Droperidol lengthens cardiac repolarization due to block of the rapid component of the delayed rectifier potassium current

INTRODUCTION: Torsades de pointes have been observed during treatment with droperidol, a butyrophenone neuroleptic agent. Our objectives were (1) to characterize the effects of droperidol on cardiac repolarization and (2) to evaluate effects of droperidol on a major time-dependent outward potassium current involved in cardiac repolarization (I(K)r). METHODS AND RESULTS: Isolated, buffer-perfused guinea pig hearts (n = 32) were stimulated at different pacing cycle lengths (150 to 250 msec) and exposed to droperidol in concentrations ranging from 10 to 300 nmol/L. Droperidol increased monophasic action potential duration measured at 90% repolarization (MAPD90) in a concentration-dependent manner by 9.8+/-2.3 msec (7.3%+/-0.7%) at 10 nmol/L but by 32.7+/-3.6 msec (25.7%+/-2.2%) at 300 nmol/L (250-msec cycle length). Increase in MAPD90 also was reverse frequency dependent. As noted previously, droperidol 300 nmol/L increased MAPD90 by 32.7+/-3.6 msec (25.7%+/-2.2%) at a pacing cycle length of 250 msec but by only 14.1+/-1.3 msec (13.6%+/-2.3%) at a pacing cycle length of 150 msec. Patch clamp experiments performed in isolated guinea pig ventricular myocytes demonstrated that droperidol decreases the time-dependent outward K+ current elicited by short depolarizations (250 msec; I(K)250) in a concentration-dependent manner. Estimated IC50 for I(K)250, which mostly underlies I(K)r, was 28 nmol/L. Finally, HERG K+ current elicited in HEK293 cells expressing high levels of HERG protein was decreased 50% by droperidol 32.2 nmol/L. CONCLUSION: Potent block of I(K)r by droperidol is likely to underlie QT prolongation observed in patients treated at therapeutic plasma concentrations (10 to 400 nmol/L) of the drug.