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.

项目摘要饮食中过量盐的摄入量与心血管疾病密切相关，被认为是主要的促成高血压发病机理的因素。在人类和人类和啮齿动物建议高盐饮食将血浆或脑脊液（CSF）[NACL]提高2-5mm至激活位于下丘脑室内器官（例如） Lamina末端（OVLT）和副骨质器官的细胞器血管增加交感神经神经活动（SNA）和动脉血压（ABP）。有趣的是，非电压的中央输注门控钠通道拮抗剂减弱了盐敏感高血压的每个实验模型迄今已测试。这些拮抗剂靶向酸感测离子通道，氢氢口气，钠钙泵和上皮钠通道。鉴于初步发现，我们的工作假设高盐饮食是否会升高细胞外[NaCl]以激活OVLT的NaCl敏感性神经元通过表达αβ亚基的独特上皮钠通道（ENAC）。 NaCl敏感性这些ENAC神经元和交感神经反应通过循环因素（例如血管紧张素II和醛固酮。随后的降途径激活增加了SNA和 ABP。该假设将通过3个特定目的进行检验：1）确定ENAC的程度亚基介导OVLT神经元的固有NaCl敏感性和交感神经反应急性NaCl负载，2）确定血管紧张素II是否增强了ENAC阳性的NaCl敏感性 OVLT中的神经元以及这些神经元有助于血管紧张素II-盐的神经元高血压，3）确定醛固酮和脱氧核酮盐的程度高血压改变ENAC表达，增强NaCl敏感性并取决于 OVLT。我们对该项目的理由是鉴定NaCl-基础的细胞元素大脑中的传感将为开发新的治疗疗法提供一个框架盐敏感高血压。