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

摘要 高血压的流行，据预测，高血压将成为全球死亡和残疾的主要原因 2020年，年龄从20-44岁的美国成年人的46%增加到20岁以上的美国成年人的78% 65.不到一半的老年高血压患者实现了足够的血压控制，而老年患者 高血压患者接受噻嗪类处方药(一线抗高血压药)的可能性显著降低 而不是年轻的病人。这表明，当代给老年人开处方的做法并不理想。 此外，抗高血压药物的开发成果远远低于预期， 使得对年龄相关血压调节的新机制洞察变得至关重要。此应用程序将 检验削弱机械敏感型肾传入神经交感抑制反射的全球假设 诱发氯化钠辅助转运体介导的肾钠滞留和年龄依赖性高血压。这些 研究将采用我们的选择性肾传入神经消融的新技术，这是一种独特的活体外科手术 激活机械敏感性肾传入神经的方法，以及遗传和药物工具 和16个月龄的SD大鼠(正常衰老模型)表现出年龄依赖性高血压到 为年龄依赖性高血压的病理生理学提供新的机制洞察力。以下是 具体目标将被用来检验这一假说：具体目标1：肾交感神经受损 神经对年龄依赖性高血压起作用。具体目标2：机械感受器的衰减- 激活的交感神经抑制性传入肾神经钠尿剂肾-肾反射的年龄依赖性 高血压。具体目标3：交感神经张力随年龄的升高而增加NCC的活性，通过NE- α1-肾上腺素受体门控的WNK1-OXSR1信号转导通路激活肾神经依赖性钠离子 滞留和高血压。这些以高血压为重点的研究是NIA使命的核心，这是 了解衰老过程的本质和与衰老相关的疾病，以延长健康寿命 生命和NHLBI，这是为了促进心肺和血液疾病的预防和治疗。 具体目标1将确立肾交感神经在钠排泄和尿液中的年龄依赖性作用。 在急、慢性盐和水平衡挑战期间的血压调节。特定目标2将 确定损伤在感觉性肾机械感受器激活中的关键作用 交感神经抑制信号在年龄依赖性高血压的病理生理中的作用。具体目标3将 建立交感神经系统调节氯化钠的年龄依赖性作用 辅转运体，通过一条新的α1-肾上腺素能受体信号转导途径。我们的创新研究战略将 确定一种新的年龄依赖的肾交感神经依赖机制，通过这种机制排钠 血压受到控制，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.