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

1 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 μ m ) concentrations of the drug modify I K in guinea‐pig ventricular myocytes. 2 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. 3 Inhibition of I Kr by 5 μ m E4031 was completely occluded by pretreatment with 3 μ m 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. 4 Inhibition of I Kr by terodiline appeared to be voltage‐independent, and the parameters of the Hill equation describing the inhibition were IC 50 =0.7 μ m and n H =1.6. High concentrations of the drug also affect I Ks ; in experiments with K + ‐free Tyrode's, 10 μ m terodiline inhibited tail I Ks by 27±3% ( n = 5 ) ( P < 0.001 ). 5 These data suggest that QT lengthening at therapeutic concentrations of the drug (≈amp;1.5 μ m ) 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.British Journal of Pharmacology (1998) 125 , 1138–1143; doi: 10.1038/sj.bjp.0702173