Brain NaCl-sensing in salt-sensitive hypertension.

盐敏感性高血压中的大脑 NaCl 感应。

• 批准号: 10400857
• 负责人: SEAN D STOCKER
• 金额: $ 55.95万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-10 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10400857
• 关键词: ASIC channel; Ablation; Acute; Aldosterone; Amiloride; Angiotensin II; Attenuated; Blood Pressure; Brain; Ca(2+)-Transporting ATPase; Cardiovascular Diseases; Cerebrospinal Fluid; Chronic; Controlled Study; DOCA; Data; Deoxycorticosterone; Development; Electrophysiology (science); Elements; Excess Dietary Salt; Experimental Models; Goals; Human; Hypernatremia; Hypertension; Hypothalamic structure; Impairment; In Vitro; Infusion procedures; Ingestion; Light; Mediating; Modeling; Mus; Nerve; Neural Pathways; Neurons; Organ; Pathogenesis; Pathway interactions; Peripheral Resistance; Pharmacology; Plasma; Rodent; Rodent Model; Sodium; Sodium Channel; Sodium Chloride; Sodium-Hydrogen Antiporter; Subfornical Organ; System; Telemetry; Testing; Time; Viral; antagonist; benzamil; cellular targeting; epithelial Na+ channel; experimental study; extracellular; high salt diet; human model; in vivo; kidney vascular structure; novel therapeutics; optogenetics; organum vasculosum of the lamina terminalis; patch clamp; response; salt intake; salt sensitive hypertension; sensor

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.

项目总结 饮食中盐的过量摄入与心血管疾病密切相关，并被认为是主要的 参与高血压发病的因素。时间控制研究在人类和 啮齿类动物建议高盐饮食可使血浆或脑脊液(CSF)[氯化钠]升高2-5 mm，达到 激活位于下丘脑室周器官的特殊的氯化钠感觉神经元，如 终板血管器和穹隆下器增加交感神经 神经活动(SNA)和动脉血压(ABP)。有趣的是，中心输液无电压 门控钠通道拮抗剂减弱所有盐敏感型高血压的实验模型 目前为止已经测试过了。这些拮抗剂针对的是酸敏离子通道、钠氢交换器、钠 钙泵和上皮性钠通道。根据初步发现，我们的工作假设 高盐饮食使OVLT的细胞外[氯化钠]升高，从而激活对氯化钠敏感的神经元 通过表达αβ亚基的独特上皮钠通道。它对氯化钠的敏感性 这些ENaC神经元和交感兴奋反应被循环因子增强，如 血管紧张素II和醛固酮。随后下行通路的激活增加了SNA和 总部基地。这一假设将通过3个具体目标进行检验：1)确定ENaC的程度 亚基介导OVLT神经元固有的氯化钠敏感性和交感兴奋反应 急性氯化钠负荷，2)确定血管紧张素II是否增强ENaC阳性的氯化钠敏感性 OVLT中的神经元及其对血管紧张素II-盐的贡献程度 高血压，以及3)确定醛固酮和脱氧皮质酮-盐的程度 高血压改变ENaC表达，增强盐敏感性，并依赖于ENaC亚单位 OVLT。我们这个项目的基本原理是确定构成氯化钠的细胞元素- 大脑的感知将为开发新的治疗方法提供一个框架 盐敏性高血压。