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

基本信息

批准号：
10669257
负责人：
Jeanie Park
金额：
$ 69.9万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-01-01 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10669257
关键词：
ASIC channel Acidosis Acids Activities of Daily Living Acute Adult Aerobic Exercise Affect Bicarbonates Biological Availability Biological Markers Blood Pressure Buffers Cardiovascular system Chronic Kidney Failure Clinical Combined Modality Therapy Disease Event Excretory function Exercise Funding Gene Expression Generations Goals Human Hypertension Imaging Techniques Impairment Individual Inflammation Intravenous infusion procedures Ischemia Isometric Exercise Isotonic Exercise Kidney Kidney Diseases Knee Magnetic Resonance Imaging Magnetic Resonance Spectroscopy Measures Mediating Metabolic acidosis Methods Muscle Near-Infrared Spectroscopy Nerve Nerve Endings Oral Outcome Patients Periodicity Physical Capacity Physical Function Physical activity Physiological Placebos Play Population Quality of life Randomized Recommendation Reflex action Regulation Renal function Research Rest Risk Role Serum Spinal Ganglia Sudden Death Supplementation Sympathetic Nervous System Testing Translating Translational Research Work afferent nerve blood pressure elevation cardiovascular risk factor clinical practice exercise capacity exercise intolerance exercise training hemodynamics high risk improved innovation insight interstitial lean body mass mortality neural neurovascular novel therapeutic intervention patient population prevent primary outcome programs protein expression receptor rehabilitation strategy response restoration secondary outcome systemic inflammatory response therapeutic target treatment guidelines

项目摘要

~37 million (or 15% of US adults) have chronic kidney disease (CKD) and are at profoundly increased risk of cardiovascular mortality by virtue of having reduced renal function. CKD patients have exaggerated increases in blood pressure (BP) during physical activity that contributes to increased cardiovascular risk and poor physical capacity. Our prior work has demonstrated that this augmented pressor response in CKD is due to exaggerated increases in reflex activation of the sympathetic nervous system (SNS) during exercise that is mediated by muscle afferent nerve activation, referred to as the exercise pressor reflex. Importantly, such heightened SNS and pressor responses contribute to increased risk of adverse cardiovascular events, including sudden death, during physical activity, as well as exercise intolerance that has a profound negative impact on quality of life. While we now know that exaggerated muscle afferent nerve activation underlies the exaggerated exercise pressor reflex in CKD, the mechanisms that mediate heightened muscle afferent nerve activation to induce heightened BP reactivity remain unknown. Elucidating mechanisms of augmented exercise pressor reflex is critical for revealing new treatment targets to improve cardiovascular risk and physical functioning in this highly prevalent, high-risk patient population. We have compelling preliminary evidence that muscle interstitial acidosis plays a major role in activating muscle afferent nerves, leading to an exaggerated exercise pressor reflex in CKD. During exercise, ischemic metabolites including H+ accumulate in the muscle interstitium and activate receptors on muscle afferent nerve endings to induce reflex increases in SNS activation. Bicarbonate (HCO3-) is the major buffer preventing excessive reductions in muscle interstitial pH during exercise; however, CKD patients have decreased HCO3- bioavailability starting at CKD Stage IIIB due to an impaired ability of the diseased kidneys to excrete the daily acid load, resulting in decreased buffering capacity. Our central hypothesis is that muscle interstitial acidosis resulting from decreased muscle buffering capacity augments the exercise pressor reflex in CKD. We will test this hypothesis using direct microneurographic recording of SNS activity, hemodynamics, biomarkers and innovative imaging techniques at rest and during exercise in CKD patients. We will also determine if acute restoration of HCO3- bioavailability ameliorates exercise-induced hypertension in CKD, and whether oral bicarbonate supplementation enhances the beneficial effects of exercise training in CKD. Current treatment guidelines recommend bicarbonate therapy only in CKD patients with overt acidosis ([HCO3-] ≤21 mmol/L); however, bicarbonate may be a simple, safe and innovative method to target muscle afferent nerve activation and improve exercise hemodynamics and function in CKD patients even without overt resting acidosis. Thus, these studies have high potential to impact clinical practice regarding serum [HCO3-] goals, indications for bicarbonate therapy and renal rehabilitation strategies to improve long-term cardiovascular risk in CKD.

约 3700 万人（或 15% 的美国成年人）患有慢性肾病 (CKD)，并且这一数字正在急剧增加 CKD 患者因肾功能下降而导致心血管死亡的风险被夸大了。体力活动期间血压 (BP) 升高，导致心血管风险增加我们之前的研究表明，CKD 中升压反应的增强是由于身体能力差造成的。运动期间交感神经系统 (SNS) 反射激活的过度增加重要的是，由肌肉传入神经激活介导，称为运动升压反射。 SNS 和升压反应会增加不良心血管事件的风险，包括体力活动期间的猝死，以及具有深远负面影响的运动不耐受虽然我们现在知道过度的肌肉传入神经激活是造成这种现象的原因。 CKD 中过度运动加压反射，介导肌肉传入神经的机制增强运动的激活机制仍不清楚。升压反射对于揭示新的治疗目标以改善心血管风险和身体健康至关重要我们有初步证据表明，在这一高度流行、高风险的患者群体中发挥作用。肌肉间质性酸中毒在激活肌肉传入神经中起主要作用，导致过度酸中毒 CKD 中的运动升压反射运动期间，包括 H+ 在内的缺血代谢物会在肌肉中积聚。间质并激活肌肉传入神经末梢上的受体以诱导 SNS 反射增加碳酸氢盐 (HCO3-) 是防止肌肉间质 pH 过度降低的主要缓冲剂。然而，从 CKD IIIB 期开始，CKD 患者的 HCO3- 生物利用度降低，原因是患病肾脏排泄每日酸负荷的能力受损，导致缓冲能力下降我们的中心假设是肌肉间质性酸中毒是由于肌肉缓冲能力下降所致。能力增强 CKD 中的运动加压反射我们将使用直接测试来检验这一假设。 SNS 活动、血流动力学、生物标志物和创新成像技术的显微神经影像记录我们还将确定 CKD 患者休息和运动期间 HCO3- 生物利用度的急性恢复情况。改善 CKD 运动诱发的高血压，以及口服碳酸氢盐补充剂是否可以增强目前的治疗指南推荐碳酸氢盐疗法。仅适用于明显酸中毒的 CKD 患者（[HCO3-] ≤21 mmol/L）；然而，碳酸氢盐可能是一种简单、安全的方法。以及针对肌肉传入神经激活和改善运动血流动力学的创新方法即使没有明显的静息酸中毒，这些研究也具有很大的影响潜力。关于血清 [HCO3-] 目标、碳酸氢盐治疗指征和肾脏康复的临床实践改善 CKD 长期心血管风险的策略。

项目成果

期刊论文数量（20）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Middle Cerebral Artery Pulsatility Index is Elevated in Chronic Kidney Disease.

慢性肾病患者大脑中动脉搏动指数升高。

DOI：
发表时间：
2022
期刊：
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
影响因子：
0
作者：
Jones,Touré;Sprick,Justin;DaCosta,Dana;Park,Jeanie
通讯作者：
Park,Jeanie

Exercise modulates sympathetic and vascular function in chronic kidney disease.

DOI：
10.1172/jci.insight.164221
发表时间：
2023-02-22
期刊：
JCI INSIGHT
影响因子：
8
作者：
Jeong, Jinhee;Sprick, Justin D.;DaCosta, Dana R.;Mammino, Kevin;Nocera, Joe R.;Park, Jeanie
通讯作者：
Park, Jeanie

α-Adrenergic receptor blockade attenuates pressor response during mental stress in young black adults.