Inhibition of the rapid component of the delayed-rectifier K+ current by therapeutic concentrations of the antispasmodic agent terodiline

Abstract

Prolongation of the QT interval and malignant ventricular arrhythmia have been observed in patients administered terodiline for urinary incontinence. Since this adverse reaction might be caused by inhibition of delayed-rectifier K⁺ current (I_K), we investigated whether clinically relevant (⩽10 μM) concentrations of the drug modify I_K in guinea-pig ventricular myocytes.
Myocytes superfused with normal Tyrode's solution were pulsed from −40 mV to more positive test potentials (V) for 0.2–1 s to elicit tail I_K on repolarization and measure tail I_K-V relationships. I_Kr was distinguished from I_Ks by its sensitivity to the selective blocker E4031.
Inhibition of I_Kr by 5 μM E4031 was completely occluded by pretreatment with 3 μM terodiline. In addition, action potential lengthening by E4031 in guinea-pig papillary muscles (29±3%) was abolished (3±2%) (P<0.001) by terodiline pretreatment.
Inhibition of I_Kr by terodiline appeared to be voltage-independent, and the parameters of the Hill equation describing the inhibition were IC₅₀=0.7 μM and n_H=1.6. High concentrations of the drug also affect I_Ks; in experiments with K⁺-free Tyrode's, 10 μM terodiline inhibited tail I_Ks by 27±3% (n=5) (P<0.001).
These data suggest that QT lengthening at therapeutic concentrations of the drug (≈amp;1.5 μM) is primarily due to inhibition of I_Kr. Inhibition of other K⁺ currents such as I_Ks is likely to be important at higher concentrations.

Keywords: Guinea-pig ventricular myocytes, guinea-pig papillary muscles, K⁺ currents, E4031, action potentials