Reactive Oxygen Species in Intermittent Hypoxia induced Sympathoexcitation

描述（由申请人提供）：尚不清楚中枢活性氧（ROS）的产生是否在持续的交感神经兴奋中发挥作用，是否独立于外周化学感受器激活或与外周化学感受器激活相关。一个候选机制是脑中的ROS-一氧化氮（NO）相互作用。中枢NO的交感神经抑制作用已被充分确立，并且在缺氧期间产生的ROS清除中枢NO导致中枢交感神经流出增加是合理的。急性间歇性缺氧（IH）引起肌肉交感神经活动（MSNA）持续增加，并重置动脉压力感受性反射（ABR）功能。然而，它仍然是未知的，如果在ABR功能的这种改变是预防和/或逆转使用抗氧化剂治疗。此外，是否抗氧化剂，通过血脑屏障（BBB）是更交感神经抑制比抗氧化剂仅作用于外周化学感受器是未知的。为了探索ROS的这种潜在的“交流”作用，我们假设IH诱导的ROS产生增加了中枢交感神经流出，并重置了MSNA的动脉压力反射控制的操作点（OP），以使MSNA持续增加。我们以前证明，IH 20分钟导致MSNA持续增加至少180分钟。我们的睡眠顾问教师已经确定了两个亚组的OSA患者使用持续气道正压通气（CPAP）治疗成功的创新临床指数。我们最近注意到，用N-乙酰半胱氨酸（NAC）预处理可防止IH诱导的MSNA增加。因为抗氧化剂N-乙酰半胱氨酸（NAC）是脂溶性的，并且减少外周和中枢的氧化应激，所以难以确定NAC的交感神经抑制作用是由于其单独在中枢神经系统（CNS）中还是在外周化学感受器中的作用。相反，抗坏血酸（AA）是一种水溶性抗氧化剂，不能有效地穿过血脑屏障。因此，在这组拟议的实验中，我们将比较NAC的中枢和外周效应与AA在减少急性和慢性IH诱导的交感兴奋中的外周效应。由于OSA的发病率和严重程度在中年人（45-64岁）中达到峰值，我们建议在成功治疗和治疗失败的中年OSA患者中使用具有不同BBB渗透性的新型双抗氧化剂方案，并将反应措施与年龄匹配的中年健康成人进行比较。我们预计，这组实验的结果将确定中央活性氧产生的作用，引起与OSA相关的交感神经兴奋。

DESCRIPTION (provided by applicant): It is not known if central reactive oxygen species (ROS) generation plays a role in the sustained sympathoexcitation independent of, or in association with, peripheral chemoreceptor activation. One candidate mechanism is the ROS-nitric oxide (NO) interaction in the brain. The sympathoinhibitory role of central NO is well established and it is plausible that ROS generated during hypoxia scavenges NO centrally resulting in increased central sympathetic outflow. Acute intermittent hypoxia (IH) causes a sustained increase in muscle sympathetic nerve activity (MSNA) and resets arterial baroreflex (ABR) function. However, it remains unknown if this alteration in ABR function is prevented and/or reversed by using antioxidant therapy. Furthermore, whether an antioxidant that crosses the blood brain barrier (BBB) is more sympathoinhibitory than the antioxidant acting only at the peripheral chemoreceptors is unknown. To explore this potential 'communicative' role of ROS, we hypothesize that the IH induced generation of ROS increases central sympathetic outflow and resets the operating point (OP) of the arterial baroreflex control of MSNA to enable a sustained increase in MSNA. We previously demonstrated that IH for 20 min leads to a sustained increase in MSNA for at least 180 min. Our Sleep Consultant Faculty has identified two subgroups of OSA patients using an innovative clinical index of continuous positive airway pressure (CPAP) treatment success. We have recently noted that pretreatment with N-acetylcysteine (NAC) prevents the increase in IH induced increase in MSNA. Because the anti-oxidant N-acetyl cysteine (NAC) is lipid soluble and reduces oxidative stress peripherally and centrally, it is difficult to identify whether NAC's sympathoinhibitory effect is due to its action in the central nervous system (CNS) or at the peripheral chemoreceptors, alone. In contrast ascorbic acid (AA) is a water-soluble antioxidant which does not cross the BBB effectively. Hence, in this set of proposed experiments, we will compare the central and peripheral effects of NAC to that of the peripheral effects of AA in reducing acute and chronic IH induced sympathoexcitation. As the incidence and severity of OSA peaks in middle aged adults (45-64 years), we propose to use our novel two-antioxidant protocol with differential BBB penetrability in middle-aged successfully and unsuccessfully treated OSA patients and compare the response measures with age-matched middle-aged healthy adults. We anticipate that the findings of this set of experiments will identify the role of central ROS generation in causing the sympathoexcitation associated with OSA.