Novel role of acetylcholine in regulating vascular tone: effects of age and exercise training

乙酰胆碱在调节血管张力中的新作用：年龄和运动训练的影响

• 批准号: 9754587
• 负责人: Janee Terwoord
• 金额: $ 3.62万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9754587
• 关键词: Acetylcholine; Activities of Daily Living; Address; Adenosine Triphosphate; Adrenergic Agonists; Age; Aging; Atropine; Attenuated; Binding; Biology; Blood; Blood Pressure; Blood Vessels; Blood flow; Blood gas; Cardiovascular Diseases; Cardiovascular Physiology; Catecholamines; Catheters; Clinical; Clinical Research; Contracts; Data; Development; Doppler Ultrasonography; Doppler Ultrasound; Educational Intervention; Elderly; Electromyography; Endothelial Cells; Endothelium; Ensure; Exercise; Exercise Tolerance; Fatigue; Forearm; Foundations; Goals; Human; Hypertension; Impairment; Individual; Intra-Arterial Infusions; Measures; Mediating; Metabolic; Mission; Muscarinic Acetylcholine Receptor; Muscle; National Heart, Lung, and Blood Institute; Nerve; Outcome; Oxygen; Oxygen Consumption; Periodicity; Pharmacology; Phenylephrine; Physiological; Physiology; Play; Population; Quality of life; Regional Blood Flow; Regulation; Research; Research Priority; Resistance; Rest; Risk; Rodent; Role; Signal Transduction; Skeletal Muscle; Sympathetic Nervous System; Testing; Therapeutic; Time; Tissues; Training; Vasodilation; Work; Workload; age effect; age related; brachial artery; career; constriction; exercise intensity; exercise intervention; exercise intolerance; exercise training; functional disability; functional independence; functional outcomes; improved; in vivo; insight; novel; peripheral blood; preservation; pressure; relating to nervous system; research to practice; response; skeletal preservation; skills; vasoconstriction; young adult

PROJECT SUMMARY The ability of contracting skeletal muscle to modulate sympathetic vasoconstriction (“functional sympatholysis”) is essential to ensure adequate blood flow and oxygen delivery to active muscle in the face of elevated sympathetic outflow during exercise. With advancing age, impaired functional sympatholysis, together with elevated sympathetic nerve activity, contributes to malperfusion of contracting skeletal muscle. Thus, elucidating the signaling mechanisms that underlie the ability of active muscle to modulate sympathetic vasoconstriction will advance our understanding of the basic mechanisms of blood flow regulation in humans and lay the foundation for new strategies to improve peripheral blood flow and exercise tolerance in aging and clinical populations. Accordingly, the overall goal of the proposed research is to investigate endogenous acetylcholine (ACh) as a novel mechanism of sympatholysis and determine whether a reduced contribution of ACh explains impairments in functional sympatholysis in older adults. Specific Aim 1 will test the hypothesis that endogenous ACh limits sympathetic vasoconstriction in contracting skeletal muscle in young, healthy humans. To test this, forearm blood flow (Doppler ultrasound) and arterial pressure (brachial artery catheter) will be measured to assess vasoconstriction in response to local, intra-arterial infusion of phenylephrine (α1- adrenergic receptor agonist) at rest and during rhythmic forearm exercise under control conditions and during local inhibition of muscarinic ACh receptors via atropine. Specific Aim 2 will test the hypothesis that the contribution of ACh to functional sympatholysis is reduced with advancing age. This will be achieved by comparing the effect of atropine on sympathetic vasoconstriction during exercise in older adults to that in young adults. Because exercise training improves vascular sensitivity to ACh, Specific Aim 3 will test the hypothesis that a four week handgrip training intervention will improve functional sympatholysis in older adults through an increased contribution of ACh, and further, that this will be associated with improvements in functional outcomes including maximal forearm work rate and time to fatigue during a submaximal workload. The expected outcomes will provide novel insight to the basic physiology underlying vascular control in humans. Moreover, the findings will provide mechanistic insight to the age-related decline in the ability of contracting skeletal muscle to blunt sympathetic vasoconstriction, and will assess the therapeutic utility of an exercise intervention to improve functional outcomes in older individuals. This research is relevant to NHLBI’s mission and the research priorities of the Vascular Biology and Hypertension Branch, as impaired vascular control with advancing age leads to a decline in functional capacity and quality of life and increases the risk of ischemic cardiovascular disease.

项目概要 收缩骨骼肌调节交感血管收缩的能力（“功能性交感神经松解”） 对于确保在面对升高的情况下向活跃肌肉提供足够的血流和氧气至关重要 随着年龄的增长，交感神经功能受损，运动期间交感神经流出。 交感神经活动升高，导致收缩骨骼肌灌注不良。 阐明活跃肌肉调节交感神经能力的信号传导机制 血管收缩将促进我们对人类血流调节基本机制的理解 并为改善衰老和运动耐量的新策略奠定基础 因此，拟议研究的总体目标是研究内源性。 乙酰胆碱（ACh）作为一种新的交感神经机制，并确定乙酰胆碱（ACh）的贡献是否减少 ACh 解释了老年人的功能性交感神经损伤，具体目标 1 将检验这一假设。 内源性乙酰胆碱限制年轻、健康的骨骼肌收缩时的交感血管收缩 为了测试这一点，需要测量前臂血流量（多普勒超声）和动脉压（肱动脉导管）。 将进行测量以评估局部动脉内输注去氧肾上腺素（α1- 肾上腺素能受体激动剂）在休息时和在控制条件下进行有节奏的前臂运动期间以及在 通过阿托品局部抑制毒蕈碱 ACh 受体将检验以下假设： 随着年龄的增长，ACh 对功能性交感神经的贡献会减少。 比较阿托品对老年人运动期间交感血管收缩的影响 由于运动训练可以提高血管对乙酰胆碱的敏感性，因此特定目标 3 将测试 假设四个星期的握力训练干预将改善老年人的功能性交感神经 通过增加乙酰胆碱的贡献，此外，这将与改善 功能结果，包括最大前臂工作率和次最大工作负荷期间的疲劳时间。 预期的结果将为血管控制的基本生理学提供新的见解。 此外，这些发现将为与年龄相关的能力下降提供机制见解。 收缩骨骼肌以减弱交感血管收缩，并将评估治疗效用 运动干预可改善老年人的功能结果 这项研究与 NHLBI 相关。 血管生物学和高血压分支的使命和研究重点，因为受损的血管 随着年龄的增长，控制能力会导致功能能力和生活质量下降，并增加以下风险： 缺血性心血管疾病。