Neurohumoral Adaptations to Chronic Intermittent Hypoxia: Insights into the Pathophysiology of Sleep Apnea

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 DESCRIPTION (provided by applicant): Sleep apnea poses a significant health risk and is associated with increased blood pressure and exaggerated sympathetic nerve discharged. 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 elevated blood pressure and sympathetic outflow as observed in humans with sleep apnea. During the past funding period our program provided novel insights into how CIH alters synaptic processing among sympathetic regulatory neurons in the central nervous system 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 chemoreceptor, the HPA axis and angiotensin (ANG II) acting within the forebrain. Three projects are proposed: Project 1, led by S. Mifflin, will test the hypothesis that repetitive activation of the arterial chemoreceptors by CH 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 and that these adaptations may actually be protective when faced with ischemia. Achieving the goals of these projects will be facilitated by 2 Core facilities (Administrative, Analytical). The Analytical Core will provide genomic and proteomic analysis of gene expression and protein levels as well as post-translational modifications of proteins. The studies will determine mechanisms that mediate neuronal plasticity and are important in the development of CIH-hypertension. 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).