Central Sodium Sensing in Older Humans: Implications for Blood Pressure Regulation

老年人的中枢钠感应：对血压调节的影响

• 批准号: 10387589
• 负责人: William B Farquhar
• 金额: $ 24万
• 依托单位: UNIVERSITY OF DELAWARE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10387589
• 关键词: Acute; Adult; Anterior; Area; Argipressin; Attenuated; Blood; Blood - brain barrier anatomy; Blood Circulation; Blood Pressure; Blood Volume; Brain; Brain region; Cells; Coupled; Data; Dehydration; Elderly; Foundations; Functional Magnetic Resonance Imaging; Funding Mechanisms; Furosemide; Goals; Homeostasis; Human; Hypernatremia; Hypertension; Hypothalamic structure; In Vitro; Individual; Infusion procedures; Intake; Intravenous; Measures; Mediating; Molecular; Nerve; Neuraxis; Neurons; Organ; Pharmaceutical Preparations; Phenotype; Play; Prevalence; Public Health; Publishing; Regulation; Resistance; Rest; Rodent; Role; Saline; Signal Transduction; Sodium; Sodium Chloride; Stimulus; Subfornical Organ; Thirst; Translating; Water; antagonist; base; blood oxygen level dependent; blood pressure elevation; blood pressure regulation; cingulate cortex; cost; human subject; in vivo; innovation; normotensive; novel therapeutic intervention; patch clamp; response; salt sensitive; salt sensitive hypertension; symporter

PROJECT SUMMARY/ABSTRACT The prevalence of hypertension is very high in older adults, and a major factor in hypertension is salt sensitivity of blood pressure (BP) and elevated sympathetic nerve activity (SNA). However, we know very little about how the human brain ‘senses’ sodium, and what molecular mechanisms are involved. Rodent studies have identified specialized sodium chloride (NaCl)-sensing neurons in the circumventricular organs (CVOs), which mediate NaCl-induced changes in SNA, arginine vasopressin (AVP), and BP. 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. In addition, NKCC2 is accessible by drugs in the circulation since the CVOs lack a complete blood brain barrier. The objective of this R21 is to identify key NaCl-sensing regions of the brain in older adults and determine if NKCC2 mediates the neurohumoral response to acute hypernatremia. We seek to translate the prior rodent findings to humans by assessing neuronal activation (using blood oxygen level dependent functional magnetic resonance imaging, BOLD fMRI) as well as thirst, AVP, SNA and BP during an acute hypernatremic stimulus, with and without an NKCC2 antagonist (furosemide). This will enable us to assess the role of NKCC2 in NaCl sensing. The overall hypothesis is that acute hypernatremia will elicit detectable changes in the BOLD fMRI signal and increase thirst, AVP, SNA, and BP largely through NKCC2 in healthy older adults. Accordingly, the first specific aim is to identify the areas of the human brain that respond to acute hypernatremia and determine the role of NKCC2 in central NaCl- sensing. Acute hypernatremia will be induced with a 30-minute infusion of 3% NaCl delivered intravenously. Brain activity during the hypertonic saline infusion will be measured in regions such as the organum vasculosum laminae terminalis, subfornical organ, anterior cingulate cortex, hypothalamus, and insular cortex. The second specific aim is to determine the effect of acute hypernatremia on thirst, AVP, SNA, and BP, and determine the role of NKCC2 in mediating these responses. Salt sensitivity of BP will be individually assessed and comparisons will be made between those with a salt resistant and salt sensitive phenotype; we anticipate that acute hypernatremia will elicit changes in the BOLD fMRI signal and SNA & AVP in all subjects, but the responses will be greater in those who are classified as salt sensitive. This would represent the first trial in healthy human subjects to identify a putative brain NaCl-sensing co-transporter, and we think the scope and innovative approaches are ideal for the R21 funding mechanism. Older adults are prone to hypertension, so it is critically important to understand how normotensive older adults centrally sense sodium, to provide a needed foundation for exploring the mechanistic underpinning of salt sensitive hypertension.

项目摘要/摘要 高血压在老年人中的患病率非常高，高血压的一个主要因素是盐敏感性 血压（BP）和交感神经活动（SNA）升高。然而，我们对它是如何运作的知之甚少。 人类大脑“感知”钠，以及其中涉及的分子机制。啮齿动物研究 确定了室周器官（CVOs）中专门的氯化钠（NaCl）感应神经元， 介导NaCl诱导的SNA、精氨酸加压素（AVP）和BP的变化。最近的数据显示，Na-K- 2Cl协同转运蛋白（NKCC 2）不是肾脏特异性的，但也表达于调节整体代谢的脑区。 体内NaCl和水的稳态。此外，NKCC 2可被流通中的药物获得，因为 CVO缺乏完整的血脑屏障。该R21的目的是确定关键的NaCl敏感区域， 老年人的大脑，并确定NKCC 2是否介导急性脑损伤的神经体液反应。 高钠血症我们试图通过评估神经元激活将先前的啮齿动物发现转化为人类 （使用血氧水平依赖性功能磁共振成像，BOLD fMRI）以及口渴， 急性高钠刺激期间的AVP、SNA和BP，有和没有NKCC 2拮抗剂 （呋塞米）。这将使我们能够评估NKCC 2在NaCl传感中的作用。总的假设是， 急性高钠血症将引起BOLD fMRI信号的可检测变化，并增加口渴、AVP、SNA和 在健康的老年人中，BP主要通过NKCC 2。因此，第一个具体目标是确定 人脑对急性高钠血症的反应和决定NKCC 2在中枢NaCl- 传感。通过静脉输注3% NaCl 30分钟诱导急性高钠血症。 高渗盐水输注期间的脑活动将在器官等区域进行测量 终板血管膜、穹窿下器、前扣带回皮质、下丘脑和岛叶皮质。 第二个具体目标是确定急性高钠血症对口渴、AVP、SNA和BP的影响， 确定NKCC 2在介导这些反应中的作用。将单独评估BP的盐敏感性 并将耐盐和盐敏感表型之间进行比较;我们预计 急性高钠血症会引起所有受试者BOLD fMRI信号和SNA & AVP的变化，但 在那些被归类为作为盐敏感的人中反应更大。这将是第一次审判， 健康的人类受试者，以确定一个假定的大脑NaCl传感协同转运蛋白，我们认为范围和 创新方法是R21供资机制的理想选择。老年人容易患高血压，因此， 了解血压正常的老年人如何中枢感知钠， 为探讨盐敏感性高血压的发病机制奠定了基础。