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 μmol/L) and LQT2-like states by E4031 (10 ±mol/L). Computational analysis was performed using the Luo-Rudy dynamic model. Data are given as mean ± SEM. RESULTS: In control myocytes, droperidol lengthened action potentials in a concentrationdependent manner with a maximal prolongation of 37% ± 13% (n ± 4) at a concentration of 0.6 μmol/L. In LQT1-like myocytes, droperidol (0.6 ±mol/L) further prolonged action potentials by 31% ± 6% (n ± 6) but shortened action potentials of LQT2-like myocytes by 11% ± 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±-Ca²⁺ 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. (Anesth Analg 2010;111:638-46)