Mar 1, 2010Lisa Nainggolan
Toronto, ON - The COX-2 inhibitor celecoxib completely abolished the beneficial preconditioning effect of rosuvastatin in a small mechanistic study in human volunteers . Dr Andrew Liuni (University of Toronto, ON) and colleagues report their findings in the March 9, 2010 issue of the Journal of the American College of Cardiology.Senior author Dr John D Parker (University of Toronto) explained to heartwire that it has been known for some time that exposure to brief periods of ischemia prior to a prolonged period of ischemia can reduce the amount of damage that occurs. This is known as "preconditioning," and some pharmacologic agents, including statins, are thought to have the same effect, a phenomenon termed pharmacological preconditioning. "We decided we would like to pursue the mechanisms of how that occurs, how a statin could favorably precondition," he noted, adding that research in animal models of preconditioning has shown upregulation of the COX-2 enzyme.
Statin did protect from reperfusion injury; COX-2 inhibitor overrides this
They randomized 20 volunteers to a single 40-mg dose of rosuvastatin or placebo and 24 hours later measured endothelium-dependent, flow-mediated dilation (FMD) of the radial artery before and after 15 minutes of upper-arm ischemia followed by 15 minutes of reperfusion. In a separate experiment, 18 volunteers received 200 mg of celecoxib twice daily for five days; on day four, they were randomized to single-dose rosuvastatin (40 mg) or placebo and 24 hours later underwent the same above protocol (ie, 15 minutes of upper-arm ischemia followed by 15 minutes of reperfusion).Rosuvastatin prevented the development of ischemia and reperfusion-induced endothelial dysfunction, but pretreatment with celecoxib completely abolished this protective effect. "This study provides the first evidence in humans of a direct endothelial preconditioning effect by rosuvastatin and may provide a mechanistic explanation of previous observations from clinical settings," says Parker. In addition, it is the first look at the interaction between a statin and a selective COX-2 inhibitor. "The results show that celecoxib completely prevents the preconditioning effect of the statin. So, theoretically, there could be a net negative effect on a patient taking a COX-2 inhibitor who has an acute cardiac event who also happens to be on a statin or is given a statin acutely," he observes. The findings suggest a possible mechanistic explanation for the negative cardiovascular side effects of COX-2 inhibitors observed in clinical trials, say Parker and colleagues.We are a long way from clinical relevance here, because we've made just a mechanistic observation. Parker cautioned, however, that "we are a long way from clinical relevance here, because we've made just a mechanistic observation, but it is interesting. The next step will be to do this in patients." And there are many other unanswered questions, he says, "such as whether the pharmacologic 'preconditioning' effect of statins is maintained when they are given long-term, whether this effect is seen in those who already have overt coronary disease, and how celecoxib or other COX-2 inhibitors might affect these observations." The study was funded by a grant from the Heart and Stroke Foundation of Canada.
Liuni A, Luca MC, Tommaso G, et al. Rosuvastatin prevents conduit artery endothelial dysfunction induced by ischemia and reperfusion by a cyclooxygenase-2-dependent mechanism. J Am Coll Cardiol 2010; 55:1002-1006.
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Discovery of new pathway reveals small molecule that may prevent ischemic damage [Acute Coronary Syndromes > Acute coronary syndromes; Sep 11, 2008]