Central Osmosensory Mechanisms in Salt-Sensitive Hypertension

描述(申请人提供)：过量的食盐摄入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，饮食盐的摄入与其他因素一起起着中心作用，从而提高交感神经活性和动脉血压。尽管最近的研究表明，这些效应是通过血浆钠浓度的升高来调节的，但在盐敏感型高血压患者中，饮食盐摄入量或血钠过多是如何在大脑内作用于增加交感神经流出的机制尚不清楚。我们的长期目标是确定盐敏感型高血压患者交感神经活性增加的神经通路和细胞机制(S)。这项应用目前的目标是确定中枢神经系统如何感知饮食盐摄入量和血浆钠浓度的变化，以激活交感神经回路，从而提高动脉血压。中心假设是，血浆钠浓度的增加通过瞬时受体香草素或苯胺嘧啶敏感通道激活终板血管器(OVLT)中的渗透敏感性神经元。随后通过下丘脑和延髓腹外侧部的下游通路的激活增加了交感神经流出和血压。我们还假设渗透感觉转导通路在盐敏感型高血压中是敏化的。我们这个项目的基本原理是，识别介导这些神经元内在渗透敏感性的细胞元件，并如何将其转化为动脉血压的变化，将为开发新的治疗方法提供框架。在强大的初步数据的支持下，我们将通过三个具体的目标来验证这一假说：1)目标1将确定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、基础放电频率和膜特性是否在盐敏感型高血压中发生改变；以及3)目的3将确定在盐敏感型高血压中OVLT内增加交感神经流出和动脉血压的细胞机制。这种方法是创新的，因为这些实验将首次识别中枢神经系统中检测血浆钠浓度变化以调节交感神经流出和动脉血压的细胞成分。这项拟议的研究意义重大，因为这些发现将为开发新的治疗方法提供平台，以针对血脑屏障外的神经元治疗盐敏感型高血压和心血管疾病。

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.