The role of intracellular calcium in antimony-induced toxicity in cultured cardiac myocytes.
Trivalent antimony, delivered as potassium antimonyl tartrate (PAT), has been previously shown to induce an oxidative stress and toxicity in cultured neonatal rat cardiac myocytes. The present study investigates the effect of PAT on intracellular free calcium ([Ca2+]i), which has been implicated in the toxicity of agents inducing oxidative stress, and explores its role in PAT toxicity. Exposure to 50 or 200 microM PAT led to progressive elevation in diastolic or resting [Ca2+]i and eventually a complete loss of [Ca2+]i transients that occurred well before cell death as assessed by LDH release. Prior loading of myocytes with the intracellular calcium chelator BAPTA (10 to 40 microM), protected against PAT toxicity in the presence and absence of extracellular calcium, and demonstrated a crucial role for [Ca2+]i in PAT toxicity. Exposure to 200 microM PAT in the absence of extracellular calcium slightly elevated [Ca2+]i, but only to levels comparable to resting [Ca2+]i for cells in 1.8 mM extracellular calcium. This demonstrated that although PAT toxicity was dependent on [Ca2+]i, a large increase above resting levels was not needed, and also that some calcium was mobilized from intracellular stores. However, the caffeine-releasable pool of sarcoplasmic reticulum calcium was increased, not depleted, by exposure to 200 microM PAT. These results demonstrate that PAT disrupts [Ca2+]i handling and support a role for a calcium-dependent event, but do not support the necessity of events in PAT-induced cell death that are mediated by a large elevation in [Ca2+]i.
Wey
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Division of Biomedical and Behavioral Science, National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention, Cincinnati, Ohio 45226, USA.
Richards
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Tirmenstein
M A
MA
Mathias
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Toraason
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M
D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D000966:Antimony Potassium Tartrate / Q000633:toxicity*; D002110:Caffeine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D006321:Heart / Q000187:drug effects*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D009206:Myocardium / Q000166:cytology* / Q000201:enzymology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism
D000697:Central Nervous System Stimulants; D002110:Caffeine; D000966:Antimony Potassium Tartrate; D007770:L-Lactate Dehydrogenase; D002118:Calcium