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 (less than or equal to 10 mu M) concentrations of the drug modify IK 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-Ks by 5 mu M E4031 was completely occluded by pretreatment with 3 mu 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 IC50 = 0.7 mu M and n(H) = 1.6. High concentrations of the drug also affect I-Ks; in experiments with K+-free Tyrode's, 10 mu 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 (approximate to 1.5 mu 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.