Pharmacologic Interventions for Cardiovascular Disease in Obstructive Sleep Apnea

描述(申请人提供)：阻塞性睡眠呼吸暂停(OSA)是一种相对常见的情况，导致夜间间歇性低氧，已成为高血压的风险因素；然而，其潜在机制尚不完全清楚。目前的概念是交感神经系统过度活动和血管内皮功能障碍起着重要作用。这项拟议的研究将验证我们的假设，即OSA的间歇性低氧激活了颈动脉体肾素-血管紧张素系统(RAS)，导致NADPH氧化酶(NOX)和黄嘌呤氧化酶(XO)产生的超氧离子增加。颈动脉小体中过多的超氧化物反过来又加强了对交感神经流出和通风的化学反射控制。同时，阻力动脉RAS和XO的激活导致内皮依赖性血管扩张功能受损。我们进一步假设，在选定的受试者中，间歇性低氧的这两种后果都会通过增加呼吸控制系统的增益而加剧睡眠障碍呼吸的严重程度，从而导致呼吸不稳定。这项试验的目的是将我们之前在大鼠身上的机制发现转化为药物策略，以预防或逆转颈动脉化学反射超敏反应，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综合征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)确定血管紧张素I型受体(AT1R)拮抗剂氯沙坦或XO抑制剂别嘌醇治疗是否使交感神经流出和通风的化学反射控制正常化，并改善局部血管调节和僵硬；以及2)确定这些干预措施是否降低了睡眠呼吸紊乱的严重程度和降低了昼夜血压。这项研究具有创新性，因为它可能确定用于CPAP的新靶点和干预措施，以减少交感神经过度活动，潜在地降低OSA严重程度，并将OSA患者的相关心血管异常降至最低。相关性(参见说明)：睡眠呼吸暂停是一种相对常见的情况，导致夜间暴露在间歇性低氧中，已成为高血压的危险因素。这项拟议的研究将在人类和大鼠身上调查抑制XO和血管紧张素II是否可以减少OSA对化学反射、交感神经和血管的负面影响。这些干预措施新颖、相关、不引人注目、相对便宜，可能会极大地改变阻塞性睡眠呼吸暂停综合征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.