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

血栓素在外周动脉疾病运动加压反射中的作用

• 批准号: 8262671
• 负责人: Anna Katherine Leal
• 金额: $ 5.22万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8262671
• 关键词: Address; Affect; Animal Disease Models; Animals; Arachidonic Acids; Attenuated; Back; Blood flow; Cardiovascular Diseases; Cardiovascular system; Chemicals; Coronary Arteriosclerosis; Disease model; Ensure; Environmental air flow; Excretory function; Exercise; Feedback; Functional disorder; Heart Rate; Hindlimb; Human; Hypertension; Hyporeflexia; Individual; Intermittent Claudication; Ischemia; Isometric Contraction; Isometric Exercise; Lead; Leg; Limb structure; Metabolic; Microcirculation; Muscle; Myocardial Infarction; Nerve; Nerve Fibers; Oxygen; Pain; Pain in lower limb; Patients; Pattern; Peripheral arterial disease; Physical activity; Plasma; Platelet aggregation; Population; Production; Prostaglandin Endoperoxides; Prostaglandin-Endoperoxide Synthase; Prostaglandins; Quality of life; Rattus; Reflex action; Rest; Risk; Role; Simulate; Skeletal Muscle; Sprague-Dawley Rats; Stroke; Swimming; Testing; Thromboxane A2; Thromboxane A2 Receptor; Thromboxane B2; Thromboxane Production; Thromboxanes; Training; Training Programs; Vasoconstrictor Agents; Vasodilator Agents; Walking; Work; afferent nerve; arm; artery occlusion; base; feeding; fitness; improved; muscle metabolism; novel; physical conditioning; pressure; public health relevance; receptor; research study; response; sedentary; urinary

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.

描述（由申请人提供）：在身体活动期间，运动加压反射（一种源自骨骼肌的反馈机制）会增加平均动脉压和心率，以确保为工作肌肉提供足够的血流和氧气。运动加压反射由第 III 组传入神经和第 IV 组传入神经组成，已证明它们是由肌肉代谢的化学副产物激活的。有趣的是，运动升压反射已被证明会在患有模拟外周动脉疾病的大鼠中引起夸张的循环反应。周围动脉疾病会导致四肢缺血，并可能导致间歇性跛行。肌肉代谢物，特别是前列腺素，可能是在这种疾病的大鼠模型中观察到的对运动升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升压反射激活。运动已被证明可以通过增加侧支血流量和血管扩张剂的微循环表达以及减少血栓素 B2（血栓素 A2 的稳定代谢物）的尿排泄来改善外周动脉疾病患者的步行经济性。因此，拟议的研究将检验以下假设：前列腺素羟基化时形成的血栓素 A2 在外周动脉疾病中增加，并导致运动升压反射过度，而跑步机训练会减少血栓素 A2 的产生，从而降低模拟外周动脉疾病大鼠对运动升压反射激活的心血管反应。 通过所提出的实验，我将尝试描述有或没有模拟外周动脉疾病的大鼠在休息和静态收缩期间的骨骼肌血栓素 A2 水平。此外，通过使用血栓素 A2 受体拮抗剂减弱对后肢收缩的循环反应，将阐明血栓素 A2 对外周动脉疾病运动升压反射的贡献。然后，这些实验将在已接受跑步机训练计划的患有或未患有模拟外周动脉疾病的大鼠中重复进行。具体来说，这些研究将探讨运动训练如何影响休息和等长收缩期间血栓素 A2 的产生，并描述运动如何增强健康大鼠和患有模拟外周动脉疾病的大鼠对运动升压反射激活的循环反应。 公共健康相关性：拟议的研究将确定肌肉代谢副产物血栓素 A2 及其受体对外周动脉疾病中观察到的过度运动升压反射反应有何作用。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诱导动脉供血不足的大鼠中血栓素 A2 的产生来减轻由运动升压反射激活引起的过度升压和交感神经反应。这些研究可能会带来新的治疗方法，可能会增加患有外周动脉疾病的个体的行走耐受性，并减少与体力活动相关的风险和疼痛。