© 2003 by European Society of Cardiology
Copyright © 2003, European Society of Cardiology
Effects of propafenone and its main metabolite, 5-hydroxypropafenone, on HERG channels
Institute of Pharmacology and Toxicology, CSIC/UCM, School of Medicine, Universidad Complutense, 28040 Madrid, Spain
c.arias{at}ift.csic.es
* Corresponding author. Tel.: +34-91-394-1474; fax: +34-91-394-1470.
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 µM) inhibited HERG current by 78.7±2.3% (n=7) and 71.1±4.1% (n=7, P0.05) 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, P0.05) 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.
KEYWORDS Antiarrhythmic agents; Arrhythmia (mechanisms); Ion channels; K-channel; Membrane currents
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