Exercise pressor reflex in peripheral artery disease: beneficial effects of heating and mechanisms

外周动脉疾病中的运动加压反射：加热的有益作用和机制

• 批准号: 10133124
• 负责人: JIAN CUI
• 金额: $ 73.21万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-05 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10133124
• 关键词: Afferent Neurons; Animals; Arteries; Atherosclerosis; Attenuated; Blood Pressure; Blood flow; Cardiovascular Diseases; Cardiovascular system; Control Animal; Data; Disease; Down-Regulation; Exercise; Exercise Tolerance; Exertion; Goals; Heating; Human; Hypertension; Intermittent Claudication; Intervention; Kidney; Knowledge; Leg; Lower Extremity; Muscle; Muscle Contraction; Nerve; Neurons; Oxygen; P2X-receptor; Pain in lower limb; Patients; Peripheral arterial disease; Play; Protocols documentation; Rattus; Reflex action; Role; Skeletal Muscle; Strenuous Exercise; Symptoms; Temperature; Testing; Thinness; Time; Translating; Walking; Work; afferent nerve; base; cardiovascular risk factor; clinically relevant; design; improved; interstitial; novel therapeutics; protein expression; receptor; response; treadmill; vasoconstriction

PROJECT SUMMARY ABSTRACT Peripheral artery disease (PAD) is atherosclerotic disease with a decrease in blood flow to the arteries of the lower extremities. Exaggerated sympathetic nerve activity (SNA) and blood pressure (BP) are observed during intense exercise activity in this disease and these responses worsen exercise tolerance. The major goal of this proposal is to examine if heat exposure and heat treatment have beneficial effects on PAD. We will explore this clinically relevant hypothesis via examining the following specific aims utilizing both animal and human studies. 1. To examine the effects of heat exposure (i.e. whole body heating or local heating) on the exercise pressor reflex (EPR). We hypothesize that heat exposure attenuates amplified EPR in PAD. In human studies, muscle sympathetic nerve activity (MSNA) and BP responses to exercise will be examined during whole body heating or local muscle heating in PAD patients and healthy control subjects. We speculate that MSNA and BP responses will be accentuated in PAD patients as compared with healthy controls and these augmented responses will be significantly attenuated by heat exposure. In animal studies, renal SNA and BP responses to static muscle contraction will be examined in PAD rats and in control rats. We speculate that EPR will be enhanced in PAD rats and increasing muscle temperature by heat exposure will attenuate the amplified reflex. 2. To examine the engagement of temperature-sensitive P2X receptors in the effects of heat exposure on the EPR. We hypothesize that heat exposure decreases the levels of ATP in the muscle insterstitium and thereby attenuates amplification of the EPR in PAD. In animal studies, we speculate that heat exposure will attenuate the levels of interstitial ATP to a greater degree in PAD rats than in control rats. We further speculate that P2X subtype (i.e., P2X3) will play a role in regulating the EPR in PAD after heat exposure. 3. To examine the effects of heat treatment (i.e. a prior heat exposure) on BP response during walking in PAD patients and further to examine potential P2X mechanisms using animal studies. After a heat treatment, walking ability in PAD patients will be estimated on a treadmill with a Gardner protocol. We speculate that the BP response will be lower and the skeletal muscle oxygenation (SmO2) level will be higher than those without the heat treatment at the same stage of the walk protocol. Moreover, the heat treatment may increase peak treadmill walking time. In animal studies, we hypothesize that heat treatment attenuates expression, function and response of P2X3 in PAD. We will examine the protein expression levels of P2X3 in muscle afferent nerves of PAD rats. We speculate that heat treatment will decrease P2X3 in PAD rats. We further speculate that heat treatment will attenuate the amplification of P2X3 current amplitude in sensory neurons innervating muscle afferents in PAD rats and this thereby inhibits the exaggerated EPR.

项目概要摘要 外周动脉疾病（PAD）是一种动脉粥样硬化性疾病，表现为流向动脉的血流量减少 下肢。期间观察到交感神经活动（SNA）和血压（BP）过度 在这种疾病中，剧烈的运动活动和这些反应会恶化运动耐量。此次活动的主要目标 建议检查热暴露和热处理是否对 PAD 产生有益影响。我们将探讨这个 通过利用动物和人类研究检查以下特定目标来得出临床相关假设。 1. 检查热暴露（即全身加热或局部加热）对运动的影响 升压反射（EPR）。我们假设热暴露会减弱 PAD 中放大的 EPR。在人类研究中， 将在全身过程中检查肌肉交感神经活动（MSNA）和血压对运动的反应 PAD 患者和健康对照受试者的加热或局部肌肉加热。我们推测 MSNA 和 BP 与健康对照相比，PAD 患者的反应会增强，并且这些增强 热暴露会显着减弱反应。在动物研究中，肾脏 SNA 和 BP 对 将在 PAD 大鼠和对照大鼠中检查静态肌肉收缩。我们推测 EPR 将是 在 PAD 大鼠中增强，通过热暴露增加肌肉温度会减弱放大的反射。 2. 检查温度敏感的 P2X 受体在热暴露影响中的作用 在 EPR 上。我们假设热暴露会降低肌肉间质中的 ATP 水平， 从而减弱 PAD 中 EPR 的扩增。在动物研究中，我们推测热暴露会 与对照大鼠相比，PAD 大鼠间质 ATP 水平的降低程度更大。我们进一步推测 P2X 亚型（即 P2X3）将在热暴露后调节 PAD 中的 EPR 中发挥作用。 3. 检查热处理（即之前的热暴露）对走进时血压反应的影响 PAD 患者并通过动物研究进一步检查潜在的 P2X 机制。一阵热气过后 治疗期间，PAD 患者的步行能力将根据加德纳方案在跑步机上进行评估。我们推测 与那些人相比，血压反应会更低，骨骼肌氧合（SmO2）水平会更高 在步行协议的同一阶段无需热处理。此外，热处理可能会增加 跑步机行走的峰值时间。在动物研究中，我们假设热处理会减弱表达， P2X3 在 PAD 中的功能和反应。我们将检查肌肉传入神经中 P2X3 的蛋白表达水平 PAD 大鼠的神经。我们推测热处理会降低 PAD 大鼠的 P2X3。我们进一步推测 热处理会减弱支配肌肉的感觉神经元中 P2X3 电流振幅的放大 PAD 大鼠的传入神经，从而抑制过度的 EPR。