Effects of propafenone and its main metabolite, 5-hydroxypropafenone, on HERG channels.
OBJECTIVE
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.
Arias
Cristina
C
Institute of Pharmacology and Toxicology, CSIC/UCM, School of Medicine, Universidad Complutense, 28040 Madrid, Spain. c.arias@ift.csic.es
González
Teresa
T
Moreno
Ignacio
I
Caballero
Ricardo
R
Delpón
Eva
E
Tamargo
Juan
J
Valenzuela
Carmen
C
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D016466:CHO Cells; D027682:Cation Transport Proteins; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D051638:Ether-A-Go-Go Potassium Channels; D008564:Membrane Potentials / Q000187:drug effects; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D015221:Potassium Channels / Q000187:drug effects* / Q000502:physiology; D024642:Potassium Channels, Voltage-Gated; D011405:Propafenone / Q000031:analogs & derivatives* / Q000494:pharmacology*
D000889:Anti-Arrhythmia Agents; D027682:Cation Transport Proteins; D051638:Ether-A-Go-Go Potassium Channels; C092509:KCNH6 protein, human; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D011405:Propafenone; C044307:5-hydroxypropafenone