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.

项目摘要/摘要 我们的目标是确定外周动脉疾病（PAD）中心血管残疾的机制 然后检查将减少这些病理生理过程影响的疗法。我们有 证明在腿部运动中，在PAD患者中夸大了运动训练后反射（EPR）。这 尚未对PAD患者夸张的EPR机制进行彻底检查。利用两个人 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）诱导的夸张的EPR的压力。我们预计会封锁酸感测离子通道（ASIC） 与氨基化的使用将减少夸张的EPR并提高PAD患者的步行耐受性。目标1： 确定BFR在诱导的EPR中的作用。我们假设BFR导致 运动肌肉的间隙中的H+/较低pH值，从而通过刺激增强EPR ASIC。我们建议在健康受试者中使用BFR来模拟BFR。我们推测BFR会 在安慰剂试验中增加EPR，惠米利将减少EPR，并增加运动时间/负载 BFR条件。我们还推测，惠洛德将在PAD患者中发挥相同的有益作用。在动物中 研究，我们推测股动脉闭塞BFR会增加间隙H+/减少pH 通过ASIC亚型3（ASIC3）和长时间的遮挡夸大EPR将上调ASIC3表达 在肌肉传入垫中。 AIM 2：确定IR在诱导的PAD中夸大的EPR中的作用。 我们假设IR在PAD中有助于夸张的EPR，淀粉样蛋白会减少夸张的EPR 由IR压力通过阻止ASIC诱导。健康受试者将在自由流下进行足底屈曲运动 疾病和20分钟后的缺血后，然后再灌注20分钟。我们推测不压力会突出 EPR。腿部血运重建前后的PAD患者也将进行足底屈曲运动。我们 推测氨基化物将改善EPR并增加IR压力后受试者的运动时间/负载 血运重建患者。在动物研究中，我们将在不同时间检查IR大鼠的EPR 课程并猜测，在IR大鼠中，满足再灌注将减轻EPR和施加响应 通过激活传入神经的ASIC3诱导。目标3：确定ASIC对运动能力的影响 垫和基本机制。我们推测，算法将减少施加响应 步行并增加了laud毛的发作时间和垫子患者的步行距离/时间。在动物研究中， 我们将猜测，IR引起的夸张的EPR会在ASIC3敲除大鼠中衰减。我们将 比较IR大鼠之间ASIC3的蛋白质水平及其在肌肉传入神经元中的当前反应 不同的时间课程及其对手作为控件。我们推测ASIC3表达及其 在启动IR阶段和IR的影响期间，肌肉传入神经元的当前反应将得到扩增 通过ASIC3敲除或有足够的再灌注时间来减少。