Hypercholesterolemia blunts NO donor-induced late preconditioning against myocardial infarction in conscious rabbits
Hypercholesterolemia blunts NO donor-induced late preconditioning against myocardial infarction in conscious rabbits
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DOI：
10.1007/s00395-004-0485-4
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发表时间：
2004-11-01
影响因子：
9.5
通讯作者：
Bolli, R
中科院分区：
文献类型：
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作者：
Tang, XL;Stein, AB;Bolli, R
尽管NO供体已被证明可以对健康兔子的心肌缺血/再灌注损伤进行后期预处理（PC），但尚不清楚并发的全身性疾病是否会影响NO供体诱导的心脏保护作用。由于许多冠状动脉疾病患者患有高胆固醇血症 (HC)，我们研究了这种情况对 NO 供体二亚乙基三胺/一氧化氮 (DETA/NO) 诱导的晚期 PC 的影响。长期使用仪器的兔子被喂食正常饮食（正常胆固醇血症，NC）或富含 1% 胆固醇（HC）的饮食 4 周。在用胆固醇饮食喂养的兔子中，血浆胆固醇水平显着升高，动脉压对内皮依赖性血管舒张剂缓激肽的反应减弱。清醒的兔子接受 30 分钟的冠状动脉闭塞，然后进行 3 天的再灌注。当 NC 兔在 30 分钟闭塞前 24 小时接受 DETA/NO（0.1 mg/kg，静脉注射 x 4，第 II 组，n = 7）预处理时，梗塞面积减少了 52%（NC 对照中危险区域的面积为 29.7 +/- 3.4% 对比 62.4 +/- 4.0% [第 I 组，n = 5]，P < 0.05），表明DETA/NO 诱导 PC 对抗心肌梗塞的晚期效应。相比之下，当 HC 兔接受相同剂量的 DETA/NO 预处理时（IV 组，n = 6），梗塞面积并未显着减小（HC 中危险区域的梗死面积为 61.0 +/- 5.7% 对比 68.1 +/- 4.5% [III 组，n = 5]，P = NS），表明 DETA/NO 未能诱导延迟的心脏保护作用。这些数据首次证明，HC 会减弱 NO 供体诱导的晚期 PC 对抗心肌梗塞的作用，这意味着 HC 对缺血诱导的和 NO 供体诱导的晚期 PC 的抑制作用是由触发这些适应的 NO 生成远端的生化途径破坏引起的。
Although NO donors have been shown to confer late preconditioning (PC) against myocardial ischemia/reperfusion injury in healthy rabbits, it is unknown whether concurrent systemic disorders affect NO donor-induced cardioprotection. Since many patients with coronary artery disease have hypercholesterolemia (HC), we examined the effect of this condition on late PC induced by the NO donor diethylenetriamine/nitric oxide (DETA/ NO). Chronically instrumented rabbits were fed a normal diet (normocholesterolemia, NC) or a diet enriched with 1% cholesterol (HC) for 4 weeks. Plasma cholesterol levels were significantly elevated and the arterial pressure response to the endothelium-dependent vasodilator bradykinin was blunted in cholesterol diet-fed rabbits. Conscious rabbits underwent a 30-minute coronary occlusion followed by 3 days of reperfusion. When NC rabbits were pretreated with DETA/NO (0.1 mg/kg, i. v. x 4, group II, n = 7) 24 hours before the 30-minute occlusion, infarct size was reduced by 52% (29.7 +/- 3.4% versus 62.4 +/- 4.0% of the region at risk in NC controls [group I, n = 5], P < 0.05), indicating that DETA/NO induced a late PC effect against myocardial infarction. In contrast, when HC rabbits were pretreated with the same dose of DETA/NO (group IV, n = 6), infarct size was not significantly reduced (61.0 +/- 5.7% versus 68.1 +/- 4.5% of the region at risk in HC [group III, n = 5], P = NS), suggesting that DETA/NO failed to induce a delayed cardioprotective effect. These data demonstrate, for the first time, that HC blunts NO donor-induced late PC against myocardial infarction, implying that the inhibitory effects of HC on ischemia-induced and NO donor-induced late PC are caused by disruption of biochemical pathways distal to the generation of NO that triggers these adaptations.