrate that only NO 2 − reflects acute changes in regional eNOS activity. Our results further demonstrate that physiological levels of nitrite are vasodilator-inactive.
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NOX1 is expressed in VSMCs and in lower levels is also found in ECs.
“The isoform NOX1 is expressed in VSMCs and in lower levels is also found in ECs (556, 909) (FIGURE 9, Table 5).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [556]
Plasma concentrations of nitrite reflect acute changes in regional eNOS activity and NO bioavailability that are sensitive to pharmacological modulation of the L-arginine - NO pathway.
“Lauer et al have shown that plasma concentrations of nitrite reflect acute changes in regional eNOS activity and NO bioavailability that are sensitive to pharmacological modulation of the L-arginine - NO pathway [147].”
From Inorganic nitrite therapy: historical perspective and future directions (2011) · cites this paper as [147]
Nitrite is continuously converted to nitrate and supplying more nitrite results only in its oxidation to nitrate.
“Together, these findings suggest that nitrite is continuously converted to nitrate and that supplying more nitrite results only in its oxidation to nitrate.”
From Sodium nitrite downregulates vascular NADPH oxidase and exerts antihypertensive effects in hypertension (2011) · cites this paper as [6]
Most plasma NOx levels correspond to nitrate.
“Indeed, most plasma NO x levels correspond to nitrate [6,43]”
From Sodium nitrite downregulates vascular NADPH oxidase and exerts antihypertensive effects in hypertension (2011) · cites this paper as [6]
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- Authors
- Lauer, T., Preik, M., Rassaf, T., Strauer, B. E., Deussen, A., Feelisch, M., & Kelm, M.
- Affiliations
- Louisiana State University in Shreveport (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2001-10-16
- Volume
- 98
- Issue
- 22
- Pages
- 12814-12819
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC60136
- OpenAlex
- W2163889067
- Cited by
- 585
- References
- 6
- Citations by year
- 2026: 12 · 2025: 14 · 2024: 14 · 2023: 11 · 2022: 15 · 2021: 10 · 2020: 17 · 2019: 22 · 2018: 26 · 2017: 24 · 2016: 30 · 2015: 30 · 2014: 31 · 2013: 29 · 2012: 23
- FWCI
- 9.38
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- ePrints Soton (University of Southampton) (submittedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Health and Disease Prevention
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Eicosanoids and Hypertension Pharmacology
- Keywords
- plasma nitrite, plasma nitrate, nitric oxide bioavailability, endothelial nitric oxide synthase, vasodilation, forearm blood flow, acetylcholine-induced vasodilation, L-NMMA
- MeSH terms
- Acetylcholine, Adult, Female, Forearm, Humans, Male, Nitrates, Nitric Oxide, Nitrites, Papaverine, Regional Blood Flow, Vasodilation, Nitric Oxide Synthase, omega-N-Methylarginine, Nitric Oxide Synthase Type III
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