Exercise Hyperemia in Humans

描述（由申请人提供）：运动性充血是一种重要的生物医学现象，因为骨骼肌血流是健康和疾病中运动能力的关键决定因素。然而，尽管至少自19世纪70年代以来一直在进行研究，但控制运动充血的机制（将肌肉血流量与代谢相匹配）仍然知之甚少。最近，ATP被认为是一种血管舒张因子，可能与收缩肌肉的氧气输送和代谢需求相匹配。其原理是，红细胞中的血红蛋白在去饱和时释放ATP，导致收缩肌肉的高氧需求区域扩张。ATP的释放也会抑制交感血管收缩（功能性交感神经溶解），从而进一步促进血流/代谢匹配。这些观察结果，加上ATP有效的血管扩张作用，使其成为解释运动性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，我们试图了解是否：a)当动脉氧含量增加~25%时，ATP介导的收缩骨骼肌血管舒张减弱；b)在体外红细胞缺乏ATP释放能力的ΔF508突变型囊性纤维化患者中，血管扩张剂对运动的反应对动脉O2含量的变化不太敏感；c)如果运动后的血管扩张反应对健康老年志愿者收缩肌中动脉氧含量的变化不太敏感，这些志愿者可能也改变了红细胞中ATP的释放。在Aim 1中，我们将确定在高压高氧运动中ATP释放是否减少。当动脉氧含量增加25%时，骨骼肌血流量减少25%。在Aim 2中，我们将确定CF患者的肌肉血流量是否对动脉氧含量的变化敏感。在Aim 3中，我们将确定健康老年受试者的肌肉血流量是否对动脉氧含量的变化敏感。我们还将在分离红细胞中进行平行体外研究，作为高度机械和转化实验策略的一部分。我们的目的是评估在高压高氧或常压缺氧时，当动脉O2含量改变20-25%时，前臂血流量、O2输送和深静脉ATP反应之间的关系。我们的方法还利用了我们之前在缺氧和高压高氧、ATP测量和我们在老年人和CF患者中的研究历史方面的经验。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。我们的研究也有可能确定循环ATP，也许还有红细胞，作为随着年龄增长而增加的疾病状态的治疗靶点，这些疾病状态与肌肉灌注减少（例如心力衰竭）或其他血管床的氧气输送不足有关。最后，我们的建议是一致的

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.