Pharmacological action of a new spin trapping compound, 2-phenyl DMPO, in the adriamycin-induced cardiotoxicity.
Adriamycin (ADR)-induced cardiotoxicity was adopted in this investigation as a reliable model of radical-dependent myocardial pathology allowing both quantitative studies of drug activity in the isolated organ and in vivo comparison of the cardio-protection vs. general toxicity. Since commercially available lipophilic spin trapping compounds were shown to develop significant protective activity, in this investigation a newly synthesized spin trap (2-phenyl-DMPO) was studied. In Langendorff rat heart, 200 microM ADR induced a significant impairment of contractile performance, while 2-phenyl-DMPO was not cardiotoxic up to the 5 mM concentration. By this dose, 2-phenyl-DMPO induced a significant protection against the ADR-induced contractile impairment. In in vivo experiments, ADR (9 mg/kg i.v.) produced a significant impairment of ECG, coronary flow and contractility. The continuous administration of 2-phenyl-DMPO i.p. by osmotic pump delivering 0.3 mumol/hr was unable to protect the animals against the cardiotoxic signs. Seven days after ADR administration, severe general toxicity (arrest of body weight increase) and myelotoxicity were also observed. 2-phenyl-DMPO was unable to protect the animals from these toxic signs. The present results confirm that lipophilic spin traps can be a new class of antiradical drugs, as confirmed by the experiments performed in the isolated heart with the 2-phenyl-DMPO; however, this last compound is probably metabolized in vivo to inactivate derivatives.
Piccinini
F
F
Institute of Pharmacology, University of Milan, Italy.
Bradamante
S
S
Monti
E
E
Zhang
Y K
YK
Janzen
E G
EG
D000704:Analysis of Variance; D000818:Animals; D003497:Cyclic N-Oxides / Q000494:pharmacology*; D004195:Disease Models, Animal; D004317:Doxorubicin; D016166:Free Radical Scavengers; D005609:Free Radicals; D006325:Heart Atria / Q000187:drug effects; D006331:Heart Diseases / Q000139:chemically induced*; D066298:In Vitro Techniques; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013113:Spin Labels
D003497:Cyclic N-Oxides; D016166:Free Radical Scavengers; D005609:Free Radicals; D013113:Spin Labels; C095292:5,5-dimethyl-2-phenyl-1-pyrroline-N-oxide; D004317:Doxorubicin