Mechanisms of Central Sodium Sensing and Salt-Sensitive Hypertension

中枢钠感觉与盐敏感性高血压的机制

• 批准号: 10620626
• 负责人: Joseph Stock
• 金额: $ 6.95万
• 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: 2022-01-03 至 2025-01-02
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10620626
• 关键词: Acute; Adult; Area; Argipressin; Attenuated; Black race; Blood; Blood - brain barrier anatomy; Blood Pressure; Blood Volume; Brain; Brain region; Cardiovascular Diseases; Central Nervous System; Consumption; Data; Dietary Sodium; Functional Magnetic Resonance Imaging; Furosemide; Goals; Homeostasis; Human; Hypernatremia; Hypertension; Infusion procedures; Kidney; Mediating; Nerve; Neurons; Organ; Play; Population; Positioning Attribute; Public Health; Publishing; Regulation; Rodent; Role; Saline; Serum; Signal Transduction; Sodium; Sodium Chloride; Stimulus; Testing; Translating; United States; Water; antagonist; attenuation; blood oxygen level dependent; blood pressure regulation; combat; cost; dietary excess; innovation; neurovascular; novel; novel therapeutic intervention; pressure; receptor; response; salt sensitive; salt sensitive hypertension; symporter; translational approach

PROJECT SUMMARY/ABSTRACT Excessive dietary sodium consumption is ubiquitous in the United States and is a large contributor to hypertension and cardiovascular disease. This is especially problematic for Black adults, who are known to have high rates of salt-sensitive hypertension. Although the mechanisms underlying salt-sensitive hypertension are poorly understood in humans, rodent studies document a neurohumoral component. Rodent studies have identified specialized sodium chloride (NaCl)-sensing neurons in the circumventricular organs (CVOs) in the brain (which lack a complete blood brain barrier (BBB)), that mediate NaCl-induced changes in sympathetic nerve activity (SNA), arginine vasopressin (AVP), and regulation of blood pressure (BP). Recent data suggests Na+-K+-2Cl- co-transporter (NKCC2) is not kidney specific but is in fact expressed in brain regions that regulate whole body NaCl and water homeostasis. Interestingly, Black adults have greater basal level NKCC2 renal activity, but it is unknown if these differences are present in sodium sensing areas of the brain. The objective of this F32 is to determine if NKCC2 contributes toward NaCl-sensitivity in a population that is more prone to salt- sensitive hypertension, Black adults. 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 SNA, AVP, and BP during an acute hypernatremic stimulus, with and without an NKCC2 antagonist. This will enable us to isolate the role of NKCC2 in NaCl sensitivity in Black and White adults. The overall hypothesis is that Black adults have increased central sodium sensing and neurohumoral BP responses due to greater NKCC2 activity in the brain. Accordingly, the first specific aim is to determine if NKCC2 contributes to the differences observed in the neurohumoral regulation of blood pressure to acute hypernatremia between Black and White adults. We hypothesize that the NKCC2 antagonist furosemide will attenuate the increase in SNA, AVP, and BP during hypertonic saline infusion more in Black compared to White adults. The second specific aim is to determine if there are differences in sodium sensing areas in the brain that are influenced by NKCC2 between Black and White adults. We hypothesize that furosemide will attenuate the increase in BOLD fMRI signal during hypertonic saline infusion more in Black compared to White adults. This comprehensive assessment of sodium sensing and neurohumoral regulation of BP in response to hypertonic saline infusion, with and without a NKCC2 antagonist, will provide novel information on the mechanisms contributing to salt- sensitive BP. Understanding the central origins of sodium sensing and salt-sensitivity may lead to novel therapeutic approaches to combat hypertension, a costly public health problem. Innovative and translational approaches such as those employed in this proposal are needed to advance the field.

项目概要/摘要 在美国，膳食钠摄入过多是普遍存在的现象，也是导致肥胖的一个重要原因。 高血压和心血管疾病。这对于黑人成年人来说尤其成问题，众所周知，他们 盐敏感性高血压的发病率很高。尽管盐敏感性高血压的机制是 对人类知之甚少，啮齿动物研究记录了神经体液成分。啮齿动物研究有 确定了脑室周围器官（CVO）中专门的氯化钠（NaCl）感应神经元 大脑（缺乏完整的血脑屏障（BBB）），介导氯化钠诱导的交感神经变化 神经活动 (SNA)、精氨酸加压素 (AVP) 和血压 (BP) 调节。最近的数据表明 Na+-K+-2Cl-协同转运蛋白 (NKCC2) 不是肾脏特异性的，但实际上在调节的大脑区域中表达 全身氯化钠和水的稳态。有趣的是，黑人成年人的 NKCC2 肾基础水平更高 活动，但尚不清楚这些差异是否存在于大脑的钠感应区域。的目标 该 F32 的目的是确定 NKCC2 是否有助于更容易出现盐敏感性的人群中的 NaCl 敏感性。 敏感高血压，黑人成人。我们寻求通过评估将先前的啮齿类动物发现转化为人类 神经元激活（使用血氧水平依赖性功能磁共振成像，BOLD fMRI） 以及急性高钠刺激期间的 SNA、AVP 和 BP，无论是否使用 NKCC2 拮抗剂。 这将使我们能够分离出 NKCC2 在黑人和白人成年人的 NaCl 敏感性中的作用。整体 假设认为，黑人成年人的中枢钠感应和神经体液血压反应增加，原因是 大脑中的 NKCC2 活性更强。因此，第一个具体目标是确定 NKCC2 是否有助于 在血压对急性高钠血症的神经体液调节中观察到的差异 黑人和白人成人。我们假设 NKCC2 拮抗剂呋塞米会减弱 与白人成人相比，黑人成人在高渗盐水输注期间的 SNA、AVP 和 BP 更高。第二个 具体目的是确定大脑中钠感应区域是否存在受以下因素影响的差异： 黑人和白人成年人之间的 NKCC2。我们假设速尿会减弱 BOLD 的增加 与白人成人相比，黑人在高渗盐水输注期间的功能磁共振成像信号更多。这个全面的 评估高渗盐水输注对血压的钠感应和神经体液调节， 有或没有 NKCC2 拮抗剂，将提供有关盐- 敏感血压。了解钠传感和盐敏感性的核心起源可能会带来新的发现 对抗高血压这一代价高昂的公共卫生问题的治疗方法。创新和转化 需要诸如本提案中所采用的方法来推进该领域的发展。