Abstract

BACKGROUND: Animal studies have demonstrated that rosuvastatin (RSV) can limit the damage induced by ischemia-reperfusion (IR) in the cardiac, cerebral and mesenteric circulation. It remains unknown whether this beneficial effect of RSV can also be demonstrated in humans, and by what mechanism this may occur. METHODS AND RESULTS: Twenty healthy volunteers were randomized to a single dose of oral RSV (40 mg) or placebo. 24 hours later, endothelium-dependent, flow-mediated dilation (FMD) of the radial artery was measured before and after IR (15 minutes of ischemia at the level of the brachial artery followed by 15 minutes of reperfusion). There was no difference in pre-IR FMD between groups (P=NS). In the placebo group, FMD was significantly blunted after IR (FMD pre-IR: 6.4+/−0.4%, post-IR: 1.1+/−1.2%, P<0.01). This impairment in FMD with IR was prevented with RSV (Table ; FMD before IR: 7.5+/−1.0%; after IR: 6.2+/−1.2%, P =NS compared with RSV before IR; P<0.05 vs. placebo). In a separate protocol, 18 healthy volunteers received the cyclooxygenase-2 (COX-2) inhibitor celecoxib (200mg BID p.o.) for 5 days. On day 4, subjects were randomized to a single dose of RSV (40mg) or placebo and 24 hours later underwent the same protocol as above. Pretreatment with celecoxib completely abolished RSV’s protective effect (Table ; FMD pre-IR: 8.0±2.2%, post-IR: 1.4±2.0%, P<0.001 before versus after IR, P=NS vs. placebo). IR did not modify resting arterial diameter, baseline blood flow or peak hyperemic blood flow during FMD in either protocol (Table ; P=NS for all). CONCLUSIONS: The present findings demonstrate, for the first time in humans, the ability of RSV to pharmacologically prevent the development of IR-induced endothelial dysfunction. In addition, these data demonstrate the importance of COX-2 in the manifestation of this preconditioned phenotype, evidence that also provides potential mechanistic insight into the observed cardiovascular toxicity with COX-2 inhibitors.

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