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

Year: 2013

Type: article

Abstract: BACKGROUND AND PURPOSE: 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). EXPERIMENTAL APPROACH: 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). KEY RESULTS: 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. CONCLUSIONS AND IMPLICATIONS: 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.

Source: British Journal of Pharmacology

DOI: 10.1111/bph.12152