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

摘要 高血压的流行，预计是全球死亡和残疾的主要原因， 到2020年，随着年龄的增长，从20-44岁的美国成年人的46%增加到超过78%的美国成年人。 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处方（一线抗高血压药物）的可能性明显降低 比年轻的病人。这表明当代老年人的处方实践是次优的。 此外，抗高血压药物的开发比预期的要少得多， 这使得对年龄依赖性血压调节的新的机械见解变得至关重要。此应用程序将 测试减弱机械敏感性传入肾神经交感抑制反射的整体假设 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。这些 研究将采用我们的选择性传入肾神经消融新技术，一种独特的体内手术 激活机械敏感性传入肾神经的方法，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），其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。以下 将进行特定目的以检验该假设：特定目的1：肾交感神经损伤 神经会导致年龄依赖性高血压。具体目标2：机械感受器的衰减- 交感神经抑制性传入肾神经利钠性肾-肾反射在年龄依赖性 高血压具体目标3：交感神经张力的NCC依赖性升高通过NE- α1-肾上腺素受体门控的WNK 1-OxSR 1信号转导通路，引起肾神经依赖性钠离子 尿潴留和高血压。这些以高血压为重点的研究是NIA使命的核心， 了解衰老过程的本质和与衰老相关的疾病，以延长健康的岁月， 生命和NHLBI，这是促进预防和治疗心脏，肺和血液疾病。 具体目标1将确立肾交感神经在钠排泄中的年龄依赖性作用， 在盐和水平衡的急性和慢性挑战期间的血压调节。具体目标2将 确定感觉肾机械感受器激活障碍的关键作用， 交感神经抑制信号在年龄依赖性高血压的病理生理学。第3章将 建立交感神经系统调节氯化钠的年龄依赖性作用 协同转运蛋白，通过一种新的α1-肾上腺素受体信号转导途径。我们的创新研究战略将 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 和血压是受管制的，并将支持美国处方指南，并确定新的治疗 交感神经介导的年龄依赖性高血压的靶点和治疗方法。

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.