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: 10386518
• 负责人: Joseph Stock
• 金额: $ 6.72万
• 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/10386518
• 关键词: Acute; Adult; Area; Argipressin; Attenuated; Black race; Blood; Blood - brain barrier anatomy; Blood Pressure; Blood Volume; Brain; Brain region; Cardiovascular Diseases; Consumption; Data; Dietary Sodium; Functional Magnetic Resonance Imaging; Furosemide; Goals; Homeostasis; Human; Hypernatremia; Hypertension; Infusion procedures; Kidney; Lead; Mediating; Nerve; Neuraxis; 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.

项目摘要/摘要 过量的膳食钠摄入量在美国无处不在，是导致 高血压和心血管疾病。这对黑人成年人来说尤其成问题，众所周知，他们有 盐敏感型高血压患病率高。尽管盐敏感型高血压的潜在机制是 在人类中知之甚少，啮齿动物的研究记录了一种神经体液成分。对啮齿动物的研究已经 在大鼠的脑室周器官(CVO)中发现了特殊的氯化钠(氯化钠)感受神经元。 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)和血压调节(BP)。最近的数据表明 Na+-K+-2Cl-共转运蛋白(NKCC2)不是肾脏特有的，但实际上表达于大脑中调节 全身氯化钠和水的动态平衡。有趣的是，成年黑人的NKCC2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敏感区域。的目标是 这个F32是为了确定NKCC2是否有助于在更倾向于盐的种群中对氯化钠敏感- 敏感高血压，黑人成年人。我们试图通过评估将先前的啮齿动物发现转化为人类 神经元激活(使用血氧水平依赖的功能磁共振成像，BOLD功能磁共振成像) 以及在有和没有NKCC2拮抗剂的情况下，急性高钠刺激期间的SNA、AVP和BP。 这将使我们能够分离NKCC2在黑人和白人成年人对氯化钠敏感性中的作用。整体而言 假说认为，成年黑人中枢钠感觉和神经体液BP反应增加是由于 大脑中NKCC2活性增强。因此，第一个具体目标是确定NKCC2是否有助于 急性高钠血症患者血压神经体液调节的差异 黑人和白人成年人。我们假设NKCC2拮抗剂呋塞米将减弱这种增加。 与白人成年人相比，黑人在高渗盐水输注过程中的SNA、AVP和BP更多。第二 具体目的是确定大脑中钠感受区是否存在差异，这些区域受 黑人和白人成年人之间的NKCC2。我们假设速尿将减弱BOLD的增加。 与白人成年人相比，高渗盐水输注过程中黑人的fMRI信号更多。这一全面的 高渗盐水输注对血压的钠敏感和神经体液调节的评价， 使用和不使用NKCC2拮抗剂，将提供有关盐分形成机制的新信息。 敏感的BP。了解钠敏感和盐敏感的中心来源可能会带来新的 对抗高血压的治疗方法，这是一个代价高昂的公共卫生问题。创新和翻译性 需要采取本提案中所采用的办法来推动这一领域的发展。