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).

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL088052-04
Application #
8100466
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Thrasher, Terry N
Project Start
2008-09-05
Project End
2013-06-30
Budget Start
2011-07-01
Budget End
2012-06-30
Support Year
4
Fiscal Year
2011
Total Cost
$1,855,720
Indirect Cost
Name
University of North Texas
Department
Physiology
Type
Other Domestic Higher Education
DUNS #
110091808
City
Fort Worth
State
TX
Country
United States
Zip Code
76107
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Wu, Qiong; Cunningham, J Thomas; Mifflin, Steve (2018) Transcription factor ?FosB acts within the nucleus of the solitary tract to increase mean arterial pressure during exposures to intermittent hypoxia. Am J Physiol Heart Circ Physiol 314:H270-H277
Holbein, Walter W; Blackburn, Megan B; Andrade, Mary Ann et al. (2018) Burst patterning of hypothalamic paraventricular nucleus-driven sympathetic nerve activity in ANG II-salt hypertension. Am J Physiol Heart Circ Physiol 314:H530-H541
Blackburn, Megan B; Andrade, Mary Ann; Toney, Glenn M (2018) Hypothalamic PVN contributes to acute intermittent hypoxia-induced sympathetic but not phrenic long-term facilitation. J Appl Physiol (1985) 124:1233-1243
Wang, Lei A; Nguyen, Dianna H; Mifflin, Steve W (2018) CRHR2 (Corticotropin-Releasing Hormone Receptor 2) in the Nucleus of the Solitary Tract Contributes to Intermittent Hypoxia-Induced Hypertension. Hypertension 72:994-1001
Lalley, Peter M; Mifflin, Steve W (2017) Oscillation patterns are enhanced and firing threshold is lowered in medullary respiratory neuron discharges by threshold doses of a ?-opioid receptor agonist. Am J Physiol Regul Integr Comp Physiol 312:R727-R738
Snyder, Brina; Shell, Brent; Cunningham, J Thomas et al. (2017) Chronic intermittent hypoxia induces oxidative stress and inflammation in brain regions associated with early-stage neurodegeneration. Physiol Rep 5:
Granato, Álisson Silva; Gomes, Paula Magalhães; Martins Sá, Renato William et al. (2017) Cardiovascular responses to l-glutamate microinjection into the NTS are abrogated by reduced glutathione. Neurosci Lett 642:142-147
Faulk, Katelynn E; Nedungadi, T Prashant; Cunningham, J Thomas (2017) Angiotensin converting enzyme 1 in the median preoptic nucleus contributes to chronic intermittent hypoxia hypertension. Physiol Rep 5:
Faulk, Katelynn; Shell, Brent; Nedungadi, T Prashant et al. (2017) Role of angiotensin-converting enzyme 1 within the median preoptic nucleus following chronic intermittent hypoxia. Am J Physiol Regul Integr Comp Physiol 312:R245-R252

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