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Research Article

Iron-Mediated Cardiotoxicity Develops Independently of Extracellular Hydroxyl Radicals in Isolated Rat Hearts

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Pages 19-28 | Published online: 22 Feb 1999
 

Abstract

Background: Myocardial iron toxicity is often attributed to free radical damage. Present studies examine the role of extracellular hydroxyl radical formation in this process. Methods: In vitro reactions examined the rate of hydroxyl radical formation using salicylate trapping with high-pressure liquid chromatography separation and electrochemical detection of 2,3- and 2,5-dihydroxybenzoic acid. Isolated rat hearts were perfused by the Langendorff technique under the same buffer conditions to determine changes in myocardial contractility, release of tissue lactate dehydrogenase activity, and formation of lipid peroxidation products when iron was added to the perfusate with or without the formation of extracellular radicals. Results: In vitro reactions, performed in Krebs buffer alone or with addition of iron (25 μM), produced levels of hydroxyl radicals that were nondetectable with salicylate trapping. Addition of iron/ascorbate (FeSO4 = 25 μM, ascorbate = 1 mM), or iron/ascorbate/histidine (FeSO4 = 25 μM, ascorbate = 1 mM, histidine = 15 mM) produced significant and equivalent accumulation of hydroxyl radicals. Isolated rat hearts were perfused under the same 4 conditions. Control heart contractile function was stable with little release of lactate dehydrogenase activity and low levels of thiobarbituric acid reactive substances (TBARS). There was significant and equal injury to contractile function, release of lactate dehydrogenase activity, and accumulation of TBARS in hearts in the presence (iron/ascorbate) and absence (iron alone) of extracellular hydroxyl radicals. In addition, there was significant reduction in injury with iron/ascorbate/histidine, where the formation of extracellular hydroxyl radicals was equal to those observed with iron/ascorbate alone. Additional control hearts, perfused with histidine alone, showed stable heart function. Conclusions: These findings indicate that the extracellular formation of hydroxyl radicals is not responsible for iron-mediated cardiotoxicity.

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