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

Benoit Drolet, Shetuan Zhang, Dominic Deschênes, Jimmy Rail, Sylvie Nadeau, Zhengfeng Zhou, Craig T. January, Jacques Turgeon

Research output: Contribution to journalArticlepeer-review

107 Scopus citations

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 languageEnglish (US)
Pages (from-to)1597-1604
Number of pages8
JournalJournal of cardiovascular electrophysiology
Volume10
Issue number12
DOIs
StatePublished - Jan 1 1999
Externally publishedYes

Keywords

  • Cardiac repolarization
  • Delayed rectifier
  • Droperidol
  • QT interval
  • Torsades de pointes

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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