Project 3: Role Played by ASIC, P2X and EP4 Receptors in the Exercise Pressor Reflex in Health and Simulated PAD

项目摘要/摘要--项目3 后肢骨骼肌收缩产生的反射是一种重要的神经机制，即 负责心血管调节运动。这些调整，包括增加 外周血管阻力、心脏收缩能力和心率、增加动脉血流量和氧气的功能 提供给锻炼的肌肉，进而支持他们收缩的能力。这种神经机制一直是 运动加压反射及其传入臂由III和IV类纤维组成，它们的末梢 位于肌肉间质及其附近。外周动脉疾病(PAD)患者的运动 升压反射被夸大了。本单元中提出的实验的总体目标是阐明 收缩肌肉中的代谢因子负责唤起这种垫诱导的 条件反射的夸张。骨骼肌收缩产生的代谢因子被认为是信号 供工作肌肉的动脉供血不能满足其代谢需求的脊髓和大脑。 因此，这些代谢物是刺激负责 在PAD中引起夸张的运动加压反射。在拟议的实验中，我们将特别支付 注意收缩的三个重要的代谢副产品，即乳酸，它刺激 ASIC3通道，刺激内过氧化(EP)4受体的前列腺素E2，以及 刺激P2X3受体。我们将在去大脑的未麻醉大鼠身上检测对 III组和IV组肌肉传入在药物阻断前和期间的收缩 在受体之上或在它们被siRNA“击倒”之后。拟议中的实验还将 检查这些细纤维传入在被击倒之前和期间对收缩的反应 小腿三头肌中的肌磷酸酶。拟议的实验将在两种情况下进行 在自由血流的股动脉和股动脉结扎前72小时的大鼠中 实验开始。后一种制剂模拟了慢性阻塞性肺疾病患者的动脉血流模式 PAD，因此可作为该疾病的有用动物模型。拟议的实验是可以预见的。 提供有关导致运动加压反射被夸大的代谢因素的新信息 垫子。

PROJECT SUMMARY/ABSTRACT – PROJECT 3 A reflex arising from the contraction of hindlimb skeletal muscles is an important neural mechanism that is responsible for the cardiovascular adjustments to exercise. These adjustments, which include increases in peripheral vascular resistance, cardiac contractility and rate, function to increase arterial blood flow and oxygen supply to the exercising muscles, and in turn support their ability to contract. This neural mechanism has been named the exercise pressor reflex and its afferent arm is comprised of group III and IV fibers whose endings are located in and near the muscle interstitium. In patients with peripheral artery disease (PAD) the exercise pressor reflex is exaggerated. The overall goal of the experiments proposed in this unit is to shed light on the metabolic factors occurring in contracting muscles that are responsible for evoking this PAD-induced exaggeration of the reflex. Metabolic factors produced by contracting skeletal muscles are believed to signal the spinal cord and brain that the arterial blood supply to working muscle does not meet its metabolic demand. These metabolites are therefore prime candidates for stimulating the group III and IV afferents responsible for evoking the exaggerated exercise pressor reflex in PAD. In the proposed experiments, we will pay particular attention to three important metabolic by-products of contraction, namely Lactic Acid, which stimulates the ASIC3 channel, Prostaglandin E2, which stimulates the endoperoxide (EP)4 receptor, and ATP which stimulates the P2X3 receptor. We will examine in decerebrated unanesthetized rats the responses to contraction of group III and IV muscle afferents both before and during either pharmacological blockade of the above receptors or after they have been “knocked down” with siRNA. The proposed experiments will also examine the responses to contraction of these thin fiber afferents before and during knockdown of myophosphorylase in the triceps surae muscles. The proposed experiments will be performed both in rats with freely perfused femoral arteries and in rats with femoral arteries that have been ligated for 72 hours before the start of the experiment. The latter preparation simulates the arterial blood flow patterns seen in patients with PAD and therefore serves as a useful animal model of this disease. The proposed experiments are anticipated to provide new information about metabolic factors that cause the exercise pressor reflex to be exaggerated in PAD.