Neurohumoral adaptations to chronic intermittent hypoxia

对慢性间歇性缺氧的神经体液适应

• 批准号: 7685308
• 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/7685308
• 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; 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)： 睡眠呼吸暂停对健康构成重大风险，并迅速被认为是被诊断为代谢综合征的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过度的交感神经放电之间存在很强的相关性，即使在没有呼吸暂停发作的白天也是如此。动物夜间慢性暴露于间歇性低氧(CIH)可模拟睡眠呼吸暂停期间反复发作的动脉低氧血症。正如在患有睡眠呼吸暂停的人类中观察到的那样，暴露于CIH的大鼠会出现持续性的血压升高。关于睡眠呼吸暂停和脑出血如何改变交感神经调节神经元之间的突触处理，以及这些变化如何导致交感神经放电持续增加和血压持续上升，信息令人惊讶地匮乏。该计划的目标是解决中枢神经系统内调节CIH引起的高血压和交感神经系统活动增加的机制，并为潜在的治疗目标和策略提供见解。我们的工作已经证明，在接触CIH的前7天内，血压的持续升高依赖于动脉化学感受器和前脑内的血管紧张素(Ang II)。提出了三个项目，它们将利用最先进的神经解剖学、体内和体外电生理和分子方法来全面分析调节CIH引起的血压持续升高的中枢回路。由S.Mifflin领导的项目1将检验这一假设，即CIH重复激活动脉化学感受器会导致孤束核(NTS)中调节交感神经和HPA轴功能的神经元活动依赖的变化。由T.Cunningham领导的项目2将检验这一假设，即在CIH期间肾素-血管紧张素系统的活性增加导致终板神经元投射到PVN并增加交感神经流出的活动依赖性变化。由G.Toney领导的项目3将测试化学感受器和AngⅡ敏感的输入在交感兴奋的PVN神经元中诱导活动依赖的变化，从而增加其放电和兴奋性的假设。4个核心设施(行政、动物、神经解剖学、生化/分子)将促进实现这些项目的目标。这些研究将确定调节神经元可塑性的机制，并在脑出血高血压的发展中起重要作用。拟议的研究将确定可能对睡眠呼吸暂停患者有利的治疗靶点和机制。这一结果还将有助于我们理解与中枢神经系统缺氧(心力衰竭、中风)以及其他钠依赖和血管依赖高血压模型(肥胖)相关的其他情况。