Anticholinergic antiparkinson drug orphenadrine inhibits HERG channels: block attenuation by mutations of the pore residues Y652 or F656.
The anticholinergic antiparkinson drug orphenadrine is an antagonist at central and peripheral muscarinic receptors. Orphenadrine intake has recently been linked to QT prolongation and Torsade-de-Pointes tachycardia. So far, inhibitory effects on I (Kr) or cloned HERG channels have not been examined. HERG channels were heterologously expressed in a HEK 293 cell line and in Xenopus oocytes and HERG current was measured using the whole cell patch clamp and the double electrode voltage clamp technique. Orphenadrine inhibits cloned HERG channels in a concentration dependent manner, yielding an IC(50) of 0.85 microM in HEK cells. Onset of block is fast and reversible upon washout. Orphenadrine does not alter the half-maximal activation voltage of HERG channels. There is no shift of the half-maximal steady-state-inactivation voltage. Time constants of direct channel inactivation are not altered significantly and there is no use-dependence of block. HERG blockade is attenuated significantly in mutant channels lacking either of the aromatic pore residues Y652 and F656. In conclusion, we show that the anticholinergic agent orphenadrine is an antagonist at HERG channels. These results provide a novel molecular basis for the reported proarrhythmic side effects of orphenadrine.
Scholz
Eberhard P
EP
Department of Internal Medicine III, University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany. eberhard.scholz@med.uni-heidelberg.de
Konrad
Franziska M
FM
Weiss
Daniel L
DL
Zitron
Edgar
E
Kiesecker
Claudia
C
Bloehs
Ramona
R
Kulzer
Martin
M
Thomas
Dierk
D
Kathöfer
Sven
S
Bauer
Alexander
A
Maurer
Martin H
MH
Seemann
Gunnar
G
Katus
Hugo A
HA
Karle
Christoph A
CA
D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology*; D002460:Cell Line; D018680:Cholinergic Antagonists / Q000494:pharmacology*; D003001:Cloning, Molecular; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics / Q000502:physiology*; D005260:Female; D006801:Humans; D009154:Mutation; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D009966:Orphenadrine / Q000494:pharmacology*; D014982:Xenopus laevis
D000978:Antiparkinson Agents; D018680:Cholinergic Antagonists; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D009966:Orphenadrine