Neurovascular Regulation During Exercise In Humans With Chronic Kidney Disease

项目总结/摘要 慢性肾病（CKD）患者的心血管（CV）死亡风险显著较高。一 与CV风险增加独立相关的CKD的突出特征是运动不耐受。我们 先前的研究表明，CKD患者在两种治疗期间的血压（BP）都有夸大的升高， 中等和低强度的运动。这种夸大的BP反应可能会增加 心血管事件不仅在运动中，而且在日常活动中，代表了一个新的和未探索的 CKD患者运动不耐受与心血管风险之间的机械联系。我们的长期目标是阐明 CKD患者体力活动期间异常血流动力学反应的潜在机制， 开发针对这些潜在异常的治疗，改善静息时和 并最终改善CV结局。我们以前表明， 运动期间交感神经活动（SNA）增加相同程度，血压增加， CKD患者中，与对照组相比显著更高。这些发现表明，CKD患者有 增强的血管收缩反应，即更大的神经血管转导，对运动诱导的 SNS激活，导致增强的运动升压反应。目标1旨在阐明 差异调节CKD中SNA神经血管转导的机制。具体来说，我们将测试 假设CKD患者抵抗SNS介导的血管收缩的能力受损， 运动骨骼肌，定义为功能性交感神经溶解，这与增强的 运动中SNA的神经血管转导。我们还将检验CKD患者有以下假设： 血管α1-肾上腺素能受体（AR）敏感性升高，导致血管收缩程度更大， 对运动引起的SNS激活的反应。为了将这些研究转化为临床竞技场，在目标2中，我们 将进行一项临床试验，测试针对潜在疾病的多方面干预的潜在益处。 功能性交感神经溶解受损和血管α1-AR敏感性升高的紊乱。由于两 一氧化氮（NO）调节功能性交感神经溶解和血管α1-AR敏感性，CKD患者 降低了NO的生物利用度，我们将确定是否有策略来提高NO的生物利用度 非氨蝶呤（通过有氧运动训练）和氨蝶呤（通过四氢生物蝶呤（BH 4）） 补充）改善CKD患者运动期间的血液动力学和神经血管反应。使用2x2 析因设计的随机对照试验，我们将测试的假设，运动训练和BH 4 补充剂可独立和协同地改善过度运动的主要结果 CKD中的升压反应、功能性交感神经溶解受损和血管α1-AR敏感性升高。 这些研究将为潜在的生理紊乱提供重要的新见解， 高血压和CV风险增加。

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.