Aging, Obstructive Sleep Apnea, and Impaired Peripheral Vascular Control During S

描述（由申请人提供）：人类外周血管内皮功能随着年龄的增长而逐渐下降，阻塞性睡眠呼吸暂停（OSA）患者的内皮功能进一步受损，增加了动脉粥样硬化和缺血性血管疾病的风险。除了维持血管健康的作用外，内皮在调节局部血管张力方面也起着重要作用。此外，交感肾上腺系统是血管张力的关键调节器，特别是在人类应激条件下。我们的初步数据表明，健康衰老与急性动脉血氧含量减少（缺氧）期间外周血管控制受损有关，这是一种生理和病理生理应激，可引起交感肾上腺活性反射性增加，以及局部内皮源性血管活性因子的合成。老年OSA患者经历频繁和反复的全身性缺氧，心血管疾病发病率和死亡率的风险升高。因此，本研究项目的总体目标是确定老年健康受试者和老年中度OSA患者缺氧应激时血管张力的综合交感肾上腺和局部内皮依赖因子。我们的一般工作假设是，交感肾上腺和内皮依赖控制血管张力的平衡发生改变，导致老年人外周血管舒张反应严重受损，而这种损害在老年OSA患者中更为严重。为了验证我们的假设，我们将解决以下具体目标：(1)我们将确定老年健康成人和老年中度OSA患者对分级全身性缺氧的交感肾上腺和周围血管反应；(2)我们将确定局部阻断-肾上腺素能血管收缩和-肾上腺素能介导的血管舒张是否会降低周围血管对分级全身缺氧反应的年龄和疾病组差异；(3)我们将确定外周血管舒张剂对全身缺氧的反应受损是否是由于年龄和疾病相关的内皮源性一氧化氮和前列腺素对这种反应的局部贡献减少，以及通过抗坏血酸输注内皮依赖性血管舒张的急性改善是否增强了老年健康和老年OSA患者局部缺氧诱导的血管舒张；(4)我们将确定内皮素-1介导的血管收缩增强是否会限制老年健康成人的缺氧血管舒张，并进一步限制老年OSA患者的这种反应。为了实现这些目标所采用的方法是最先进的，包括直接记录交感神经活动和局部（动脉内）给药各种研究药物，以确定这种年龄和疾病相关损伤的机制。这些研究结果将为老年健康和患病成人缺氧时外周血管张力的综合控制提供新的见解，并可能对了解相关患者群体（如充血性心力衰竭、缺血性血管疾病）的血管功能具有重要的临床意义。

DESCRIPTION (provided by applicant): Peripheral vascular endothelial function declines progressively with advancing age in humans, and is further impaired in patients with obstructive sleep apnea (OSA), increasing the risk for atherosclerotic and ischemic vascular disease. In addition to its role in maintaining vascular health, the endothelium plays an important role in the regulation of local vascular tone. Further, the sympathoadrenal system is a key regulator of vascular tone, particularly during stress conditions in humans. Our preliminary data indicates that healthy aging is associated with impaired peripheral vascular control during acute reductions in arterial oxygen content (hypoxia), a physiological and pathophysiological stress that evokes reflex increases in sympathoadrenal activity as well as the synthesis of local endothelium-derived vasoactive factors. Older OSA patients experience frequent and recurrent systemic hypoxia and are at elevated risk for cardiovascular morbidity and mortality. Thus, the overall goal of this research program is to determine the integrative sympathoadrenal and local endothelium-dependent contributors to vascular tone during hypoxic stress in older healthy subjects and older moderate OSA patients. Our general working hypothesis is that there is an alteration in the balance of sympathoadrenal and endothelium-dependent control of vascular tone which leads to a severely impaired peripheral vasodilatory response in older humans, and that this impairment is even greater in older OSA patients. To test our hypothesis we will address the following specific aims: (1) we will determine the sympathoadrenal and peripheral vascular responses to graded systemic hypoxia in older healthy adults and older moderate OSA patients; (2) we will determine whether local blockade of -adrenergic vasoconstriction and -adrenergic mediated vasodilation reduces the age- and disease-group differences in peripheral vascular responses to graded systemic hypoxia; (3) we will determine whether the impaired peripheral vasodilator responses to systemic hypoxia is due to age- and disease-related reductions in the local contribution of endothelium-derived nitric oxide and prostaglandins to this response, and whether acute improvements in endothelium-dependent vasodilation via ascorbic acid infusion augments local hypoxia- induced vasodilation in older healthy and older OSA humans; and (4) we will determine whether augmented endothelin-1 mediated vasoconstriction limits hypoxic vasodilation in older healthy adults and further limits this response in older OSA patients. The methods employed to address these aims are state-of-the-art and involve direct recordings of sympathetic neural activity and local (intra-arterial) administration of various study drugs to determine the mechanisms underlying this age- and disease-related impairment. The findings from the proposed studies will provide novel insight into the integrative control of peripheral vascular tone during hypoxia in older healthy and diseased adults and could have significant clinical implications for understanding vascular function in related patient populations (e.g., congestive heart failure, ischemic vascular disease). PUBLIC HEALTH RELEVANCE: Older healthy adults and patients with obstructive sleep apnea are at elevated risk for the development of cardiovascular disease. The studies in this application are designed to understand how impairments in the control of blood vessel function might contribute to a reduced ability of older healthy adults and sleep apnea patients to respond to conditions in which not enough blood and oxygen are being delivered to specific tissues, and could provide ideas on how to eventually improve cardiovascular health of older healthy and diseased adults.