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

项目 3：ASIC、P2X 和 EP4 受体在健康和模拟 PAD 运动加压反射中的作用

• 批准号: 10117112
• 负责人: Marc Peter Kaufman
• 金额: $ 41.82万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10117112
• 关键词: Acute; Animal Disease Models; Antioxidants; Arrhythmia; Arteries; Ascorbic Acid; Attention; Attenuated; Blood Vessels; Blood flow; Brain; Cardiac; Cardiovascular system; Chest Pain; Chronic; Contracts; Coronary artery; Dinoprostone; Disease; Event; Exercise; Fiber; Gastrocnemius Muscle; Goals; Health; Heart; Heart Contractilities; Heart Rate; Hindlimb; Hour; Individual; Infusion procedures; Intermittent Claudication; Ischemia; Kidney; Lactic acid; Light; Mechanics; Mediating; Metabolic; Muscle; Muscle Contraction; Muscle Fibers; Muscle Form Glycogen Phosphorylase; Myocardial; Names; Nerve; Neurons; Organ; Oxidative Stress; Oxygen; P2X-receptor; Pain; Patients; Pattern; Peripheral; Peripheral arterial disease; Peroxides; Pharmacology; Play; Preparation; Prostaglandins; Rattus; Reflex action; Resistance; Role; Signal Transduction; Skeletal Muscle; Small Interfering RNA; Spinal Cord; Spinal Ganglia; Stimulus; Sympathetic Nervous System; Testing; Thinness; Tiron; Trees; Triceps Brachii Muscle; Vascular blood supply; Vascular resistance; Ventricular Fibrillation; afferent nerve; arm; experimental study; femoral artery; knock-down; neuromechanism; pressure; receptor; response; vasoconstriction

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.

项目总结/摘要-项目3 由后肢骨骼肌收缩引起的反射是一种重要的神经机制， 负责心血管对运动的调节。这些调整，其中包括增加 外周血管阻力、心脏收缩力和心率、增加动脉血流量和氧气的功能 供应给运动的肌肉，并反过来支持他们的收缩能力。这种神经机制已经被 称为运动加压反射，其传入臂由III和IV组纤维组成， 位于肌筋膜内和附近。在外周动脉疾病（PAD）患者中， 升压反射被放大。本单元提出的实验的总体目标是阐明 发生在收缩肌肉中的代谢因子，负责引起这种PAD诱导的 反射的放大。骨骼肌收缩产生的代谢因子被认为是 脊髓和大脑的动脉血液供应工作肌肉不能满足其代谢需求。 因此，这些代谢物是刺激负责以下功能的III和IV组传入神经的主要候选物： 引起PAD的过度运动升压反射。在拟议的实验中，我们将特别注意 注意收缩的三个重要代谢副产物，即乳酸，它刺激收缩。 ASIC 3通道，前列腺素E2，刺激内过氧化物（EP）4受体，和ATP， 刺激P2 X3受体。我们将在去大脑的未麻醉大鼠中检查对 收缩组III和IV肌肉传入之前和期间，无论是药理学封锁的 或在它们被siRNA“敲低”之后。拟议的实验还将 检查这些细纤维传入的收缩反应之前和期间敲低， 小腿三头肌中的肌磷酸化酶拟进行的实验将在大鼠中进行， 自由灌注的股动脉和股动脉结扎72小时的大鼠， 实验的开始。后一种制剂模拟了在患有以下疾病的患者中观察到的动脉血流模式： PAD，因此作为这种疾病的一个有用的动物模型。预计拟议的实验 提供了关于代谢因素的新信息，这些代谢因素导致运动加压反射被夸大， 垫.