Cardiotoxicity induced by doxorubicin in vivo: protective activity of the spin trap alpha-phenyl-tert-butyl nitrone.
The role of free radical generation in the development of the acute cardiotoxicity induced by doxorubicin (DXR) in the rat and the protective activity of anti-radical drugs were investigated in in vivo experiments by evaluating the body weight curve, ECG, contractile performance and coronary flow up to 10 days after DXR. A lipophilic spin trap (alpha-phenyl-tert-butyl nitrone, PBN) was continuously administered at a dose of 0.65 mg/kg every hour for 2 weeks by an intraperitoneal osmotic pump. DXR was administered i.v. at a dose of 9 mg/kg 3 days after beginning the PBN infusion. DXR impaired ECG and body weight gain after 3 days (partly reversible at later times), while contractility and coronary flow were significantly impaired throughout the experimental time. PBN was shown to prevent the DXR-induced alterations of contractility and coronary flow, while ECG was non-significantly improved. The body weight curve was not affected. Since the dose of PBN used does not produce pharmacological effects, the protective activity in rats receiving DXR indicates that free radicals may play a causal role in the acute cardiotoxicity in vivo. The use of suitable spin traps and administration schedules seems to be an interesting approach for the prevention of radical-dependent pathologies.
Jotti
A
A
Istituto di Farmacologia, Università di Milano, Italy.
Paracchini
L
L
Perletti
G
G
Piccinini
F
F
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D003497:Cyclic N-Oxides; D004317:Doxorubicin; D004562:Electrocardiography / Q000187:drug effects; D005260:Female; D005609:Free Radicals; D006331:Heart Diseases / Q000139:chemically induced / Q000517:prevention & control*; D006439:Hemodynamics / Q000187:drug effects; D009200:Myocardial Contraction / Q000187:drug effects; D009589:Nitrogen Oxides / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013113:Spin Labels
D003497:Cyclic N-Oxides; D005609:Free Radicals; D009589:Nitrogen Oxides; D013113:Spin Labels; C029217:phenyl-N-tert-butylnitrone; D004317:Doxorubicin