PHARMACOLOGICAL ACTION OF A NEW SPIN-TRAPPING COMPOUND, 2-PHENYL DMPO, IN THE ADRIAMYCIN-INDUCED CARDIOTOXICITY

Adriamycin (ADR)-induced cardiotoxicity was adopted in this investigat ion as a reliable model of radical-dependent myocardial pathology allo wing 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 s hown to develop significant protective activity, in this investigation a newly synthesized spin trap (2-phenyl-DMPO) was studied. In Langend orff rat heart, 200 mu M ADR induced a significant impairment of contr actile 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 vivo exp eriments, ADR (9 mg/kg i.v.) produced a significant impairment of EGG, coronary flow and contractility. The continuous administration of 2-p henyl-DMPO i.p. by osmotic pump delivering 0.3 mu mol/hr was unable to protect the animals against the cardiotoxic signs. Seven days after A DR administration, severe general toxicity (arrest of body weight incr ease) and myelotoxicity were also observed. 2-phenyl-DMPO was unable t o protect the animals from these toxic signs. The present results conf irm 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 metabolize d in vivo to inactive derivatives.