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物种(ROS)的产生是否独立于或与外周化学感受器激活相关地在持续的交感神经兴奋中发挥作用。一种可能的机制是大脑中的ROS-一氧化氮(NO)相互作用。中枢NO的交感神经抑制作用已得到证实，缺氧时产生的ROS可能通过中枢清除NO，导致中枢性交感神经流出增加。急性间歇性低氧(IH)导致肌肉交感神经活动(MSNA)持续增加，并使动脉压力感受性反射(ABR)功能恢复。然而，ABR功能的这种改变是否可以通过使用抗氧化剂治疗来预防和/或逆转，目前还不清楚。此外，一种跨越血脑屏障(BBB)的抗氧化剂是否比只作用于外周化学感受器的抗氧化剂更能抑制交感神经，目前尚不清楚。为了探索ROS的这种潜在的“沟通”作用，我们假设，IH诱导的ROS的产生增加了中枢交感神经流出，并重置了MSNA的动脉压力感受性反射控制的工作点(OP)，从而使MSNA持续增加。我们先前证明，IH持续20分钟会导致MSNA持续增加至少180分钟。我们的睡眠咨询师使用持续正压(CPAP)治疗成功的创新临床指标确定了OSA患者的两个亚组。我们最近注意到，用N-乙酰半胱氨酸(NAC)预处理可以阻止IH诱导的MSNA增加。由于抗氧化剂N-乙酰半胱氨酸(NAC)是脂溶的，可以在外周和中枢减少氧化应激，因此很难确定NAC的交感神经抑制作用是由于它在中枢神经系统(CNS)中的作用，还是仅仅在外周化学感受器上。相比之下，抗坏血酸(AA)是一种水溶性抗氧化剂，不能有效地通过血脑屏障。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的外周效应在减少急性和慢性IH诱导的交感兴奋方面的作用。由于OSA的发病率和严重程度在中年成年人(45-岁)中达到高峰，我们建议在治疗成功和失败的中年OSA患者中使用我们的具有不同血脑屏障渗透率的新型双抗氧化剂方案，并与年龄匹配的中年健康成年人比较应对措施。我们期望这一系列实验的结果将确定中枢ROS的产生在引起与OSA相关的交感兴奋中的作用。

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.