Neurohumoral adaptations to chronic intermittent hypoxia

对慢性间歇性缺氧的神经体液适应

• 批准号: 7900661
• 负责人: Steven W Mifflin
• 金额: $ 185.57万
• 依托单位: UNIVERSITY OF NORTH TEXAS HLTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-05 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7900661
• 关键词: ANG gene; Address; Angiotensins; Animals; Arts; Atherosclerosis; Biochemical; Blood Pressure; Breathing; Cardiovascular Physiology; Chemoreceptors; Chronic; Core Facility; Coronary Arteriosclerosis; Denervation; Development; Diagnosis; Disease; Environmental air flow; Epidemiologic Studies; Exposure to; Goals; Health; Heart failure; Human; Hyperactive behavior; Hypertension; Hypoxemia; Hypoxia; In Vitro; Investigation; Lamina Terminalis; Lead; Maintenance; Mediating; Metabolic syndrome; Modality; Modeling; Molecular; Myocardial Infarction; National Heart, Lung, and Blood Institute; Nerve; Neuraxis; Neuroanatomy; Neuronal Plasticity; Neurons; Nucleus solitarius; Obesity; Oxygen; Pathogenesis; Pathway interactions; Patients; Peripheral; Process; Prosencephalon; Rattus; Renin-Angiotensin System; Risk; Role; Site; Sleep Apnea Syndromes; Sodium; Stroke; Sympathetic Nervous System; Synapses; Synaptic plasticity; Testing; Translational Research; Work; angiotensin hypertension; hypothalamic-pituitary-adrenal axis; in vivo; insight; neurochemistry; novel therapeutics; paraventricular nucleus; programs; response; therapeutic target

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).

描述（由申请人提供）：