Hypaconitine-induced QT prolongation mediated through inhibition of KCNH2 (hERG) potassium channels in conscious dogs

Ethnopharmacological relevance: Hypaconitine is one of the main aconitum Alkaloids in traditional Chinese medicines prepared with herbs from the genus Acotinum. These herbs are widely used for the treatment of cardiac insufficiency and arrhythmias. However, Acotinum Alkaloids are known for their toxicity as well as their pharmacological activity, especially cardiotoxicity including QT prolongation, and the mechanism of this toxicity is not clear.

Material and methods: In this study, hypaconitine was administered orally to conscious Beagle dogs, and electrocardiograms were recorded by telemetry. Pharmacokinetic studies (6h) were conducted to evaluate the relationship between QT prolongation and exposure level. HEK293 cells stably transfected with KCNH2 (hERG) cDNA were used to examine the effects of hypaconitine on the KCNH2 channel by using the manual patch clamp technique.

Results: In the conscious dogs, all doses of hypaconitine induced QTcV (QT interval corrected according to the Van de Water formula) prolongation by more than 23% (67ms) of control in a dose-dependent manner. The maximum QTcV prolongation was observed at 2h after dosing. Maximum prolongation percentages were plotted against plasma concentrations of hypaconitine and showed a strong correlation (R(2)=0.789). In the in vitro study in HEK293 cells, hypaconitine inhibited the KCNH2 currents in a concentration-dependent manner with an IC50 of 8.1nM.

Conclusion: These data suggest that hypaconitine inhibits KCNH2 potassium channels and this effect might be the molecular mechanism underlying QT prolongation in conscious dogs.

ECG telemetry; Hypaconitine; QT prolongation; Safety assessment; hERG channels.