Cardiac Ion Channel Effects of Tolterodine

Abstract

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 ϩ 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 ϩ channel at concentrations of up to 1 M. Inhibition of L-type Ca 2ϩ 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 2ϩ channel blockade, may serve to attenuate the QT prolonging effects of this potent HERG channel antagonist.

In Vitro Electrocardiographic and Cardiac Ion Channel Effects of (−)-Epigallocatechin-3-Gallate, the Main Catechin of Green Tea

“…4B). We also tested the effects of EGCG using a step-step protocol at room temperature identical to what we have described previously (Kang et al, 2004). Under these experimental conditions, 10 M EGCG produced no inhibition of HERG current, whereas 30 M produced a modest 13 Ϯ 5% reduction (n ϭ 5).…”

“…The external solution contained 130 mM NaCl, 4 mM KCl, 2.8 mM sodium acetate, 1 mM MgCl 2 , 10 mM HEPES, 10 mM glucose, and 1 mM CaCl 2 (pH 7.4 with NaOH). The internal and external solutions for Na ϩ and Ca 2ϩ channels recordings have been described previously (Kang et al, 2004). All ionic currents were recorded using an Axopatch 200B amplifier (Danaher Corporation, Sunnyvale, CA) and were analyzed using the Clampfit program within the pCLAMP suite of software (Danaher Corporation).…”

Ca2+ Channel Activators Reveal Differential L-Type Ca2+ Channel Pharmacology between Native and Stem Cell-Derived Cardiomyocytes

“…Single ventricular myocytes were isolated from guinea pigs as described previously (Kang et al, 2004). Male Hartley guinea pigs were anesthetized with 5% isoflurane (Baxter Healthcare Corp., Deerfield IL) in a mixture of nitrous oxide and oxygen (1:1).…”

Discovery of a Small Molecule Activator of the Human Ether-a-go-go-Related Gene (HERG) Cardiac K+ Channel

“…The external solution contained 130 mM NaCl, 5 mM KCl, 2.8 mM sodium acetate, 1 mM MgCl 2 , 10 mM HEPES, 10 mM glucose, and 1 mM CaCl 2 , pH 7.4, with NaOH. The internal and external solutions for Na ϩ and Ca 2ϩ channel recordings have been described previously (Kang et al, 2004). All ionic currents were recorded using an Axopatch 200B amplifier (Axon Instruments Inc., Union City, CA).…”