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.

项目摘要 收缩骨骼肌调节交感神经的能力（“功能性交感解可以”） 必须在升高时确保充足的血流和氧气递送到活性肌肉至关重要 运动过程中的同情出口。随着年龄的增长，功能性交感解立受损 交感神经活动升高，导致骨骼肌的疏松症。那， 阐明主动肌肉调节交感神经能力的信号传导机制 血管收缩将提高我们对人类血流调节基本机制的理解 并为改善外周血流动和衰老和运动耐受性的新策略奠定了基础 临床人群。彼此之间，拟议研究的总体目标是研究内源性 乙酰胆碱（ACH）是一种新颖的交感解释机制，并确定是否减少了贡献 ACH解释了老年人功能性交感解的损害。具体目标1将检验假设 这种内源性ACH限制了年轻，健康的年轻，健康的骨骼肌的交感神经。 人类。为了测试这一点，森林血流（多普勒超声）和动脉压（臂动脉导管） 将测量以评估响应局部，动脉内输注苯酚的血管收缩（α1- 在控制条件下和期间 局部抑制毒蕈碱ACH受体通过香氨酸抑制。具体目标2将检验以下假设 随着年龄的增长，ACH对功能性交感解论的贡献减少了。这将通过 比较阿托品对老年人运动过程中的交感神经血管收缩的影响与 年轻人。由于运动训练可以提高对ACH的血管敏感性，因此特定目标3将测试 假设为期四周的手夹训练干预将改善老年人的功能性交感解 通过增加ACH的贡献，进一步，这将与改进有关 功能结果，包括最大的前臂工作率和在次最大工作期间疲劳的时间。 预期的结果将为基本生理学基础血管控制提供新颖的见解 人类。此外，这些发现将为年龄相关的能力下降提供机械洞察力 收缩骨骼肌以钝性交感联合血管收缩，并将评估一种治疗效用 运动干预以改善老年人的功能结果。这项研究与NHLBI的 血管生物学和高血压分支的任务以及研究的重点 随着年龄的增长，控制会导致功能能力和生活质量的下降，并增加 缺血性心血管疾病。