Exercise Hyperemia in 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，但运动充血使肌肉血流量与代谢相匹配的机制仍然知之甚少。最近，三磷酸腺苷作为一种血管扩张因子出现，可能与收缩肌肉中的氧气输送和代谢需求相匹配。这个想法是，红细胞(RBC)中的血红蛋白在脱饱和度时释放三磷酸腺苷，在氧气需求高的收缩肌肉区域引起扩张。这种ATP释放也反对交感神经血管收缩(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，加上三磷酸腺苷强大的血管扩张作用，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。在此背景下，我们试图了解：a)当动脉氧含量增加~25%时，高压氧是否会减弱收缩骨骼肌中三磷酸腺苷介导的血管扩张；b)ΔF508突变形式囊性纤维化患者的血管扩张反应对动脉O2含量的变化不那么敏感，这些患者的红细胞在体外缺乏释放三磷酸腺苷的能力；以及c)如果运动的血管扩张反应对收缩肌肉中的动脉O2含量的变化不那么敏感，这些健康老年志愿者可能也改变了红细胞的三磷酸腺苷释放。在目标1中，我们将确定在高压氧运动过程中，ATP释放是否减少。高压氧使动脉血氧含量增加~25%，骨骼肌血流量减少~25%。在目标2中，我们将确定肌肉血流是否对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是否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，作为高度机械化和平移实验策略的一部分。我们的目的是评估在高压氧或常压低氧下，当动脉血氧含量变化20%-25%时，握手时前臂血流量、氧气输送和深静脉ATP反应之间的关系。我们的方法还利用了我们先前在低氧和高压氧方面的经验、ATP测量以及我们在老年人和CF患者中的研究历史。因此，我们正在提出创新和新颖的方法来全面测试ATP假说和运动充血。我们的研究还有可能确定循环中的ATP，也许还有红细胞，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)或其他血管床上氧气供应不足有关。最后，我们的建议与 NHLBI和NIH的优先事项与翻译研究有关，这些研究试图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。

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.