Pharmacologic Interventions for Cardiovascular Disease in Obstructive Sleep Apnea

描述（由申请人提供）：阻塞性睡眠呼吸暂停（OSA）是一种相对常见的疾病，导致夜间间歇性缺氧，已成为高血压的危险因素;然而，其潜在机制尚未完全了解。目前的观点认为交感神经系统过度活跃和血管内皮功能障碍起重要作用。本研究将验证我们的假设，即OSA间歇性缺氧激活颈动脉体中的肾素-血管紧张素系统（RAS），导致NADPH氧化酶（NOX）和黄嘌呤氧化酶（XO）产生超氧离子增加。过量的超氧化物在颈动脉体，反过来，增强化学反射控制交感神经流出和通气。同时，阻力动脉中RAS和XO的激活导致内皮依赖性血管舒张功能受损。我们进一步假设，这两个间歇性缺氧的后果恶化睡眠呼吸障碍的严重程度，在选定的科目，通过增加呼吸控制系统增益，导致呼吸不稳定。本试验的目的是将我们以前在大鼠中的机制发现转化为预防或逆转颈动脉化学反射超敏反应的药理学策略，从而改善OSA的心血管后果，如果我们的假设是正确的，甚至可能减轻睡眠呼吸障碍事件的严重程度。我们的长期目标是阐明阻塞性睡眠呼吸暂停患者心血管疾病的病理生理机制，并确定干预措施，以尽量减少相关的并发症，发病率和死亡率。本申请的具体目的是：1）确定氯沙坦（一种血管紧张素I型受体（AT 1 R）拮抗剂）或别嘌呤醇（一种XO抑制剂）治疗是否使交感神经流出和通气的化学反射控制正常化，并改善局部血管调节和僵硬度; 2）确定这些干预是否降低睡眠呼吸障碍的严重程度和降低昼夜血压。这项研究具有创新性，因为它可以确定与CPAP一起使用的新靶点和干预措施，这些靶点和干预措施可以减少交感神经过度活跃，可能降低OSA的严重程度，并最大限度地减少OSA患者的相关心血管异常。相关性（参见说明）：睡眠呼吸暂停是一种相对常见的疾病，导致夜间间歇性缺氧，已成为高血压的危险因素。这项研究将在人类和大鼠中研究抑制XO和血管紧张素II是否可以减少OSA的负化学反射，交感神经和血管效应。这些干预措施是新颖的，相关的，不引人注目的，相对便宜的，并可能会彻底改变OSA心血管疾病的治疗和可能的预防。

DESCRIPTION (provided by applicant): Obstructive sleep apnea (OSA), a relatively common condition that causes nightly exposure to intermittent hypoxia, has emerged as a risk factor for hypertension; however, the underlying mechanisms are incompletely understood. The current concept is that sympathetic nervous system overactivity and vascular endothelial dysfunction play important roles. The proposed research will test our hypothesis that the intermittent hypoxia of OSA activates the renin-angiotensin-system (RAS) in the carotid body, resulting in increased production of superoxide ion by NADPH oxidase (NOX) and xanthine oxidase (XO). Excess superoxide in the carotid body, in turn, augments chemoreflex control of sympathetic outflow and ventilation. At the same time, activation of RAS and XO in resistance arteries leads to impairment in endothelium- dependent vasodilation. We further hypothesize that both of these consequences of intermittent hypoxia worsen the severity of sleep disordered breathing, in selected subjects, by increasing respiratory control system gains leading to ventilatory instability. The objective of this trial is to translate our previous mechanistic findings in rats into pharmacologic strategies for preventing or reversing carotid chemoreflex hypersensitivity, thereby ameliorating the cardiovascular consequences of OSA and, if our hypothesis is correct, perhaps even lessening the severity of sleep disordered breathing events. Our long-range goal is to elucidate pathophysiologic mechanisms for cardiovascular disease in patients with OSA and identify interventions that minimize associated complications, morbidity and mortality. The specific aims of this application are: 1) Determine if treatment with losartan, an angiotensin type I receptor (AT1R) antagonist, or allopurinol, a XO inhibitor, normalize chemoreflex control of sympathetic outflow and ventilation and improve local vascular regulation and stiffness; and 2) Determine if these Interventions reduce the severity of sleep disordered breathing and lower diurnal blood pressure. This research is innovative because it may identify novel targets and interventions to be used with CPAP that reduce sympathetic overactivity, potentially reduce OSA severity, and minimize associated cardiovascular abnormalities in patients with OSA. RELEVANCE (See instructions): Sleep apnea, a relatively common condition that results in nightly exposure to intermittent hypoxia, has emerged as a risk factor for hypertension. The proposed research will investigate, in humans and rats, whether inhibition of XO and angiotensin II can decrease negative chemoreflex, sympathetic and vascular effects of OSA. These interventions are novel, relevant, unobtrusive, relatively inexpensive, and could drasticallv change the treatment and possible prevention of cardiovascular disease in OSA.