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


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.


CONCLUSIONS
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.
Drolet
B
B
Quebec Heart Institute, Laval Hospital and Faculties of Pharmacy and Medicine, Laval University, Sainte-Foy, Québec, Canada.
Zhang
S
S
Deschênes
D
D
Rail
J
J
Nadeau
S
S
Zhou
Z
Z
January
C T
CT
Turgeon
J
J
D000200:Action Potentials / Q000187:drug effects*; D000818:Animals; D004195:Disease Models, Animal; D018492:Dopamine Antagonists / Q000494:pharmacology*; D004329:Droperidol / Q000494:pharmacology*; D004562:Electrocardiography; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000378:metabolism; D016171:Torsades de Pointes / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology
D018492:Dopamine Antagonists; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D004329:Droperidol