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）：运动充血是一种具有生物医学意义的现象，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，尽管如此，控制肌肉血流量与新陈代谢相匹配的运动充血的机制仍然知之甚少。至少从 1870 年代以来，ATP 已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。红细胞 (RBC) 去饱和时会释放 ATP，导致需要高水平 O2 的收缩肌肉区域扩张。这种 ATP 释放还会对抗交感血管收缩（功能性交感神经溶解），以进一步促进血流/代谢匹配。这些观察结果加上 ATP 的有效血管舒张作用。 ，使其成为解释运动充血反应的几个主要特征的有吸引力的候选者。在这种情况下，我们试图了解：a) ATP 介导的血管舒张。当动脉 O2 含量增加约 25% 时，骨骼肌收缩在高压氧期间减弱 b) 患有 ΔF508 突变型囊性纤维化且红细胞缺乏这种能力的患者，运动对血管舒张剂的反应对动脉 O2 含量的变化不太敏感；体外释放 ATP；以及 c) 如果血管舒张剂对运动的反应对收缩时动脉 O2 含量的变化不太敏感健康老年志愿者的肌肉也可能改变了红细胞的 ATP 释放。在目标 1 中，我们将确定在高压高氧运动期间，当动脉 O2 含量增加约 25% 时，骨骼肌血流量是否会减少。 25% 患有高压氧血症 在目标 2 中，我们将确定 CF 患者的肌肉血流量是否对动脉血氧含量的变化敏感。对健康老年受试者动脉 O2 含量的变化敏感。我们还将在分离的红细胞中进行平行的体外研究，作为高度机械化和转化性实验策略的一部分，我们的目标是评估前臂血流与 O2 输送之间的关系。当使用高压高氧或常压低氧使动脉 O2 含量改变 20-25% 时，我们的方法还利用了我们之前的经验。缺氧和高压氧、ATP 测量以及我们对老年人和 CF 患者的研究历史因此，我们提出了创新和新颖的方法来全面测试 ATP 假说和人类运动充血。 ATP，也许还有红细胞，作为疾病状态的治疗靶标，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）或其他血管床中氧气输送不足有关。最后，我们的建议与以下观点一致。 NHLBI 和 NIH 的优先事项与转化研究相关，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。