Cyclooxygenase inhibition and rosuvastatin-induced vascular protection in the setting of ischemia-reperfusion: A human in vivo study

The 3-hydroxy-3-methylglutaryl coenzyme A (HMG Co-A) reductase inhibitors have preconditioning effects involving up-regulation of cyclooxygenase (COX)-2. We investigated the effect of selective and non-selective COX inhibition on rosuvastatin-mediated protection against ischemia-reperfusion (IR)-induced endothelial dysfunction in the human forearm. Healthy volunteers (n = 66) were allocated to placebo, acetylsalicylic acid (ASA) 81 mg daily, ASA 325 mg daily, celecoxib 200 mg twice daily or 400 mg ibuprofen four times daily, each administered for 5 to 7 days. On the last day of study drug therapy, subjects received a single dose of 40 mg rosuvastatin. Twenty-four hours later flow-mediated dilation (FMD) of the radial artery was evaluated before and after IR. In the placebo group, FMD was similar before and after IR (8.1 +/- 1.0 vs 7.2 +/- 0.8%; P = NS) indicating a significant protective effect of rosuvastatin. There was also no effect of IR on FMD in the ASA 81 mg group (6.7 +/- 0.6 vs 6.1 +/- 0.7%; P = NS). In contrast, following IR there was a significant decrease in FMD in the ASA 325 mg group (7.2 +/- 0.8 vs 33 +/- 0.7%, P < 0.001), the celecoxib group (7.3 +/- 1.5 vs 2.6 +/- 1.5%, P < 0.01) as well as the ibuprofen group (6.8 +/- 0.7 vs 2.6 +/- 0.8%; P < 0.01). Therefore, nonselective COX inhibition with ASA 325 mg and ibuprofen completely inhibit the protective effects of rosuvastatin in the setting of IR injury, as does therapy with the specific COX-2 antagonist celecoxib. In contrast, therapy with low dose ASA (81 mg daily) does not have such inhibitory effects. (C) 2015 Elsevier Inc All rights reserved.