Neurovascular Dysfunction and Oxidative Stress in Renal Failure

描述(由申请者提供)：本申请旨在通过严格的培训计划，在具有翻译血管研究悠久传统的杰出科学环境中，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，研究慢性肾功能衰竭(CRF)患者心血管(CV)风险的神经血管机制。慢性肾功能衰竭的发病率正在以惊人的速度增长，其中绝大多数患者死于心血管疾病。在这一人群中，心血管死亡的一个主要独立危险因素是运动不耐受和较差的体能，其机制在很大程度上仍不清楚。我们的初步数据显示，CRF患者在等长和有节奏的运动中血压(BP)有夸大的增加，这表明异常的血流动力学反应可能起到了作用。该项目的目标是研究CRF患者运动时血压反应过度的机制，并测试四氢生物蝶呤(BH4)治疗对运动期间和基线状态下的神经和血管反应的潜在益处。了解运动不耐受背后的血流动力学机制将有助于开发迫切需要的治疗靶点，以改善身体功能、生活质量，并最终降低CRF的心血管死亡率。运动中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和一氧化氮(NO)依赖的血管扩张引起的血管舒张力之间的平衡所介导的。可以想象，运动中这些血管收缩和血管扩张反应的不平衡可能导致血压反应增强，并通过增加心肌负荷而导致运动功能障碍，并增加在体力活动中发生不良心血管事件的风险。在目标1中，我们将通过使用显微神经图测量静态和节奏运动中SNS活动的变化来确定CRF患者在运动过程中是否存在过度的反射SNS激活。在目标2中，我们将通过测量全身运动时肱动脉血流介导的血管扩张的变化，来确定CRF患者是否损害了运动诱导的NO介导的血管扩张。急性运动还会增加活性氧(ROS)，刺激神经SNs外流，并降低NO的生物利用度。目的2b将确定CRF患者在急性运动过程中是否产生更多的ROS(即氧化应激)，从而导致夸大的升压反应。最后，四氢生物蝶呤(BH4)是内皮一氧化氮合酶的重要辅助因子，通过增加一氧化氮的生物利用度来改善CRF动物模型的内皮功能和血压。在目标3中，我们将进行第一个试点试验，以测试口服BH4治疗对CRF患者静息和运动时SNS过度活动、内皮功能障碍和氧化应激的影响。我们推测，BH4可能是一种潜在的影响运动耐量以及CRF患者心血管发病率和死亡率的新型治疗剂。 公共卫生相关性： 在美国，慢性肾功能衰竭(CRF)的发病率正以惊人的速度增长，这些患者遭受体能低下和运动不耐受的困扰，这是该人群心血管(CV)死亡的独立危险因素。对CRF患者运动过程中血流动力学异常反应的研究将有助于深入了解导致心血管风险增加的基线神经血管和内皮异常的机制，并有助于开发迫切需要的治疗目标，以改善身体功能，最终降低心血管死亡率。BH4疗法可能是这样一种新型的治疗剂，它有可能影响运动耐量，并降低CRF患者的基线心血管风险。(摘要结束)

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)