Effects of obstructive sleep apnea on cerebral circulation

描述(申请人提供)：阻塞性睡眠呼吸暂停(OSA)的定义是由于上呼吸道软组织塌陷而导致睡眠期间呼吸中断。它影响高达25%的成年人口，而且经常被忽视，因为它是许多病理状况的潜在原因。虽然OSA与包括中风和痴呆症在内的脑血管疾病有很强的相关性，但OSA对血管内皮细胞和平滑肌的影响机制尚不清楚，这是脑血流(CBF)控制的部位。这项建议的目的是启动必要的研究，以了解阻塞性睡眠呼吸暂停后脑血管功能障碍的病理机制。这些研究的一个独特方面涉及到我们的阻塞性睡眠呼吸暂停大鼠模型。在这个新开发的模型中，我们将在未麻醉的自由活动的大鼠的睡眠周期中阻塞呼吸道。这个模型有几个重要的特征，更接近于OSA在人类中的发生，并将有助于提供更完整的了解与OSA在脑循环中相关的病理事件。我们认为ROS和内皮素在一个病理循环中起作用，在脑动脉和小动脉中产生过度收缩的表型。也就是说，在OSA过程中，ROS的产生上调了ET途径，而ET途径产生了ROS。此外，我们认为，通过清除ROS或抑制内皮素途径来打破这一病理循环将抑制脑血管的病理变化。我们将验证以下假设：在阻塞性睡眠呼吸暂停综合征期间，ROS的产生和内皮素之间的循环会在脑血管壁产生病理变化，并扰乱脑血流。我们将在三个具体目标上检验我们的假设。(SA1)确定通过降低ROS来打破ROS和ET-1之间的循环是否会减轻OSA 28天后大鼠动脉和小动脉的脑血管功能障碍。(SA2)通过阻断内皮素受体来阻断ROS和ET-1之间的循环，以确定是否可以缓解OSA 28天后大鼠动脉和小动脉的脑血管功能障碍。(SA3)确定28天的OSA是否降低了CBF、减弱了CBF对胡须刺激的反应、减弱了自身调节或减弱了CBF对高碳酸血症的反应。确定降低ROS和/或阻断内皮素受体是否能在体内恢复这些反应。我们将使用分离的加压脑动脉和小动脉，并用放射自显影技术和激光多普勒血流计测量脑血流量，以完成这些特定的目标。这些研究的完成将有助于我们更好地了解脑血管功能障碍的潜在机制，并朝着更有效的治疗方法发展，以减少OSA对脑循环的破坏性影响，从而降低中风的发生率和痴呆的严重程度。

DESCRIPTION (provided by applicant): Obstructive sleep apnea (OSA) is defined by interrupted breathing during sleep due to a collapse of the soft tissues in the upper airway. It affects up to 25% of the adult population and is often overlooked as being an underlying cause for a number of pathological conditions. Although OSA has strong associations to cerebrovascular diseases including stroke and dementia, mechanisms that underlie the effects of OSA on endothelium and smooth muscle, the sites for cerebral blood flow (CBF) control, are unknown. The purpose of this proposal is to initiate studies required for understanding the pathological mechanisms associated with cerebrovascular dysfunction following OSA. One unique aspect of these studies involves our rat model of OSA. In this newly developed model, we will obstruct the airway during the sleep cycle in unanesthetized, freely- ranging rats. This model has several important features that more closely mimics OSA as it occurs in the human and will help to provide a more complete understanding of the pathological events associated with OSA in the cerebral circulation. We propose that ROS and endothelin act in a pathological cycle to produce a hypercontractile phenotype in cerebral arteries and arterioles. That is, during OSA, generation of ROS upregulates the endothelin pathway and the endothelin pathway generates ROS. Further, we propose that breaking this pathological cycle by either scavenging ROS or inhibiting the endothelin pathway will inhibit the pathological alterations in cerebral vessels. We will test the following hypothesis: During OSA a cycle between ROS generation and endothelin produces pathological alterations in the cerebrovascular wall and disrupts cerebral blood flow. We will test our hypothesis in three specific aims. (SA1) Determine if breaking the cycle between ROS and ET-1 by reducing ROS will alleviate the cerebrovascular dysfunction in arteries and arterioles in rats following 28 days of OSA. (SA2) Determine if breaking the cycle between ROS and ET-1 by blocking endothelin receptors will alleviate the cerebrovascular dysfunction in arteries and arterioles in rats following 28 days of OSA. (SA3) Determine if 28 days of OSA decreases CBF, attenuates the CBF response to whisker stimulation, attenuates autoregulation, or attenuates the CBF response to hypercapnia. Determine if reducing ROS and/or blocking endothelin receptors restores these responses in vivo. We will complete these specific aims using isolated pressurized cerebral arteries and arterioles and measurement of CBF with autoradiographic techniques and laser Doppler flowmetry. Completion of these studies will move us toward a better understanding of the underlying mechanisms of cerebrovascular dysfunction and towards more effective treatments to reduce the devastating effects of OSA on the cerebral circulation with a goal of reducing the incidence of stroke and the severity of dementias.