title: Comparison of various iron chelators used in clinical practice as protecting agents against catecholamine-induced oxidative injury and cardiotoxicity.
abstract: Catecholamines are stress hormones and sympathetic neurotransmitters essential for control of cardiac function and metabolism. However, pathologically increased catecholamine levels may be cardiotoxic by mechanism that includes iron-catalyzed formation of reactive oxygen species. In this study, five iron chelators used in clinical practice were examined for their potential to protect cardiomyoblast-derived cell line H9c2 from the oxidative stress and toxicity induced by catecholamines epinephrine and isoprenaline and their oxidation products. Hydroxamate iron chelator desferrioxamine (DFO) significantly reduced oxidation of catecholamines to more toxic products and abolished redox activity of the catecholamine-iron complex at pH 7.4. However, due to its hydrophilicity and large molecule, DFO was able to protects cells only at very high and clinically unachievable concentrations. Two newer chelators, deferiprone (L1) and deferasirox (ICL670A), showed much better protective potential and were effective at one or two orders of magnitude lower concentrations as compared to DFO that were within their clinically relevant plasma levels. Ethylenediaminetetraacetic acid (EDTA), dexrazoxane (ICRF-187, clinically approved cardioprotective agent against anthracycline-induced cardiotoxicity) as well as selected beta adrenoreceptor antagonists and calcium channel blockers exerted no effect. Hence, results of the present study indicate that small, lipophilic and iron-specific chelators L1 and ICL670A can provide significant protection against the oxidative stress and cardiomyocyte damage exerted by catecholamines and/or their reactive oxidation intermediates. This potential new application of the clinically approved drugs L1 and ICL670A warrants further investigation, preferably using more complex in vivo animal models.
authors.affiliation: Charles University in Prague, Faculty of Pharmacy in Hradec Králové, Czech Republic.
authors.forename: Pavlína
authors.initials: P
authors.lastname: Hašková
authors.forename: Lucie
authors.initials: L
authors.lastname: Koubková
authors.forename: Anna
authors.initials: A
authors.lastname: Vávrová
authors.forename: Eliška
authors.initials: E
authors.lastname: Macková
authors.forename: Kateřina
authors.initials: K
authors.lastname: Hrušková
authors.forename: Petra
authors.initials: P
authors.lastname: Kovaříková
authors.forename: Kateřina
authors.initials: K
authors.lastname: Vávrová
authors.forename: Tomáš
authors.initials: T
authors.lastname: Simůnek
mesh_terms: D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D054715:Cardiotoxins / Q000037:antagonists & inhibitors / Q000633:toxicity*; D002395:Catecholamines / Q000037:antagonists & inhibitors / Q000633:toxicity*; D002460:Cell Line; D007502:Iron Chelating Agents / Q000494:pharmacology*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D051381:Rats
chemical_list: D002316:Cardiotonic Agents; D054715:Cardiotoxins; D002395:Catecholamines; D007502:Iron Chelating Agents