Abstract
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 (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(K250)) in a concentration- dependent manner. Estimated IC50 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.
Original language | English (US) |
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Pages (from-to) | 1597-1604 |
Number of pages | 8 |
Journal | Journal of cardiovascular electrophysiology |
Volume | 10 |
Issue number | 12 |
DOIs | |
State | Published - 1999 |
Externally published | Yes |
Keywords
- Cardiac repolarization
- Delayed rectifier
- Droperidol
- QT interval
- Torsades de pointes
ASJC Scopus subject areas
- Cardiology and Cardiovascular Medicine
- Physiology (medical)