PROTECTIVE EFFECT OF THE NITROXIDE TEMPOL AGAINST THE CARDIOTOXICITY OF ADRIAMYCIN

Nitroxides are cell permeable, stable radicals that have been shown to exert antioxidant effects in several experimental models. In the pres ent study, the ability of the piperidine nitroxide TEMPOL to prevent t he acute cardiac toxicity of Adriamycin (ADR), which depends on oxygen -derived free radical generation, was assessed in isolated rat hearts. The results obtained show that TEMPOL (2.5 mM) significantly reduces the contractile impairment as well as the lipid peroxidation observed in rat heart preparations perfused with 100 mu g/ml of ADR for 60 min. Both direct interaction with free radicals and decrease of Fe(II) ava ilability (by stable oxidation and/or by chelation) seem to contribute to the cardioprotective effect of TEMPOL. HPLC and EPR studies of the subcellular distribution of TEMPOL indicate that substantial amounts of the nitroxide localize to the mitochondrial and microsomal fraction s, in an ordered environment possibly corresponding to the interface b etween membrane and aqueous compartments.