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

衰老、阻塞性睡眠呼吸暂停和睡眠期间外周血管控制受损

• 批准号: 7900179
• 负责人: FRANK A DINENNO
• 金额: $ 35.84万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-15 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7900179
• 关键词: Acute; Address; Adrenergic Agents; Adult; Affect; Age; Aging; Arts; Ascorbic Acid; Biological Availability; Blood; Blood Vessels; Cardiovascular Diseases; Cardiovascular system; Cerebrovascular Disorders; Clinical; Complex; Congestive Heart Failure; Data; Development; Disease; Elderly; Endothelin-1; Endothelium; Equilibrium; Forearm; Functional disorder; Goals; Health; Human; Hypoxia; Impairment; Infusion procedures; Laboratories; Limb structure; Link; Mediating; Methods; Morbidity - disease rate; Myocardial Ischemia; Nervous system structure; Nitric Oxide; Obstructive Sleep Apnea; Oxygen; Patients; Peripheral; Pharmaceutical Preparations; Physiological; Play; Prevalence; Prostaglandins; Recurrence; Reflex action; Regional Blood Flow; Regulation; Research; Risk; Role; Series; Sleep Apnea Syndromes; Stress; System; Testing; Tissues; Vascular Diseases; Vasodilation; Vasodilator Agents; Work; adrenergic; base; cardiovascular risk factor; clinically significant; design; experience; healthy aging; improved; in vivo; innovation; insight; interest; mortality; novel; older patient; patient population; programs; public health relevance; relating to nervous system; response; vasoconstriction; young adult

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.

描述（由申请人提供）：周围血管内皮功能随着人类的年龄增长而逐渐下降，并且在阻塞性睡眠呼吸暂停（OSA）的患者中进一步受损，从而增加了动脉粥样硬化和缺血性血管疾病的风险。除了其在维持血管健康中的作用外，内皮在调节局部血管张力方面起着重要作用。此外，交感神经系统是血管张力的关键调节剂，尤其是在人类压力条件下。我们的初步数据表明，健康的衰老与动脉氧含量（缺氧）急性减少期间的外周血管控制受损有关，这是一种生理和病理生理胁迫，它唤起了交感神经活动的反射增加以及局部内层内膜源自源自源自源自的肾上腺素的合成。 OSA年龄较大的患者经常患有全身性缺氧，并且患心血管发病率和死亡率的风险升高。因此，该研究计划的总体目标是确定在较老的健康受试者和较老的中度OSA患者中，在低氧应激期间，综合性交感神经和局部内皮依赖性依赖于血管张力的贡献者。我们的一般性工作假设是，在老年人中，交感神经和内皮依赖性控制血管张力的控制的平衡发生了变化，这会导致严重受损的外周血管舒张反应，而在老年OSA患者中，这种损害甚至更大。为了检验我们的假设，我们将解决以下具体目的：（1）我们将确定老年健康成年人和年龄较大的中度OSA患者对分级全身性缺氧的副作用和周围血管反应； （2）我们将确定 - 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减少外周血管对分级缺氧的年龄和疾病组差异； (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人类（4）我们将确定增强的内皮素-1介导的血管收缩是否会限制老年人健康成年人的低氧血管舒张，并进一步限制了OSA老年患者的这种反应。解决这些目标的方法是最新的，涉及各种研究药物的交感神经活动和局部（动脉内）给药的直接记录，以确定与年龄和疾病相关障碍的机制。拟议研究的发现将提供对老年健康和患病成年人缺氧期间周围血管张力综合控制的新见解，并且可能对了解相关患者人群的血管功能具有重要的临床意义（例如，充血性心力衰竭，缺血性血管疾病）。 公共卫生相关性：年龄较大的健康成年人和阻塞性睡眠呼吸暂停患者的心血管疾病发展风险较高。该应用中的研究旨在了解控制血管功能的损害如何有助于降低老年健康的成年人的能力和睡眠呼吸暂停患者，以应对没有足够的血液和氧气供应到特定组织的状况，并可以提供有关如何最终改善老年健康和患病的成年人的心血管健康的想法。