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

Plasma nitrite rather than nitrate reflects regional endothelial nitric oxide synthase activity but lacks intrinsic vasodilator action
Plasma nitrite rather than nitrate reflects regional endothelial nitric oxide synthase activity but lacks intrinsic vasodilator action
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 microg/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 micromol/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.
endotheliu, blood flo, red blood cell, endothelial dysfunction
0027-8424
12814-12819
Lauer, Thomas
57e1e8b6-cfc8-40ac-a946-5ad6e3387477
Preik, Michael
59d2d820-b12d-4020-a3a2-b89c636a8ba3
Rassaf, Tienush
a820a375-219a-4fa2-ae10-e77f4b1eb37c
Strauer, Bodo E.
7343fe67-ccf3-4079-94a0-ea6238979951
Deussen, Andreas
cc66975e-8cf4-40fd-a531-bcf52af65dc2
Feelisch, Martin
8c1b9965-8614-4e85-b2c6-458a2e17eafd
Kelm, Malte
db2bb062-32d7-4b50-9f65-8ba89ffa5f42
Lauer, Thomas
57e1e8b6-cfc8-40ac-a946-5ad6e3387477
Preik, Michael
59d2d820-b12d-4020-a3a2-b89c636a8ba3
Rassaf, Tienush
a820a375-219a-4fa2-ae10-e77f4b1eb37c
Strauer, Bodo E.
7343fe67-ccf3-4079-94a0-ea6238979951
Deussen, Andreas
cc66975e-8cf4-40fd-a531-bcf52af65dc2
Feelisch, Martin
8c1b9965-8614-4e85-b2c6-458a2e17eafd
Kelm, Malte
db2bb062-32d7-4b50-9f65-8ba89ffa5f42

Lauer, Thomas, Preik, Michael, Rassaf, Tienush, Strauer, Bodo E., Deussen, Andreas, Feelisch, Martin and Kelm, Malte (2001) Plasma nitrite rather than nitrate reflects regional endothelial nitric oxide synthase activity but lacks intrinsic vasodilator action. Proceedings of the National Academy of Sciences, 98 (22), 12814-12819. (doi:10.1073/pnas.221381098). (PMID:11606734)

Record type: Article

Abstract

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 microg/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 micromol/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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More information

e-pub ahead of print date: 16 October 2001
Published date: 23 October 2001
Keywords: endotheliu, blood flo, red blood cell, endothelial dysfunction
Organisations: Clinical & Experimental Sciences

Identifiers

Local EPrints ID: 337868
URI: https://eprints.soton.ac.uk/id/eprint/337868
ISSN: 0027-8424
PURE UUID: 88961e68-b4a5-410b-baa1-fb973b9bd910
ORCID for Martin Feelisch: ORCID iD orcid.org/0000-0003-2320-1158

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Date deposited: 22 Jun 2012 13:38
Last modified: 15 Aug 2019 00:37

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