Perfusion of Active Muscles: Metabolites and Nerves

描述(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流向活跃肌肉的血液。这项更新集中于局部和系统对肌肉血流量、氧气输送和代谢之间的“不匹配”的反应，以探索在人类中a)肌肉低灌流时对有节奏运动的升压反应是否改善了流向活动肌肉的血流量；b)与活跃肌肉低灌流相关的潜在血管扩张“错误信号”；c)这些反应之间的相互作用；以及d)在低氧和低灌流对骨骼肌氧输送的挑战引起类似的代偿调整的程度。在此背景下，将解决以下具体目标：1)我们将使用一个小的动脉内导管/球囊系统，在有节奏的握手过程中创造分级的骨骼肌低灌流，以评估肌肉低灌流运动的升压反应是否改善了流向活跃肌肉的血流量。我们假设，有节奏的运动和低灌流相结合引起的血管收缩肌肉交感神经活动(MSNA)的增加阻止了升压反应改善对收缩肌肉的血液流动。2)利用导管/球囊系统，测量运动过程中局部血管扩张对肌肉低灌流的反应，并利用药理学手段探讨其本质。我们假设，当MSNA可能上升时，局部血管扩张剂对低灌注率的有节奏运动的反应有助于在轻度和中度但不是重度有节奏的握手时维持肌肉血流量。我们还假设腺苷(可能与NO一起)将是导致代偿性扩张的主要因素。3)我们将测试在轻度低氧运动中维持氧气输送到活动肌肉的代偿性血管扩张信号与在常氧低灌流运动中引起代偿性血管扩张的信号是否相同或不同。我们假设在两种情况下，腺苷(可能与NO一起)将是导致代偿性扩张的主要因素。摘要和意义：肌肉血流量是运动能力的关键决定因素，目前尚不清楚全身交感神经兴奋和局部血管扩张反应是如何在低灌流或低氧的情况下相互作用来调节流向收缩人体骨骼肌的血流量的。我们提出了新颖和创新的战略，以解决一些目前尚未解决的问题和争议与这些主题有关的人类。

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.