Droperidol inhibits fits 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 Ca2+ concentration ([Ca2+](i)). Because [Ca2+](i) and myofilament Ca2+ sensitivity are key regulators of myocardial contractility, the authors' objective was to identify whether droperidol alters [Ca2+](i) or myofilament Ca2+ 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, [Ca2+](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 mu m) caused concentration-dependent decreases in peak [Ca2+](i) and shortening. Droperidol inhibited 35 mm KCl-induced increase in [Ca2+](i), with little direct effect on sarcoplasmic reticulum Ca2+ stores. Droperidol had no effect on action potential duration but caused a rightward shift in the concentration-response curve to extracellular Ca2+ for shortening, with no concomitant effect on peak [Ca2+](i) Droperidol decreased pH, and increased nitric oxide production. Droperidol exerted a negative inotropic effect in Langendorff perfused hearts. Conclusion: These data demonstrate that droperidol decreases cardiomyocyte function, which is mediated by a decrease in [Ca2+](i) and a decrease in myoftlament Ca2+ sensitivity. The decrease in [Ca2+](i) is mediated by decreased sarcolemmal Ca2+ influx. The decrease in myofilament Ca2+ sensitivity is likely mediated by a decrease in pH(i) and an increase in nitric oxide production.