During exercise, there is a lag in the rate at which oxygen uptake (VO2) rises to meet energy demand. It is uncertain whether this limitation is due to inadequate O2 delivery to working muscle, limitations to the rate at which mitochondria can generate ATP to meet demand, or by a combination of both. Both of these limitations may be modulated by nitric oxide. Nitric oxide (NO) has been implicated in numerous physiological functions, including control of skeletal muscle vasodilation and oxidative metabolism. During exercise, NO will both vasodilate skeletal muscle and modulate (inhibit) mitochondrial respiration. The latter effect could either decrease oxygen extraction by limiting the ability of mitochondria to utilize oxygen, or paradoxically increase oxygen utilization by inhibiting mitochondria proximal to blood vessels, an effect that facilitates oxygen diffusion to distal tissue and mitochondria (NO dependent facilitated oxygen diffusion). Previous studies have demonstrated that NO production increases during exercise and regional inhibition of NO production from endothelial NO synthase reduces exercise-dependent blood flow by approximately 10%. NOS inhibitors such as NG nitro-L-arginine methyl ester (L-NAME) have been shown to decrease exercise tolerance, and NO precursors (L-arginine) to increase exercise tolerance. Administration of inhaled NO during exercise has not been shown to increase exercise tolerance. Considering the potential role of nitrite bioconversion to NO during hypoxia, is likely that nitrite plays an important role in modulating exercise physiology. We therefore hypothesize that during aerobic, and in particular anaerobic exercise, erythrocyte and plasma nitrite will be converted to NO and modulate muscle blood flow, mitochondrial respiration, oxygen diffusion and ultimately maximal oxygen consumption. While we expect these effects will increase maximal oxygen consumption and increase work output, it is also distinctly possible that NO production from nitrite during exercise will inhibit mitochondrial respiration and decrease maximal oxygen consumption. The purpose of the present study was to investigate the effects of aerobic-to-anaerobic exercise on circulating nitrite stores in erythrocytes and plasma in the arterial and central venous circulation and the effects of systemic nitrite infusion on aerobic and anaerobic exercise capacity. Physiological parameters including maximal oxygen consumption (VO2max), maximal CO2 and NO production (VCO2max and VNOmax), maximal work, rate of perceived exertion (RPE), anaerobic threshold, and pulmonary gas exchange (VO2, VCO2, VE) will be monitored during exercise with and without nitrite infusions. Our primary endpoint will be VO2 max with nitrite infusion compared to VO2 max with saline placebo infusion. We began enrolling subjects in March 2005. All six participants have completed the study and the study is open only for data analysis, data storage, and manuscript preparation. Data analysis for the study has been completed and a manuscript is currently in preparation. Six healthy subjects, aged 25.5 3.6 years old, participated in the study. Four of the study participants were males and two were females. Two subjects were Whites, three were Blacks, and one was Hispanic. There were no significant differences between nitrite and saline infusion in maximal oxygen consumption (VO2max), maximal work, anaerobic threshold (AT), and oxygen pulse. Longitudinal analysis of the hemodynamic measurements showed that mean arterial pressure (MAP) was significantly lower prior to and during exercise when nitrite was infused. On the contrary, pulmonary artery pressure (PA), pulmonary capillary wedge pressure (PCWP), and pulmonary vascular resistance/systemic vascular resistance (PVR/SVR) were higher during exercise with nitrite infusion. Cardiac output (CO) was significantly higher during exercise and at recovery in 5 out of 6 subjects, while CO was lower in 1 subject. These results are consistent with vasodilatory effects of nitrite infusion in human subjects. As expected, methemoglobin levels were slightly increased after nitrite infusion.

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National Heart, Lung, and Blood Institute
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