Central Osmosensory Mechanisms in Salt-Sensitive Hypertension

盐敏感性高血压的中枢渗透感觉机制

基本信息

批准号：
8438620
负责人：
SEAN D STOCKER
金额：
$ 37.45万
依托单位：
PENNSYLVANIA STATE UNIV HERSHEY MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-02-01 至 2017-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8438620
关键词：
Acute Animals Blood - brain barrier anatomy Blood Pressure Brain Cardiovascular Diseases Cardiovascular Physiology Cardiovascular system Cells Controlled Study Data Development Diet Electrophysiology (science)Elements Epithelial Event Genetic Goals Hormonal Human Hypernatremia Hypertension Hypothalamic structure In Vitro Indium Infusion procedures Lesion Mediating Membrane Monitor Nerve Neural Pathways Neuraxis Neurons Osmolalities Pathogenesis Pathway interactions Peripheral Resistance Plasma Play Property Prosencephalon Publishing Rattus Research Reverse Transcriptase Polymerase Chain Reaction Risk Role Saline Sodium Sodium Channel Sodium Chloride Testing Time Translating Vanilloid Work benzamil capsaicin receptor channel blockers dietary excess epithelial Na+ channel feeding in vivo innovation novel therapeutics organum vasculosum of the lamina terminalis osmoreceptor paraventricular nucleus patch clamp prevent public health relevance receptor research study response salt intake salt sensitive small hairpin RNA

项目摘要

DESCRIPTION (provided by applicant): Excess dietary salt intake is strongly correlated with cardiovascular disease and is regarded as a major contributing factor to the pathogenesis of hypertension. Recent evidence suggests that dietary salt intake acts centrally with other factors to elevate sympathetic nerve activity and arterial blood pressure. Despite recent studies to indicate these effects are mediated by elevations in plasma sodium concentration, the mechanisms by which dietary salt intake or hypernatermia act within the brain to increase sympathetic outflow in salt-sensitive hypertension is not known. Our long-term goal is to identify the neural pathways and cellular mechanism(s) that increase sympathetic nerve activity in salt- sensitive hypertension. The current objective of this application is to identify how changes in dietary salt intake and plasma sodium concentration are sensed by the central nervous system to activate sympathetic circuits to raise arterial blood pressure. The central hypothesis is that increases in plasma sodium concentration activate osmosensitive neurons in the organum vasculosum of the lamina terminalis (OVLT) through transient receptor vanilloid or benzamil-sensitive channels. Subsequent activation of downstream pathways through the hypothalamus and ventrolateral medulla increase sympathetic outflow and blood pressure. We also hypothesize the osmosensory transduction pathways are sensitized in salt-sensitive hypertension. Our rationale for this project is that identification of the cellular elements that mediate the intrinsic osmosensitivity of these neurons and how this translates to changes in arterial blood pressure will provide a framework for the development of novel therapeutic treatments. Supported by strong preliminary data, we will test this hypothesis through 3 specific aims: 1) Aim 1 will identify the cellular elements in OVLT neurons that detect changes in plasma osmolality and subsequently regulate sympathetic outflow and arterial blood pressure, 2) Aim 2 will determine whether the discharge responses, basal firing rates, and membrane properties of OVLT neurons is altered in salt- sensitive hypertension, and 3) Aim 3 will identify the cellular mechanisms within OVLT that increase sympathetic outflow and arterial blood pressure in salt-sensitive hypertension. The approach is innovative because these experiments, for the first time, will identify the cellular element in the central nervous system that detects changes in plasma sodium concentration to regulate sympathetic outflow and arterial blood pressure. The proposed research is significant as these findings will provide a platform for the development of novel therapeutic treatments to target neurons outside the blood brain barrier for the treatment of salt-sensitive hypertension and cardiovascular disease.

描述（申请人提供）：膳食盐摄入过多与心血管疾病密切相关，并被认为是高血压发病的主要因素。最近的证据表明，膳食盐摄入量与其他因素共同作用，可提高交感神经活动和动脉血压。尽管最近的研究表明这些作用是由血浆钠浓度升高介导的，但饮食盐摄入或高钠血症在大脑内作用以增加盐敏感性高血压的交感神经流出的机制尚不清楚。我们的长期目标是确定增加盐敏感性高血压交感神经活动的神经通路和细胞机制。该应用程序当前的目标是确定中枢神经系统如何感知膳食盐摄入量和血浆钠浓度的变化，以激活交感神经回路以升高动脉血压。中心假设是血浆钠浓度的增加通过瞬时受体香草酸或苯扎米尔敏感通道激活终板血管器官（OVLT）中的渗透敏感神经元。随后激活通过下丘脑和腹外侧延髓的下游通路，增加交感神经流出和血压。我们还假设渗透感觉转导途径在盐敏感性高血压中是敏感的。我们这个项目的基本原理是，鉴定介导这些神经元固有渗透敏感性的细胞元件以及它如何转化为动脉血压的变化将为开发新型治疗方法提供框架。在强有力的初步数据的支持下，我们将通过 3 个具体目标来检验这一假设：1) 目标 1 将识别 OVLT 神经元中检测血浆渗透压变化并随后调节交感神经流出和动脉血压的细胞元件，2) 目标 2 将确定OVLT 神经元的放电反应、基础放电率和膜特性是否在盐敏感性高血压中发生改变，以及 3) 目标 3 将确定 OVLT 内增加的细胞机制盐敏感性高血压中的交感神经流出和动脉血压。该方法具有创新性，因为这些实验将首次识别中枢神经系统中的细胞元件，该元件可检测血浆钠浓度的变化以调节交感神经流出和动脉血压。拟议的研究意义重大，因为这些发现将为开发针对血脑屏障外神经元的新型治疗方法提供平台，以治疗盐敏感性高血压和心血管疾病。