Inhibition of HERG channels stably expressed in a mammalian cell line by the antianginal agent perhexiline maleate.
Perhexiline has been used as an anti-anginal agent for over 25 years, and is known to cause QT prolongation and torsades de pointes. We hypothesized that the cellular basis for these effects was blockade of I(Kr). A stable transfection of HERG into a CHO-K1 cell line produced a delayed rectifier, potassium channel with similar properties to those reported for transient expression in Xenopus oocytes. Perhexiline caused voltage- and frequency-dependent block of HERG (IC50 7.8 microM). The rate of inactivation was increased and there was a 10 mV hyperpolarizing shift in the voltage-dependence of steady-state inactivation, suggestive of binding to the inactivated state. In conclusion, perhexiline potently inhibits transfected HERG channels and this is the probable mechanism for QT prolongation and torsades de pointes. Channel blockade shows greatest affinity for the inactivated state.
Walker
B D
BD
Department of Clinical Pharmacology, University of New South Wales, Victor Chang Cardiac Research Institute, St Vincent's Hospital, Darlinghurst, Australia. b.walker@garvan.unsw.edu.au
Valenzuela
S M
SM
Singleton
C B
CB
Tie
H
H
Bursill
J A
JA
Wyse
K R
KR
Qiu
M R
MR
Breit
S N
SN
Campbell
T J
TJ
D000465:Algorithms; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D016466:CHO Cells; D002317:Cardiovascular Agents / Q000494:pharmacology*; D027682:Cation Transport Proteins; D006224:Cricetinae; D004558:Electric Stimulation; D051638:Ether-A-Go-Go Potassium Channels; D066298:In Vitro Techniques; D008564:Membrane Potentials; D009865:Oocytes; D018408:Patch-Clamp Techniques; D010480:Perhexiline / Q000031:analogs & derivatives* / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism*; D024642:Potassium Channels, Voltage-Gated; D011725:Pyridines / Q000494:pharmacology; D014982:Xenopus laevis
D000889:Anti-Arrhythmia Agents; D002317:Cardiovascular Agents; D027682:Cation Transport Proteins; D051638:Ether-A-Go-Go Potassium Channels; C092509:KCNH6 protein, human; D010880:Piperidines; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D011725:Pyridines; C063968:E 4031; C023470:perhexiline maleate; D010480:Perhexiline