Calcium dynamics in cardiac myocytes as a target of dichloromethane cardiotoxicity.
The purpose of the present study was to determine if cardiac actions of dichloromethane (DCM) in vivo correlate with in vitro alterations of Ca2+ dynamics in cardiac myocytes. Neonatal rat ventricular myocytes were obtained from 2- to 4-day-old rats, and electrically induced fluctuations of cytosolic free Ca2+ concentration ([Ca2+]i) in single cardiomyocytes were investigated using spectrofluorometric analysis of fura-2-[Ca2+]i binding. In cultured myocytes, cumulative exposure to 0.64-40.96 mM DCM resulted in a concentration-dependent and reversible decrease in the magnitude of [Ca2+]i transients with IC10 and IC50 values of 7.98 and 18.82 mM, respectively. Total inhibition of [Ca2+]i transients and cessation of beating were observed at 40.96 mM DCM. Suffusion with DCM for 40 min did not cause morphological alterations of the myocytes. In a urethane-anesthetized rat model, left ventricular pressure was measured by introducing a tip catheter via the carotid artery into the left ventricle, the ECG was recorded by two needle electrodes applied subcutaneously to the chest wall, and arterial pressure was measured via the femoral artery. Oral administration of 3.1-12.4 mmol DCM/kg resulted in DCM blood concentrations between 1.0 and 1.6 mM, accompanied by a dose-dependent decrease in contractile force and heart rate without influencing blood pressure and ECG tracings. Moreover, DCM treatment provided significant protection against arrhythmia development due to CaCl2-infusion. In spite of the slight discrepancy between DCM blood concentrations and in vitro concentrations of DCM for [Ca2+]i transient inhibition, present data are consistent with the view that cardiac effects after DCM exposure are mediated by alterations of Ca2+ dynamics during excitation-contraction coupling.
Hoffmann
P
P
SANOFI Recherche, Centre de Toulouse, France.
Müller
S P
SP
Heinroth
K
K
Büchner
E
E
Richards
D
D
Toraason
M
M
D000758:Anesthesia; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced; D002118:Calcium / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002122:Calcium Chloride / Q000494:pharmacology; D002469:Cell Separation; D002478:Cells, Cultured; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D006334:Heart Function Tests / Q000187:drug effects; D008297:Male; D008752:Methylene Chloride / Q000633:toxicity*; D009206:Myocardium / Q000166:cytology*; D051381:Rats; D017208:Rats, Wistar
D008752:Methylene Chloride; D002122:Calcium Chloride; D002118:Calcium