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）是一种相对常见的导致夜间间歇性缺氧的疾病，已成为高血压的危险因素；然而，其潜在的机制还不完全清楚。目前的概念是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）产生超氧化物离子增加。颈动脉体中过量的超氧化物反过来又增强了交感神经流出和通气的化学反射控制。同时，抵抗动脉中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，在选定的受试者中，间歇性缺氧的这两种后果通过增加呼吸控制系统增益导致通气不稳定，加重了睡眠呼吸障碍的严重程度。本试验的目的是将我们之前在大鼠身上的机制发现转化为预防或逆转颈动脉化学反射超敏感的药理学策略，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OSA患者心血管疾病的病理生理机制，并确定将相关并发症、发病率和死亡率降至最低的干预措施。该应用的具体目的是：1)确定氯沙坦（一种血管紧张素I型受体（AT1R）拮抗剂）或别嘌呤醇（一种XO抑制剂）治疗是否能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)确定这些干预措施是否降低了睡眠呼吸障碍的严重程度和降低了日血压。这项研究具有创新性，因为它可能确定新的靶点和干预措施用于CPAP，以减少交感神经过度活动，潜在地降低OSA严重程度，并最大限度地减少OSA患者相关的心血管异常。相关性（见说明）：睡眠呼吸暂停是一种相对常见的导致夜间间歇性缺氧的疾病，已成为高血压的危险因素。本研究将在人类和大鼠中研究抑制XO和血管紧张素II是否能降低OSA的负性化学反射、交感和血管效应。这些干预措施新颖、相关、不显眼、相对便宜，可能彻底改变阻塞性睡眠呼吸暂停患者心血管疾病的治疗和预防。

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.