INHIBITION OF THE RAPID COMPONENT OF THE DELAYED-RECTIFIER K+ CURRENTBY 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 in continence. Since this adverse reaction might be caused by inhibition of delayed-rectifier K+ current (I-K), we investigated whether clinica lly relevant (less than or equal to 10 mu M) concentrations of the dru g 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 gui nea-pig papillary muscles (29+3%) was abolished (3+/-2%) (P<0.001) by terodiline pretreatment. 4 Inhibition of I-Kr by terodiline appeared t o be voltage-independent, and the parameters of the Hill equation desc ribing the inhibition were IC50 = 0.7 mu M and n(H) = 1.6. High concen trations of the drug also affect I-Ks; in experiments with K+-free Tyr ode'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 concen trations of the drug (approximate to 1.5 mu M) is primarily due to inh ibition of I-Kr. Inhibition of other K+ currents such as I-Ks is likel y to be important at higher concentrations.