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

• 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
• 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; 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

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杰出的科学环境中发展候选人的科学增长，该计划在翻译血管研究方面具有悠久的传统。候选人的长期目标是建立独立的临床研究职业，研究慢性肾衰竭（CRF）患者心血管风险（CV）风险的神经血管机制。 CRF的发生率正在以惊人的速度增长，这些患者的绝大多数死于CV疾病。该人群中简历死亡率的一个主要独立危险因素是行使不耐受性和身体能力差，其机制在很大程度上未知。我们的初步数据表明，在等距和节奏运动期间，CRF患者的血压升高（BP）夸大，这表明血液动力学异常可能起作用。该项目的目标是检查CRF运动过程中夸张的BP反应的基础机制，并测试四氢无生蛋白（BH4）治疗在运动期间和基线期间对神经和血管反应的潜在益处。了解运动不耐受性的血液动力学机制将有助于开发迫切需要改善身体功能，生活质量并最终降低CRF中CV死亡率的治疗靶标。 运动过程中的BP反应是由交感神经系统（SNS）反射激活引起的血管收缩力之间的平衡与一氧化氮（NO）依赖性血管舒张引起的血管舒张力的平衡。可以想象，在运动过程中这些血管收缩和血管舒张反应的失衡可能会导致BP的增强反应，并通过增加心肌工作量来导致运动障碍，并增加体育活动期间不良CV事件的风险。在AIM 1中，我们将通过使用微功能学期间在静态和节奏运动过程中测量SNS活动的变化来确定CRF患者在运动过程中是否夸大了反射SNS激活。在AIM 2中，我们将确定CRF患者是否通过测量臂动脉流介导的血管扩张的变化而响应全身运动来降低运动诱导的NO介导的血管舒张。急性运动还会产生刺激神经SNS流出的活性氧（ROS）的增加，并且不会降低生物利用度。 AIM 2B将确定在急性运动过程中，CRF患者在急性运动过程中是否有更大的ROS产生（即氧化应激），这有助于夸张的压力反应。最后，四氢无生蛋白（BH4）是内皮NO合酶的必不可少的辅助因子，可通过增加无生物利用度来改善CRF动物模型中的内皮功能和BP。在AIM 3中，我们将在CRF患者的休息和运动过程中进行首次试点试验，以测试口服BH4治疗对SNS过度活动，内皮功能障碍和氧化应激的影响。我们假设BH4可能是一种新型的治疗剂，具有影响运动耐受性的潜力，以及CRF患者的CV发病率和死亡率。