Exercise Pressor Reflex in Peripheral Artery Disease: Roles of Flow Limitation and Reperfusion

运动加压反射在外周动脉疾病中的作用：血流限制和再灌注的作用

• 批准号: 10501850
• 负责人: JIAN CUI
• 金额: $ 80.91万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-15 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10501850
• 关键词: ASIC channel; Afferent Neurons; Amiloride; Animals; Arachidonic Acids; Atherosclerosis; Attenuated; Blood Pressure; Blood flow; Cardiovascular Diseases; Cardiovascular system; Contracts; Data; Exercise; Experimental Models; FDA approved; Goals; Grant; Hindlimb; Human; Ischemia; Knock-out; Leg; Ligation; Lower Extremity; Modeling; Muscle; Nerve; Obstruction; Oxidative Stress; Patients; Peripheral arterial disease; Placebos; Play; Process; Proteins; Rattus; Reflex action; Reperfusion Injury; Reperfusion Therapy; Role; Stress; Supervision; Time; Tissues; Walking; afferent nerve; artery occlusion; base; blood pressure elevation; cardiovascular risk factor; claudication; disability; exercise training; experimental study; femoral artery; improved; interstitial; limb ischemia; response; treadmill

PROJECT SUMMARY/ABSTRACT Our goal is to identify the mechanisms responsible for cardiovascular disability in peripheral artery disease (PAD) and to then examine therapies that will reduce the impact of these pathophysiologic processes. We have demonstrated that the exercise pressor reflex (EPR) during leg exercise is exaggerated in PAD patients. The mechanisms for the exaggerated EPR in PAD patients have not been examined thoroughly. Utilizing both human and animal studies, we propose to examine the roles of blood flow restriction (BFR) and ischemia-reperfusion (IR) stress in inducing the exaggerated EPR. We anticipate that a blockade of acid sensing ion channels (ASICs) with amiloride will reduce the exaggerated EPR and enhance the walking tolerance in PAD patients. Aim 1: Determine the role of BFR in inducing the exaggerated EPR in PAD. We hypothesize that BFR leads to a greater H+/lower pH in the interstitium of exercising muscles and thereby accentuates the EPR via stimulating ASICs. We propose to employ BFR in healthy subjects to simulate the BFR in PAD. We speculate that BFR will augment the EPR in the placebo trial and amiloride will reduce the EPR and increase exercise time/load under BFR condition. We also speculate that amiloride will play the same beneficial role in PAD patients. In animal studies, we speculate that BFR by femoral artery occlusion will increase interstitial H+/decrease pH thereby exaggerating the EPR via ASIC subtype 3 (ASIC3) and prolonged occlusion will upregulate ASIC3 expression in muscle afferent nerves of PAD. Aim 2: Determine the role of IR in inducing the exaggerated EPR in PAD. We hypothesize that IR contributes to the exaggerated EPR in PAD and amiloride reduces the exaggerated EPR induced by IR stress via blocking ASICs. Healthy subjects will perform plantar flexion exercise under free flow conditions and after 20 min ischemia followed by 20 min reperfusion. We speculate that IR stress will accentuate the EPR. PAD patients before and after leg revascularization will also perform plantar flexion exercise. We speculate that amiloride will improve the EPR and increase exercise time/load in subjects after IR stress and in PAD patients with revascularization. In animal studies, we will examine the EPR in IR rats at different time courses and speculate that in IR rats satisfied reperfusion will alleviate the EPR and the pressor response induced by activation of afferent nerves’ ASIC3. Aim 3: Determine the effects of ASIC on exercise ability in PAD and fundamental mechanisms. We speculate that amiloride will decrease the pressor response to walking and increase the claudication onset time and walking distance/time in PAD patients. In animal studies, we speculate that exaggerated EPR induced by the IR will be attenuated in ASIC3 knockout rats. We will compare the protein levels of ASIC3 and its current response in muscle afferent neurons between IR rats at different time courses and their counterparts serving as controls. We speculate that ASIC3 expression and its current response in muscle afferent neurons will be amplified during the initiating IR stage and the effects of IR will be reduced by ASIC3 knockout or with sufficient time of reperfusion.

项目概要/摘要 我们的目标是确定导致外周动脉疾病 (PAD) 心血管功能障碍的机制 然后研究可以减少这些病理生理过程影响的疗法。 运动加压反射 (EPR) 表明，PAD 患者腿部运动时的运动加压反射 (EPR) 被夸大。 PAD 患者 EPR 夸大的机制尚未利用人类进行彻底研究。 和动物研究，我们建议检查血流限制（BFR）和缺血再灌注的作用 (IR) 压力会导致过度的 EPR，我们预计酸传感离子通道 (ASIC) 会被阻断。 与阿米洛利合用可减少 PAD 患者过度的 EPR 并增强步行耐受力。 目标 1： 确定 BFR 在诱发 PAD 中夸张的 EPR 中的作用 我们认为 BFR 会导致 PAD。 运动肌肉间质中的 H+ 更高/pH 更低，从而通过刺激增强 EPR 我们建议在健康受试者中使用 BFR 来模拟 PAD 中的 BFR 我们推测 BFR 会。 在安慰剂试验中增加 EPR，阿米洛利将减少 EPR 并增加运动时间/负荷 我们还推测阿米洛利对动物 PAD 患者也能起到同样的有益作用。 研究中，我们推测通过股动脉闭塞进行 BFR 会增加间质 H+/降低 pH 值，从而 通过 ASIC 亚型 3 (ASIC3) 夸大 EPR 和长期闭塞将上调 ASIC3 表达 目标 2：确定 IR 在诱导 PAD 中过度 EPR 中的作用。 我们认为 IR 会导致 PAD 中夸大的 EPR，而阿米洛利可降低夸大的 EPR 通过阻断 ASIC 引起的 IR 压力健康受试者将在自由流动下进行跖屈运动。 缺血 20 分钟后再灌注 20 分钟，我们推测 IR 应激会加剧。 EPR.腿部血运重建前后的PAD患者也会进行跖屈运动。 推测阿米洛利将改善受试者在 IR 应激后和在 进行血运重建的 PAD 患者在动物研究中，我们将在不同时间检查 IR 大鼠的 EPR。 并推测在 IR 大鼠中，满意的再灌注将减轻 EPR 和升压反应 目标 3：确定 ASIC 对运动能力的影响。 PAD 和基本机制我们推测阿米洛利会降低升压反应。 在动物研究中，步行并增加 PAD 患者的跛行发作时间和步行距离/时间。 我们推测 IR 诱导的过度 EPR 在 ASIC3 敲除大鼠中会减弱。 比较 IR 大鼠肌肉传入神经元中 ASIC3 的蛋白水平及其当前反应 我们推测ASIC3表达及其作为对照的不同时间进程及其辅助。 在 IR 起始阶段，肌肉传入神经元的电流反应将会被放大，并且 IR 的影响 将通过 ASIC3 敲除或足够的再灌注时间来减少。