Neurovascular Dysfunction and Oxidative Stress in Renal Failure

肾衰竭中的神经血管功能障碍和氧化应激

基本信息

批准号：
8459604
负责人：
Jeanie Park
金额：
$ 13.37万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-15 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8459604
关键词：
Acute Animal Model Biological Availability Blood Pressure Blood Vessels Blood flow Cardiovascular Diseases Cardiovascular system Cessation of life Chronic Kidney Failure Clinical Research Data End stage renal failure Environment Equilibrium Etiology Event Exercise Exercise Tolerance Functional disorder Goals Growth Human Incidence Isometric Exercise Kidney Failure Lead Measures Mediating Morbidity - disease rate Muscle Myocardial Nitric Oxide Oral Oxidative Stress Patients Physical Capacity Physical Function Physical activity Play Population Production Quality of life Reactive Oxygen Species Reflex action Research Rest Risk Role Sudden Death Supplementation Sympathetic Nervous System Testing Therapeutic Agents Training Vasodilation Workload abstracting brachial artery cardiovascular disorder risk cardiovascular risk factor career cofactor hemodynamics human NOS3 protein improved insight mortality novel therapeutics pilot trial public health relevance relating to nervous system response tetrahydrobiopterin therapeutic target

项目摘要

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.

描述（由申请人提供）：本申请旨在通过严格的培训计划，在具有转化血管研究悠久传统的杰出科学环境中促进候选人的科学成长。该候选人的长期目标是建立一个独立的临床研究职业，研究慢性肾衰竭（CRF）患者心血管（CV）风险的神经血管机制。 CRF 的发病率正在以惊人的速度增长，其中绝大多数患者死于心血管疾病。该人群心血管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，其机制仍不清楚。我们的初步数据表明，CRF 患者在等长运动和节律运动期间血压 (BP) 过度升高，表明异常的血流动力学反应可能发挥了作用。该项目的目标是检查 CRF 运动期间血压过度反应的机制，并测试四氢生物蝶呤 (BH4) 治疗对运动期间和基线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制定改善身体功能、生活质量并最终降低 CRF 心血管死亡率急需的治疗目标。运动期间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）依赖性血管舒张引起的血管舒张力之间的平衡介导的。可以想象，运动期间这些血管收缩和血管舒张反应的不平衡可能会导致血压反应增强，并通过增加心肌负荷而导致运动功能障碍，并增加体力活动期间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造影测量静态和节律运动期间 SNS 活动的变化来确定 CRF 患者在运动期间是否过度反射 SNS 激活。在目标 2 中，我们将通过测量全身运动引起的肱动脉血流介导的血管舒张变化来确定 CRF 患者运动诱导的 NO 介导的血管舒张是否受损。急性运动还会导致活性氧 (ROS) 增加，从而刺激神经 SNS 流出，并降低一氧化氮的生物利用度。目标 2b 将确定 CRF 患者在急性运动期间是否会产生更多的 ROS（即氧化应激），从而导致升压反应过度。最后，四氢生物蝶呤 (BH4) 是内皮 NO 合酶的重要辅助因子，可通过增加 NO 生物利用度来改善 CRF 动物模型中的内皮功能和血压。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 患者静息时和运动时 SNS 过度活跃、内皮功能障碍和氧化应激的影响。我们假设 BH4 可能是一种新型治疗剂，有可能影响 CRF 患者的运动耐量以及心血管发病率和死亡率。