Reactive Oxygen Species in Intermittent Hypoxia induced Sympathoexcitation

间歇性缺氧引起的交感神经兴奋中的活性氧

• 批准号: 8305515
• 负责人: PETER Bernard RAVEN
• 金额: $ 18.13万
• 依托单位: UNIVERSITY OF NORTH TEXAS HLTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-15 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8305515
• 关键词: 6 year old; Accounting; Acetylcysteine; Acute; Address; Adult; Age; Amino Acids; Angiotensin II; Antioxidants; Apnea; Ascorbic Acid; Baroreflex; Binding; Blood - brain barrier anatomy; Brain; Cardiovascular system; Chemoreceptors; Chronic; Clinical; Continuous Positive Airway Pressure; Cysteine; Enzymes; Faculty; Generations; Human; Hypertension; Hypoxia; Incidence; Ingestion; Intervention; Investigation; Lipids; Measures; Mediating; Mediator of activation protein; Modality; Molecular; Morbidity - disease rate; Muscle; NADPH Oxidase; Nerve; Neuraxis; Nitric Oxide; Obstructive Sleep Apnea; Oral; Outcome; Oxidative Stress; Pathogenesis; Patients; Peripheral; Play; Population; Prevalence; Production; Protocols documentation; Reactive Oxygen Species; Reporting; Role; Severities; Signal Transduction; Site; Sleep; Subgroup; Superoxide Dismutase; Superoxides; Testing; Therapeutic; Translating; Water; aged; antioxidant therapy; design; follow-up; human old age (65+); improved; indexing; innovation; middle age; mortality; nCPAP Ventilation; neutrophil; novel; preempt; prevent; prophylactic; relating to nervous system; research study; response; restraint; success; transmission process

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.

描述（由申请人提供）：尚不清楚中央活性氧（ROS）生成是否在持续的交感神经兴趣中起作用，与周围化学感受器激活无关或与外周化学感受器的激活无关。一种候选机制是大脑中的ROS氮（NO）相互作用。中央NO的交感神经抑制作用已得到很好的确定，并且在缺氧期间产生的ROS在中间没有中心导致中央交感神经流出增加。急性间歇性缺氧（IH）导致肌肉交感神经活性（MSNA）持续增加，并重置动脉压力反射（ABR）功能。但是，是否通过使用抗氧化剂治疗来预防和/或逆转ABR功能的这种变化仍然未知。此外，越过血脑屏障（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抑制性。为了探索ROS的这种潜在的“交流”作用，我们假设IH诱导的ROS产生增加了中央交感神经流出，并重置了MSNA的动脉压力反射控制的工作点（OP），以促进MSNA持续增加。以前，我们证明IH持续20分钟可导致MSNA持续增加至少180分钟。我们的睡眠顾问教职员工使用了连续气道压力（CPAP）治疗成功的创新临床指数确定了OSA患者的两个亚组。我们最近指出，N-乙酰半胱氨酸（NAC）预处理可防止IH诱导的MSNA增加。由于抗氧化剂N-乙酰基半胱氨酸（NAC）是脂溶性的，并在中心降低氧化应激，因此很难确定NAC的交感抑制作用是由于其在中枢神经系统（CNS）中的作用还是单独的外周化学感染者。相反，抗坏血酸（AA）是一种水溶性抗氧化剂，不能有效地越过BBB。因此，在这组提出的实验中，我们将比较NAC的中心和周围效应与AA在减少急性和慢性IH诱导的交感神经激素中的外围效应。随着中年成年人OSA峰的发病率和严重程度（45 - 64年），我们建议在成功和失败治疗的OSA患者中使用具有差异性BBB渗透性的新型两种抗氧化剂方案，并将反应措施与年龄与年龄相匹配的中级健康成年人进行比较。我们预计，这组实验的发现将确定中央ROS生成在引起与OSA相关的交感神经兴奋中的作用。