Aging, Sleep Apnea, & Vascular Control During Systemic Hypoxia

衰老、睡眠呼吸暂停、

• 批准号: 8625819
• 负责人: FRANK A DINENNO
• 金额: $ 34.58万
• 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 2015-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8625819
• 关键词: Acute; Address; Adrenergic Agents; Adult; Affect; Age; Aging; 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; 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; endothelial dysfunction; 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).

描述（由申请人提供）：随着人类年龄的增长，外周血管内皮功能逐渐下降，并且在患有阻塞性睡眠呼吸暂停（OSA）的患者中进一步受损，增加了动脉粥样硬化和缺血性血管疾病的风险。内皮细胞除了在维持血管健康方面发挥作用外，在调节局部血管张力方面也发挥着重要作用。此外，交感肾上腺系统是血管张力的关键调节器，特别是在人类处于应激状态时。我们的初步数据表明，健康老龄化与动脉氧含量急剧减少（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，会引起交感肾上腺活动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 患者经常经历反复的全身缺氧，心血管发病和死亡的风险较高。因此，该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，交感肾上腺和内皮依赖性血管张力控制的平衡发生了变化，导致老年人的外周血管舒张反应严重受损，并且这种损害在老年 OSA 患者中更为严重。为了检验我们的假设，我们将实现以下具体目标：（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系统性缺氧的反应； (2)我们将确定局部阻断β-肾上腺素能血管收缩和β-肾上腺素能介导的血管舒张是否可以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) 我们将确定对全身性缺氧的外周血管舒张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此反应的局部贡献减少所致，以及通过抗坏血酸输注对内皮依赖性血管舒张的急性改善是否会增强老年健康和老年 OSA 中局部缺氧诱导的血管舒张 人类； (4)我们将确定增强的内皮素-1介导的血管收缩是否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。用于实现这些目标的方法是最先进的，涉及直接记录交感神经活动和局部（动脉内）施用各种研究药物，以确定这种与年龄和疾病相关的损伤的机制。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，并且可能对了解相关患者群体（例如充血性心力衰竭、缺血性血管疾病）的血管功能具有重要的临床意义。

项目成果

Inhibition of Na+ /K+ -ATPase and KIR channels abolishes hypoxic hyperaemia in resting but not contracting skeletal muscle of humans.

Na /K -ATP 酶和 KIR 通道的抑制消除了人类骨骼肌静息但不收缩时的缺氧充血。

• DOI: 10.1113/jp275913
• 发表时间: 2018
• 期刊: The Journal of physiology
• 作者: Racine,MatthewL;Crecelius,AnneR;Luckasen,GaryJ;Larson,DennisG;Dinenno,FrankA
• 通讯作者: Dinenno,FrankA

Role of α-adrenergic vasoconstriction in regulating skeletal muscle blood flow and vascular conductance during forearm exercise in ageing humans.

α-肾上腺素能血管收缩在调节老年人前臂运动过程中骨骼肌血流和血管电导中的作用。

• DOI: 10.1113/jphysiol.2014.278358
• 发表时间: 2014
• 期刊: The Journal of physiology
• 作者: Richards,JenniferC;Luckasen,GaryJ;Larson,DennisG;Dinenno,FrankA
• 通讯作者: Dinenno,FrankA