Forebrain electroneutral transporters in salt-sensitive hypertension

项目摘要/摘要 饮食中盐的过量摄入与心血管疾病有关，是导致肥胖的主要因素 高血压的发病机制。人类和啮齿动物模型中的盐敏感型高血压与 血浆或脑脊液中的高度[氯化钠]。由此产生的相对高钠血症激活了中枢回路。 增加交感神经活动(SNA)和动脉血压(ABP)。有大脑的氯化钠传感器 在室周器官中，如终板的血管细胞器(OVLT)和 穹隆下器(SFO)；激活OVLT/SFO神经元刺激口渴、加压素(AVP)分泌，以及 SNA，而阻断OVLT/SFO的神经传递可降低盐敏感模型的ABP。然而， OVLT/SFO神经元感知细胞外[氯化钠]的机制尚不清楚。最近的数据表明 Na+-K+-2Cl-共转运体(NKCC2)不是肾脏特异的，但也在大脑调节的区域表达 全身氯化钠和水的动态平衡。这一提议的中心假设是摄取过量 食盐通过NKCC2升高细胞外[氯化钠]以激活OVLT/SFO中对氯化钠敏感的神经元。 反过来，这激活了下行通路来提升SNA和ABP。此外，我们假设这些 由于我们的初步数据显示，盐敏感的人类对氯化钠的感知机制是敏感的。 高钠血症引起Dahl盐敏感大鼠与Dahl盐抵抗大鼠OVLT放电的更大增加 喂食高盐饮食。我们提出了两个具体目标。具体目标1将决定NKCC2的程度 介导OVLT/SFO神经元对盐的感觉，并使SNA和ABP升高到急性盐负荷或慢性盐负荷。 啮齿类动物的敏感性高血压。特定目标2将检验NKCC2拮抗剂将钝化的假设 高钠血症诱导耐盐和盐敏感成人高血压的中枢神经活动和SNA， 在对盐敏感的成年人中，中枢神经的激活程度会更高，这表明钠的敏感度更高。 这些目标的成功完成将提供所需的关于调节细胞元素的信息 下丘脑神经元的本征盐敏反应，为盐的中枢性钠反应提供了新的数据 敏感的人类。这是一款可翻译的R01，将两个有以下记录的实验室结合在一起 成功的合作，这些研究将为开发新的治疗方法提供框架 盐敏感型高血压的治疗。

PROJECT SUMMARY/ABSTRACT Excess dietary salt intake is associated with cardiovascular disease and is a major contributing factor to the pathogenesis of hypertension. Salt-sensitive hypertension in both humans and rodent models is associated with elevations in plasma or cerebrospinal fluid [NaCl]. The resultant relative hypernatremia activates central circuits to increase sympathetic nerve activity (SNA) and arterial blood pressure (ABP). There are brain NaCl-sensors in the circumventricular organs such as the organum vasculosum of the lamina terminalis (OVLT) and subfornical organ (SFO); activation of OVLT/SFO neurons stimulates thirst, vasopressin (AVP) secretion, and SNA, whereas interruption of neurotransmission in OVLT/SFO lowers ABP in salt-sensitive models. However, the mechanisms by which OVLT/SFO neurons sense extracellular [NaCl] are not known. Recent data suggest the Na+-K+-2Cl- co-transporter (NKCC2) is not kidney specific but is also expressed in brain regions that regulate whole body NaCl and water homeostasis. The central hypothesis of this proposal is that the ingestion of excess dietary salt elevates extracellular [NaCl] to activate NaCl-sensitive neurons in the OVLT/SFO through NKCC2. In turn, this activates descending pathways to elevate SNA and ABP. Furthermore, we hypothesize that these NaCl-sensing mechanisms are sensitized in salt-sensitive humans, since our preliminary data show hypernatremia evokes a greater increase in OVLT discharge of Dahl-salt sensitive versus Dahl-salt resistant rats fed a high salt diet. We propose 2 specific aims. Specific Aim 1 will determine the extent by which NKCC2 mediates NaCl-sensing in OVLT/SFO neurons and elevate SNA and ABP to acute NaCl loading or chronic salt- sensitive hypertension in rodents. Specific Aim 2 will test the hypothesis that an NKCC2 antagonist will blunt hypernatremia-induced central neural activation and SNA in salt resistant and salt sensitive adults with high BP, and that central neural activation will be greater in salt sensitive adults, suggesting heightened sodium sensing. Successful completion of these aims will provide needed information on the cellular elements that mediate intrinsic NaCl-sensing of hypothalamic neurons and provide novel data on central sodium sensing in salt sensitive humans. This is a translational R01, bringing two laboratories together that have a track record of successful collaboration, and these studies will provide a framework for the development of novel therapeutic treatments of salt-sensitive hypertension.