Cardiac ion channel effects of tolterodine.
Tolterodine is a muscarinic antagonist widely used in the treatment of urinary incontinence. Although tolterodine has not been reported to alter cardiac repolarization, it is chemically related to other muscarinic antagonists known to prolong cardiac repolarization. For this reason, we studied the effects of tolterodine on cardiac ion channels and action potential recordings. Using patch-clamp electrophysiology, we found that tolterodine was a potent antagonist of the human ether-a-go-go-related gene (HERG) K(+) channel, displaying an IC(50) value of 17 nM. This potency was similar to that observed for the antiarrhythmic drug dofetilide (IC(50) of 11 nM). Tolterodine block of HERG displayed a positive voltage dependence, suggesting an interaction with an activated state. Tolterodine had little effect on the human cardiac Na(+) channel at concentrations of up to 1 microM. Inhibition of L-type Ca(2+) currents by tolterodine was frequency-dependent with IC(50) values measuring 143 and 1084 nM at 1 and 0.1 Hz, respectively. Both tolterodine and dofetilide prolonged action potential duration in single guinea pig myocytes over the concentration range of 3 to 100 nM. However, prolongation was significantly larger for dofetilide compared with tolterodine. Tolterodine seems to be an unusual drug in that it blocks HERG with high affinity, but produces little QT prolongation clinically. Low plasma levels after therapeutic doses combined with mixed ion channel effects, most notably Ca(2+) channel blockade, may serve to attenuate the QT prolonging effects of this potent HERG channel antagonist.
Kang
Jiesheng
J
Department of Drug Safety Evaluation, Bridgewater, NJ, USA.
Chen
Xiao-Liang
XL
Wang
Hongge
H
Ji
Junzhi
J
Reynolds
William
W
Lim
Sungtaek
S
Hendrix
James
J
Rampe
David
D
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D001559:Benzhydryl Compounds / Q000494:pharmacology*; D016466:CHO Cells; D003408:Cresols / Q000494:pharmacology*; D006224:Cricetinae; D004594:Electrophysiology; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D007473:Ion Channels / Q000378:metabolism*; D010665:Phenylpropanolamine; D000068737:Tolterodine Tartrate
D001559:Benzhydryl Compounds; D003408:Cresols; D007473:Ion Channels; D010665:Phenylpropanolamine; D000068737:Tolterodine Tartrate