Effects of propafenone and its main metabolite, 5-hydroxypropafenone, on HERG channels.

OBJECTIVES: Propafenone is a class Ic antiarrhythmic drug used to maintain sinus rhythm in patients with atrial fibrillation. During chronic therapy, it undergoes extensive first-pass hepatic metabolism to 5-hydroxypropafenone. In the present study we have analysed the effects of propafenone and 5-hydroxypropafenone on HERG current.
METHODS: The whole-cell configuration of the patch-clamp technique was used in CHO cells stably transfected with the gene encoding HERG channels.
RESULTS: Propafenone and 5-hydroxypropafenone (2 microM) inhibited HERG current by 78.7+/-2.3% (n=7) and 71.1+/-4.1% (n=7, P>0.05) when measured at the end of 5-s depolarizing pulses to -10 mV. Block measured at the maximum peak of tail currents recorded at -60 mV was similar for propafenone (78.3+/-2.0%, n=7, P>0.05) and higher for 5-hydroxypropafenone (79.3+/-1.5%, n=7, P<0.05). Propafenone and 5-hydroxypropafenone shifted the midpoint of the activation curve by -10.2+/-0.9 mV (n=7, P<0.01) and -7.4+/-1.1 mV (n=10, P<0.01), respectively. Both drugs accelerated the deactivation and the inactivation process of HERG current. Propafenone, but not 5-hydroxypropafenone, inhibited to a higher extent HERG current at the end of 5-s depolarizing pulses to 0 mV than after promoting the transition of HERG channels from the inactivated to the opened state.
CONCLUSIONS: These results indicate that propafenone and its main active metabolite, 5-hydroxypropafenone, block HERG channels to a similar extent by binding predominantly to the open state of the channel.