Cerebrovascular Consequences of Sleep Apnea

描述（由申请人提供）：阻塞性睡眠呼吸暂停（OSA）是当今社会中一个重要但经常被忽视的问题。阻塞性睡眠呼吸暂停被定义为睡眠时呼吸中断，最常见的原因是上呼吸道软组织塌陷。据估计，在西方世界超过25%的成年人患有临床上明显的OSA。除了是情绪和行为障碍的潜在原因外，阻塞性睡眠呼吸暂停也是心血管疾病和中风的独立危险因素。目前，OSA的动物模型主要包括使啮齿动物在睡眠周期中暴露于间歇性缺氧。对呼吸暂停的生理反应与间歇性缺氧在许多重要方面有所不同。在具体目标1中，我们提出建立阻塞性睡眠呼吸暂停大鼠模型。我们将在未麻醉的自由活动大鼠的睡眠周期中阻塞气道。可以控制呼吸暂停的频率和/或持续时间，以改变OSA的严重程度。包括阻塞性呼吸暂停将更接近模拟OSA在人类。虽然阻塞性睡眠呼吸暂停是中风的独立危险因素，可能导致认知能力下降，但对阻塞性睡眠呼吸暂停对脑循环的影响知之甚少。我们之前已经表明，一氧化氮（NO）和内皮源性超极化因子（EDHF）是参与脑循环内皮控制的重要扩张机制。在病理条件下，如缺血/再灌注和创伤性脑损伤，通过内皮来源的NO的扩张减弱，而edhf介导的扩张增强。阻塞性睡眠呼吸暂停对脑动脉扩张内皮机制的影响尚未得到研究。在具体目标2中，我们将使用我们的模型来验证OSA通过内皮来源的NO减弱舒张并上调EDHF介导的舒张的假设。在Specific Aim 2的研究中，我们将使用OSA 1个月后的大鼠分离的加压和灌注的大脑中动脉。这项R21资助提案涉及“早期和概念阶段”的“探索性和发展性研究”，以开发一种改进的OSA动物模型，并确定OSA对脑动脉的影响。改进后的模型将更好地模拟OSA在人类中的发生，并将有助于更全面地了解与OSA相关的心功能和脑循环控制的病理事件。

DESCRIPTION (provided by applicant): Obstructive sleep apnea (OSA) is a significant, but often overlooked, problem in today's society. OSA is defined by interrupted breathing during sleep, most often due to a collapse of the soft tissues in the upper airway. It has been estimated that more than 25% of the adult population in the Western world suffers from clinically significant OSA. In addition to being the underlying cause of mood and behavioral disorders, OSA is an independent risk factor for cardiovascular disease and stroke. Currently, animal models of OSA predominately consist of exposing rodents to intermittent hypoxia during the sleep cycle. The physiological response to apnea differs from intermittent hypoxia in a number of significant ways. In Specific Aim 1, we propose to develop a rat model of obstructive sleep apnea. We will obstruct the airway during the sleep cycle in unanesthetized, freely-moving rats. The frequency and/or duration of apnea can be controlled to vary the severity of OSA. Inclusion of obstructive apnea will more closely model OSA in the human. While OSA is an independent risk factor for stroke and may be responsible for cognitive decline, very little is known about the effects of OSA on cerebral circulation. We have previously shown that nitric oxide (NO) and endothelium derived hyperpolarizing factor (EDHF) are important dilatory mechanisms involved with the endothelial control of cerebral circulation. During pathological conditions such as ischemia/reperfusion and traumatic brain injury, dilations through endothelium- derived NO are diminished, whereas, EDHF-mediated dilations are enhanced. The effects of OSA on endothelial mechanisms of dilation in cerebral arteries have not been studied. In Specific aim 2 we will use our model to test the hypothesis that OSA attenuates dilation through endothelium- derived NO and upregulates EDHF mediated dilations. For studies in Specific Aim 2, we will use isolated pressurized and perfused middle cerebral arteries from rats after 1 month of OSA. This R21 Grant proposal involves "exploratory and developmental research" in the "early and conceptual stages" of developing an improved animal model for OSA and determining the effects of OSA on cerebral arteries. The improved model will better mimic OSA as it occurs in the human and will help to provide a more complete understanding of the pathological events associated with OSA in cardiac function and control of the cerebral circulation. PUBLIC HEALTH RELEVANCE: We propose to (a) improve the current rodent models of obstructive sleep apnea to more closely mimic the human condition and (b) study the effects of obstructive sleep apnea on the cerebral circulation using our newly developed model. Very little is known about the effects of obstructive sleep apnea on the cerebral circulation. The proposed studies will provide an important foundation for understanding cerebrovascular dysfunction related to obstructive sleep apnea.