Cocaine-induced mitochondrial dysfunction in primary cultures of rat cardiomyocytes.
Morphological alterations of cardiac mitochondria have been observed in rats chronically treated with cocaine. Whether cocaine directly causes heart mitochondrial dysfunction remains unclear. The present study was undertaken to investigate the effect of cocaine on mitochondrial function in cultured myocardial cells. Cells were incubated with cocaine (10(-5)-10(-3) M) for 3-72 h, using either a repeated or single exposure protocol. Cocaine (10(-3) M) produced severe cytotoxicity after repeated exposure (24-72 h), as elevated by leakage of lactate dehydrogenase. Treatment of the cultures with a single exposure protocol (10(-5)-10(-3) M for 24 h or less) produced a very modest cytotoxic effect, as shown by a small increase in LDH leakage. However, cellular ATP levels showed a time-dependent decline in cultures treated with the single exposure protocol. Experiments using a digitized fluorescence imaging system revealed that cocaine (single exposure protocol) caused a dose- and time-dependent decrease in mitochondrial membrane potential, and the decline in membrane potential occurred prior to manifestation of cytotoxicity shown with the repeated exposure protocol. Cytosolic and mitochondrial calcium levels, as determined by fura-2, were not affected during treatment with cocaine. Our results suggest that cocaine may compromise cardiac mitochondrial function and may lead to cardiotoxicity.
Yuan
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Division of Pharmacology and Toxicology, College of Pharmacy, University of Texas at Austin 78712, USA.
Acosta
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D000255:Adenosine Triphosphate / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D003042:Cocaine / Q000633:toxicity*; D018765:Dopamine Uptake Inhibitors / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D016257:Fura-2 / Q000737:chemistry; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects; D008856:Microscopy, Fluorescence; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000201:enzymology; D009206:Myocardium / Q000166:cytology; D051381:Rats; D017207:Rats, Sprague-Dawley
D018765:Dopamine Uptake Inhibitors; D000255:Adenosine Triphosphate; D007770:L-Lactate Dehydrogenase; D003042:Cocaine; D002118:Calcium; D016257:Fura-2