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

• 批准号: 10023251
• 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
• 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/10023251
• 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; attenuation; biological adaptation to stress; blood pressure regulation; dietary salt; disability; 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

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，这被认为是全球死亡和残疾的主要原因 2020年，随着年龄的46％的年龄增长，年龄在20-44岁以上的美国成年人中的78％以上 65。不到一半的高血压患者可实现足够的血压控制和更老 高血压患者接受噻嗪类处方的可能性较小（第一线抗高血压） 比年轻患者。这表明，当代的处方实践是次级最佳的。 此外，降压药的开发的生产力远低于预期 对依赖年龄的血压调节的新机械洞察力必不可少。此应用程序将 测试全球假设，即减弱机械敏感的传入肾脏神经交感抑制作用反射 唤起氯化钠共转运蛋白介导的肾钠保留率和年龄依赖性高血压。这些 研究将采用我们选择性传入的肾神经消融的新技术，这是一种独特的体内手术 激活机械传入的肾神经以及3，8中的遗传和药物工具的方法 和16个月大的Sprague-Dawley大鼠（正常衰老的模型），表现出年龄依赖性高血压 提供有关年龄依赖性高血压的病理生理学的新机械洞察力。下列 将进行具体目的来检验这一假设：具体目的1：肾同情障碍 神经有助于年龄依赖性高血压。特定目的2：机制受体的衰减 - 活化的交感神经传入肾脏神经纳地尿素肾脏反射发生在年龄依赖性 高血压。特定目标3：通过NE- α1-肾上腺肾上腺门控的WNK1-OXSR1信号转移途径，以唤起肾神经依赖性钠 保留和高血压。这些以高血压为中心的研究对于NIA的使命是核心 了解与衰老相关的衰老过程和疾病的性质，以延长健康的年份 生命和NHLBI，旨在促进心脏，肺和血液疾病的预防和治疗。 具体目标1将确定肾交感神经在钠排泄中的年龄依赖性作用 急性和慢性水平挑战期间的血压调节。具体目标2将 在感觉肾脏机制受体激活中建立损害的关键作用，从而降低中央 依赖年龄依赖性高血压的病理生理学中的交感抑制信号。具体的目标3将 建立交感神经系统的年龄依赖性动作来调节氯化钠 通过新型的α1-肾上腺肾上腺受体信号转移途径，共转运蛋白。我们的创新研究策略将 定义一种新型依赖年龄的肾交感神经依赖机制 和血压受到调节，并将支持美国处方指南并确定新疗法 对称介导的年龄依赖性高血压的靶标和治疗方法。