Ionic mechanisms underlying cardiac toxicity of the organochloride solvent trichloromethane.
Trichloromethane (chloroform) is widely used for industrial chemical synthesis and also as an organic solvent in laboratories or ingredient of pesticides. Sudden death resulted from cardiac arrhythmias has been reported in clinic with acute trichloromethane intoxication. The present study was designed to investigate ionic mechanisms underlying arrhythmogenic effect (cardiac toxicity) of trichloromethane in isolated rat hearts and ventricular myocytes and HEK 293 cells stably expressing human Nav1.5, HCN2, or hERG channel using conventional electrophysiological approaches. It was found that trichloromethane (5mM) induced bradycardia and atrial-ventricular conduction blockade or ventricular fibrillation, and inhibited cardiac contractile function in isolated rat hearts. It shortened action potential duration (APD) in isolated rat ventricular myocytes, and increased the threshold current for triggering action potential, but had no effect on the inward rectifier K(+) current I(K1). However, trichloromethane significantly inhibited the L-type calcium current I(Ca.L) and the transient outward potassium current I(to) in a concentration-dependent manner (IC(50)s: 1.01 and 2.4mM, respectively). In HEK 293 cells stably expressing cardiac ion channel genes, trichloromethane reduced hNav1.5, HCN2, and hERG currents with IC(50)s of 8.2, 3.3, and 4.0mM, respectively. These results demonstrate for the first time that trichloromethane can induce bradycardia or ventricular fibrillation, and the arrhythmogenic effect of trichloromethane is related to the inhibition of multiple ionic currents including I(Ca.L), I(to), I(Na), HCN2, and hERG channels.
Department of Physiology, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Pokfulam, Hong Kong, China.
Yuan
Y
Zhou
Hui-Jun
HJ
Wu
Yan-Hui
YH
Zhang
Hai-Ying
HY
Sun
Tak-Ming
TM
Wong
Gui-Rong
GR
Li
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001919:Bradycardia / Q000139:chemically induced*; D002725:Chloroform / Q000008:administration & dosage / Q000633:toxicity*; D057809:HEK293 Cells; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D006352:Heart Ventricles / Q000187:drug effects / Q000473:pathology; D006801:Humans; D020128:Inhibitory Concentration 50; D007473:Ion Channels / Q000037:antagonists & inhibitors*; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012997:Solvents / Q000008:administration & dosage / Q000633:toxicity*; D014693:Ventricular Fibrillation / Q000139:chemically induced*
D007473:Ion Channels; D012997:Solvents; D002725:Chloroform