Impact of chronic congestive heart failure on pharmacokinetics and vasomotor effects of infused nitrite
Date
2013
Authors
Maher, A.
Arif, S.
Madhani, M.
Abozguia, K.
Ahmed, I.
Fernandez, B.
Feelisch, M.
O'Sullivan, A.
Christopoulos, A.
Sverdlov, A.
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Journal article
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British Journal of Pharmacology, 2013; 169(3):659-670
Statement of Responsibility
Abdul 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
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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.
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© 2013 The Authors