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

项目摘要/摘要 高血压在老年人中的患病率很高，而高血压的一个主要因素是对盐的敏感性 血压(BP)和交感神经活动(SNA)升高。然而，我们对此知之甚少。 人类大脑对钠的感官，以及其中涉及的分子机制。对啮齿动物的研究已经 在脑室周围器官(CVO)中发现了特殊的氯化钠(NaC L)感受神经元，这是 调节氯化钠诱导的SNA、精氨酸加压素(AVP)和血压的变化。最近的数据表明，Na-K- 2Cl共转运蛋白(NKCC2)不是肾脏特异性的，但也在大脑中调节整个区域表达 体内氯化钠和水的动态平衡。此外，NKCC2可供流通中的药物使用，因为 CVO缺乏完整的血脑屏障。该R21的目标是确定关键的盐敏感区 并确定NKCC2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的激活来将先前啮齿动物的发现转化为人类 (使用血氧水平依赖的功能磁共振成像，BOLD fMRI)以及口渴， NKCC2拮抗剂对急性高钠刺激时AVP、SNA和BP的影响 (速尿)。这将使我们能够评估NKCC2在盐感应中的作用。总体假设是 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NKCC2。因此，第一个具体目标是确定以下领域 人类大脑对急性高钠血症做出反应，并确定NKCC2在中枢氯化钠中的作用。 感官。静脉输注3%氯化钠30分钟可诱发急性高钠血症。 在高渗盐水输注过程中，将在器官等区域测量大脑活动 终板血管、穹隆下器、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，以及 确定NKCC2在调节这些反应中的作用。BP的盐敏性将单独进行评估 我们将对耐盐表型和盐敏感表型进行比较；我们预计 急性高钠血症将导致所有受试者的BOLD fMRI信号和SNA和AVP的变化，但 那些被归类为盐敏感的人的反应将会更大。这将是第一次 健康的人类受试者确定了一个可能的大脑氯化钠感知共转运体，我们认为范围和 创新的方法是R21筹资机制的理想选择。老年人容易患高血压，所以 对于理解血压正常的老年人是如何中枢感觉到钠，以提供所需的 为探索盐敏感型高血压的发病机制奠定基础。

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.