Neurovascular control during hypoxic stress

缺氧应激期间的神经血管控制

• 批准号: 7643256
• 负责人: URS A LEUENBERGER
• 金额: $ 39.1万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7643256
• 关键词: Acute; Address; Adenosine; Aging; Animals; Arts; Attenuated; Blood Vessels; Blood flow; Chemicals; Clinical; Complex; Conscious; Data; Disease; Exposure to; Future; Health; Human; Hypoxia; Intramuscular; Measures; Mediating; Mediator of activation protein; Metabolic; Metabolic stress; Microdialysis; Nerve; Neurotransmitters; Nitric Oxide; Numbers; Organ; Other Finding; Oxygen; Peripheral; Plethysmography; Preparation; Production; Program Research Project Grants; Prostaglandin Production; Prostaglandins; Publishing; Research; Research Personnel; Role; Series; Signal Transduction; Site; Skeletal Muscle; Source; Stimulus; Stress; Sympathetic Nervous System; Synaptic Transmission; Techniques; Testing; Tissues; Ultrasonography; Vascular Smooth Muscle; Vasoconstrictor Agents; Vasodilation; Vasodilator Agents; Vasomotor; attenuation; base; concept; neuromechanism; relating to nervous system; response; trafficking; vasoconstriction

Systemic hypoxia evokes a series of neural, humoral and direct cellular effects that act to preserve oxygen (O2) delivery to metabolically active tissues. In human skeletal muscle vasodilation occurs during systemic hypoxia despite a substantial increase in sympathetic nerve traffic. This vasodilation has been attributed to local release of vasodilator metabolites such as adenosine, nitric oxide (NO) and/or prostaglandins. The precise mechanism of hypoxia-induced skeletal muscle vasodilation in humans, the source of the vasodilator metabolites and their interaction with the sympathetic nervous system are poorly understood. The principal hypothesis of this proposal is that during systemic hypoxia, neural vasoconstrictor influences are offset by the peripheral production of vasodilator substances resulting in functional sympatholysis. In this project we propose to address four specific aims. We hypothesize that: 1) Adenosine and NO are released during systemic hypoxia in skeletal muscle and cause vasodilation; 2) Systemic hypoxia leads to release of prostaglandins that contribute to skeletal muscle vasodilation; 3) K + (ATP) channels are important mediators of skeletal muscle vasodilation induced by metabolites that are released during hypoxia; and, 4) Cellular/tissue metabolites produced during systemic hypoxia interfere with sympathetic neural vasoconstriction. The site of this interference is not known. These hypotheses will be tested in conscious humans and with the use of a series of state-of-the-art experimental techniques. We will use microneurography to measure peripheral sympathetic nerve activity (the neural vasoconstrictor signal), intramuscular and intravascular microdialysis to measure sympathetic neurotransmitters and vasoactive metabolites (the chemical vasomotor signals) and ultrasound/plethysmography to measure blood flow (the target organ effect). A number of pharmacological probes will be applied to interfere specifically with hypoxia-induced vasodilation. The scientific concepts developed and the experimental approaches planned in this proposal will be enhanced importantly by the collective expertise of the investigators on this Program Project Grant. Because sympathetic and vascular function may be altered importantly by disease and/or by aging, the findings of these studies may have important clinical implications.

全身缺氧会引起一系列神经、体液和直接细胞效应，从而保护氧气 (O2) 输送到代谢活跃的组织。在人体骨骼肌中，尽管交感神经流量大幅增加，但全身缺氧期间仍会发生血管舒张。这种血管舒张作用归因于血管舒张代谢物的局部释放，如腺苷、一氧化氮 (NO) 和/或前列腺素。人们对缺氧引起的骨骼肌血管舒张的确切机制、血管舒张代谢物的来源及其与交感神经系统的相互作用知之甚少。该提议的主要假设是，在全身缺氧期间，神经血管收缩的影响被外周血管舒张物质的产生所抵消，从而导致功能性交感神经松弛。在这个项目中，我们建议实现四个具体目标。我们假设：1）骨骼肌全身缺氧时释放腺苷和NO，引起血管舒张； 2）全身缺氧导致前列腺素释放，有助于骨骼肌血管舒张； 3）K+（ATP）通道是缺氧时释放的代谢产物诱导骨骼肌血管舒张的重要介质； 4) 全身缺氧期间产生的细胞/组织代谢物干扰交感神经血管收缩。这种干扰的位置尚不清楚。这些假设将在有意识的人类中进行测试，并使用一系列最先进的实验技术。我们将使用显微神经造影来测量外周交感神经活动（神经血管收缩信号），使用肌内和血管内微透析来测量交感神经递质和血管活性代谢物（神经血管收缩信号）。 化学血管舒缩信号）和超声/体积描记法来测量血流量（靶器官效应）。许多药理学探针将用于特异性干扰缺氧引起的血管舒张。本提案中制定的科学概念和计划的实验方法将通过本计划项目拨款研究人员的集体专业知识得到重要加强。由于交感神经和血管功能可能会因疾病和/或衰老而发生重大改变，因此这些研究的结果可能具有重要的临床意义。