The Role of Neurovascular Dysfunction and Oxidative Stress in the Exercise Intole

描述（由申请人提供）：本申请旨在通过严格的培训计划，在具有悠久转化血管研究传统的优秀科学环境中发展候选人的科学成长。候选人的长期目标是建立一个独立的临床研究生涯，研究慢性肾衰竭（CRF）患者心血管（CV）风险的神经血管机制。CRF的发病率正以惊人的速度增长，其中绝大多数患者死于CV疾病。在这一人群中，CV死亡的一个主要独立危险因素是运动不耐受和身体能力差，其机制在很大程度上仍不清楚。我们的初步数据表明，CRF患者在等长和节律性运动期间血压（BP）升高过高，表明异常的血流动力学反应可能起作用。本项目的目的是研究CRF运动中血压反应夸大的机制，并测试四氢生物蝶素（BH4）治疗在运动期间和基线时对神经和血管反应的潜在益处。了解运动不耐受的血流动力学机制将有助于制定治疗靶点，以改善CRF患者的身体功能、生活质量，并最终降低CV死亡率。运动时的血压反应是由交感神经系统（SNS）反射激活引起的血管收缩力和一氧化氮（NO）依赖性血管扩张引起的血管舒张力之间的平衡介导的。可以想象，运动时这些血管收缩和血管扩张反应的不平衡可能导致BP反应增强，并通过增加心肌负荷导致运动功能障碍，同时增加体育活动期间不良心血管事件的风险。在目的1中，我们将通过使用微神经摄影测量静态和节律性运动时SNS活动的变化来确定CRF患者在运动中是否有过度的反射性SNS激活。在Aim 2中，我们将通过测量肱动脉血流介导的血管舒张在全身运动后的变化，来确定CRF患者是否存在运动诱导的no介导的血管舒张受损。急性运动还会产生活性氧（ROS）的增加，刺激神经SNS流出，并降低NO的生物利用度。Aim 2b将确定CRF患者是否在急性运动中产生更多的ROS（即氧化应激），从而导致过度的降压反应。最后，四氢生物蝶呤（BH4）是内皮NO合成酶的重要辅助因子，通过提高NO的生物利用度来改善CRF动物模型的内皮功能和血压。在Aim 3中，我们将进行第一个试点试验，以测试口服BH4治疗对CRF患者休息和运动时SNS过度活跃、内皮功能障碍和氧化应激的影响。我们假设BH4可能是一种新的治疗药物，有可能影响CRF患者的运动耐量，以及CV发病率和死亡率。

DESCRIPTION (provided by applicant): This application seeks to develop the candidate's scientific growth through a rigorous training plan, within an outstanding scientific environment that has a long tradition in translational vascular research. The candidate's long-term goal is to establish an independent clinical research career studying neurovascular mechanisms of cardiovascular (CV) risk in patients with chronic renal failure (CRF). The incidence of CRF is growing at an alarming rate, and the vast majority of these patients die from CV disease. One major independent risk factor for CV mortality in this population is exercise intolerance and poor physical capacity, the mechanisms of which remain largely unknown. Our preliminary data demonstrate that CRF patients have an exaggerated increase in blood pressure (BP) during isometric and rhythmic exercise, suggesting that abnormal hemodynamic responses may play a role. The goals of this project are to examine the mechanisms underlying the exaggerated BP response during exercise in CRF, and to test the potential benefits of tetrahydrobiopterin (BH4) treatment on neural and vascular responses both during exercise and at baseline. Understanding the hemodynamic mechanisms underlying exercise intolerance will help develop therapeutic targets that are urgently needed to improve physical functioning, quality of life, and ultimately reduce CV mortality in CRF. The BP response during exercise is mediated by a balance between vasoconstrictive forces induced by reflex activation of the sympathetic nervous system (SNS), and vasodilatory forces induced by nitric oxide (NO)-dependent vasodilatation. Conceivably, an imbalance in these vasoconstrictive and vasodilatory responses during exercise could lead to an augmented BP response and contribute to exercise dysfunction by increasing myocardial workload, as well as increase the risk of adverse CV events during physical activity. In aim 1, we will determine if CRF patients have exaggerated reflex SNS activation during exercise by measuring changes in SNS activity during static and rhythmic exercise using microneurography. In Aim 2, we will determine if CRF patients have impaired exercise-induced NO-mediated vasodilation, by measuring changes in brachial artery flow-mediated vasodilatation in response to whole-body exercise. Acute exercise also generates an increase in reactive oxygen species (ROS) that stimulates neural SNS outflow, as well as decreases NO bioavailability. Aim 2b will determine if CRF patients have greater production of ROS (i.e. oxidative stress) during acute exercise that contributes to the exaggerated pressor response. Finally, tetrahydrobiopterin (BH4) is an essential cofactor for endothelial NO synthase that improves endothelial function and BP in animal models of CRF by increasing NO bioavailability. In Aim 3, we will conduct the first pilot trial to test the effects of oral BH4 treatment on SNS overactivity, endothelial dysfunction, and oxidative stress, both at rest and during exercise in CRF patients. We hypothesize that BH4 may be a novel therapeutic agent with potential to impact exercise tolerance, as well as CV morbidity and mortality in patients with CRF. PUBLIC HEALTH RELEVANCE: The incidence of chronic renal failure (CRF) is growing at an alarming rate in the U.S., and these patients suffer from poor physical capacity and exercise intolerance, which is an independent risk factor for cardiovascular (CV) mortality in this population. The study of abnormal hemodynamic responses during exercise in CRF patients will give insight into mechanisms of baseline neurovascular and endothelial abnormalities that contribute to increased CV risk, and help develop therapeutic targets that are urgently needed to improve physical functioning, and ultimately reduce CV mortality. BH4 therapy may be such a novel therapeutic agent that has the potential to impact exercise tolerance, as well as decrease baseline cardiovascular risk in patients with CRF. (End of Abstract)