Intermittent Hypoxia: A Model to Study Circulatory Control in Humans

间歇性缺氧：研究人类循环控制的模型

• 批准号: 7986094
• 负责人: URS A LEUENBERGER
• 金额: $ 15.45万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7986094
• 关键词: Acute; Adenosine; Antioxidants; Arachidonic Acids; Ascorbic Acid; Attenuated; Autonomic nervous system; Biological Availability; Blood Circulation; Blood Vessels; Blood flow; Cardiovascular system; Cessation of life; Characteristics; Continuous Positive Airway Pressure; Cytochrome P450; Data; Dilator; Disease; Endothelium; Exercise; Exposure to; Functional disorder; Goals; Health; Human; Hypoxia; Intervention; Ischemia; Laboratories; Lead; Link; Measures; Metabolic Control; Modeling; Nerve; Nitric Oxide; Obstructive Sleep Apnea; Outcome; Oxidative Stress; Oxygen; Patients; Physiological; Play; Prevention; Preventive; Process; Reflex action; Reflex control; Regulation; Reporting; Research; Role; Skeletal Muscle; Sleep Apnea Syndromes; Smoker; Stress; Sympathetic Nervous System; System; Time; Training; Vasoconstrictor Agents; Vasodilation; Vasodilator Agents; Work; autonomic reflex; base; cardiovascular risk factor; cigarette smoking; design; improved; insight; peripheral blood; premature; public health relevance; response; smoking cessation; therapeutic development; trafficking; vascular bed

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.

描述（由申请人提供）： PI的长期目标是确定低氧应激所带来的自主和血管机制，并探索其在疾病中的作用。在这个项目中，我们将研究急性和间歇性缺氧的影响，两种普遍的生理应激类型对神经循环控制的影响。低氧应激在多种疾病状态和吸烟者中很常见，间歇性缺氧是阻塞性睡眠呼吸暂停的特征。这些疾病的特征是心血管风险增加。运动过程中还存在骨骼肌缺氧，但运动训练似乎可以改善血管和自主反射功能。已经表明，系统性和区域缺氧（即缺血）通过综合但有时会反对对自主神经系统和局部代谢控制的影响对循环产生影响。我们实验室的初步数据表明，在健康的人类中，间歇性缺氧引起持续的交感神经激活，并增强了对缺氧的反射反应。由于抗氧化剂抗坏血酸会减轻间歇性缺氧的互惠兴奋作用，因此氧化应激可能是造成的。我们还发现，睡眠呼吸暂停患者对缺氧的交感反射反应得到了增强，并且部分通过持续阳性气道压力疗法进行了标准化。然而，尽管交感神经交神经流量增加并增强了化学反射激活，但急性缺氧诱导的血管舒张仍保留在睡眠呼吸暂停患者中。总的来说，这些发现支持了一个中心假设，即间歇性缺氧会改变交感神经和反射功能，并可能通过氧化应激唤起血管适应。该提案的具体目的是确定：（1）睡眠呼吸暂停患者的实验性间歇性缺氧或夜间间歇性缺氧是否可以通过抗氧化剂干预措施恢复交感反射功能（抗虫酸性的施抗酸酸，运动训练，运动训练）； （2）骨骼肌血管对间歇性低氧应激的适应性部分是由于内皮血管舒张系统（例如内皮衍生的超极化因子（EDHF））的作用增强所致； （3）吸烟会改变神经循环控制，可以部分通过抗氧化剂干预来恢复。拟议的研究扩大了我们先前在缺氧期间神经循环调节的工作的范围，并将为将间歇性缺氧与不良心血管结局联系起来的机制提供新的见解。 公共卫生相关性： 这项研究检查了在暴露于与低氧供应相关的生理压力期间控制外周血流量的机制。这些机制似乎在高度普遍的条件下以重要的方式改变了，例如阻塞性睡眠呼吸暂停（和吸烟者中）。}对这些过程的新见解将有助于我们更好地理解这些机制是否以及如何对疾病有效，并使我们能够设计出更好的治疗方法和预防措施。