Ionic mechanisms of chloroform induced arrhythmia

Abstract

Chloroform, an organic solvent widely used in industrial production, is found to cause intoxication of lethal arrhythmias. However, the ionic mechanisms of its arrhythmogenic effects are still unknown. The present study was designed to investigate the electrophysiological basis involved. METHODS: In isolated rat heat model, ECGs were recorded and analyzed to investigate the arrhythmogenic effects of chloroform. Whole-cell patch clamp was employed to study its effects on pacemaker channel (HCN2), Nav1.5 channel, human cardiac ether-a-go-go related (hERG) K+ channel or inward rectifier K+ channel (Kir2.1), which were stably expressed in HEK 239 cells respectively. RESULTS: In Langendoff-perfused rat hearts, ECG recording showed that chloroform (5 mM) slowed the heart rate. In addition, chloroform inhibited HCN2, Nav1.5 and hERG channels in a concentration-dependent manner; however, it had no effect on Kir2.1 channel. Specifically, chloroform inhibited HCN2 channel with IC50 at 3.4 mM. In addition, it shifted the activation curve of HCN2 channel toward hyperpolarized potential. Similarly, chloroform suppressed Nav1.5 currents to 75.5%, 52.4%, and 17.2% of basal levels at 5, 10 and 15 mM, respectively. Furthermore, it slowed down the recovery of Nav1.5 channel from inactivation, and it shifted the inactivation curve toward hyperpolarized potential, leaving no difference on the activation curve. For hERG channel, chloroform inhibited it with IC50 at 4.3 mM. CONCLUSION: These results demonstrate that chloroform blocks multiple cardiac ion channels including HCN2 channel, Nav1.5 channel and hERG channels, which might contribute to the chloroform- induced lethal arrhythmias. These findings provide potential targets for effective treatments of acute chloroform intoxication.