Neurovascular Regulation During Exercise In Humans With Chronic Kidney Disease

慢性肾病患者运动期间的神经血管调节

• 批准号: 9220029
• 负责人: Jeanie Park
• 金额: $ 36.48万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9220029
• 关键词: Adrenergic Receptor; Aerobic Exercise; Biological Availability; Biological Markers; Blood Pressure; Blood Vessels; Blood flow; Cardiovascular system; Chronic Kidney Failure; Clinical; Clinical Trials; Combined Modality Therapy; Data; Event; Exercise; Experimental Models; Functional disorder; Generations; Goals; Human; Hypertension; Impairment; Incidence; Inflammation; Inflammatory; Intervention; Kidney Diseases; Knowledge; Lead; Life; Link; Mediating; Muscle; Nerve; Nitric Oxide; Nitric Oxide Synthase; Outcome; Oxygen; Pathogenicity; Patients; Peripheral Resistance; Pharmacology; Physical Capacity; Physical Exercise; Physical Function; Physical activity; Physiological; Play; Population; Randomized Controlled Trials; Receptor Activation; Reflex action; Regulation; Rest; Role; Skeletal Muscle; Supplementation; Sympathetic Nervous System; Testing; Therapeutic Effect; Translating; cardiovascular risk factor; cofactor; design; exercise capacity; exercise intensity; exercise intolerance; exercise training; functional disability; hemodynamics; high risk; impaired capacity; improved; insight; mortality; multi-component intervention; neurovascular; novel therapeutic intervention; patient population; primary outcome; receptor sensitivity; response; secondary outcome; targeted treatment; tetrahydrobiopterin; therapeutic evaluation; therapeutic target; therapy development; vasoconstriction

Project Summary/Abstract Chronic kidney disease (CKD) patients are at significantly higher risk of cardiovascular (CV) mortality. One prominent feature of CKD that is independently associated with increased CV risk is exercise intolerance. Our prior studies show that CKD patients have an exaggerated increase in blood pressure (BP) during both moderate and low-intensity exercise. Such exaggerated BP responses could contribute to an increased risk of CV events not only during exercise, but also during day to day activities, and represent a new and unexplored mechanistic link between exercise intolerance and CV risk in CKD. Our long-term goals are to elucidate the mechanisms underlying abnormal hemodynamic responses during physical activity in CKD, which can inform development of therapies that target these underlying aberrancies, improve hemodynamics both at rest and during physical activity, and ultimately improve CV outcomes. We previously showed that the degree of increase in BP for the same degree of increase in sympathetic nerve activity (SNA) during exercise is significantly higher in CKD patients compared to Controls. These findings suggest that CKD patients have an augmented vasoconstrictive response, i.e. greater neurovascular transduction, in response to exercise-induced SNS activation, leading to an augmented exercise pressor response. Aim 1 seeks to elucidate the mechanisms that differentially modulate neurovascular transduction of SNA in CKD. Specifically, we will test the hypothesis that CKD patients have an impaired capacity to oppose SNS-mediated vasoconstriction within exercising skeletal muscle, defined as functional sympatholysis, which is associated with enhanced neurovascular transduction of SNA during exercise. We will also test the hypothesis that CKD patients have heightened vascular α1-adrenergic receptor (AR) sensitivity, leading to a greater degree of vasoconstriction in response to exercise-induced SNS activation. To translate these studies into the clinical arena, in Aim 2, we will conduct a clinical trial testing the potential benefits of a multifaceted intervention targeting the underlying derangements of impaired functional sympatholysis and heightened vascular α1-AR sensitivity. Since both functional sympatholysis and vascular α1-AR sensitivity are modulated by nitric oxide (NO), and CKD patients have decreased NO bioavailability, we will determine if strategies to improve NO bioavailability nonpharmacologically (via aerobic exercise training), and pharmacologically (via tetrahydrobiopterin (BH4) supplementation) improves hemodynamic and neurovascular responses during exercise in CKD. Using a 2x2 factorial design randomized controlled trial, we will test the hypothesis that exercise training and BH4 supplementation independently and synergistically improve the primary outcomes of exaggerated exercise pressor responses, impaired functional sympatholysis, and heightened vascular α1-AR sensitivity in CKD. These studies will provide important new insights into underlying physiologic derangements that contribute to high blood pressure and increased CV risk in this highly prevalent patient population.

项目摘要/摘要 慢性肾脏疾病（CKD）患者的心血管（CV）死亡率的风险明显更高。一 CKD与CV风险增加的重要特征是运动率。我们的 先前的研究表明，CKD患者在两者中的血压升高（BP）夸大了 中度和低强度运动。这种夸张的BP回应可能导致增加的风险 简历事件不仅在锻炼过程中，而且在日常活动中，并代表一个新的和出乎意料的 CKD中的运动intlerance和CV风险之间的机械联系。我们的长期目标是阐明 CKD中体育活动期间血液动力学反应异常的机制，可以告知 开发针对这些基本异常的疗法，在休息和 在体育锻炼期间，并最终改善了简历结果。我们以前证明了 锻炼过程中交感神经活动（SNA）相同程度增加的BP的增加为 与对照组相比，CKD患者的明显更高。这些发现表明CKD患者有 增强血管收缩反应，即对运动引起的响应 SNS激活，导致增强的运动式响应。 AIM 1试图阐明 CKD中SNA的神经血管转导差异的机制。具体来说，我们将测试 CKD患者具有反对SNS介导的血管收缩的能力受损的假设 锻炼骨骼肌，定义为功能性交感解，这与增强 运动过程中SNA的神经血管转导。我们还将检验以下假设：CKD患者具有 血管α1-肾上腺素能受体（AR）敏感性提高，导致更大程度的血管收缩 对运动引起的SNS激活的反应。为了将这些研究转化为临床领域，在AIM 2中，我们 将进行临床试验，以测试针对基础的多方面干预的潜在益处 功能性交感神经解析和血管α1-ar敏感性增强的进化。两者既是 一氧化氮（NO）和CKD患者调节功能性交感解析和血管α1-AR敏感性 没有改善生物利用度，我们将确定是否没有改善生物利用度的策略 非药理学（通过有氧运动训练）和药物（通过四氢无生蛋白（BH4） 补充）在CKD运动过程中改善了血液动力学和神经血管反应。使用2x2 阶乘设计随机对照试验，我们将测试锻炼训练和BH4的假设 独立和协同补充夸张的锻炼的主要结果 施加反应，功能性交感神经解释以及CKD中的血管α1-AR灵敏度提高。 这些研究将为基本的生理发展提供重要的新见解，这有助于 在这个高度普遍的患者人群中，高血压和CV风险增加。