PRETREATMENT WITH ISCHEMIA ATTENUATES ACUTE EPIRUBICIN-INDUCED CARDIOTOXICITY IN ISOLATED RAT HEARTS

We investigated whether a brief ischaemic episode (ischaemic pretreatm ent) preconditioning might attenuate the acute cardiotoxicity of the a nthracycline, epirubicin. Isolated rat hearts perfused at a constant f low rate of 10 ml/min. were preconditioned with 5 min. of global ischa emia and 10 min. of reperfusion (preconditoned hearts), or were perfus ed for 15 min. (control hearts). The hearts were then subjected to 20 min. of infusion with epirubicin (2 mg/ml) or vehicle by a side arm of the perfusion system at a rate of 0.1 ml/min. (0.2 mg epirubicin/min. ). Attenuation of cardiotoxicity of a total dose of 4 mg of epirubicin was assessed by functional and metabolic parameters during infusion a nd during the following 30 min. recovery period. Cardiotoxic effects w ere reduced in preconditioned hearts compared to control hearts. Thus left ventricular developed pressure and heart rate product after 20 mi n. of epirubicin infusion was depressed to 27+/-7% (mean+/-S.D.) and 4 0+/-4% (mean+/-S.D.) of baseline values in the control group and the p reconditioned group, respectively (P<0.05). Furthermore, we observed l ess contracture during epirubicin infusion and more effective reversal of contracture during the recovery period in the preconditioned heart s. Improvement in cardiac function was associated with a significantly lower (P<0.05) myocardial content of epirubicin in the preconditioned group at the end of the infusion period. We conclude that ischaemic p reconditioning attenuates the acute cardiotoxicity of epirubicin, prob ably by reducing the myocardial accumulation of the anthracycline.