Exercise Hyperemia in Humans

人类运动充血

• 批准号: 8769650
• 负责人: FRANK A DINENNO
• 金额: $ 76.6万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8769650
• 关键词: Adult; Aging; Animal Model; Area; Attenuated; Blood; Blood flow; Cells; Contracts; Cystic Fibrosis; Data; Disease; Elderly; Erythrocytes; Exercise; Forearm; Goals; Health; Heart failure; Hemoglobin; Human; Hyperemia; Hyperoxia; Hypoxia; In Vitro; Investigation; Measurement; Mediating; Metabolic; Metabolism; Modeling; Muscle; Mutation; National Heart, Lung, and Blood Institute; Nature; Nitric Oxide Synthase; Patients; Perfusion; Positioning Attribute; Productivity; Recording of previous events; Skeletal Muscle; Source; Sympathetic Nervous System; Technical Expertise; Testing; Translational Research; Translations; United States National Institutes of Health; Vasodilation; Vasodilator Agents; Venous; base; cystic fibrosis patients; design; experience; in vivo; innovation; novel strategies; research study; response; therapeutic target; tool; vascular bed; vasoconstriction; volunteer

DESCRIPTION (provided by applicant): Exercise hyperemia is a biomedically significant phenomenon because skeletal muscle blood flow is a key determinant of exercise capacity in health and disease. However, the mechanisms governing exercise hyperemia that match muscle blood flow with metabolism remain poorly understood in spite of ongoing investigation since at least the 1870s. Recently, ATP has emerged as a vasodilating factor that might match O2 delivery and metabolic demand in contracting muscles. The idea is that hemoglobin in red blood cells (RBCs) releases ATP as it desaturates to cause dilation in areas of contracting muscle with high levels of O2 demand. This ATP release also opposes sympathetic vasoconstriction (functional sympatholysis) to further facilitate flow/metabolism matching. These observations, plus ATP's potent vasodilator actions, make it an attractive candidate to explain several major features of the exercise hyperemia response. In this context, we seek to understand if: a) ATP mediated vasodilation in contracting skeletal muscle is attenuated during hyperbaric hyperoxia when arterial O2 content is increased by ~25%; b) the vasodilator responses to exercise are less sensitive to changes in arterial O2 content in patients with the ΔF508 mutation form of cystic fibrosis whose RBCs lack the ability to release ATP in vitro; and c) if the vasodilator responses to exercise are less sensitive to changes in arterial O2 content in the contracting muscle of healthy older volunteers who may also have altered ATP release from RBCs. In Aim 1 we will determine if ATP release is reduced during exercise with hyperbaric hyperoxia. Skeletal muscle blood flow is reduced by ~25% when arterial O2 content is increased by ~25% with hyperbaric hyperoxia. In Aim 2 we will determine if muscle blood flow is sensitive to changes in arterial O2 content in patients with CF. In Aim 3 we will determine if muscle blood flow is sensitive to changes in arterial O2 content in healthy older subjects. We will also conduct parallel in vitro studies in isolated RBCs as part of a highly mechanistic and translational experimental strategy. Our aims are designed to evaluate the relationships between forearm blood flow, O2 delivery and deep venous ATP responses during handgripping when arterial O2 content is altered by 20-25% using either hyperbaric hyperoxia or normobaric hypoxia. Our approach also leverages our prior experience with hypoxia and hyperbaric hyperoxia, ATP measurements and our history of studies in older humans and patients with CF. Thus, we are proposing innovative and novel approaches to comprehensively test the ATP hypothesis and exercise hyperemia in humans. Our studies also have the potential to identify circulating ATP, and perhaps the red blood cell, as a therapeutic target in disease states that increase with advancing age and are associated with reduced muscle perfusion (e.g. heart failure) or inadequate O2 delivery in other vascular beds. Finally, our proposal is consistent with NHLBI and NIH priorities related to translational research that seek to understand the contribution of mechanisms identified in animal models and in vitro experimental paradigms to humans.

描述（由申请人提供）：运动性充血是一种生物医学显著现象，因为骨骼肌血流量是健康和疾病中运动能力的关键决定因素。然而，运动性充血的机制，肌肉血流与代谢相匹配，仍然知之甚少，尽管正在进行的调查，至少自19世纪70年代。最近，ATP已经成为一种血管舒张因子，可能与收缩肌肉中的O2输送和代谢需求相匹配。这个想法是红细胞（RBC）中的血红蛋白释放ATP，因为它去饱和，导致收缩肌肉的区域扩张，需要高水平的O2。这种ATP释放还对抗交感神经血管收缩（功能性交感神经溶解）以进一步促进流动/代谢匹配。这些观察结果，加上ATP的强大的血管扩张作用，使其成为一个有吸引力的候选人来解释运动充血反应的几个主要特征。在此背景下，我们试图了解：a）当动脉氧含量增加约25%时，在高压高氧期间，ATP介导的收缩骨骼肌的血管舒张是否减弱; B）在患有ΔF508突变型囊性纤维化的患者中，其RBC缺乏体外释放ATP的能力，对运动的血管舒张反应对动脉氧含量的变化不太敏感;以及c）对于运动的血管舒张反应是否对健康老年志愿者的收缩肌肉中的动脉O2含量的变化不太敏感，所述志愿者也可能改变了RBC的ATP释放。在目标1中，我们将确定在高压高氧运动期间ATP释放是否减少。当高压高氧使动脉O2含量增加~25%时，骨骼肌血流量减少~25%。在目标2中，我们将确定肌血流量是否对CF患者动脉O2含量的变化敏感。在目标3中，我们将确定肌肉血流量是否对健康老年受试者的动脉O2含量变化敏感。作为高度机械和转化实验策略的一部分，我们还将对分离的红细胞进行平行的体外研究。我们的目的是评估前臂血流，O2输送和深静脉ATP反应之间的关系，在手握时，动脉O2含量改变了20-25%，无论是高压高氧或常压缺氧。我们的方法还利用了我们先前在缺氧和高压高氧、ATP测量方面的经验以及我们在老年人和CF患者中的研究历史。因此，我们提出了创新和新颖的方法来全面测试ATP假说和人体运动充血。我们的研究也有可能确定循环ATP，也许是红细胞，作为疾病状态的治疗靶点，这些疾病状态随着年龄的增长而增加，并与肌肉灌注减少（例如心力衰竭）或其他血管床中的O2输送不足有关。最后，我们的建议符合 NHLBI和NIH的优先事项与转化研究有关，这些研究旨在了解动物模型和体外实验范式中确定的机制对人类的贡献。