The Role of Reactive Oxygen Species in Intermittent Hypoxia induced Sympathoexcit

描述（由申请人提供）：尚不清楚中枢活性氧（ROS）的产生是否在独立于或与外周化学受体激活相关的持续交感神经兴奋中起作用。一个候选机制是ros -一氧化氮（NO）在大脑中的相互作用。中枢NO的交感神经抑制作用已得到证实，缺氧时产生的ROS清除NO，导致中枢交感神经外流增加，这似乎是合理的。急性间歇性缺氧（IH）引起肌肉交感神经活动（MSNA）的持续增加，并重置动脉压力反射（ABR）功能。然而，这种ABR功能的改变是否可以通过抗氧化治疗来预防和/或逆转尚不清楚。此外，通过血脑屏障（BBB）的抗氧化剂是否比仅作用于外周化学感受器的抗氧化剂更具交感神经抑制作用尚不清楚。为了探索ROS的潜在“交流”作用，我们假设IH诱导的ROS的产生增加了中央交感神经流出，并重置了动脉压反射控制MSNA的操作点（OP），从而使MSNA持续增加。我们之前证明，IH 20分钟导致MSNA持续增加至少180分钟。我们的睡眠咨询师使用创新的持续气道正压（CPAP）治疗成功的临床指标确定了OSA患者的两个亚组。我们最近注意到，n -乙酰半胱氨酸（NAC）预处理可以防止IH诱导的MSNA增加。由于抗氧化剂n -乙酰半胱氨酸（NAC）是脂溶性的，可以降低外周和中枢氧化应激，因此很难确定NAC的交感神经抑制作用是由于其作用于中枢神经系统（CNS）还是仅作用于外周化学感受器。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，在本实验中，我们将比较NAC和AA在减少急性和慢性IH诱导的交感神经兴奋方面的中枢和外周作用。由于OSA的发病率和严重程度在中年人（45-64岁）中达到高峰，我们建议在治疗成功和治疗失败的中年OSA患者中使用我们的新型双抗氧化方案，区分血脑屏障穿透性，并与年龄匹配的中年健康成年人进行比较。我们预计这组实验的发现将确定中枢ROS的产生在引起与OSA相关的交感神经兴奋中的作用。

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. PUBLIC HEALTH RELEVANCE: This investigation will explore the role of centrally and peripherally generated reactive oxygen species in mediating transient and sustained sympathoexcitation in middle-aged healthy and age-matched continuous positive airway pressure treated obstructive sleep apnea patients.