UJF, Laboratoire HP2, Grenoble F-38000, France.
Exp Biol Med (Maywood). 2013 Feb;238(2):223-32. doi: 10.1177/1535370212473696. Epub 2013 Feb 12.
Chronic intermittent hypoxia (IH), a major component of obstructive sleep apnea (OSA), contributes to the high risk of cardiovascular morbidity. We have previously demonstrated that IH-induced oxidative stress is involved in the hypertension and in the hypersensitivity to myocardial infarction. However, the mechanisms underlying these cardiovascular alterations are still unclear, as well as the role of potential protective treatment. Atorvastatin has pleiotropic actions, including increasing nitric oxide (NO) bioavailability and reducing inflammation and oxidative damage. The aim of this study was to evaluate the beneficial effect of a two time course of this treatment against the deleterious cardiovascular consequences of IH. Rats were divided into two groups subjected to chronic IH or normoxic (N) exposure. IH consisted of repetitive one-minute cycles (with only 30 s of a 5% inspired O2 fraction) and was applied for eight hours during daytime, for 14 (simultaneous protocol) or 28 d (delayed protocol). Atorvastatin (10 mg/kg/ d) or its vehicle was administered during the 14 d simultaneous protocol or the last 14 d of the delayed protocol. For both protocols, systolic arterial pressure was significantly increased by 14 d IH exposure. Atorvastatin prevented this deleterious effect in the simultaneous protocol. Carotid artery compliance and endothelial function were significantly altered after 28 d but not after 14 d of IH exposure. Delayed atorvastatin administration preserved these vascular parameters. IH also increased hypersensitivity to myocardial infarction after 14 d exposure, and atorvastatin abolished this deleterious effect. IH also enhanced cardiac NADPH expression and decreased aortic superoxide dismutase activity after 14 d exposure. Atorvastatin significantly restored these activities. In conclusion, whereas IH rapidly increased blood pressure, myocardial infarction hypersensitivity and oxidative stress, compliance, endothelial function and the structural wall of the carotid artery were only altered after a longer IH exposure. Atorvastatin prevented all these deleterious cardiovascular effects, leading to a potentially novel pharmacological therapeutic strategy for OSA syndrome.
慢性间歇性低氧（IH）是阻塞性睡眠呼吸暂停（OSA）的主要组成部分，它增加了心血管疾病发病风险。我们之前已经证明，IH 引起的氧化应激与高血压和心肌梗死的高敏性有关。然而，这些心血管改变的机制尚不清楚，潜在的保护治疗作用也不清楚。阿托伐他汀具有多种作用，包括增加一氧化氮（NO）的生物利用度，减少炎症和氧化损伤。本研究旨在评估该治疗方法的两个疗程对 IH 引起的心血管不良后果的有益作用。将大鼠分为两组，分别接受慢性 IH 或常氧（N）暴露。IH 由重复的一分钟周期组成（仅 5%吸入 O2 分数持续 30 秒），在白天持续 8 小时，持续 14 天（同时方案）或 28 天（延迟方案）。阿托伐他汀（10 mg/kg/d）或其载体在同时方案的 14 天内或延迟方案的最后 14 天内给药。对于两个方案，14 天的 IH 暴露显著增加了收缩压。阿托伐他汀在同时方案中预防了这种有害作用。在 28 天而不是 14 天的 IH 暴露后，颈动脉顺应性和内皮功能显著改变。延迟阿托伐他汀给药可维持这些血管参数。IH 还增加了 14 天暴露后的心肌梗死高敏性，而阿托伐他汀消除了这种有害作用。IH 还增加了 14 天暴露后心脏 NADPH 的表达和主动脉超氧化物歧化酶的活性。阿托伐他汀显著恢复了这些活性。总之，尽管 IH 迅速增加了血压、心肌梗死高敏性和氧化应激，但颈动脉顺应性、内皮功能和结构壁仅在较长时间的 IH 暴露后才会改变。阿托伐他汀预防了所有这些有害的心血管作用，为 OSA 综合征提供了一种潜在的新的药物治疗策略。
