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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（或15%的美国成年人）患有慢性肾病（CKD），由于肾功能下降而导致的心血管死亡风险。CKD患者夸大了体力活动期间血压（BP）升高，导致心血管风险增加，身体能力差。我们先前的工作已经证明，CKD患者的这种增强的升压反应是由于运动期间交感神经系统（SNS）的反射激活过度增加，由肌肉传入神经激活介导，称为运动加压反射。重要的是，这样的提高的SNS和升压反应有助于增加不良心血管事件的风险，包括猝死，在身体活动中，以及运动不耐受，影响生活质量。虽然我们现在知道，夸张的肌肉传入神经激活的基础， CKD中的过度运动升压反射，介导肌肉传入神经升高的机制激活以诱导升高的BP反应性仍然未知。增强运动的机制升压反射对于揭示新的治疗靶点以改善心血管风险和身体健康至关重要。在这个高流行率高风险的患者群体中发挥作用。我们有令人信服的初步证据肌肉间质性酸中毒在激活肌肉传入神经中起主要作用，导致过度的运动加压反射在CKD中的作用。在运动过程中，包括H+在内的缺血代谢物在肌肉中积累并激活肌肉传入神经末梢上的受体，以诱导SNS中的反射增加 activation.碳酸氢盐（HCO 3-）是防止肌肉间质pH过度降低的主要缓冲剂然而，CKD患者从CKD IIIB期开始HCO 3生物利用度降低，患病肾脏排泄每日酸负荷的能力受损，导致缓冲能力下降容量我们的中心假设是由于肌肉缓冲能力下降导致的肌肉间质性酸中毒在CKD患者中，容量增加运动升压反射。我们将使用直接 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摄影记录 CKD患者的休息和运动期间。我们还将确定是否急性恢复HCO 3-生物利用度改善CKD患者的运动性高血压，以及口服碳酸氢盐补充剂是否能增强运动训练对CKD的有益影响。目前的治疗指南推荐碳酸氢盐治疗仅在伴有明显酸中毒（[HCO 3-] ≤21 mmol/L）的CKD患者中;然而，碳酸氢盐可能是一种简单、安全的和创新的方法来靶向肌肉传入神经激活和改善运动血液动力学，即使没有明显的静息酸中毒，CKD患者的功能也是如此。因此，这些研究具有很高的影响潜力，关于血清[HCO 3-]目标、碳酸氢盐治疗适应症和肾康复的临床实践改善CKD患者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.