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Forebrain electroneutral transporters in salt-sensitive hypertension

盐敏感性高血压中的前脑电中性转运蛋白

基本信息

批准号：
10736529
负责人：
SEAN D STOCKER
金额：
$ 72.04万
依托单位：
UNIVERSITY OF DELAWARE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-08 至 2028-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10736529
关键词：
Acute Adult Age Animal Model Animals Attenuated Blood Blood - brain barrier anatomy Blood Pressure Blood Vessels Brain Brain region Cardiovascular Diseases Cells Cerebrospinal Fluid Chronic Collaborations Dahl Salt-Resistant Rats Data Development Elements Excess Dietary Salt Functional Magnetic Resonance Imaging Furosemide Goals Homeostasis Human Hypernatremia Hypertension Hypothalamic structure Impairment In Vitro Infusion procedures Ingestion Interruption Intravenous infusion procedures Kidney Laboratories Lesion Mediating Modeling Molecular Nerve Neural Pathways Neurons Organ Pathogenesis Pathway interactions Peripheral Resistance Plasma Population Prosencephalon Protein Isoforms Public Health Rattus Regulation Resistance Rest Rodent Rodent Model Sodium Sodium Chloride Subfornical Organ System Techniques Testing Thirst Vasopressins Water antagonist blood pressure regulation cost experimental study extracellular high salt diet human model human subject in vivo neural neurotransmission novel novel therapeutic intervention novel therapeutics optogenetics organum vasculosum of the lamina terminalis patch clamp pharmacologic prevent response salt intake salt sensitive salt sensitive hypertension sensor sex symporter transcriptomics

项目摘要

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.

项目总结/文摘