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

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.

Effects of nitrite infusion on skeletal muscle vascular control during exercise in rats with chronic heart failure

“…13). Fortunately, this does not appear to be a concern with inorganic NO-based interventions (39), and, given the selective effects of NO 2 Ϫ infusion on skeletal muscle BF and VC demonstrated presently, these results highlight the therapeutic potential of this approach. In particular, NO 2 Ϫ -based therapies would likely compliment other CHF interventions that are exercise based, such as cardiac rehabilitation programs.…”

Pharmacology and therapeutic role of inorganic nitrite and nitrate in vasodilatation

“…In contrast there was reduced venodilation in the heart failure patients, however at any given nitrite infusion dose the venous levels of plasma nitrite were lower in the heart failure patients vs controls indicating increased clearance across the forearm vascular bed and possibly explaining the apparent venous hyporesponsiveness (Maher et al, 2013). The results from these studies in patients with CVD highlights complications which may arise when translating results from both animal models and healthy human models into clinical settings, and more research in the presence of particular disease states may be required to fully understand how nitrite, and indeed other forms of therapy, can be applied for maximum patient benefit and improved clinical outcome.…”

“…Studies have shown that the level of nitrite in plasma appears with an apparent arteriovenous gradient, showing greater vasodilatation activity in the capacitance vessels under normoxic conditions and in the resistance vessels under hypoxic conditions (Maher et al, 2008(Maher et al, , 2013. This effect has also been observed in studies of human FBF, most notably during exercise (Gladwin et al, 2000;Cosby et al, 2003).…”

“…With regard to nitrite administration in pathophysiological conditions, a study comparing the intraarterial effects of nitrite administration in healthy volunteers with congestive heart failure (CHF) patients highlighted differing effects of nitrite administration between the two groups (Maher et al, 2013), with evidence of hyperresponsiveness in forearm resistance vessels in the latter (Maher et al, 2013). In contrast there was reduced venodilation in the heart failure patients, however at any given nitrite infusion dose the venous levels of plasma nitrite were lower in the heart failure patients vs controls indicating increased clearance across the forearm vascular bed and possibly explaining the apparent venous hyporesponsiveness (Maher et al, 2013).…”

Skeletal Muscle Vascular Control During Exercise

“…These results extend to humans as several laboratories have demonstrated ergogenic effects of dietary NO 3 À supplementation in healthy [8][9][10][11][12][13] and diseased [14][15][16][17] populations. Interestingly, while these studies employ a dietary means of increasing endogenous [NO 2 À ], vasoactivity of the directly infused anion is evident in humans [18][19][20][21] and animals, [22][23][24][25] suggesting that bolus delivery may afford an expedited method of augmenting vascular and metabolic control in vivo.…”