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 (IK), we investigated whether clinically relevant (< or = 10 microM) concentrations of the drug modify IK 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 IK on repolarization and measure tail IK-V relationships. IKr was distinguished from IKs by its sensitivity to the selective blocker E4031. Inhibition of IKr by 5 microM E4031 was completely occluded by pretreatment with 3 microM 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 IKr by terodiline appeared to be voltage-independent, and the parameters of the Hill equation describing the inhibition were IC50 = 0.7 microM and nH = 1.6. High concentrations of the drug also affect IKs; in experiments with K+-free Tyrode's, 10 microM terodiline inhibited tail IKs by 27+/-3% (n=5) (P< 0.001). These data suggest that QT lengthening at therapeutic concentrations of the drug (approximately equal to 1.5 microM) is primarily due to inhibition of IKr. Inhibition of other K+ currents such as IKs is likely to be important at higher concentrations.