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The novel iron chelator, 2-pyridylcarboxaldehyde 2-thiophenecarboxyl hydrazone, reduces catecholamine-mediated myocardial toxicity
P Mladenka, DS Kalinowski, P Haskova, Z Bobrovova, R Hrdina, T Simunek, P Nachtigal, V Semecky, J Vavrova, M Holeckova, V Palicka, Y Mazurova, PJ Jansson, DR Richardson
Jazyk angličtina Země Spojené státy americké
- MeSH
- buněčné linie MeSH
- chelátory železa farmakologie MeSH
- deferoxamin aplikace a dávkování MeSH
- financování organizované MeSH
- isoprenalin antagonisté a inhibitory metabolismus toxicita MeSH
- kardiomyocyty metabolismus účinky léků MeSH
- katecholaminy antagonisté a inhibitory metabolismus toxicita MeSH
- krysa rodu rattus MeSH
- oxidace-redukce MeSH
- potkani Wistar MeSH
- thiofeny farmakologie MeSH
- železo metabolismus MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
Iron (Fe) chelators are used clinically for the treatment of Fe overload disease. Iron also plays a role in the pathology of many other conditions, and these potentially include the cardiotoxicity induced by catecholamines such as isoprenaline (ISO). The current study examined the potential of Fe chelators to prevent ISO cardiotoxicity. This was done as like other catecholamines, ISO contains the classical catechol moiety that binds Fe and may form redox-active and cytotoxic Fe complexes. Studies in vitro used the cardiomyocyte cell line, H9c2, which was treated with ISO in the presence or absence of the chelator, desferrioxamine (DFO), or the lipophilic ligand, 2-pyridylcarboxaldehyde 2-thiophenecarboxyl hydrazone (PCTH). Both of these chelators were not cardiotoxic and significantly reduced ISO cardiotoxicity in vitro. However, PCTH was far more effective than DFO, with the latter showing activity only at a high, clinically unachievable concentration. Further studies in vitro showed that interaction of ISO with Fe(II)/(III) did not increase cytotoxic radical generation, suggesting that this mechanism was not involved. Studies in vivo were initiated using rats pretreated intravenously with DFO or PCTH before subcutaneous administration of ISO (100 mg/kg). DFO at a clinically used dose (50 mg/kg) failed to reduce catecholamine cardiotoxicity, while PCTH at an equimolar dose totally prevented catecholamine-induced mortality and reduced cardiotoxicity. This study demonstrates that PCTH reduced ISO-induced cardiotoxicity in vitro and in vivo, demonstrating that Fe plays a role, in part, in the pathology observed.
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- $a Mladěnka, Přemysl. $7 xx0233006
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- $a The novel iron chelator, 2-pyridylcarboxaldehyde 2-thiophenecarboxyl hydrazone, reduces catecholamine-mediated myocardial toxicity. / $c P Mladenka, DS Kalinowski, P Haskova, Z Bobrovova, R Hrdina, T Simunek, P Nachtigal, V Semecky, J Vavrova, M Holeckova, V Palicka, Y Mazurova, PJ Jansson, DR Richardson
- 314 __
- $a Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Kralove, Charles University in Prague, Czech Republic.
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- $a Iron (Fe) chelators are used clinically for the treatment of Fe overload disease. Iron also plays a role in the pathology of many other conditions, and these potentially include the cardiotoxicity induced by catecholamines such as isoprenaline (ISO). The current study examined the potential of Fe chelators to prevent ISO cardiotoxicity. This was done as like other catecholamines, ISO contains the classical catechol moiety that binds Fe and may form redox-active and cytotoxic Fe complexes. Studies in vitro used the cardiomyocyte cell line, H9c2, which was treated with ISO in the presence or absence of the chelator, desferrioxamine (DFO), or the lipophilic ligand, 2-pyridylcarboxaldehyde 2-thiophenecarboxyl hydrazone (PCTH). Both of these chelators were not cardiotoxic and significantly reduced ISO cardiotoxicity in vitro. However, PCTH was far more effective than DFO, with the latter showing activity only at a high, clinically unachievable concentration. Further studies in vitro showed that interaction of ISO with Fe(II)/(III) did not increase cytotoxic radical generation, suggesting that this mechanism was not involved. Studies in vivo were initiated using rats pretreated intravenously with DFO or PCTH before subcutaneous administration of ISO (100 mg/kg). DFO at a clinically used dose (50 mg/kg) failed to reduce catecholamine cardiotoxicity, while PCTH at an equimolar dose totally prevented catecholamine-induced mortality and reduced cardiotoxicity. This study demonstrates that PCTH reduced ISO-induced cardiotoxicity in vitro and in vivo, demonstrating that Fe plays a role, in part, in the pathology observed.
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