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.

项目摘要摘要 外围动脉疾病（PAD）是动脉粥样硬化疾病，血液流向流向的动脉 下肢。夸张的交感神经活动（SNA）和血压（BP）在期间观察到 在这种疾病中的强烈运动活动，这些反应使运动耐受性恶化。主要目标 建议是检查热暴露和热处理是否对PAD具有有益的影响。我们将探索这个 通过检查以下特定目的利用动物和人类研究，临床上相关的假设。 1。检查热暴露（即全身加热或局部加热）的影响 压力反射（EPR）。我们假设热暴露会减弱PAD中EPR的扩增。在人类研究中， 肌肉交感神经活动（MSNA）和BP对运动的反应将在全身进行检查 PAD患者和健康对照组的加热或局部肌肉加热。我们推测MSNA和BP 与健康对照组相比，PAD患者的反应将在PAD患者中得到强调，并且这些增强 热暴露会大大减弱反应。在动物研究中，肾脏SNA和BP对 将在垫大鼠和对照大鼠中检查静态肌肉收缩。我们推测EPR将是 垫大鼠增强并通过热量暴露增加肌肉温度将减轻放大的反射。 2。检查温度敏感的P2X受体在热暴露的影响中的参与 在EPR上。我们假设热暴露会降低肌肉插义和 从而减轻EPR在PAD中的扩增。在动物研究中，我们推测热暴露会 与对照大鼠相比，在垫大鼠中，降低间质ATP的水平更大。我们进一步推测 P2X亚型（即P2X3）将在调节热暴露后的EPR中发挥作用。 3。检查热处理（即先前的热暴露）对行走过程中BP反应的影响 PAD患者并进一步检查使用动物研究的潜在P2X机制。加热后 治疗，PAD患者的步行能力将在具有Gardner方案的跑步机上估算。我们推测 BP反应将较低，并且骨骼肌氧合（SMO2）水平将高于 在步行协议的同一阶段没有热处理。而且，热处理可能会增加 高峰跑步机步行时间。在动物研究中，我们假设热处理减弱了表达， PAD中P2X3的功能和响应。我们将检查肌肉传入中P2X3的蛋白质表达水平 垫大鼠神经。我们推测热处理将减少垫大鼠的P2X3。我们进一步推测 热处理将减轻感官神经元中P2X3电流幅度的扩增 PAD大鼠的传入，因此抑制了夸张的EPR。