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 present study, the ability of the piperidine nitroxide TEMPOL to prevent the 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 micrograms/ml of ADR for 60 min. Both direct interaction with free radicals and decrease of Fe(II) availability (by stable oxidation and/or by chelation) seem to contribute to the cardioprotective effect to TEMPOL. HPLC and EPR studies of the subcellular distribution of TEMPOL indicate that substantial amounts of the nitroxide localize to the mitochondrial and microsomal fractions, in an ordered environment possibly corresponding to the interface between membrane and aqueous compartments.
Monti
E
E
Applied Pharmacology Section, Institute of Pharmacology, University of Milan, Italy.
Cova
D
D
Guido
E
E
Morelli
R
R
Oliva
C
C
D000704:Analysis of Variance; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D003497:Cyclic N-Oxides / Q000494:pharmacology*; D004317:Doxorubicin / Q000037:antagonists & inhibitors / Q000633:toxicity*; D004578:Electron Spin Resonance Spectroscopy; D005609:Free Radicals; D006321:Heart / Q000187:drug effects*; D066298:In Vitro Techniques; D007501:Iron / Q000378:metabolism; D007700:Kinetics; D015227:Lipid Peroxidation / Q000187:drug effects*; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D008563:Membrane Lipids / Q000378:metabolism; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013113:Spin Labels; D013997:Time Factors
D000975:Antioxidants; D003497:Cyclic N-Oxides; D005609:Free Radicals; D008563:Membrane Lipids; D013113:Spin Labels; D008315:Malondialdehyde; D004317:Doxorubicin; D007501:Iron; C001803:tempol