Central and Peripheral Mechanisms of Sleep Apnea

描述（由申请人提供）：基于我们最近在睡眠人类和狗身上的发现，我们提出呼吸暂停下对二氧化碳的通气反应是高度不稳定的，这取决于主要通气驱动的类型和方向，是许多类型的呼吸不稳定和呼吸暂停的关键决定因素。我们提出了五个主要目标来研究不稳定呼吸暂停阈值对二氧化碳储备的原因和后果（即PETCO2 EUPNEA - PETCO2APNEA；呼吸不稳定倾向指数）。首先，我们将使用睡狗模型和我们的压力支持通气（PSV）方法来确定CO2储备和充血性心力衰竭时左房压升高引起的呼吸暂停易感性的变化。目的2和3将使用我们完整的睡狗准备，其中颈动脉化学受体被分离并通过体外循环灌注。我们将确定中枢和外周化学感受器对短暂性PaCO2减少的敏感性及其对呼吸暂停发生的相对贡献。我们在完整睡眠动物中分离中枢和外周化学感受器的能力也将用于确定外周化学感受器缺氧与中枢神经系统缺氧在决定二氧化碳储备和通气不稳定倾向方面的相对重要性。在Aim 4中，我们将使用睡眠中的人类来研究缺氧睡眠期间伴随周期性呼吸的脑血流量动态变化对通气稳定性的原因和后果。最后，我们将验证阻塞性睡眠呼吸暂停患者由于长期暴露于夜间低氧血症，有不稳定的呼吸运动输出和敏感的窒息阈值（即二氧化碳储备变窄）的倾向。我们将通过将狗暴露于慢性间歇性缺氧来进一步验证这一假设，以确定它们的通气不稳定倾向是否会随着慢性间歇性缺氧暴露的持续时间而增加。

DESCRIPTION (provided by applicant): Based on our recent findings in sleeping humans and dogs we propose that the ventilatory responsiveness to CO2 below eupnea is highly labile depending on the type and direction of prevailing ventilatory drive and is a critical determinant of many types of breathing instability and apnea. We propose five major aims to study causes and consequences of a labile apneic threshold on the CO2 reserve (i.e., PETCO2 EUPNEA -- PETCO2APNEA ; an index of propensity for ventilatory instability). First, we will use the sleeping dog model and our pressure support ventilation (PSV) method to determine the CO2 reserve and change in the susceptibility to apnea caused by raised left atrial pressure, as occurs in congestive heart failure. Aims 2 & 3 will utilize our intact sleeping dog preparation in which the carotid chemoreceptor is isolated and perfused via extracorporeal circulation. We will determine the sensitivities of the central vs. peripheral chemoreceptors to transient reductions in PaCO2 and their relative contributions to the genesis of apnea. Our capability for isolating central from peripheral chemoreceptors in the intact sleeping animal will also be used to determine the relative importance of peripheral chemoreceptor hypoxia vs. CNS hypoxia in determining CO2 reserve and the propensity for ventilatory instability. In Aim 4, we will use sleeping humans to study the causes and consequences to ventilatory stability of the dynamic changes in cerebral blood flow which accompany periodic breathing during sleep in hypoxia. Finally, we will test the hypothesis that obstructive sleep apnea patients have a propensity for unstable respiratory motor output and a sensitive apneic threshold (i.e., narrowed CO2 reserve) because of their chronic exposure to nocturnal hypoxemia. We will test this hypothesis further by exposing dogs to chronic intermittent hypoxia to determine if their propensity for ventilatory instability increases over the duration of chronic intermittent hypoxic exposure.