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

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 havedemonstrated that the exercise pressor reflex (EPR) during leg exercise is exaggerated in PAD patients. Themechanisms for the exaggerated EPR in PAD patients have not been examined thoroughly. Utilizing both humanand 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 agreater H+/lower pH in the interstitium of exercising muscles and thereby accentuates the EPR via stimulatingASICs. We propose to employ BFR in healthy subjects to simulate the BFR in PAD. We speculate that BFR willaugment the EPR in the placebo trial and amiloride will reduce the EPR and increase exercise time/load underBFR condition. We also speculate that amiloride will play the same beneficial role in PAD patients. In animalstudies, we speculate that BFR by femoral artery occlusion will increase interstitial H+/decrease pH therebyexaggerating the EPR via ASIC subtype 3 (ASIC3) and prolonged occlusion will upregulate ASIC3 expressionin 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 EPRinduced by IR stress via blocking ASICs. Healthy subjects will perform plantar flexion exercise under free flowconditions and after 20 min ischemia followed by 20 min reperfusion. We speculate that IR stress will accentuatethe EPR. PAD patients before and after leg revascularization will also perform plantar flexion exercise. Wespeculate that amiloride will improve the EPR and increase exercise time/load in subjects after IR stress and inPAD patients with revascularization. In animal studies, we will examine the EPR in IR rats at different timecourses and speculate that in IR rats satisfied reperfusion will alleviate the EPR and the pressor responseinduced by activation of afferent nerves’ ASIC3. Aim 3: Determine the effects of ASIC on exercise ability inPAD and fundamental mechanisms. We speculate that amiloride will decrease the pressor response towalking 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 willcompare the protein levels of ASIC3 and its current response in muscle afferent neurons between IR rats atdifferent time courses and their counterparts serving as controls. We speculate that ASIC3 expression and itscurrent response in muscle afferent neurons will be amplified during the initiating IR stage and the effects of IRwill be reduced by ASIC3 knockout or with sufficient time of reperfusion.