Brain NaCl-sensing in salt-sensitive hypertension.

项目摘要 过量的饮食盐摄入与心血管疾病密切相关，被认为是主要的 高血压的发病机制。在人类和 啮齿动物表明高盐饮食会使血浆或脑脊液（CSF）[NaCl]升高2- 5 mM， 激活位于下丘脑室周器官的专门的NaCl感受神经元， 终板血管器（OVLT）和穹窿下器，以增加交感神经 神经活动（SNA）和动脉血压（ABP）。有趣的是，非电压的中央输注 门控钠通道拮抗剂减弱盐敏感性高血压的每一个实验模型 测试至今。这些拮抗剂靶向酸敏感离子通道、钠氢交换器、钠离子通道、钙离子通道、钙离子通道和钙离子通道。 钙泵和上皮钠通道。根据初步发现，我们的工作假设 高盐饮食升高细胞外[NaCl]以激活OVLT的NaCl敏感神经元 通过表达αβ亚基的独特上皮钠通道（ENaC）。NaCl敏感性 这些ENaC神经元和交感神经兴奋反应被循环因子增强， 血管紧张素II和醛固酮。随后的下行通路的激活增加SNA， ABP。这一假设将通过3个具体目标进行检验：1）确定ENaC 亚基介导OVLT神经元的内在NaCl敏感性和交感兴奋性反应， 急性NaCl负荷，2）确定血管紧张素II是否增强ENaC阳性细胞的NaCl敏感性， OVLT中的神经元和这些神经元对血管紧张素II-盐的贡献程度 高血压，3）确定醛固酮和脱氧皮质酮盐 高血压改变ENaC表达，增强NaCl敏感性，并依赖于ENaC亚基的表达。 OVLT。我们这个项目的基本原理是，确定细胞的元素，基础NaCl- 大脑中的感知将为开发新的治疗方法提供一个框架。 盐敏感性高血压

PROJECT SUMMARY Excess dietary salt intake is strongly correlated with cardiovascular disease and is regarded as a major contributing factor to the pathogenesis of hypertension. Time-controlled studies in both humans and rodents suggest a high salt diet elevates plasma or cerebrospinal fluid (CSF) [NaCl] by 2-5mM to activate specialized NaCl-sensing neurons located in hypothalamic circumventricular organs such as the organum vasculosum of the lamina terminalis (OVLT) and subfornical organ to increase sympathetic nerve activity (SNA) and arterial blood pressure (ABP). Interestingly, central infusion of non-voltage gated sodium channel antagonists attenuates every experimental model of salt-sensitive hypertension tested to date. These antagonists target acid sensing ion channel, sodium hydrogen exchanger, sodium calcium pump, and the epithelial sodium channel. In light of preliminary findings, our working hypothesis is that a high salt diet elevates extracellular [NaCl] to activate NaCl-sensitive neurons of the OVLT through a unique epithelial sodium channel (ENaC) expressing αβ subunits. The NaCl-sensitivity of these ENaC neurons and sympathoexcitatory responses are enhanced by circulating factors such as angiotensin II and aldosterone. Subsequent activation of descending pathways increases SNA and ABP. This hypothesis will be tested through 3 specific aims: 1) determine the extent by which ENaC subunits mediate the intrinsic NaCl-sensitivity of OVLT neurons and sympathoexcitatory responses to an acute NaCl load, 2) determine whether angiotensin II enhances the NaCl-sensitivity of ENaC-positive neurons in the OVLT and the extent by which these neurons contribute to angiotensin II-salt hypertension, and 3) determine the extent by which aldosterone and deoxycorticosterone-salt hypertension alter ENaC expression, enhance NaCl-sensitivity and depend on ENaC subunits of the OVLT. Our rationale for this project is that identification of the cellular elements that underlie NaCl- sensing in the brain will provide a framework for the development of novel therapeutic treatments of salt-sensitive hypertension.