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

项目总结摘要 外周动脉疾病(PAD)是一种动脉粥样硬化性疾病，主要表现为动脉血流量减少。 四肢受伤。在治疗过程中观察到交感神经活动(SNA)和血压(BP)的夸大 这种疾病中剧烈的运动活动和这些反应会恶化运动耐量。这一行动的主要目标是 建议检查热暴露和热处理是否对PAD有有益影响。我们将对此进行探索 通过利用动物和人体研究检验以下特定目的，提出临床相关假说。 1.研究热暴露(即全身加热或局部加热)对运动的影响 升压反射(EPR)。我们假设热暴露减弱了PAD中扩增的EPR。在人体研究中， 将在全身范围内检测肌肉交感神经活动(MSNA)和对运动的血压反应 PAD患者和健康对照组的热疗或局部肌肉热疗。我们推测MSNA和BP 与健康对照组相比，PAD患者的反应将增强，并且这些反应增强 热暴露会使反应显著减弱。在动物研究中，肾脏SNA和BP对 将在PAD大鼠和对照组大鼠中检测静态肌肉收缩。我们推测，EPR将是 PAD大鼠的增强和热暴露引起的肌肉温度升高将减弱放大的反射。 2.研究温度敏感型P2X受体在热暴露中的作用 在EPR上。我们假设热暴露降低了肌肉间质和肌肉组织中的ATP水平 从而减弱了PAD中EPR的放大。在动物研究中，我们推测热暴露会 能更大程度地降低PAD大鼠肾间质中的ATP水平。我们进一步推测 该P2X亚型(即P2X3)在热暴露后对PAD的EPR起调节作用。 3.检查热处理(即先前的热暴露)对步行时血压反应的影响 并进一步利用动物研究来检验潜在的P2X机制。一场热浪过后 治疗后，PAD患者的行走能力将在跑步机上按照Gardner方案进行评估。我们推测 血压反应会更低，骨骼肌氧合(SmO2)水平会比 不需要在步行方案的同一阶段进行热处理。此外，还可以增加热处理 跑步机步行高峰期。在动物研究中，我们假设热处理会减弱表达， P2X3在PAD中的作用和反应。我们将检测P2X3在肌肉传入中的蛋白表达水平 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的P2X3电流幅度的放大 在PAD大鼠中传入，从而抑制夸大的EPR。

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.