Effects of cocaine and norepinephrine on primary cultures of neonatal rat myocardial cells.
Sudden cardiac death associated with cocaine (Coc) abuse in healthy, physically active individuals became a grave concern in the late 1980s. It is well documented that physical activity increases circulating plasma catecholamine levels. Catecholamines as well as Coc are independently capable of inducing toxic cardiac effects. The purpose of this investigation was to evaluate the synergistic or additive toxic effects of norepinephrine (NE) and Coc in primary myocardial cell cultures obtained from 3- to 5-d-old Sprague-Dawley rats. Alterations in lactate dehydrogenase release (LDH), lysosomal neutral red retention (NR), beating activity, and morphology were evaluated after treatment of the cells for 1-24 h with 1 x 10(-3) M Coc alone, 1 x 10(-5) M Coc alone, 1 x 10(-5) M NE alone, 1 x 10(-3) M Coc with 1 x 10(-5) M NE, or 1 x 10(-5) M Coc with 1 x 10(-5) M NE. LDH release was elevated significantly after 24 h only with those cells exposed to 1 x 10(-3) M Coc alone and 1 x 10(-3) M Coc + 1 x 10(-5) M NE. Using NR retention as a score for lysosomal treatment of the cells with 1 x 10(-5) M Coc and 1 x 10(-3) M Coc alone did not decrease dye retention significantly. However, 1 x 10(-5) M NE combined with 1 x 10(-3) M Coc significantly reduced lysosomal dye retention as early as 1 h after treatment. After 24 h, 1 x 10(-5) M NE alone and 1 x 10(-5) M NE combined with 1 x 10(-5) M Coc significantly increased lysosomal fragility. Beating activity was altered in all treatment groups. Contractile activity was slow and irregular or completely absent with 1 x 10(-5) and 1 x 10(-3) M Coc, respectively. When NE (1 x 10(-5) M) was combined with both concentrations of Coc, there was distinct focalization of sharp, rapid contractions within the cells, which were asynchronous and/or arrhythmic in nature. Those cells exposed to 1 x 10(-5) M NE with 1 x 10(-5) M Coc for 24 h appeared hypercontracted with marked pseudopodia and cytoplasmic granule formation distinctly different from that exhibited by the cells exposed to 1 x 10(-5) M Coc alone. These data demonstrate that NE potentiates the adverse effects of Coc on contractile activity and morphology of spontaneously contracting neonatal myocardial cells maintained in culture.
Welder
A A
AA
College of Pharmacy, University of Oklahoma Health Sciences Center, Oklahoma City 73190.
Eselin
J A
JA
Melchert
R B
RB
Davis
S K
SK
O'Dell
J F
JF
D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D003042:Cocaine / Q000494:pharmacology / Q000633:toxicity*; D004357:Drug Synergism; D006321:Heart / Q000187:drug effects*; D007770:L-Lactate Dehydrogenase / Q000187:drug effects; D008247:Lysosomes / Q000378:metabolism; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000166:cytology / Q000201:enzymology; D009499:Neutral Red; D009638:Norepinephrine / Q000494:pharmacology / Q000633:toxicity*; D051381:Rats; D011919:Rats, Inbred Strains
D009499:Neutral Red; D007770:L-Lactate Dehydrogenase; D003042:Cocaine; D009638:Norepinephrine