The subtype-specific effects of droperidol on action potential duration in cellular and computational models of long QT syndrome.
BACKGROUND
Droperidol is a highly potent butyrophenone used for the therapy of postoperative nausea and vomiting. Its cardiac safety in cardiovascular-healthy patients and those with long QT (LQT) syndrome is a matter of debate. In this study, we investigated whether droperidol has subtype-specific effects in cellular and computational models of LQT syndrome.


METHODS
Left ventricular cardiac myocytes were isolated from adult guinea pig hearts. LQT1-like behavior was pharmacologically induced by chromanol 293B (10 micromol/L) and LQT2-like states by E4031 (10 micromol/L). Computational analysis was performed using the Luo-Rudy dynamic model. Data are given as mean + or - SEM.


RESULTS
In control myocytes, droperidol lengthened action potentials in a concentration-dependent manner with a maximal prolongation of 37% + or - 13% (n = 4) at a concentration of 0.6 micromol/L. In LQT1-like myocytes, droperidol (0.6 micromol/L) further prolonged action potentials by 31% + or - 6% (n = 6) but shortened action potentials of LQT2-like myocytes by 11% + or - 2% (n = 8). Computational modeling supported the concept that droperidol, in addition to the rapid component of the delayed K(+) current, blocks depolarizing targets, such as the L-type Ca(2+) current, the Na(+)-Ca(2+) exchanger, and the Na(+)-K(+) adenosine triphosphatase.


CONCLUSIONS
Droperidol has more detrimental effects on cardiac repolarization of LQT1-like than of LQT2-like myocytes suggesting subtype-specific cardiotoxic effects in patients with LQT syndrome. The subtype specificity of droperidol seems to be caused by a complex interaction of droperidol with several different molecular targets. This interaction deserves further investigation to establish the feasibility of a subtype-directed approach in the perioperative management of patients with LQT syndrome.
Schwoerer
Alexander P
AP
Department of Vegetative Physiology and Pathophysiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. schwoerer@uke.de
Kebernik
Julia
J
Ehmke
Heimo
H
Friederich
Patrick
P
D000200:Action Potentials / Q000187:drug effects*; D000328:Adult; D000818:Animals; D000889:Anti-Arrhythmia Agents; D000932:Antiemetics / Q000494:pharmacology*; D002314:Cardioplegic Solutions; D002469:Cell Separation; D002839:Chromans; D003198:Computer Simulation; D003627:Data Interpretation, Statistical; D004329:Droperidol / Q000494:pharmacology*; D006168:Guinea Pigs; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced / Q000473:pathology*; D015233:Models, Statistical; D032383:Myocytes, Cardiac / Q000187:drug effects; D018408:Patch-Clamp Techniques; D010880:Piperidines; D026902:Potassium Channel Blockers; D011725:Pyridines; D013449:Sulfonamides
D000889:Anti-Arrhythmia Agents; D000932:Antiemetics; D002314:Cardioplegic Solutions; D002839:Chromans; D010880:Piperidines; D026902:Potassium Channel Blockers; D011725:Pyridines; D013449:Sulfonamides; C063968:E 4031; C103474:6-cyano-4-(N-ethylsulfonyl-N-methylamino)-3-hydroxy-2,2-dimethylchromane; D004329:Droperidol