Intermittent Hypoxia: A Model to Study Circulatory Control in Humans

描述(由申请人提供)： PI的长期目标是确定低氧应激所涉及的自主神经和血管机制，并探索它们在疾病中的作用。在这个项目中，我们将研究急性和间歇性低氧对神经循环控制的影响，这是两种普遍的生理应激类型。低氧应激在各种疾病状态和吸烟者中很常见，间歇性低氧是阻塞性睡眠呼吸暂停的特征。这些情况的特点是心血管风险增加。运动过程中也会出现骨骼肌缺氧，但运动训练似乎能改善血管和自主神经反射功能。已有研究表明，全身和局部缺氧(即缺血)通过对自主神经系统和局部代谢控制的综合但有时相反的影响来影响循环。我们实验室的初步数据表明，在健康人中，间歇性低氧引起持续的交感神经激活和增强的对低氧的反射反应。由于抗氧化剂抗坏血酸减弱了间歇性低氧的交感兴奋效应，氧化应激可能是原因之一。我们还发现，睡眠呼吸暂停患者对低氧的交感反射反应增强，并通过持续气道正压治疗部分恢复正常。然而，尽管交感血管收缩神经流量增加，化学反射激活增强，急性缺氧引起的血管扩张在睡眠呼吸暂停患者中仍得以保留。总而言之，这些发现支持了中心假设，即间歇性低氧改变交感神经活动和反射功能，并可能通过氧化应激引起血管适应。该建议的具体目的是确定：(1)睡眠呼吸暂停患者的实验性间歇性低氧或夜间间歇性低氧是否改变了可通过抗氧化干预(给予抗坏血酸、运动训练)恢复的交感反射功能；(2)骨骼肌对间歇性低氧应激的适应部分是由于内皮衍生超极化因子(EDHF)等内皮血管扩张系统的作用增强；以及(3)吸烟改变了可通过抗氧化干预部分恢复的神经循环控制。拟议的研究扩大了我们先前关于低氧期间神经循环调节的工作范围，并将为间歇性低氧与不良心血管后果之间的联系提供新的见解。 公共卫生相关性： 这项研究考察了在暴露于与低氧供应相关的生理应激期间控制外周血流量的机制。这些机制似乎在非常常见的情况下发生了重要的变化，如阻塞性睡眠呼吸暂停和吸烟者。对这些过程的新见解将帮助我们更好地理解这些机制是否以及如何导致疾病，并将使我们能够设计更好的治疗和预防措施。

DESCRIPTION (provided by applicant): The long-term goal of the PI is to determine autonomic and vascular mechanisms engaged by hypoxic stress, and to explore their role in disease. In this project we will examine the effects of acute and intermittent hypoxia, two prevalent types of physiologic stress, on neurocirculatory control. Hypoxic stress is common in a variety of disease states and in smokers, and intermittent hypoxia is characteristic of obstructive sleep apnea. These conditions are marked by increased cardiovascular risk. Skeletal muscle hypoxia is also present during exercise, yet exercise training appears to improve vascular and autonomic reflex function. It has been shown that systemic and regional hypoxia (i.e., ischemia) exert their effects on the circulation via integrated but at times opposing influences on the autonomic nervous system and local metabolic control. Preliminary data from our laboratory suggest that in healthy humans intermittent hypoxia elicits sustained sympathetic activation and enhanced reflex responses to hypoxia. Because the antioxidant ascorbic acid attenuates the sympatho- excitatory effect of intermittent hypoxia, oxidative stress may be responsible. We also found that sympathetic reflex responses to hypoxia are enhanced in patients with sleep apnea and are normalized in part by continuous positive airway pressure therapy. However, despite increased sympathetic vasoconstrictor nerve traffic and enhanced chemoreflex activation, the vasodilation induced by acute hypoxia is preserved in patients with sleep apnea. Collectively, these findings support the central hypothesis that intermittent hypoxia alters sympathetic activity and reflex function, and evokes vascular adaptations, possibly via oxidative stress. The specific aims of this proposal are to determine whether: (1) experimental intermittent hypoxia or nocturnal intermittent hypoxia in patients with sleep apnea alters sympathetic reflex function that can be restored by antioxidant interventions (administration of ascorbic acid, exercise training); (2) skeletal muscle vascular adaptations to intermittent hypoxic stress are in part due to an enhanced role of endothelial vasodilator systems such as endothelium-derived hyperpolarizing factor (EDHF); and, (3) cigarette smoking alters neurocirculatory control that can be restored in part by antioxidant interventions. The proposed studies expand the scope of our prior work on neurocirculatory regulation during hypoxia and will provide new insight into the mechanisms that link intermittent hypoxia to adverse cardiovascular outcomes. PUBLIC HEALTH RELEVANCE: This research examines mechanisms that govern the control of peripheral blood flow during exposure to physiological stress associated with low oxygen supply. These mechanisms appear to be altered in important ways in highly common conditions such as obstructive sleep apnea {and in smokers.} New insight into these processes will help us better understand whether and how these mechanisms contribute to disease and will allow us to design better therapies and preventive measures.