Division of Cardiology, Mount Sinai and University Health Network Hospitals, Toronto, Canada.
Am J Physiol Heart Circ Physiol. 2012 Jan 1;302(1):H153-8. doi: 10.1152/ajpheart.00083.2011. Epub 2011 Oct 14.
Studies have demonstrated that the acute administration of 3-hydroxy-3 methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors has protective effects in the setting of ischemia-reperfusion (IR). Previously, we demonstrated that a single dose of rosuvastatin prevented IR-induced endothelial dysfunction in humans through a cyclooxygenase-2-dependent mechanism. Whether the chronic administration of HMG-CoA reductase inhibitors provides similar protection remains controversial and is unknown in humans. Eighteen male volunteers were randomized to receive a single dose of rosuvastatin (20 mg) or placebo. Twenty-four hours later, endothelium-dependent, radial artery flow-mediated dilation (FMD) was measured before and after IR (15 min of upper arm ischemia followed by 15 min of reperfusion). In a separate protocol, 30 healthy volunteers were randomized in a double-blind fashion to receive oral rosuvastatin (20 mg/day) and placebo, rosuvastatin, and celecoxib (100 mg bid) or placebo alone, all for 21 days. Twenty-four hours after the final administration of study medication, FMD was measured before and after IR. Pre-IR FMD was similar between groups in both protocols. In the acute administration protocol, rosuvastatin significantly prevented the blunting of FMD associated with IR (FMD pre-IR: 8.4 ± 1.3%; post-IR: 6.2 ± 1.3%; P = 0.01 ANOVA, treatment group interaction). In the daily administration protocol, IR significantly blunted FMD in the placebo group (FMD pre-IR: 7.5 ± 0.9%; post-IR: 3.3 ± 0.7%; P < 0.001). Chronic treatment with rosuvastatin did not modify this ischemic injury (FMD pre-IR: 6.9 ± 0.4%; post-IR: 1.6 ± 1.0%; P < 0.001; P = NS ANOVA, treatment group interaction). Similarly, FMD responses post-IR in volunteers receiving rosuvastatin and celecoxib did not significantly differ from placebo (FMD pre-IR: 8.3 ± 0.9%; post-IR: 2.1 ± 0.8%; P < 0.001; P = NS ANOVA, treatment group interaction). In contrast to acute administration, chronic rosuvastatin does not prevent the development of IR-induced endothelial dysfunction in normal humans.
研究表明，3-羟基-3 甲基戊二酰基辅酶 A（HMG-CoA）还原酶抑制剂的急性给药在缺血再灌注（IR）情况下具有保护作用。此前，我们证明单次剂量的瑞舒伐他汀通过环氧化酶-2 依赖性机制预防了 IR 引起的人类内皮功能障碍。HMG-CoA 还原酶抑制剂的慢性给药是否提供类似的保护作用仍存在争议，在人类中尚不清楚。18 名男性志愿者随机接受单次瑞舒伐他汀（20mg）或安慰剂治疗。24 小时后，在 IR（上臂缺血 15 分钟后再灌注 15 分钟）前后测量内皮依赖性、桡动脉血流介导的扩张（FMD）。在另一个方案中，30 名健康志愿者以双盲方式随机分为口服瑞舒伐他汀（20mg/天）和安慰剂、瑞舒伐他汀和塞来昔布（100mg bid）或单独安慰剂组，所有组均接受 21 天治疗。在最后一次研究药物给药后 24 小时，测量 IR 前后的 FMD。两个方案中，急性给药方案中，瑞舒伐他汀显著预防了与 IR 相关的 FMD 减弱（FMD 预-IR：8.4 ± 1.3%；后-IR：6.2 ± 1.3%；P = 0.01 ANOVA，治疗组间交互作用）。在每日给药方案中，安慰剂组的 IR 显著减弱了 FMD（FMD 预-IR：7.5 ± 0.9%；后-IR：3.3 ± 0.7%；P < 0.001）。瑞舒伐他汀的慢性治疗并未改变这种缺血性损伤（FMD 预-IR：6.9 ± 0.4%；后-IR：1.6 ± 1.0%；P < 0.001；P = NS ANOVA，治疗组间交互作用）。同样，接受瑞舒伐他汀和塞来昔布的志愿者的 IR 后 FMD 反应与安慰剂相比无显著差异（FMD 预-IR：8.3 ± 0.9%；后-IR：2.1 ± 0.8%；P < 0.001；P = NS ANOVA，治疗组间交互作用）。与急性给药不同，慢性瑞舒伐他汀不能预防正常人类 IR 诱导的内皮功能障碍的发展。
