Neurohumoral adaptations to chronic intermittent hypoxia

Project: Research projectResearch Program Projects

Description

DESCRIPTION (provided by applicant): 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).
StatusActive
Effective start/end date4/1/073/31/20

Funding

  • National Institutes of Health

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Hypertension
Apnea
Hypercapnia
Glutamic Acid
Ischemia
Neuroprotection
Hypoxia
Amino Acid Transport System X-AG
Tissue Survival
Rhombencephalon
Neuroprotective Agents
Prosencephalon
Neuroglia
gamma-Aminobutyric Acid
Small Interfering RNA
Buffers
Proteins
Stroke
Wounds and Injuries
Population

Keywords

  • Medicine(all)