Division of Cardiology, Mount Sinai and University Health Network Hospitals and Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada.
J Am Coll Cardiol. 2010 Mar 9;55(10):1002-6. doi: 10.1016/j.jacc.2009.11.046.
The purpose of this study was to determine whether single-dose rosuvastatin (40 mg) protects against ischemia and reperfusion (IR)-induced endothelial dysfunction in humans and whether this effect is cyclooxygenase (COX)-2 dependent.
Animal studies have demonstrated that rosuvastatin can limit damage and improve recovery after IR.
In a double-blind, parallel design, 20 volunteers were randomized to a single dose of oral rosuvastatin (40 mg) or placebo. Twenty-four hours later, endothelium-dependent, flow-mediated dilation (FMD) of the radial artery was measured before and after IR (15 min of upper arm ischemia followed by 15 min of reperfusion). In a separate protocol, 18 volunteers received the COX-2 inhibitor celecoxib (200 mg orally twice daily) for 5 days. On day 4, subjects were randomized to single-dose rosuvastatin (40 mg) or placebo and 24 h later underwent the same protocol as described.
Pre-IR FMD was similar between groups (p = NS). IR significantly blunted FMD in the placebo group (FMD pre-IR: 6.4 +/- 1.4%; FMD post-IR: 1.1 +/- 3.8%, [p = 0.002]). Rosuvastatin prevented this impairment (FMD pre-IR: 7.5 +/- 3.1%; FMD post-IR: 6.2 +/- 3.9%, [p = NS] vs. rosuvastatin pre-IR, [p = 0.03] vs. placebo). Pre-treatment with celecoxib completely abolished rosuvastatin's protective effect (FMD pre-IR: 8.0 +/- 2.2%; FMD post-IR: 1.4 +/- 2.0%, [p < 0.001] compared with pre-IR, [p = NS] vs. placebo, [p = 0.002] vs. rosuvastatin alone).
Rosuvastatin pharmacologically prevents the development of IR-induced conduit artery endothelial dysfunction. This beneficial effect of rosuvastatin is mediated by a COX-2-dependent mechanism, evidence that may also provide potential mechanistic insight into the reported cardiotoxic effects of COX-2 inhibitors.
本研究旨在确定单次剂量的瑞舒伐他汀（40 毫克）是否可预防人类缺血再灌注（IR）引起的内皮功能障碍，以及这种作用是否依赖环氧化酶（COX）-2。
动物研究表明，瑞舒伐他汀可限制 IR 后的损伤并改善恢复。
在一项双盲、平行设计中，将 20 名志愿者随机分为单次口服瑞舒伐他汀（40 毫克）或安慰剂组。24 小时后，在 IR（上臂缺血 15 分钟，再灌注 15 分钟）前后测量桡动脉内皮依赖性、血流介导的扩张（FMD）。在另一项方案中，18 名志愿者接受 COX-2 抑制剂塞来昔布（每日 2 次，每次 200 毫克口服）治疗 5 天。第 4 天，受试者随机分为单次剂量瑞舒伐他汀（40 毫克）或安慰剂组，24 小时后进行相同的方案。
IR 前 FMD 在两组间相似（p = NS）。安慰剂组的 IR 显著减弱了 FMD（IR 前 FMD：6.4 +/- 1.4%；IR 后 FMD：1.1 +/- 3.8%，p = 0.002）。瑞舒伐他汀预防了这种损害（IR 前 FMD：7.5 +/- 3.1%；IR 后 FMD：6.2 +/- 3.9%，p = NS 与瑞舒伐他汀前，p = 0.03 与安慰剂）。预先给予塞来昔布完全消除了瑞舒伐他汀的保护作用（IR 前 FMD：8.0 +/- 2.2%；IR 后 FMD：1.4 +/- 2.0%，与 IR 前相比，p < 0.001，与安慰剂相比，p = NS，与单独使用瑞舒伐他汀相比，p = 0.002）。
瑞舒伐他汀通过 COX-2 依赖性机制在药理学上预防了 IR 引起的大血管内皮功能障碍的发生。瑞舒伐他汀的这种有益作用可能提供了对 COX-2 抑制剂报告的心脏毒性作用的潜在机制见解。
