Exercise Hyperemia in Humans

人类运动充血

• 批准号: 8901288
• 负责人: FRANK A DINENNO
• 金额: $ 73.86万
• 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 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8901288
• 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（由适用提供）：运动充血是一种生物医学意义上的现象，因为骨骼肌血流是健康和疾病运动能力的关键决定剂。然而，尽管至少1870年代以来，仍在进行持续的研究，但涉及运动充血与新陈代谢相匹配的机制仍然很糟糕。最近，ATP已成为一个血管散发因素，可能与O2递送和收缩肌肉的代谢需求相匹配。这个想法是，红细胞中的血红蛋白（RBC）释放出ATP，因为它会在较高的O2需求的肌肉中引起词典引起词典。此ATP释放还反对交感神经（功能性交感解），以进一步促进流动/代谢匹配。这些观察结果以及ATP的潜在血管扩张剂的作用，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人。在这种情况下，我们试图了解：a）ATP介导的在骨骼肌收缩骨骼肌中的血管舒张时，当动脉O2含量增加约25％时，在高压高氧期间会减弱骨骼肌； b）血管扩张器对运动的反应对囊性纤维化的ΔF508突变形式的动脉O2含量变化的敏感性较小，其RBC缺乏体外释放ATP的能力； c）如果血管舒张器对运动的反应对健康老年志愿者的肌肉含量的变化不太敏感，他们也可能改变了RBC的ATP释放。在AIM 1中，我们将确定在用高压高氧运动过程中释放ATP是否释放。当伪像含量含量增加约25％时，骨骼肌的血液流量减少了约25％。在AIM 2中，我们将确定肌肉血流是否对CF伪像的变化敏感。在AIM 3中，我们将确定肌肉的血流是否对健康老年受试者中的O2含量的变化敏感。作为高度机械和翻译的实验策略的一部分，我们还将在孤立的RBC中进行平行的体外研究。我们的目标旨在评估当使用高压高氧或正常的缺氧时，在手工夹时前臂血流，O2递送和深静脉ATP反应之间的关系。我们的方法还利用了我们先前在缺氧和高压高氧，ATP测量以及对年龄较大人类和CF患者研究的历史的经验。这是我们提出的创新和新颖的方法来全面检验人类中的ATP假设和运动充血。我们的研究还具有鉴定循环ATP，也许是红细胞的潜力，它是疾病状态下随着年龄的增长而增加的治疗靶标，并且与肌肉灌注降低（例如心力衰竭）或其他血管床中的O2递送不足有关。最后，我们的建议与 NHLBI和NIH的优先级与翻译研究有关，该研究试图了解动物模型中确定的机制和体外实验范式对人类的贡献。