Thioridazine lengthens repolarization of cardiac ventricular myocytes by blocking the delayed rectifier potassium current

Proarrhythmia has been observed with the antipsychotic agent thioridazine ( THIO). The mechanisms underlying these effects are unknown. The objectives of this study were 1) to characterize the effects of THIO on cardiac repola rization and 2) to determine whether lengthening of the Q-T interval could be explained by blocking major K+-repolarizing currents. Isolated, buffer-p erfused guinea pig hearts (n = 32) were stimulated at various pacing cycle lengths (150-250 ms) and exposed to THIO at concentrations ranging from 300 nM to 3 mu M. THIO increased monophasic action potential duration at 90% r epolarization (MAPD(90)) in a concentration-dependent manner from 14.9 +/- 1.8 at 300 nM to 37.1 +/- 3.2 ms at 3 mu M. Increase in MAPD(90) was also r everse frequency-dependent; THIO (300 nM) increased MAPD(90) by 14.9 +/-: 1 .8 ms at a pacing cycle length of 250 ms, but by only 7.7 +/- 1.2 ms at a p acing cycle length of 150 ms. Patch-clamp experiments demonstrated that THI O decreases the time-dependent outward K+ current elicited by short depolar izations (250 ms; I-K250) in a concentration-dependent manner. Estimated IC 50 for I-K250, which mostly underlies I-Kr, was 1.25 mu M. Time-dependent o utward K+ current elicited in tsA201 cells expressing high levels of HERG p rotein was also decreased approximately 50% by 1.25 mu M THIO. On the other hand, THIO was less potent (IC50 of 14 mu M) to decrease time-dependent K current elicited by long pulses (5000 ms; I-5000). Under the latter condit ions, I-K5000 corresponds mainly to I-Ks. Thus, these results demonstrate b lock of K+ currents and lengthening of cardiac repolarization by THIO in a concentration-dependent manner. This may provide an explanation of Q-T prol ongation observed in some patients treated with THIO.