Sleep apnea poses a significant health risk and has rapidly gained recognition as a common co-morbid factor in patients diagnosed with metabolic syndrome. Epidemiological studies have revealed a strong association between sleep apnea and increased blood pressure and exaggerated sympathetic nerve discharge, even during the daytime when apneic episodes are not occurring. Chronic exposure to intermittent hypoxia (CIH) during the nocturnal period in animals mimics the repetitive bouts of arterial hypoxemia that occur during sleep apnea. Rats exposed to CIH develop a persistently increased blood pressure as observed in humans with sleep apnea. There is a surprising paucity of information concerning how sleep apnea and CIH alter synaptic processing among sympathetic regulatory neurons and how these alterations lead to a persistent rise in sympathetic nerve discharge and a sustained increase in blood pressure. The Program objectives are to address mechanisms within the central nervous system that mediate CIH-induced hypertension and elevated sympathetic nervous system activity and to provide insights into potential therapeutic targets and strategies. Our work has demonstrated that the persistent increase in blood pressure during the first 7 days of exposure to CIH is dependent upon arterial chemoreceptors and angiotensin (ANG II) acting within the forebrain. Three projects are proposed which will utilize state-of-the-art neuroanatomical, in vivo and in vitro electrophysiological and molecular approaches to provide a comprehensive analysis of the central circuitry mediating the persistent increase in blood pressure induced by CIH. Project 1, led by S. Mifflin, will test the hypothesis that repetitive activation of the arterial chemoreceptors by CIH induces activity-dependent changes in neurons in the nucleus of the solitary tract (NTS) that regulate sympathetic and HPA axis function. Project 2, led by T. Cunningham, will test the hypothesis that increased activity of the renin-angiotensin system during CIH induces activity-dependent changes in neurons in the lamina terminalis that project to the PVN and increase sympathetic outflow. Project 3, led by G. Toney, will test the hypothesis that chemoreceptor- and ANG ll-sensitive inputs induce activity-dependent changes in sympatho-excitatory PVN neurons that increase their discharge and excitability. Achieving the goals of these projects will be facilitated by 4 Core facilities (Administrative, Animal, Neuroanatomy, Biochemical/Molecular). The studies will determine mechanisms that mediate neuronal plasticity and are important in the development of CIH-hypertension. The proposed studies will identify sites and mechanisms that could be beneficial therapeutic targets in sleep apnea patients. The results will also have relevance to our understanding of other conditions associated with central nervous system hypoxia (heart failure, stroke) and other sodium-dependent and ANG ll-dependent models of hypertension (obesity).

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
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Heart, Lung, and Blood Initial Review Group (HLBP)
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Maric-Bilkan, Christine
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University of North Texas
Other Domestic Higher Education
Fort Worth
United States
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Bardgett, Megan E; Chen, Qing-Hui; Guo, Qing et al. (2014) Coping with dehydration: sympathetic activation and regulation of glutamatergic transmission in the hypothalamic PVN. Am J Physiol Regul Integr Comp Physiol 306:R804-13
Saxena, Ashwini; Bachelor, Martha; Park, Yong H et al. (2014) Angiotensin II induces membrane trafficking of natively expressed transient receptor potential vanilloid type 4 channels in hypothalamic 4B cells. Am J Physiol Regul Integr Comp Physiol 307:R945-55
Holbein, Walter W; Bardgett, Megan E; Toney, Glenn M (2014) Blood pressure is maintained during dehydration by hypothalamic paraventricular nucleus-driven tonic sympathetic nerve activity. J Physiol 592:3783-99
Bardgett, Megan E; Holbein, Walter W; Herrera-Rosales, Myrna et al. (2014) Ang II-salt hypertension depends on neuronal activity in the hypothalamic paraventricular nucleus but not on local actions of tumor necrosis factor-*. Hypertension 63:527-34
Bardgett, Megan E; Sharpe, Amanda L; Toney, Glenn M (2014) Activation of corticotropin-releasing factor receptors in the rostral ventrolateral medulla is required for glucose-induced sympathoexcitation. Am J Physiol Endocrinol Metab 307:E944-53
Knight, W David; Saxena, Ashwini; Shell, Brent et al. (2013) Central losartan attenuates increases in arterial pressure and expression of FosB/?FosB along the autonomic axis associated with chronic intermittent hypoxia. Am J Physiol Regul Integr Comp Physiol 305:R1051-8
Bathina, Chandra Sekhar; Rajulapati, Anuradha; Franzke, Michelle et al. (2013) Knockdown of tyrosine hydroxylase in the nucleus of the solitary tract reduces elevated blood pressure during chronic intermittent hypoxia. Am J Physiol Regul Integr Comp Physiol 305:R1031-9
Yamamoto, Kenta; Eubank, Wendy; Franzke, Michelle et al. (2013) Resetting of the sympathetic baroreflex is associated with the onset of hypertension during chronic intermittent hypoxia. Auton Neurosci 173:22-7
Sharpe, Amanda L; Andrade, Mary Ann; Herrera-Rosales, Myrna et al. (2013) Rats selectively bred for differences in aerobic capacity have similar hypertensive responses to chronic intermittent hypoxia. Am J Physiol Heart Circ Physiol 305:H403-9
Toney, Glenn M; Vallon, Volker; Stockand, James D (2012) Intrinsic control of sodium excretion in the distal nephron by inhibitory purinergic regulation of the epithelial Na(+) channel. Curr Opin Nephrol Hypertens 21:52-60

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