Brain NaCl-sensing in salt-sensitive hypertension.

盐敏感性高血压中的大脑 NaCl 感应。

基本信息

批准号：
10400857
负责人：
SEAN D STOCKER
金额：
$ 55.95万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
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：
2019-07-10 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10400857
关键词：
ASIC channel Ablation Acute Aldosterone Amiloride Angiotensin II Attenuated Blood Pressure Brain Ca(2+)-Transporting ATPase Cardiovascular Diseases Cerebrospinal Fluid Chronic Controlled Study DOCA Data Deoxycorticosterone Development Electrophysiology (science)Elements Excess Dietary Salt Experimental Models Goals Human Hypernatremia Hypertension Hypothalamic structure Impairment In Vitro Infusion procedures Ingestion Light Mediating Modeling Mus Nerve Neural Pathways Neurons Organ Pathogenesis Pathway interactions Peripheral Resistance Pharmacology Plasma Rodent Rodent Model Sodium Sodium Channel Sodium Chloride Sodium-Hydrogen Antiporter Subfornical Organ System Telemetry Testing Time Viral antagonist benzamil cellular targeting epithelial Na+ channel experimental study extracellular high salt diet human model in vivo kidney vascular structure novel therapeutics optogenetics organum vasculosum of the lamina terminalis patch clamp response salt intake salt sensitive hypertension sensor

项目摘要

PROJECT SUMMARY Excess dietary salt intake is strongly correlated with cardiovascular disease and is regarded as a major contributing factor to the pathogenesis of hypertension. Time-controlled studies in both humans and rodents suggest a high salt diet elevates plasma or cerebrospinal fluid (CSF) [NaCl] by 2-5mM to activate specialized NaCl-sensing neurons located in hypothalamic circumventricular organs such as the organum vasculosum of the lamina terminalis (OVLT) and subfornical organ to increase sympathetic nerve activity (SNA) and arterial blood pressure (ABP). Interestingly, central infusion of non-voltage gated sodium channel antagonists attenuates every experimental model of salt-sensitive hypertension tested to date. These antagonists target acid sensing ion channel, sodium hydrogen exchanger, sodium calcium pump, and the epithelial sodium channel. In light of preliminary findings, our working hypothesis is that a high salt diet elevates extracellular [NaCl] to activate NaCl-sensitive neurons of the OVLT through a unique epithelial sodium channel (ENaC) expressing αβ subunits. The NaCl-sensitivity of these ENaC neurons and sympathoexcitatory responses are enhanced by circulating factors such as angiotensin II and aldosterone. Subsequent activation of descending pathways increases SNA and ABP. This hypothesis will be tested through 3 specific aims: 1) determine the extent by which ENaC subunits mediate the intrinsic NaCl-sensitivity of OVLT neurons and sympathoexcitatory responses to an acute NaCl load, 2) determine whether angiotensin II enhances the NaCl-sensitivity of ENaC-positive neurons in the OVLT and the extent by which these neurons contribute to angiotensin II-salt hypertension, and 3) determine the extent by which aldosterone and deoxycorticosterone-salt hypertension alter ENaC expression, enhance NaCl-sensitivity and depend on ENaC subunits of the OVLT. Our rationale for this project is that identification of the cellular elements that underlie NaCl- sensing in the brain will provide a framework for the development of novel therapeutic treatments of salt-sensitive hypertension.

项目概要膳食盐摄入过量与心血管疾病密切相关，被认为是导致心血管疾病的主要因素。人类和高血压发病机制的时间对照研究。啮齿动物表明，高盐饮食会使血浆或脑脊液 (CSF) [NaCl] 升高 2-5mM 激活位于下丘脑室周器官（例如终板血管器 (OVLT) 和穹窿下器官以增加交感神经神经活动（SNA）和动脉血压（ABP）。门控钠通道拮抗剂可减弱盐敏感性高血压的每种实验模型迄今为止，这些拮抗剂针对的是酸感应离子通道、钠氢交换剂、钠。钙泵和上皮钠通道根据初步发现，我们的工作假设。高盐饮食会升高细胞外[NaCl]，从而激活 OVLT 的 NaCl 敏感神经元通过表达 αβ 亚基的独特上皮钠通道 (ENaC) 的 NaCl 敏感性。这些 ENaC 神经元和交感神经兴奋反应通过循环因子增强，例如血管紧张素 II 和醛固酮的后续激活会增加 SNA 和 ABP。该假设将通过 3 个具体目标进行检验：1）确定 ENaC 的程度。亚基介导 OVLT 神经元的内在 NaCl 敏感性和交感神经兴奋反应急性氯化钠负荷，2) 确定血管紧张素 II 是否增强 ENaC 阳性患者的氯化钠敏感性 OVLT 中的神经元以及这些神经元对血管紧张素 II 盐的贡献程度高血压，以及 3) 确定醛固酮和脱氧皮质酮盐的程度高血压改变 ENaC 表达，增强 NaCl 敏感性并依赖于 ENaC 亚基 OVLT。我们这个项目的基本原理是鉴定 NaCl- 背后的细胞元素。大脑中的传感将为开发新的治疗方法提供框架盐敏感性高血压。