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

Droperidol Blocks Cardiac I-Kr. Introduction: Torsades de pointes have been observed during treatment with droperidol, a butyrophenone neuroleptic age nt. Our objectives were (1) to characterize the effects of droperidol on ca rdiac repolarization and (2) to evaluate effects of droperidol on a major t ime-dependent outward potassium current involved in cardiac repolarization (I-Kr). Methods and Results: Isolated, buffer-perfused guinea pig hearts (n = 32) w ere stimulated at different pacing cycle lengths (150 to 250 msec) and expo sed to droperidol in concentrations ranging from 10 to 300 nmol/L, Droperid ol increased monophasic action potential duration measured at 90% repolariz ation (MAPD(90)) 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% +/- 22%) at 300 nmol/L (250-msec cycle length). Increase in MAPD(90) also was reverse frequ ency dependent. As noted previously, droperidol 300 nmol/L increased MAPD(9 0) by 32.7 +/- 3.6 msec (25.7% +/- 2.2%) at a pacing cycle length of 250 ms ec 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 ventr icular myocytes demonstrated that droperidol decreases the time-dependent o utward K+ current elicited by short depolarizations (250 msec; I-K250) in a concentration-dependent manner. Estimated IC50 for I-K250, which mostly un derlies I-Kr, was 28 nmol/L, Finally, HERG K+ current elicited in HEK293 ce lls expressing high levels of HERG protein was decreased 50% by droperidol 32.2 nmol/L, Conclusion: Potent block of I-Kr by droperidol is likely to underlie QT pro longation observed in patients treated at therapeutic plasma concentrations (10 to 400 nmol/L) of the drug.