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Naunyn Schmiedebergs Arch Pharmacol
2007 Dec 01;3764:275-84. doi: 10.1007/s00210-007-0202-6.
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Anticholinergic antiparkinson drug orphenadrine inhibits HERG channels: block attenuation by mutations of the pore residues Y652 or F656.
Scholz EP
,
Konrad FM
,
Weiss DL
,
Zitron E
,
Kiesecker C
,
Bloehs R
,
Kulzer M
,
Thomas D
,
Kathöfer S
,
Bauer A
,
Maurer MH
,
Seemann G
,
Katus HA
,
Karle CA
.
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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.
Abbott,
MiRP1 forms IKr potassium channels with HERG and is associated with cardiac arrhythmia.
1999, Pubmed,
Xenbase
Abbott,
MiRP1 forms IKr potassium channels with HERG and is associated with cardiac arrhythmia.
1999,
Pubmed
,
Xenbase
Altomare,
Heteromeric HCN1-HCN4 channels: a comparison with native pacemaker channels from the rabbit sinoatrial node.
2003,
Pubmed
Anantharam,
RNA interference reveals that endogenous Xenopus MinK-related peptides govern mammalian K+ channel function in oocyte expression studies.
2003,
Pubmed
,
Xenbase
Barish,
A transient calcium-dependent chloride current in the immature Xenopus oocyte.
1983,
Pubmed
,
Xenbase
Brocks,
Anticholinergic drugs used in Parkinson's disease: An overlooked class of drugs from a pharmacokinetic perspective.
1999,
Pubmed
Choe,
A novel hypothesis for the binding mode of HERG channel blockers.
2006,
Pubmed
Curran,
A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome.
1995,
Pubmed
Danze,
Reversal of orphenadrine-induced ventricular tachycardia with physostigmine.
1991,
Pubmed
Dilaveris,
Non-sustained ventricular tachycardia due to low-dose orphenadrine.
2001,
Pubmed
Ellison,
Metabolic studies of 3 H-orphenadrine citrate in the rat, dog and rhesus monkey.
1972,
Pubmed
Henderson,
Life-threatening ventricular arrhythmia (torsades de pointes) after haloperidol overdose.
1991,
Pubmed
Kiehn,
Pathways of HERG inactivation.
1999,
Pubmed
,
Xenbase
Kiesecker,
Class Ia anti-arrhythmic drug ajmaline blocks HERG potassium channels: mode of action.
2004,
Pubmed
,
Xenbase
Kornhuber,
Orphenadrine is an uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist: binding and patch clamp studies.
1995,
Pubmed
Labout,
Difference between single and multiple dose pharmacokinetics of orphenadrine hydrochloride in man.
1982,
Pubmed
Lees,
Alternatives to levodopa in the initial treatment of early Parkinson's disease.
2005,
Pubmed
Luzza,
Torsades de pointes in congenital long QT syndrome following low-dose orphenadrine.
2006,
Pubmed
Madeja,
Follicular tissues reduce drug effects on ion channels in oocytes of Xenopus laevis.
1997,
Pubmed
,
Xenbase
McDonald,
A minK-HERG complex regulates the cardiac potassium current I(Kr).
1997,
Pubmed
,
Xenbase
Mitcheson,
A structural basis for drug-induced long QT syndrome.
2000,
Pubmed
,
Xenbase
Redfern,
Relationships between preclinical cardiac electrophysiology, clinical QT interval prolongation and torsade de pointes for a broad range of drugs: evidence for a provisional safety margin in drug development.
2003,
Pubmed
Sanguinetti,
A mechanistic link between an inherited and an acquired cardiac arrhythmia: HERG encodes the IKr potassium channel.
1995,
Pubmed
,
Xenbase
Scholz,
Inhibition of cardiac HERG channels by grapefruit flavonoid naringenin: implications for the influence of dietary compounds on cardiac repolarisation.
2005,
Pubmed
,
Xenbase
Scholz,
Drug binding to aromatic residues in the HERG channel pore cavity as possible explanation for acquired Long QT syndrome by antiparkinsonian drug budipine.
2003,
Pubmed
,
Xenbase
Sesti,
A common polymorphism associated with antibiotic-induced cardiac arrhythmia.
2000,
Pubmed
Sánchez-Chapula,
Block of wild-type and inactivation-deficient human ether-a-go-go-related gene K+ channels by halofantrine.
2004,
Pubmed
,
Xenbase
Thomas,
The antidepressant drug fluoxetine is an inhibitor of human ether-a-go-go-related gene (HERG) potassium channels.
2002,
Pubmed
,
Xenbase
Thomas,
Inhibition of cardiac HERG currents by the DNA topoisomerase II inhibitor amsacrine: mode of action.
2004,
Pubmed
,
Xenbase
Thomas,
The antipsychotic drug chlorpromazine inhibits HERG potassium channels.
2003,
Pubmed
,
Xenbase
Trudeau,
HERG, a human inward rectifier in the voltage-gated potassium channel family.
1995,
Pubmed
Van Herreweghe,
Orphenadrine poisoning in a child: clinical and analytical data.
1999,
Pubmed
