Aging and hypertension: Integrated renal and sympathetic control of blood pressure

衰老与高血压：肾脏和交感神经对血压的综合控制

基本信息

批准号：
10417091
负责人：
Richard David Wainford
金额：
$ 61.53万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-30 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10417091
关键词：
Ablation Acute Adrenergic Receptor Adult Age Aging American Heart Association Antihypertensive Agents Attenuated Bilateral Blood Pressure Cause of Death Cessation of life Chronic Data Development Disease Elderly Electrolytes Equilibrium Excretory function Exhibits Functional disorder Genetic Guidelines Heart Diseases Hematological Disease Homeostasis Hypertension Impairment Intake Kidney Life Liquid substance Lung diseases Lysine Mechanoreceptors Mediating Mission Modeling Morbidity - disease rate National Heart, Lung, and Blood Institute Natriuresis Nature Nerve Neuraxis Neuroanatomy Norepinephrine Operative Surgical Procedures Oxidative Stress Patients Pelvis Perfusion Pharmacology Phosphotransferases Population Prevalence Prevention Process Recommendation Reflex action Regulation Renin-Angiotensin-Aldosterone System Research Risk Role SLC12A3 gene Sensory Signal Transduction Signal Transduction Pathway Sodium Sodium Chloride Specialist Sprague-Dawley Rats Sympathetic Nervous System Techniques Testing Water afferent nerve age related aged antagonist attenuation biological adaptation to stress blood pressure control blood pressure regulation dietary salt disability hypertensive in vivo innovation insight mortality new therapeutic target normal aging normotensive novel older patient salt intake salt sensitive hypertension saluretic sensory input thiazide tool treatment strategy

项目摘要

ABSTRACT The prevalence of hypertension, which is predicted to be the leading global cause of death and disability by the year 2020, increases with age from 46% of U.S. adults aged 20-44 to >78% of U.S. adults above the age of 65. Less than half of elderly patients with hypertension achieve adequate blood pressure control and older hypertensive patients are significantly less likely to receive a thiazide prescription (first line anti-hypertensive) than younger patients. This suggests contemporary prescribing practices to the elderly are sub-optimal. Further, the development of antihypertensive drugs has been dramatically less productive than expected, making new mechanistic insights into age-dependent blood pressure regulation essential. This application will test the global hypothesis that attenuated mechanosensitive afferent renal nerve sympathoinhibitory reflexes evoke sodium chloride cotransporter-mediated renal sodium retention and age-dependent hypertension. These studies will employ our novel technique of selective afferent renal nerve ablation, a unique in-vivo surgical approach to activate the mechanosensitive afferent renal nerves, and genetic and pharmacological tools in 3, 8 and 16 month old Sprague-Dawley rats (model of normal aging) that exhibit age-dependent hypertension to provide new mechanistic insight into the pathophysiology of age-dependent hypertension. The following Specific Aims will be conducted to test this hypothesis: Specific Aim 1: Impairments in the renal sympathetic nerves contribute to age-dependent hypertension. Specific Aim 2: Attenuation of the mechanoreceptor- activated sympathoinhibitory afferent renal nerve natriuretic reno-renal reflex occurs in age-dependent hypertension. Specific Aim 3: Age-dependent elevations in sympathetic tone increase NCC activity, via a NE- α1-adrenoceptor-gated WNK1-OxSR1 signal transduction pathway, to evoke renal nerve-dependent sodium retention and hypertension. These hypertension focused studies are central to the mission of the NIA, which is to understand the nature of the aging processes and diseases associated with aging to extend healthy years of life and the NHLBI, which is to promote the prevention and treatment of heart, lung and blood diseases. Specific Aim 1 will establish an age-dependent role of the renal sympathetic nerves in sodium excretion and blood pressure regulation during acute and chronic challenges to salt and water balance. Specific Aim 2 will establish a key role of an impairment in sensory renal mechanoreceptor activation that reduces central sympathoinhibitory signaling in the pathophysiology of age-dependent hypertension. Specific Aim 3 will establish the age-dependent actions of the sympathetic nervous system to regulate the sodium chloride cotransporter, via a novel α1- adrenoceptor signal transduction pathway. Our innovative research strategy will define a novel age-dependent renal sympathetic nerve dependent mechanism through which sodium excretion and blood pressure is regulated, and will support U.S. prescribing guidelines and identify new therapeutic targets and treatment approaches for sympathetically mediated age-dependent hypertension.

抽象的高血压的患病率预计将成为全球死亡和残疾的主要原因到 2020 年，随着年龄的增长，这一比例将从 20-44 岁美国成年人的 46% 增加到 20-44 岁以上美国成年人的 78% 以上 65. 不到一半的老年高血压患者血压得到充分控制高血压患者接受噻嗪类药物（一线抗高血压药物）的可能性明显降低这表明当前对老年人的处方做法并不理想。此外，抗高血压药物的开发效率远远低于预期，使对年龄依赖性血压调节的新机制认识变得至关重要。检验减弱机械敏感传入肾神经交感抑制反射的总体假设引起氯化钠协同转运蛋白介导的肾钠潴留和年龄依赖性高血压。研究将采用我们的选择性传入肾神经消融新技术，这是一种独特的体内手术激活机械敏感传入肾神经的方法，以及 3, 8 中的遗传和药理学工具和 16 个月大的 Sprague-Dawley 大鼠（正常衰老模型），表现出年龄依赖性高血压为年龄依赖性高血压的病理生理学提供了新的机制见解：将进行具体目标来检验该假设：具体目标 1：肾交感神经损伤神经导致年龄依赖性高血压具体目标 2：机械感受器的减弱。激活的交感抑制传入肾神经钠尿肾反射发生在年龄依赖性具体目标 3：交感神经张力的年龄依赖性升高通过 NE- 增加 NCC 活性。 α1-肾上腺素受体门控 WNK1-OxSR1 信号转导通路，唤起肾神经依赖性钠这些以高血压为重点的研究是 NIA 使命的核心，即了解衰老过程的本质以及与衰老相关的疾病，以延长健康年限生命和NHLBI，其目的是促进心、肺和血液疾病的预防和治疗。具体目标 1 将建立肾交感神经在钠排泄和排泄中的年龄依赖性作用盐和水平衡的急性和慢性挑战期间的血压调节。确定感觉肾机械感受器激活损伤的关键作用，从而减少中枢神经年龄依赖性高血压病理生理学中的交感神经抑制信号传导将具体目标 3。建立交感神经系统调节氯化钠的年龄依赖性作用我们的创新研究策略将通过新型 α1- 肾上腺素受体信号转导途径来实现协同转运蛋白。定义了一种新的年龄依赖性肾交感神经依赖性机制，通过该机制钠排泄血压得到调节，并将支持美国的处方指南并确定新的治疗方法交感神经介导的年龄依赖性高血压的目标和治疗方法。