Increased consumption and vasodilatory effect of nitrite during exercise

Abstract

This study investigated the effects of aerobic-to-anaerobic exercise on nitrite stores in the human circulation and evaluated the effects of systemic nitrite infusion on aerobic and anaerobic exercise capacity and hemodynamics. Six healthy volunteers were randomized to receive sodium nitrite or saline for 70 min in two separate occasions in an exercise study. Subjects cycled on an upright electronically braked cycle ergometer 30 min into the infusion according to a ramp protocol designed to attain exhaustion in 10 min. They were allowed to recover for 30 min thereafter. The changes of whole blood nitrite concentrations over the 70-min study period were analyzed by pharmacokinetic modeling. Longitudinal measurements of hemodynamic and clinical variables were analyzed by fitting nonparametric regression spline models. During exercise, nitrite consumption/elimination rate was increased by ∼137%. Cardiac output (CO), mean arterial pressure (MAP), and pulmonary artery pressure (PAP) were increased, but smaller elevation of MAP and larger increases of CO and PAP were found during nitrite infusion compared with placebo control. The higher CO and lower MAP during nitrite infusion were likely attributed to vasodilation and a trend toward decrease in systemic vascular resistance. In contrast, there were no significant changes in mean pulmonary artery pressures and pulmonary vascular resistance. These findings, together with the increased consumption of nitrite and production of iron-nitrosyl-hemoglobin during exercise, support the notion of nitrite conversion to release NO resulting in systemic vasodilatation. However, at the dosing used in this protocol achieving micromolar plasma concentrations of nitrite, exercise capacity was not enhanced, as opposed to other reports using lower dosing.

Keywords: hemodynamics; incremental exercise test; nitrite store; pharmacokinetics; vasodilation.

Figures

Fig. 1.

Overall study schema.

Fig. 2.

A: schematic representation of a 2-compartment pharmacokinetic model. C, central compartment; P, peripheral compartment; k10, elimination rate constant; k12, transfer rate constant from the central to peripheral compartment; k21, transfer rate constant from the peripheral to the central compartment. B: venous whole blood nitrite concentration vs. time profile at rest, during exercise, and after exercise. Symbols represent observed data.

Fig. 3.

Mean ± SD changes of arterial and venous iron-nitrosyl-hemoglobin (HbNO) concentrations 30 min into nitrite infusion before exercise, and pre-anaerobic threshold (AT), post-AT, and recovery.

Fig. 4.

Mean curves of V̇o2 (A), pH (B), glucose (C), and lactate (D). Mean curves and difference in methgemoglobin during nitrite infusion and saline control throughout the study period (E).

Fig. 5.

Mean curves and difference in mean arterial pressure (MAP; A), cardiac output (CO; B), and pulmonary artery pressure (PAP) during nitrite infusion and saline control at rest, during exercise, and after exercise. *CO values obtained by thermodilution were used for the first 30 min, and values calculated by the Fick equation based on direct measurement of oxygen consumption were used for the rest of the study period.

Fig. 6.

Mean curves of central venous pressure (CVP; A), pulmonary capillary wedge pressure (PCWP; B), heart rate (HR; C), pulmonary vascular resistance (PVR; D), systemic vascular resistance (SVR; E) and PVR/SVR ratio (F) during nitrite infusion and saline control throughout the study period. *For the first 30 min, PVR and SVR values were derived from CO values obtained by thermodilution. For the rest of the study from 30 min onward, PVR and SVR were calculated by using the CO values obtained from the Fick equation.

Fig. 7.

Mean curves and difference in arterial oxygen saturation (A) and mean curves of venous oxygen saturation (B) and mixed venous oxygen saturation (SvO2; C) during nitrite infusion and saline control at rest, during exercise, and after exercise. D: oxygen saturation arteriovenous (AV) gradient.

Fig. 8.

Mean curves of plasma nitrite AV gradient (A) and whole blood nitrite AV gradient (B) during nitrite infusion and saline control throughout the study period. In the control arm, the correlation between arterial plasma nitrite concentration and arterial oxygen saturation (C), and plasma nitrite AV gradient and oxygen saturation arteriovenous (AV) gradient (D).