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

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 NO ₂^- 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.