title: Iron chelation-afforded cardioprotection against chronic anthracycline cardiotoxicity: a study of salicylaldehyde isonicotinoyl hydrazone (SIH).
abstract: Pyridoxal-derived aroylhydrazone iron chelators have been previously shown as effective cardioprotectants against chronic anthracycline cardiotoxicity. In this study we focused on a novel salicylaldehyde analogue (salicylaldehyde isonicotinoyl hydrazone, SIH), which has been recently demonstrated to possess marked and dose-dependent protective effects against oxidative injury of cardiomyocytes. Therefore, in the present study the cardioprotective potential of SIH against daunorubicin (DAU) cardiotoxicity was assessed in vitro (isolated rat ventricular cardiomyocytes; DAU 10 microM, 48 h exposure) as well as in vivo (chronic DAU-induced cardiomyopathy in rabbits; DAU 3mg/kg, i.v. weekly, 10 weeks). In vitro, SIH (3-100 microM) was able to partially, but significantly decrease the LDH leakage from cardiomyocytes. In vivo, SIH co-administration was capable to reduce (SIH dose of 0.5mg/kg, i.v.) or even to completely prevent (1.0mg/kg, i.v.) the DAU-induced mortality. Moreover, the latter dose of the chelator significantly improved the left ventricular function (LV dP/dt(max)=1185+/-80 kPa/s versus 783+/-53 kPa/s in the DAU group; P<0.05) and decreased the severity of the myocardial morphological changes as well as the plasma levels of cardiac troponin T. Unfortunately, further escalation of the SIH dose (to 2.5mg/kg) resulted in a nearly complete reversal of the protective effects as judged by the overall mortality, functional, morphological as well as biochemical examinations. Hence, this study points out that aroylhydrazone iron chelators can induce a significant cardioprotection against anthracycline cardiotoxicity; however, they share the curious dose-response relationship which is unrelated to the chemical structure or the route of the administration of the chelator.
authors: Department of Pharmacology, Faculty of Medicine in Hradec Králové, Charles University in Prague, Simkova 870, Hradec Králové 500 38, Czech Republic. sterbam@lfhk.cuni.cz
authors: Martin
authors: M
authors: Sterba
authors: Olga
authors: O
authors: Popelová
authors: Tomás
authors: T
authors: Simůnek
authors: Yvona
authors: Y
authors: Mazurová
authors: Anna
authors: A
authors: Potácová
authors: Michaela
authors: M
authors: Adamcová
authors: Ivana
authors: I
authors: Guncová
authors: Helena
authors: H
authors: Kaiserová
authors: Vladimír
authors: V
authors: Palicka
authors: Premysl
authors: P
authors: Ponka
authors: Vladimír
authors: V
authors: Gersl
mesh_terms: D000447:Aldehydes / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D003630:Daunorubicin; D006331:Heart Diseases / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D006352:Heart Ventricles / Q000473:pathology / Q000503:physiopathology; D006835:Hydrazones / Q000494:pharmacology*; D007502:Iron Chelating Agents / Q000494:pharmacology*; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology; D011817:Rabbits; D051381:Rats; D020107:Troponin T / Q000097:blood
chemical_list: D000447:Aldehydes; D006835:Hydrazones; D007502:Iron Chelating Agents; D020107:Troponin T; C413684:salicylaldehyde isonicotinoyl hydrazone; D003630:Daunorubicin