title: Dexrazoxane provided moderate protection in a catecholamine model of severe cardiotoxicity.
abstract: Positive effects of dexrazoxane (DEX) in anthracycline cardiotoxicity have been mostly assumed to be associated with its iron-chelating properties. However, this explanation has been recently questioned. Iron plays also an important role in the catecholamine cardiotoxicity. Hence in this study, the influence of DEX on a catecholamine model of acute myocardial infarction (100 mg/kg of isoprenaline by subcutaneous injection) was assessed: (i) the effects of an intravenous dose of 20.4 mg/kg were analyzed after 24 h, (ii) the effects were monitored continuously during the first two hours after drug(s) administration to examine the mechanism(s) of cardioprotection. Additional in vitro experiments on iron chelation/reduction and influence on the Fenton chemistry were performed both with isoprenaline/DEX separately and in their combination. DEX partly decreased the mortality, reduced myocardial calcium overload, histological impairment, and peripheral haemodynamic disturbances 24 h after isoprenaline administration. Continuous 2 h experiments showed that DEX did not influence isoprenaline induced atrioventricular blocks and had little effect on the measured haemodynamic parameters. Its protective effects are probably mediated by inhibition of late myocardial impairment and ventricular fibrillation likely due to inhibition of myocardial calcium overload. Complementary in vitro experiments suggested that iron chelation properties of DEX apparently did not play the major role.
authors.affiliation: Charles University in Prague, Department of Pharmacology and Toxicology, Heyrovského, Hradec Králové, Czech Republic.
authors.forename: Libuše
authors.initials: L
authors.lastname: Zatloukalová
authors.forename: Tomáš
authors.initials: T
authors.lastname: Filipský
authors.forename: Přemysl
authors.initials: P
authors.lastname: Mladěnka
authors.forename: Vladimír
authors.initials: V
authors.lastname: Semecký
authors.forename: Kateřina
authors.initials: K
authors.lastname: Macáková
authors.forename: Magdalena
authors.initials: M
authors.lastname: Holečková
authors.forename: Jaroslava
authors.initials: J
authors.lastname: Vávrová
authors.forename: Vladimir
authors.initials: V
authors.lastname: Palicka
authors.forename: Radomír
authors.initials: R
authors.lastname: Hrdina
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002316:Cardiotonic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D006439:Hemodynamics / Q000187:drug effects; D007501:Iron / Q000378:metabolism; D007502:Iron Chelating Agents / Q000494:pharmacology; D007545:Isoproterenol / Q000037:antagonists & inhibitors; D008297:Male; D009203:Myocardial Infarction / Q000139:chemically induced / Q000188:drug therapy*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D011929:Razoxane / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D002316:Cardiotonic Agents; D007502:Iron Chelating Agents; D011929:Razoxane; D007501:Iron; D007545:Isoproterenol; D002118:Calcium