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（由申请人提供）：过量的饮食盐摄入与心血管疾病密切相关，被认为是导致高血压发病机理的主要因素。最近的证据表明，饮食盐的摄入量集中在其他因素中，以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，但尚不清楚饮食盐摄入量或高网性作用以增加盐敏感高血压中交感神经流出的机制。我们的长期目标是确定在盐敏感高血压中增加交感神经活性的神经途径和细胞机制。该应用的当前目的是确定中枢神经系统如何感测饮食盐摄入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，血浆钠浓度的增加激活了通过瞬态受体香草素或苯甲胺敏感通道的层末端（OVLT）的细胞脉动脉动神经元。随后通过下丘脑和腹侧髓质激活下游途径会增加交感神经流出和血压。我们还假设在盐敏感性高血压中敏化渗透压转导途径。我们对该项目的理由是，鉴定介导这些神经元内在渗透敏感的细胞元素，以及这如何转化为动脉血压的变化，将为开发新的治疗性治疗提供框架。在强大的初步数据支持的支持下，我们将通过3个特定目的检验这一假设：1）目标1将确定OVLT神经元中检测到血浆渗透压的变化的细胞元素，并确定交感神经流出和交感神经流体和动脉血压，2）AIL 2）AIL 2）AIL 2）AIL 2）AIL 2）AIL 2）AIL 2）确定排放率的速度，伊斯特及其敏感性及量子的盐分，盐分及其量子的盐分，均为估计的估计量及其量子的估计量，估计了估计的估计估计的估计量的估计量。 3）AIM 3将确定OVLT内的细胞机制，从而增加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，因为这些实验首次将确定中枢神经系统中的细胞元素，该细胞元素检测血浆钠浓度的变化以调节交感神经流出和动脉血压。拟议的研究非常重要，因为这些发现将为开发新型治疗治疗的平台，以靶向血脑屏障外神经元以治疗盐敏感的高血压和心血管疾病。