Cardioprotective effects of long-term treatment with raloxifene, a selective estrogen receptor modulator, on myocardial ischemia/reperfusion injury in ovariectomized rats

Objective: The aim of this study was to investigate the beneficial effect of long-term treatment with raloxifene (RAL), a selective estrogen receptor modulator, on myocardial ischemia/reperfusion (MI/R) injury in ovariectomized (Ovx) rats. Methods: Ovariectomy was performed in female Sprague-Dawley rats 8 weeks old. Ovx rats were treated with RAL I or 5 mg/kg (gavage, once daily) or 17 beta-estradiol (E-2; 50 mu g/kg SC, three times a week) for 8 weeks. The cardioprotective effect of RAL was evaluated in an open-chest anesthetized rat model of MI/R, which was induced by 40-minute left coronary artery occlusion and 100-minute reperfusion. Results: Long-term treatment with RAL I mg/kg significantly suppressed the duration of ventricular tachycardia elicited by MI. After MI/R, the levels of plasma creatine kinase-MB fraction and lactate dehydrogenase in Ovx rats were significantly higher than those in the sham group, which were significantly reduced by long-term treatment with RAL I mg/kg or E-2. Neutrophil myeloperoxidase activity in ischemic myocardium markedly increased in the Ovx group, whereas long-term treatment with RAL 1 or 5 mg/kg or E-2 significantly suppressed the elevation of myeloperoxidase activity. After MI/R, the protein expression of phosphorylated inhibitory kappa B alpha and caspase-3 in ischemic myocardium pronouncedly increased in the Ovx group and was attenuated by long-term treatment with RAL 1 mg/kg or E-2. Conclusions: Long-term treatment with RAL can reduce the severity of MI-induced arrhythmias and attenuate MI/R-induced damages and apoptosis in Ovx rats. This cardioprotective effect of RAL may be associated with inhibition of neutrophil infiltration and suppression of nuclear factor-kappa B activation.