Mechanisms of Central Sodium Sensing and Salt-Sensitive Hypertension

项目总结/摘要 在美国，过量的膳食钠摄入是普遍存在的， 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， 高盐敏感性高血压的发病率。虽然盐敏感性高血压的潜在机制是 对人类了解甚少，啮齿动物研究记录了神经体液成分。啮齿动物研究 确定了专门的氯化钠（NaCl）敏感神经元在室周器官（CVOs）在 脑（缺乏完整的血脑屏障（BBB）），介导NaCl诱导的交感神经系统的变化 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（NKCC 2）不是肾脏特异性的，但实际上在调节肾脏代谢的脑区表达。 全身NaCl和水的稳态。有趣的是，黑人成年人的基础水平NKCC 2肾 活性，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是为了确定NKCC 2是否有助于更倾向于盐的人群中的NaCl敏感性， 敏感性高血压，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（使用血氧水平依赖性功能磁共振成像，BOLD fMRI） 以及SNA、AVP和BP在急性高钠刺激期间，有和没有NKCC 2拮抗剂。 这将使我们能够分离NKCC 2在黑人和白色成年人中的NaCl敏感性中的作用。整体 一种假设是，黑人成年人的中枢钠敏感和神经体液BP反应增加， 大脑中NKCC 2的活性更高。因此，第一个具体目标是确定NKCC 2是否有助于 在急性高钠血症的血压神经体液调节中观察到的差异 黑人和白色成年人。我们假设NKCC 2拮抗剂呋塞米将减弱 与白色成人相比，黑人在高渗盐水输注期间SNA、AVP和BP更多。第二 具体目的是确定大脑中的钠感应区域是否存在差异， NKCC 2在黑人和白色成年人之间。我们假设速尿会减弱BOLD的增加， 与白色成年人相比，黑人在高渗盐水输注期间的fMRI信号更多。这一全面 评估高渗盐水输注对血压的钠敏感和神经体液调节， 有和没有NKCC 2拮抗剂，将提供新的信息的机制，有助于盐- 敏感血压了解钠敏感和盐敏感的中心起源可能会导致新的 高血压是一个代价高昂的公共卫生问题。创新和翻译 需要采用本提案中所采用的方法来推动该领域的发展。

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.