Mechanisms of Central Sodium Sensing and Salt-Sensitive Hypertension

点击翻译按钮获取中文摘要

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.