Premium
Droperidol Lengthens Cardiac Repolarization due to Block of the Rapid Component of the Delayed Rectifier Potassium Current
Author(s) -
DROLET BENOIT,
ZHANG SHETUAN,
DESCHÊNES DOMINIC,
RAIL JIMMY,
NADEAU SYLVIE,
ZHOU ZHENGFENG,
JANUARY CRAIG T.,
TURGEON JACQUES
Publication year - 1999
Publication title -
journal of cardiovascular electrophysiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.193
H-Index - 138
eISSN - 1540-8167
pISSN - 1045-3873
DOI - 10.1111/j.1540-8167.1999.tb00224.x
Subject(s) - droperidol , repolarization , herg , medicine , torsades de pointes , potassium channel blocker , pharmacology , potassium channel , anesthesia , electrophysiology , qt interval , vomiting
Droperidol Blocks Cardiac I Kr . 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 Kr ). 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 (MAPD 90 ) in a concentration‐dependent manner by 9.8 ± 2.3 msec (73%± 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 MAPDW 90 also was reverse frequency dependent As noted previously, droperidol 300 nmol/L increased MAPD 90 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 demostrated that droperidol decreases the time‐dependent outward K + current elicited by short depolarizations (250 msec; 1 k250 ) in a concentration‐dependent manner. Estimated IC 50 for I K250 , which mostly underlies I Kr , 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 Kr by droperidol is likely to underlie QT prolongation observed in patients treated at therapeutic plasma concentrations (10 to 400 nmol/L) of the drug.