Iron chelation-afforded cardioprotection against chronic anthracycline cardiotoxicity: a study of salicylaldehyde isonicotinoyl hydrazone (SIH)
Language English Country Ireland Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
17459556
DOI
10.1016/j.tox.2007.03.020
PII: S0300-483X(07)00181-3
Knihovny.cz E-resources
- MeSH
- Aldehydes pharmacology MeSH
- Iron Chelating Agents pharmacology MeSH
- Daunorubicin MeSH
- Hydrazones pharmacology MeSH
- Myocytes, Cardiac drug effects physiology MeSH
- Myocardial Contraction drug effects MeSH
- Rabbits MeSH
- Rats MeSH
- Cells, Cultured MeSH
- Heart Diseases chemically induced pathology physiopathology prevention & control MeSH
- Heart Ventricles pathology physiopathology MeSH
- Troponin T blood MeSH
- Animals MeSH
- Check Tag
- Rabbits MeSH
- Rats MeSH
- Male MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Aldehydes MeSH
- Iron Chelating Agents MeSH
- Daunorubicin MeSH
- Hydrazones MeSH
- salicylaldehyde isonicotinoyl hydrazone MeSH Browser
- Troponin T MeSH
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.
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