Amelioration of ischemia- and reperfusion-induced myocardial injury by the selective estrogen receptor modulator, raloxifene, in the canine heart

OBJECTIVES We sought to investigate whether raloxifene reduces ischemia-reperfusion injury and what mechanisms are involved in the cardioprotective effects. BACKGROUND Estradiol-17-beta reduces myocardial infarct size in ischemia-reperfusion injury. Raloxifene, a selective estrogen receptor modulator, demonstrates immediate coronary artery vasorelaxing effects. METHODS The 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. RESULTS Infarct size was reduced in the raloxifene (5 mug/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 N-G-nitro-L-arginine methyl ester (L-NAME), the inhibitor of nitric oxide (NO) synthase, or charybdotoxin, the blocker of Ca2+-activated K+ (K-Ca) 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. Mycloperoxidase activity of the 6-h reperfused myocardium was also attenuated by raloxifene. CONCLUSIONS These data demonstrate that raloxifene reduces myocardial ischemia-reperfusion injury by mechanisms dependent on NO and the opening of K-Ca channels in canine hearts. Deactivation of p38 MAP kinase and myeloperoxidase by raloxifene may be involved in the cellular mechanisms of cardioprotection.