Abstract
ObjectivesWe sought to investigate whether raloxifene reduces ischemia-reperfusion injury and what mechanisms are involved in the cardioprotective effects. BackgroundEstradiol-17-beta reduces myocardial infarct size in ischemia-reperfusion injury. Raloxifene, a selective estrogen receptor modulator, demonstrates immediate coronary artery vasorelaxing effects. MethodsThe myocardial ischemia-reperfusion model included anesthetized open-chest dogs after 90-min occlusion of the left anterior descending coronary artery (LAD) and subsequent 6-h reperfusion. Raloxifene and/or other drugs were infused into the LAD from 10 min before coronary occlusion to 1 h after reperfusion without an occlusion period. ResultsInfarct size was reduced in the raloxifene (5 μg/kg per min) group compared with the control group (7.2 ± 2.5% vs. 40.9 ± 3.9% of the area at risk, p < 0.01). Either NG-nitro-l-arginine methyl ester (l-NAME), the inhibitor of nitric oxide (NO) synthase, or charybdotoxin, the blocker of Ca2+-activated K+ (KCa) channels, partially attenuated the infarct size–limiting effect, and both of them completely abolished the effect. The incidence of ventricular fibrillation was also less in the raloxifene group than in the control group (11% vs. 44%, p < 0.05). Activity of p38 mitogen-activated protein (MAP) kinase increased with 15-min ischemia, and raloxifene pretreatment inhibited the activity. Myeloperoxidase activity of the 6-h reperfused myocardium was also attenuated by raloxifene. ConclusionsThese data demonstrate that raloxifene reduces myocardial ischemia-reperfusion injury by mechanisms dependent on NO and the opening of KCa channels in canine hearts. Deactivation of p38 MAP kinase and myeloperoxidase by raloxifene may be involved in the cellular mechanisms of cardioprotection.
Published Version
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