title: Prolongation of QT interval in isolated feline hearts by antipsychotic drugs.
abstract: Some antipsychotic drugs have been found to prolong the QT interval on electrocardiographic (ECG) recordings, a phenomenon which, when severe, may facilitate the occurrence of complex ventricular arrhythmias such as torsade de pointes. However, the effects of these drugs on the cardiac repolarization process have not been evaluated extensively. This study was designed to examine the potency of five antipsychotic drugs in lengthening the QT interval of the perfused feline heart: haloperidol, risperidone, sertindole, clozapine, and olanzapine. The hearts were infused with increasing concentrations of drugs (0.1-20 micromol/L) for 40-minute intervals at each concentration. ECG recordings were made, with signals amplified and data recorded on a strip chart recorder. Four representative beats from each set of three signal recordings were chosen for QT interval measurement. Our data indicated that all tested drugs prolonged the QT interval in a concentration-dependent manner (p < 0.01). Haloperidol and risperidone were significantly more potent than sertindole, clozapine, and olanzapine (p < 0.001). At a concentration of 0.5 micromol/L over a 40-minute infusion interval, haloperidol lengthened the interval by 26.2+/-0.7%, risperidone by 19.4+/-2.2%, and sertindole by 8.9+/-3.5% (p < 0.05 compared with baseline); clozapine and olanzapine were less potent. Although species differences may limit extrapolation of our findings to humans, the cardiac potassium channels of felines clearly resemble those of humans. This model may serve as the basis for further studies of drug-induced prolongation of the QT interval and precipitation of ventricular arrhythmias.
authors.affiliation: Department of Pharmacology, Georgetown University Medical Center, Washington, DC 20007-2195, USA.
authors.forename: M D
authors.initials: MD
authors.lastname: Drici
authors.forename: W X
authors.initials: WX
authors.lastname: Wang
authors.forename: X K
authors.initials: XK
authors.lastname: Liu
authors.forename: R L
authors.initials: RL
authors.lastname: Woosley
authors.forename: D A
authors.initials: DA
authors.lastname: Flockhart
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D014150:Antipsychotic Agents / Q000009:adverse effects* / Q000378:metabolism / Q000494:pharmacology; D002415:Cats; D003024:Clozapine / Q000494:pharmacology; D004562:Electrocardiography / Q000187:drug effects*; D006220:Haloperidol / Q000494:pharmacology; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D018967:Risperidone / Q000494:pharmacology
chemical_list: D014150:Antipsychotic Agents; D007093:Imidazoles; D007211:Indoles; C066304:sertindole; D003024:Clozapine; D006220:Haloperidol; D018967:Risperidone