Ethanol and cocaine cause additive inhibitory effects on the calcium transients and contraction in single cardiomyocytes.
The heart is a major locus for the toxic actions of cocaine and ethanol, each of which has been shown to interfere with excitation-contraction coupling in cardiac muscle cells. Because these drugs are frequently used in combination, the present study was designed to investigate how they interact to modify the Ca2+ transient and associated contraction in fura2-loaded cardiomyocytes. A high-speed imaging technique using a charge-coupled device as detector and short-term image store was used to measure cytosolic Ca2+ and contraction simultaneously from fluorescence images obtained during the contractile cycle. Ethanol (100 mM) and cocaine (50 microM) caused reversible reductions in Ca2+ transient amplitude of 24.3 +/- 3.0% and 25.1 +/- 3.6%, respectively. Neither agent modified basal Ca2+. Ethanol treatment decreased peak shortening by 44.3 +/- 3.5%, whereas the contractile depression by cocaine was 31.4 +/- 5.3%. The relatively greater effect of ethanol on contraction resulted from a Ca2+-independent component of ethanol action on contractility. When cardiomyocytes were exposed simultaneously to ethanol and cocaine, Ca2+ transient amplitude was reduced by 38.7 +/- 3.0%, and peak contraction was decreased by 55.1 +/- 3.5%. These values represent a significantly greater inhibition than observed with either drug alone (p < 0.02) and are compatible with additive effects of the two drugs acting at distinct loci within the excitation-contraction coupling pathway. Thus, simultaneous use of cocaine and ethanol leads to an enhanced depression of myocardial contractility, which is likely to contribute to the cardiotoxic actions of the combination of these two drugs.
Department of Pathology, Anatomy, and Cell Biology, Jefferson Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
J M
JM
Nicolás
E
E
Rubin
A P
AP
Thomas
D000818:Animals; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000187:drug effects*; D002478:Cells, Cultured; D003042:Cocaine / Q000633:toxicity*; D004357:Drug Synergism; D000431:Ethanol / Q000633:toxicity*; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000166:cytology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D015220:Calcium Channels; D000431:Ethanol; D003042:Cocaine; D002118:Calcium