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Impact of chronic congestive heart failure on pharmacokinetics and vasomotor effects of infused nitrite

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dc.contributor.authorMaher, A.
dc.contributor.authorArif, S.
dc.contributor.authorMadhani, M.
dc.contributor.authorAbozguia, K.
dc.contributor.authorAhmed, I.
dc.contributor.authorFernandez, B.
dc.contributor.authorFeelisch, M.
dc.contributor.authorO'Sullivan, A.
dc.contributor.authorChristopoulos, A.
dc.contributor.authorSverdlov, A.
dc.contributor.authorNgo, D.
dc.contributor.authorDautov, R.
dc.contributor.authorJames, P.
dc.contributor.authorHorowitz, J.
dc.contributor.authorFrennaux, M.
dc.date.issued2013
dc.description.abstract<h4>Background and purpose</h4>Nitrite (NO₂⁻) has recently been shown to represent a potential source of NO, in particular under hypoxic conditions. The aim of the current study was to compare the haemodynamic effects of NO₂⁻ in healthy volunteers and patients with stable congestive heart failure (CHF).<h4>Experimental approach</h4>The acute haemodynamic effects of brachial artery infusion of NO₂⁻ (0.31 to 7.8 μmol·min⁻¹) was assessed in normal subjects (n = 20) and CHF patients (n = 21).<h4>Key results</h4>NO₂⁻ infusion was well tolerated in all subjects. Forearm blood flow (FBF) increased markedly in CHF patients at NO₂⁻ infusion rates which induced no changes in normal subjects (ANOVA: F = 5.5; P = 0.02). Unstressed venous volume (UVV) increased even with the lowest NO₂⁻ infusion rate in all subjects (indicating venodilation), with CHF patients being relatively hyporesponsive compared with normal subjects (ANOVA: F = 6.2; P = 0.01). There were no differences in venous blood pH or oxygen concentration between groups or during NO₂⁻ infusion. Venous plasma NO₂⁻ concentrations were lower in CHF patients at baseline, and rose substantially less with NO₂⁻ infusion, without incremental oxidative generation of nitrate, consistent with accelerated clearance in these patients. Plasma protein-bound NO concentrations were lower in CHF patients than normal subjects at baseline. This difference was attenuated during NO₂⁻ infusion. Prolonged NO₂⁻ exposure in vivo did not induce oxidative stress, nor did it induce tolerance in vitro.<h4>Conclusions and implications</h4>The findings of arterial hyper-responsiveness to infused NO₂⁻ in CHF patients, with evidence of accelerated transvascular NO₂⁻ clearance (presumably with concomitant NO release) suggests that NO₂⁻ effects may be accentuated in such patients. These findings provide a stimulus for the clinical exploration of NO₂⁻ as a therapeutic modality in CHF.
dc.description.statementofresponsibilityAbdul R Maher, Sayqa Arif, Melanie Madhani, Khalid Abozguia, Ibrar Ahmed, Bernadette O Fernandez, Martin Feelisch, AG O’Sullivan, Arthur Christopoulos, Aaron L Sverdlov, Doan Ngo, Rustem Dautov, Philip E James, John D Horowitz and Michael P Frenneaux
dc.identifier.citationBritish Journal of Pharmacology, 2013; 169(3):659-670
dc.identifier.doi10.1111/bph.12152
dc.identifier.issn0007-1188
dc.identifier.issn1476-5381
dc.identifier.orcidSverdlov, A. [0000-0003-2539-8038]
dc.identifier.orcidHorowitz, J. [0000-0001-6883-0703]
dc.identifier.urihttp://hdl.handle.net/2440/79116
dc.language.isoen
dc.publisherNature Publishing Group
dc.rights© 2013 The Authors
dc.source.urihttps://doi.org/10.1111/bph.12152
dc.subjectsodium nitrite
dc.subjectvascular effects
dc.subjectheart failure
dc.titleImpact of chronic congestive heart failure on pharmacokinetics and vasomotor effects of infused nitrite
dc.typeJournal article
pubs.publication-statusPublished

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