Forebrain electroneutral transporters in salt-sensitive hypertension

项目总结/摘要 过量的饮食盐摄入与心血管疾病有关，是导致心血管疾病的主要因素。 高血压的发病机制人类和啮齿动物模型中的盐敏感性高血压与以下因素相关： 血浆或脑脊液[NaCl]升高。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）。大脑中有氯化钠传感器 在脑室周围器官，如终板血管器（OVLT）， 穹窿下器官（SFO）; OVLT/SFO神经元的激活刺激口渴，加压素（AVP）分泌， SNA，而OVLT/SFO中神经传递的中断降低盐敏感模型中的ABP。然而，在这方面， OVLT/SFO神经元感知细胞外[NaCl]的机制尚不清楚。最近的数据表明 Na+-K+-2Cl-协同转运蛋白（NKCC 2）不是肾脏特异性的，但也在调节 全身NaCl和水的稳态。这一建议的核心假设是， 膳食盐升高细胞外[NaCl]以通过NKCC 2激活OVLT/SFO中的NaCl敏感神经元。 反过来，这激活了下行通路，以提高SNA和ABP。此外，我们假设这些 NaCl敏感机制在盐敏感的人中是敏感的，因为我们的初步数据显示， 高钠血症引起Dahl盐敏感大鼠与Dahl盐抵抗大鼠OVLT放电增加 高盐饮食我们提出两个具体目标。具体目标1将决定NKCC 2 介导OVLT/SFO神经元的NaCl感受，并升高SNA和ABP对急性NaCl负荷或慢性盐负荷的反应。 啮齿类动物的高血压。具体目标2将检验NKCC 2拮抗剂将钝化 高钠血症诱导高血压盐敏感和盐耐受成人中枢神经激活和SNA， 并且在盐敏感的成年人中，中枢神经激活将更大，这表明钠敏感性增强。 成功完成这些目标将提供所需的信息，细胞的元素，调解 下丘脑神经元内钠敏感性，并为盐环境下中枢钠敏感性研究提供了新资料 敏感的人类这是一个转换R 01，将两个实验室聚集在一起， 成功的合作，这些研究将为开发新的治疗药物提供一个框架。 盐敏感性高血压的治疗。

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.