Neurohumoral adaptations to chronic intermittent hypoxia

对慢性间歇性缺氧的神经体液适应

• 批准号: 8313978
• 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 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8313978
• 关键词: 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; Sodium Chloride; 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）： 睡眠呼吸暂停会带来重大的健康风险，并已迅速被认为是代谢综合征患者的常见共病因素。流行病学研究表明，睡眠呼吸暂停与血压升高和交感神经放电过度之间存在密切关系，即使在没有发生呼吸暂停的白天也是如此。动物在夜间长期暴露于间歇性缺氧（CIH）中，类似于睡眠呼吸暂停期间发生的动脉低氧血症的反复发作。暴露于 CIH 的大鼠血压持续升高，正如在患有睡眠呼吸暂停的人类中观察到的那样。关于睡眠呼吸暂停和 CIH 如何改变交感调节神经元之间的突触处理以及这些改变如何导致交感神经放电持续增加和血压持续升高的信息令人惊讶。该计划的目标是解决中枢神经系统内介导 CIH 诱发的高血压和交感神经系统活动升高的机制，并提供对潜在治疗目标和策略的见解。我们的工作表明，接触 CIH 的前 7 天血压持续升高取决于前脑内动脉化学感受器和血管紧张素 (ANG II) 的作用。提出的三个项目将利用最先进的神经解剖学、体内和体外电生理学和分子方法，对介导 CIH 引起的血压持续升高的中枢回路进行全面分析。由 S. Mifflin 领导的项目 1 将测试这样的假设：CIH 对动脉化学感受器的重复激活会引起孤束核 (NTS) 神经元的活动依赖性变化，从而调节交感神经和 HPA 轴功能。由 T. Cunningham 领导的项目 2 将测试这一假设，即 CIH 期间肾素-血管紧张素系统活性的增加会引起终板神经元的活动依赖性变化，这些神经元投射到 PVN 并增加交感神经流出。由 G. Toney 领导的项目 3 将测试以下假设：化学感受器和 ANG 11 敏感输入会诱导交感兴奋性 PVN 神经元发生活动依赖性变化，从而增加其放电和兴奋性。 4 个核心设施（行政、动物、神经解剖学、生化/分子）将促进这些项目目标的实现。这些研究将确定介导神经元可塑性的机制，并且对 CIH 高血压的发展具有重要意义。拟议的研究将确定可能成为睡眠呼吸暂停患者有益治疗靶点的位点和机制。该结果也将有助于我们理解与中枢神经系统缺氧（心力衰竭、中风）相关的其他疾病以及其他钠依赖性和ANG II依赖性高血压模型（肥胖）。