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) 81mg daily, ASA 325mg daily, celecoxib 200mg twice daily or 400mg ibuprofen four times daily, each administered for 5 to 7days. On the last day of study drug therapy, subjects received a single dose of 40mg 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 81mg 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 325mg group (7.2±0.8 vs 3.3±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 325mg 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 (81mg daily) does not have such inhibitory effects.