Neurohumoral adaptations to chronic intermittent hypoxia

描述（由申请人提供）： 睡眠呼吸暂停对健康构成重大风险，并已迅速被公认为代谢综合征患者的常见共病因素。流行病学研究已经揭示了睡眠呼吸暂停与血压升高和交感神经放电过度之间的强烈关联，即使在白天没有发生呼吸暂停发作时也是如此。动物在夜间长期暴露于间歇性缺氧（CIH）中，模拟了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的大鼠出现持续升高的血压，与睡眠呼吸暂停患者中观察到的情况相同。关于睡眠呼吸暂停和CIH如何改变交感神经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上升和血压持续升高的信息令人惊讶地缺乏。该计划的目标是解决中枢神经系统内介导CIH诱导的高血压和交感神经系统活动升高的机制，并提供对潜在治疗靶点和策略的见解。我们的工作已经证明，在暴露于CIH的前7天内，血压持续升高依赖于前脑内的动脉化学感受器和血管紧张素II（ANG II）。提出了三个项目，这将利用最先进的神经解剖学，在体内和体外电生理和分子的方法，提供一个全面的分析，中央电路介导的持续增加血压诱导CIH。项目1，由S. Mifflin将检验CIH对动脉化学感受器的重复激活诱导孤束核（NTS）中调节交感神经和HPA轴功能的神经元的活性依赖性变化的假设。项目2，由T. Cunningham，将测试这一假设，即在CIH期间增加的肾素-血管紧张素系统的活性诱导终板中投射到PVN的神经元的活性依赖性变化，并增加交感神经流出。项目3，由G. Toney将检验化学感受器和ANG II敏感性输入诱导交感神经兴奋性PVN神经元的活性依赖性变化的假设，所述变化增加其放电和兴奋性。实现这些项目的目标将由4个核心设施（行政，动物，神经解剖学，生物化学/分子）促进。这些研究将确定介导神经元可塑性的机制，并在CIH高血压的发展中发挥重要作用。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部位和机制。该结果还将与我们对与中枢神经系统缺氧（心力衰竭、中风）相关的其它病症以及其它钠依赖性和ANG II依赖性高血压模型（肥胖）的理解相关。

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).