Perfusion of Active Muscles: Metabolites and Nerves

描述（由申请人提供）：HL-46493的长期目标是了解收缩骨骼肌和交感神经释放的物质如何相互作用并调节血液流向活动肌肉。这一更新着重于局部和全身对肌肉血流、氧气输送和代谢之间“不匹配”的反应，以探索人类a)肌肉低灌注时节律性运动的升压反应是否能改善活跃肌肉的血流量；B)与活动肌肉灌注不足相关的潜在血管扩张剂“错误信号”；C)这些反应之间的相互作用；d)缺氧与低灌注对骨骼肌O2输送的挑战在多大程度上引起类似的代偿调整。在这种情况下，以下具体目标将被解决：1)我们将使用一个小的动脉内导管/球囊系统在有节奏的握力过程中产生分级的骨骼肌灌注不足，以评估肌肉灌注不足运动时的升压反应是否能改善活跃肌肉的血流量。我们假设，节律性运动和低灌注相结合引起的血管收缩肌交感神经活动（MSNA）的增加阻止了升压反应改善收缩肌肉的血流量。2)使用导管/球囊系统，我们将测量运动时局部血管舒张剂对肌肉灌注不足的反应，并使用药理学工具探索其性质。我们假设局部血管扩张剂对低灌注有节奏运动的反应有助于在轻度和中度而非重度有节奏握拳时维持肌肉血流量，此时MSNA可能升高。我们还假设腺苷（可能与NO一起）将是代偿性扩张的主要因素。3)我们将测试轻度缺氧运动时维持活性肌肉O2输送的代偿性血管扩张信号与低灌注常氧运动时引起代偿性血管扩张的信号是否相同或不同。我们假设腺苷（可能与NO一起）将是两种情况下代偿性扩张的主要因素。摘要与意义：肌肉血流量是运动能力的关键决定因素，目前尚不清楚低灌注或缺氧运动时全身交感神经兴奋和局部血管舒张反应如何相互作用，调节收缩人体骨骼肌的血流量。我们提出了新颖和创新的策略，以解决一些目前未解决的问题和争议相关的这些主题在人类。

DESCRIPTION (provided by applicant): The long-term goal of HL-46493 is to understand how substances released by contracting skeletal muscles and sympathetic nerves interact and regulate blood flow to the active muscles. This renewal focuses on local and systemic responses to "mismatches" between muscle blood flow, O2 delivery and metabolism to explore in humans a) whether the pressor response to rhythmic exercise during muscle hypoperfusion improves blood flow to active muscles; b) the potential vasodilator "error signals" associated with hypoperfusion in active muscles; c) the interactions between these responses; and d) the extent to which challenges to skeletal muscle O2 delivery with hypoxia vs. hypoperfusion evoke similar compensatory adjustments. In this context, the following specific aims will be addressed: 1) We will use a small intra- arterial catheter/balloon system to create graded skeletal muscle hypoperfusion during rhythmic handgripping to evaluate whether the pressor response to exercise with muscle hypoperfusion improves blood flow to the active muscles. We hypothesize that the rise in vasoconstricting muscle sympathetic nerve activity (MSNA) evoked by the combination of rhythmic exercise and hypoperfusion prevents the pressor response from improving blood flow to the contracting muscles. 2) Using the catheter/balloon system, we will measure the local vasodilator responses to muscle hypoperfusion during exercise and use pharmacological tools to explore their nature. We hypothesize that local vasodilator responses to rhythmic exercise with hypoperfusion serve to maintain muscle blood flow during mild and moderate but not heavy rhythmic handgripping when MSNA is likely to rise. We also hypothesize that adenosine (perhaps along with NO) will be the main factor responsible for the compensatory dilation. 3) We will test whether the compensatory vasodilator signals that maintain O2 delivery to active muscles during exercise with mild hypoxia are the same or different than those that cause compensatory vasodilation during normoxic exercise with hypoperfusion. We hypothesize that adenosine (perhaps along with NO) will be the main factor responsible for the compensatory dilation under both circumstances. Summary and Significance: Muscle blood flow is a key determinant of exercise capacity, and it is unknown how systemic sympathoexcitation and local vasodilator responses to exercise with either hypoperfusion or hypoxia interact to regulate blood flow to contracting human skeletal muscles. We propose novel and innovative strategies to address a number of currently unresolved issues and controversies related to these topics in humans.