A primary culture system of adult rat heart cells for the evaluation of cocaine toxicity.
The complex dose-response relationship by which cocaine (Coc) directly precipitates unfavorable cardiac consequences are not known. There appears to be two diametrically opposed cardiovascular actions of Coc. At low doses, the sympathetic nervous system responses dominate, whereas, at high doses, the local anesthetic actions exert the most powerful effects. The purpose of this study was to describe a dose- and time-dependent Coc cardiotoxicity profile in a model of spontaneously contracting adult primary myocardial cell cultures obtained from 60-90-day-old Sprague-Dawley rats. Indices of toxicity determined included contractility, morphology, lactate dehydrogenase release (LDH), mitochondrial tetrazolium formazan (MTT) production and neutral red (NR) formation. After the cells had been grown in culture for 11 days, they were exposed to 1 x 10(-3), 1 x 10(-5), 1 x 10(-7) and 1 x 10(-9) M Coc for 1-24 h. The two lowest doses of Coc (1 x 10(-7) and 1 x 10(-9) M) had little or no effect on the adult heart cell cultures. However, morphological alterations included vacuolization, granulation and pseudopodia formation as early as 1 h after exposure to the highest doses of Coc (1 x 10(-3) and 1 x 10(-5) M). For all time points observed, the two highest doses of Coc (1 x 10(-3) and 1 x 10(-5) M) significantly depressed contractility and induced significant LDH release. MTT formazan production and NR retention were not significantly different from untreated controls for all treatments. By employing an acute Coc exposure paradigm, these data demonstrate that Coc doses greater than or equal to 1 x 10(-5) M induce direct injurious local anesthetic effects on contractility and morphology of spontaneously contracting adult rat myocardial cells in culture.
Welder
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College of Pharmacy, University of Oklahoma Health Sciences Center, Department of Medicinal Chemistry and Pharmacodynamics, Oklahoma City 73190.
D000818:Animals; D002478:Cells, Cultured / Q000187:drug effects; D003042:Cocaine / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006321:Heart / Q000187:drug effects*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000201:enzymology / Q000473:pathology*; D010088:Oxidoreductases / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains
D010088:Oxidoreductases; D007770:L-Lactate Dehydrogenase; D003042:Cocaine