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）：尚不清楚中枢活性氧（ROS）的产生是否在独立于外周化学感受器激活或与之相关的持续交感神经兴奋中发挥作用。一种候选机制是大脑中活性氧与一氧化氮 (NO) 的相互作用。中枢 NO 的交感神经抑制作用已得到充分证实，缺氧期间产生的 ROS 可能会集中清除 NO，导致中枢交感神经流出增加。急性间歇性缺氧（IH）导致肌肉交感神经活动（MSNA）持续增加并重置动脉压力反射（ABR）功能。然而，目前尚不清楚是否可以通过抗氧化疗法来预防和/或逆转 ABR 功能的这种改变。此外，穿越血脑屏障（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 的这种潜在“交流”作用，我们假设 IH 诱导的 ROS 生成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)，从而实现了 MSNA 的持续增加。我们之前证明，IH 20 分钟可导致 MSNA 持续增加至少 180 分钟。我们的睡眠顾问团队使用持续气道正压通气 (CPAP) 治疗成功的创新临床指数，确定了 OSA 患者的两个亚组。我们最近注意到，用 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，可减少外周和中枢的氧化应激，因此很难确定 NAC 的交感抑制作用是否单独归因于其在中枢神经系统 (CNS) 或外周化学感受器中的作用。相比之下，抗坏血酸 (AA) 是一种水溶性抗氧化剂，不能有效穿过血脑屏障。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 诱导的交感神经兴奋方面的外周效应。由于 OSA 的发病率和严重程度在中年人（45-64 岁）达到顶峰，我们建议在成功和未成功治疗的中年 OSA 患者中使用具有不同 BBB 渗透性的新型两种抗氧化剂方案，并将反应措施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结果将确定中枢 ROS 生成在引起与 OSA 相关的交感神经兴奋中的作用。