Droperidol inhibits intracellular Ca2+, myofilament Ca2+ sensitivity, and contraction in rat ventricular myocytes.
BACKGROUND
Droperidol has recently been associated with cardiac arrhythmias and sudden cardiac death. Changes in action potential duration seem to be the cause of the arrhythmic behavior, which can lead to alterations in intracellular free Ca concentration ([Ca]i). Because [Ca]i and myofilament Ca sensitivity are key regulators of myocardial contractility, the authors' objective was to identify whether droperidol alters [Ca]i or myofilament Ca sensitivity in rat ventricular myocytes and to identify the cellular mechanisms responsible for these effects.


METHODS
Freshly isolated rat ventricular myocytes were obtained from adult rat hearts. Myocyte shortening, [Ca]i, nitric oxide production, intracellular pH, and action potentials were monitored in cardiomyocytes exposed to droperidol. Langendorff perfused hearts were used to assess overall cardiac function.


RESULTS
Droperidol (0.03-1 mum) caused concentration-dependent decreases in peak [Ca]i and shortening. Droperidol inhibited 35 mm KCl-induced increase in [Ca]i, with little direct effect on sarcoplasmic reticulum Ca stores. Droperidol had no effect on action potential duration but caused a rightward shift in the concentration-response curve to extracellular Ca for shortening, with no concomitant effect on peak [Ca]i. Droperidol decreased pHi and increased nitric oxide production. Droperidol exerted a negative inotropic effect in Langendorff perfused hearts.


CONCLUSIONS
These data demonstrate that droperidol decreases cardiomyocyte function, which is mediated by a decrease in [Ca]i and a decrease in myofilament Ca sensitivity. The decrease in [Ca]i is mediated by decreased sarcolemmal Ca influx. The decrease in myofilament Ca sensitivity is likely mediated by a decrease in pHi and an increase in nitric oxide production.
Shiga
Toshiya
T
Center for Anesthesiology Research, Division of Anesthesiology and Critical Care Medicine, Lerner Research Institute, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA.
Yong
Sandro
S
Carino
Joseph
J
Murray
Paul A
PA
Damron
Derek S
DS
D008841:Actin Cytoskeleton / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D048429:Cell Size / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004329:Droperidol / Q000494:pharmacology*; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D007424:Intracellular Fluid / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects* / Q000502:physiology; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D004329:Droperidol; D002118:Calcium