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 负责对运动进行心血管调整，其中包括增加运动量。 外周血管阻力、心肌收缩力和速率、增加动脉血流量和氧的功能 供给运动肌肉，反过来支持它们的收缩能力。 称为运动加压反射，其传入臂由 III 组和 IV 纤维组成，其末端 位于周围动脉疾病 (PAD) 患者的肌肉间质内和附近。 本单元提出的实验的总体目标是阐明升压反射。 收缩肌肉中发生的代谢因素是引起这种 PAD 诱发的原因 骨骼肌收缩产生的代谢因子被认为是夸大的信号。 脊髓和大脑认为工作肌肉的动脉血液供应不能满足其代谢需求。 因此，这些代谢物是刺激负责的 III 组和 IV 组传入神经的主要候选物。 在所提出的实验中，我们将特别关注 PAD 中的夸张运动升压反射。 注意收缩的三种重要的代谢副产物，即乳酸，它会刺激 ASIC3 通道、前列腺素 E2（刺激内过氧化物 (EP)4 受体）和 ATP 我们将在未麻醉的去大脑大鼠中检查对 P2X3 受体的反应。 在药物阻断之前和期间，第 III 组和第 IV 组肌肉传入的收缩 上述受体或被 siRNA“击倒”后，拟议的实验也将进行。 检查敲除之前和敲除过程中这些细纤维传入神经收缩的反应 小腿三头肌中的肌磷酸化酶拟议的实验将在大鼠中进行。 自由灌注的股动脉以及在实验前已结扎股动脉 72 小时的大鼠 实验开始时，后一种准备模拟了患者的动脉血流模式。 因此，PAD 可以作为这种疾病的有用动物模型，所提出的实验是预期的。 提供有关导致运动加压反射夸大的代谢因素的新信息 软垫。