Cardiac toxicity of chloroform: implication of multople ion channel inhibition

Abstract

Background: Chloroform, a widely used organic solvent in industrial production, is found to cause intoxication of lethal arrhythmias. However, the ionic mechanisms of its arrhythmogenic effects are still unknown. Methods and results: The present study was designed to investigate the electrophysiological basis of the arrhythmogenic effect of chloroform, using a whole-cell patch clamp technique in HEK 239 cells stably expressing human cardiac inward rectifier Kþ channel (Kir2.1), human cardiac ether-a-go-go related (hERG) Kþ gene, Nav1.5, and pacemaker gene (HCN2). The effect of chloroform on isolated rat heart was also studied. We found that chloroform showed an obvious arrhythmogenic effect in isolated rat heats at the concentration of 10 mM. It also inhibited the pacemaker HCN2 channel and human cardiac IKr (i.e. hERG) channels in a concentration-dependent manner, with IC50 of 4.57 and 4.29 mM, respectively. The inhibition of hERG channel was recovered to 78.3% on washout. In addition, chloroform inhibited Nav1.5 currents by 24.5, 47.6, and 82.8% at 5, 10, and 15 mM, respectively. However, chloroform (10 mM) had no effect on human cardiac Kir2.1 channels. Conclusion: These results demonstrate that chloroform blocks multiple cardiac ion channels, IKr, INa, and the pacemaker HCN2, which likely account at least in part for the chloroforminduced lethal arrhythmias. These findings may be helpful in seeking effective management of acute chloroform intoxication.