Role of Thromboxane in the Exercise Pressor Reflex in Peripheral Artery Disease

描述(申请人提供)：在体力活动中，运动加压反射，一种源于骨骼肌的反馈机制，增加平均动脉压和心率，以确保工作肌肉有足够的血流量和氧气。运动加压反射由第三类传入和第四类传入组成，已被证明是由肌肉代谢的化学副产物激活的。有趣的是，运动加压反射已被证明在模拟外周动脉疾病的大鼠中引起夸大的循环反应。外周动脉疾病会导致肢体缺血，并可能导致间歇性跛行。肌肉代谢物，特别是前列腺素，可能是在本病大鼠模型中观察到的对运动加压反射激活的过度心血管反应的部分原因，因为它们已被证明有助于运动加压反射的激活。运动通过增加血管扩张剂的侧支血流量和微循环表达，减少血栓素A2的稳定代谢产物血栓素B2的尿排出，已被证明可以改善外周动脉疾病患者的步行经济性。因此，这项拟议的研究将检验这样的假设：在外周动脉疾病中，前列腺素羟化时形成的血栓素A2增加，并有助于夸大运动加压反射，以及跑步机训练减少血栓素A2的产生，从而减少模拟外周动脉疾病大鼠对运动加压反射激活的心血管反应。通过拟议的实验，我将尝试描述患有和不患有模拟外周动脉疾病的大鼠在静息和静态收缩过程中骨骼肌血栓素A2的水平。此外，血栓素A2在外周动脉疾病运动加压反射中的作用将通过使用血栓素A2受体拮抗剂来减弱对后肢收缩的循环反应来阐明。然后，这些实验将在有和没有模拟外周动脉疾病的大鼠身上重复，这些大鼠已经接受了跑步机训练计划。具体地说，这些研究将阐述运动训练如何影响休息和等长收缩时血栓烷A2的产生，并描述运动如何增强健康大鼠和模拟外周动脉疾病大鼠对运动加压反射激活的循环反应。 公共卫生相关性：拟议的研究将确定肌肉代谢副产物血栓素A2及其受体在外周动脉疾病中观察到的夸大运动加压反射反应中起什么作用。此外，这些实验将有助于描述跑步机训练是否以及如何通过减少动脉供血不足大鼠的血栓素A2生成来减轻运动加压反射激活引起的夸大的升压和交感反应。这些研究可能会导致新的治疗方法，可能会增加患有外周动脉疾病的人的步行耐量，并减少与体力活动相关的风险和疼痛。

DESCRIPTION (provided by applicant): During physical activity, the exercise pressor reflex, a feed-back mechanism originating in skeletal muscle, increases mean arterial pressure and heart rate to ensure that the working muscle is provided with adequate blood flow and oxygen. The exercise pressor reflex is comprised of group III afferents and group IV afferents, which have been shown to be activated by the chemical by-products of muscle metabolism. Interestingly, the exercise pressor reflex has been shown to elicit exaggerated circulatory responses in rats with simulated peripheral artery disease. Peripheral arterial disease leads to ischemia of the limbs and can cause intermittent claudication. It is possible that muscle metabolites, specifically prostaglandins, are partially responsible for the exaggerated cardiovascular response to exercise pressor reflex activation observed in the rat model of this disease, as they have been shown to contribute to exercise pressor reflex activation. Exercise has been proven to improve walking economy in patients with peripheral artery disease by increasing collateral blood flow and microcirculation expression of vasodilators and by decreasing urinary excretion of thromboxane B2, the stable metabolite of thromboxane A2. Therefore, the proposed study will test the hypotheses that thromboxane A2, formed when prostaglandins are hydroxylized, is increased in peripheral artery disease and contributes to the exaggerated exercise pressor reflex and that treadmill training decreases thromboxane A2 production and, subsequently, the cardiovascular response to exercise pressor reflex activation in rats with simulated peripheral artery disease. With the proposed experiments, I will attempt to describe skeletal muscle thromboxane A2 levels both at rest and during static contraction in rats with and without simulated peripheral artery disease. Additionally, the contribution of thromboxane A2 to the exercise pressor reflex in peripheral artery disease will be elucidated by using thromboxane A2 receptor antagonists to attenuate the circulatory response to hindlimb contraction. These experiments will then be repeated in rats with and without simulated peripheral artery disease that have been subjected to a treadmill training program. Specifically, these studies will address how exercise training affects thromboxane A2 production during rest and isometric contraction and describe how exercise augments the circulatory response to exercise pressor reflex activation in healthy rats and rats with simulated peripheral artery disease. PUBLIC HEALTH RELEVANCE: The proposed studies will ascertain what role the muscle metabolic by-product thromboxane A2 and its receptor has on the exaggerated exercise pressor reflex response observed in peripheral artery disease. Additionally, these experiments will help describe if and how treadmill training alleviates the exaggerated pressor and sympathetic responses elicited by exercise pressor reflex activation via reductions in thromboxane A2 production in rats with induced arterial insufficiency. These studies may lead to novel treatments that could potentially increase walking tolerance in individuals suffering from peripheral artery disease and reduce the risks and pain associated with physical activity.