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

项目摘要 收缩骨骼肌调节交感神经血管收缩的能力（“功能性交感神经溶解”） 对于确保在面对升高的压力时有足够的血液流动和氧气输送到活动肌肉是必不可少的。 运动时交感神经流出。随着年龄的增长，功能性交感神经溶解受损， 交感神经活性升高，导致收缩的骨骼肌灌注不良。因此，在本发明中， 阐明活动肌肉调节交感神经的能力的信号机制 血管收缩将促进我们对人类血流调节基本机制的理解 并为改善外周血流量和运动耐量的新策略奠定基础， 临床人群。因此，本研究的总体目标是研究内源性的 乙酰胆碱（ACh）作为一种新的交感神经溶解机制，并确定是否减少的贡献 ACh解释了老年人功能性交感神经溶解的损伤。具体目标1将检验假设 内源性ACh限制了年轻、健康、 人类为了测试这一点，前臂血流（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苯肾上腺素（α1- 肾上腺素能受体激动剂）在休息时和在控制条件下和在 通过阿托品局部抑制毒蕈碱型ACh受体。具体目标2将检验以下假设： ACh对功能性交感神经溶解的作用随着年龄的增长而减少。为实现这些目标将 比较阿托品对老年人运动时交感神经血管收缩的影响， 年轻人因为运动训练可以提高血管对ACh的敏感性，所以《特定目标3》将测试血管对ACh的敏感性。 一个假设，一个为期四周的握力训练干预将改善功能性交感神经溶解在老年人 通过增加ACh的贡献，而且，这将与改善 功能结果包括最大前臂工作速率和次最大工作负荷期间的疲劳时间。 预期的结果将提供新的见解的基础生理血管控制， 人类此外，这些发现将为与年龄相关的认知能力下降提供机制性见解 收缩骨骼肌以钝化交感神经血管收缩，并将评估 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使命和研究重点， 随着年龄的增长，控制能力下降，生活质量下降， 缺血性心血管疾病

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.