Systemic Nitrite Infusion and its Effect on Exercise Physiology and Metabolism

全身亚硝酸盐输注及其对运动生理和代谢的影响

• 批准号: 7969119
• 负责人: Gregory Kato
• 金额: $ 2.99万
• 依托单位: NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7969119
• 关键词: Aerobic; Anaerobic Threshold; Arginine; Blood Circulation; Blood Vessels; Blood flow; Carbon Dioxide; Cell Respiration; Diffusion; Distal; Enrollment; Erythrocytes; Exercise; Exercise Physiology; Exercise Tolerance; Exertion; Hypoxia; Infusion procedures; Metabolism; Mitochondria; Monitor; Muscle; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitrites; Output; Oxygen; Oxygen Consumption; Physiological; Placebos; Plasma; Play; Production; Publications; Pulmonary Gas Exchange; Respiration; Role; Saline; Skeletal Muscle; Tissues; Vasodilation; Venous; Work; human NOS3 protein; inhaled nitric oxide; inhibitor/antagonist; meetings; uptake

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. We enrolled 15 subjects and completed 6 studies. Interim analysis is ongoing and the study is closed to new enrollments. Publication is pending.

在锻炼过程中，氧气摄取（VO2）上升以满足能源需求的速度有一个滞后。 尚不确定这种限制是由于O2向工作肌肉的递送不足所致，线粒体可以产生ATP的速度限制以满足需求，还是两者的组合。 这两种局限性都可以通过一氧化氮调节。 一氧化氮（NO）与许多生理功能有关，包括控制骨骼肌血管舒张和氧化代谢。 在运动过程中，无血管肢体骨骼肌和调节（抑制）线粒体呼吸。 后一种效应可以通过限制线粒体利用氧的能力来降低提取氧气，或者通过抑制血管近端的线粒体来增加氧气利用，从而促进氧气扩散到远端组织和线粒体（没有依赖的氧气氧化均匀的面部均匀的面部散布）。 先前的研究表明，在运动和区域抑制NO生产的过程中，内皮NO合酶的无生产量不会增加产量，可将运动依赖性的血流减少约10％。 NOS抑制剂（例如NG硝基-L-精氨酸甲酯（L-NAME））已显示可降低运动耐受性，并且没有前体（L-精氨酸）来增加运动耐受性。 尚未证明在运动过程中进行吸入NO的施用可以增加运动耐受性。 考虑到亚硝酸盐生物转化在缺氧期间NO的潜在作用，亚硝酸盐可能在调节运动生理学中起重要作用。 因此，我们假设在有氧运动中，特别是厌氧运动，红细胞和血浆亚硝酸盐将转化为无且调节肌肉的血液流动，线粒体呼吸，氧扩散以及最终最大的氧气消耗。 尽管我们预计这些影响会增加最大氧气消耗并增加工作产量，但在运动过程中，亚硝酸盐的产生也可能会抑制线粒体呼吸并降低最大氧气消耗。 本研究的目的是研究有氧运动对动脉和中央静脉循环中红细胞和血浆中循环亚硝酸盐储存的影响，以及全身硝酸盐输注对有氧运动和厌氧运动能力的影响。 生理参数包括最大氧（VO2MAX），最大CO2和无生产（VCO2MAX和VNOMAX），最大工作，感知劳动率（RPE），厌氧阈值，以及肺部气体交换（VO2，VCO2，VE）将受到监控，并在不接受NITRITE时进行锻炼。 与盐分安慰剂输注相比，我们的主要终点将是vo2 max，并具有亚硝酸盐输注。 我们从2005年3月开始招收受试者。我们招收了15名受试者并完成了6项研究。 临时分析正在进行中，研究对新入学率关闭。 出版正在等待。