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

描述(申请人提供)：人类外周血管内皮细胞功能随着年龄的增长而逐渐下降，在阻塞性睡眠呼吸暂停(OSA)患者中进一步受损，增加动脉粥样硬化和缺血性血管疾病的风险。除了在维持血管健康方面发挥作用外，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，特别是在人类的应激条件下。我们的初步数据表明，健康的衰老与动脉含氧量急剧减少(缺氧)时外周血管控制受损有关，缺氧是一种生理和病理生理学应激，可引起交感肾上腺活动的反射性增加以及局部内皮源性血管活性因子的合成。老年阻塞性睡眠呼吸暂停患者经历频繁和反复的全身性低氧，心血管发病率和死亡率的风险较高。因此，本研究计划的总体目标是确定老年健康受试者和老年中度阻塞性睡眠呼吸暂停患者在低氧应激期间对血管张力的综合交感-肾上腺和局部内皮依赖的贡献因素。我们的一般工作假设是，交感-肾上腺和内皮依赖的血管张力控制的平衡发生改变，导致老年人的外周血管扩张反应严重受损，这种损害在老年OSA患者中甚至更严重。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患者对分级全身缺氧的交感肾上腺和外周血管反应；(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扩张是否减少了外周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扩张剂对全身低氧的反应是否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一反应的局部贡献的减少所致，以及通过抗坏血酸输注内皮依赖性血管扩张的急剧改善是否增强了老年健康和老年OSA患者的局部低氧诱导的血管扩张；以及(4)我们将确定增强的内皮素-1介导的血管收缩是否限制了老年健康成年人的缺氧性血管扩张，并进一步限制了老年OSA患者的这种反应。用于解决这些目的的方法是最先进的，包括直接记录交感神经活动和局部(动脉内)给药，以确定这种与年龄和疾病相关的损害的机制。这些研究结果将为老年人、健康人和疾病患者在低氧期间对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。 公共卫生相关性：老年健康成年人和阻塞性睡眠呼吸暂停患者患心血管疾病的风险较高。本申请中的研究旨在了解血管功能控制方面的障碍如何导致老年健康成年人和睡眠呼吸暂停患者对特定组织输送的血液和氧气不足的情况做出反应的能力下降，并可能为如何最终改善老年健康和患病成年人的心血管健康提供建议。

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.