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，并且在阻塞性睡眠呼吸暂停（OSA）患者中进一步受损，增加了动脉粥样硬化和缺血性血管疾病的风险。除了在维持血管健康方面的作用外，内皮在局部血管张力的调节中起重要作用。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，健康的老龄化与受损的外周血管控制在急性减少动脉氧含量（缺氧），生理和病理生理应激，引起反射增加交感肾上腺活性，以及本地内皮衍生的血管活性因子的合成。老年OSA患者经历频繁和反复的全身缺氧，并且心血管发病率和死亡率的风险升高。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OSA患者在缺氧应激期间血管张力的综合交感肾上腺和局部内皮依赖性贡献者。我们的一般工作假设是，有一个改变的平衡交感肾上腺和内皮依赖性控制血管紧张性，导致严重受损的外周血管舒张反应，在老年人，这种损害甚至更大的阻塞性睡眠呼吸暂停综合征患者。为了验证我们的假设，我们将致力于以下具体目标：（1）我们将确定老年健康成人和老年中度OSA患者的交感肾上腺和外周血管对分级全身缺氧的反应;（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减少外周血管对分级全身缺氧反应的年龄和疾病组差异;（3）我们将确定对全身缺氧的受损外周血管舒张反应是否是由于内皮衍生的一氧化氮和胡萝卜素对该反应的局部贡献的年龄和疾病相关的减少，以及通过抗坏血酸输注的内皮依赖性血管舒张的急性改善是否增强了老年健康人和老年OSA人中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限制了老年健康成人的缺氧性血管舒张，并进一步限制了老年OSA患者的这种反应。用于解决这些目标的方法是最先进的，涉及交感神经活动的直接记录和各种研究药物的局部（动脉内）给药，以确定这种年龄和疾病相关损害的机制。拟议研究的结果将为老年健康和患病成人缺氧期间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人群（例如，充血性心力衰竭、缺血性血管疾病）。 公共卫生相关性：老年健康成人和阻塞性睡眠呼吸暂停患者患心血管疾病的风险增加。本申请中的研究旨在了解血管功能控制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中没有足够血液和氧气的条件做出反应的能力降低，并可以提供有关如何最终改善老年健康和患病成年人心血管健康的想法。

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.