Proarrhythmic effects of antidepressants and neuroleptic drugs on isolated, spontaneously beating guinea-pig Purkinje fibers.

Antidepressants and neuroleptic drugs are sometimes the reason for the occurrence of the polymorphic ventricular arrhythmia torsades de pointes in patients. Therefore, it was of interest to study the actions of some of these drugs such as imipramine, amitriptyline, doxepin, chlorpromazine, trifluoperazine and thioridazine in isolated, spontaneously beating Purkinje fibers of guinea-pig hearts using the intracellular microelectrode technique because experimentally induced early afterdepolarizations (EADs) may be associated with this special type of arrhythmia. If the extracellular K+ concentration was 2.7mM none of these drugs could elicit EADs. For that reason the K+ concentration was lowered to 1. 35mM and EADs were evoked by imipramine (2 and 5 microM). Amitriptyline (2 and 5 microM) and doxepin (2 microM) did not induce EADs. Only a concentration of 5 microM doxepin elicited EADs. Among the neuroleptic drugs, chlorpromazine at a concentration of 2 and 5 microM was responsible for the occurrence of EADs as well as thioridazine in the same concentrations. When trifluoperazine (2 and 5 microM) was applied no EADs could be observed. Tetrodotoxin (0. 2 microMl-1) abolished thioridazine-induced EADs. Several membrane depolarizing currents may participate in the initiation of these EADs. Our results demonstrate that in guinea-pig Purkinje fibers some tricyclic antidepressants and some neuroleptic drugs are responsible for the rare occurrence of EADs under hypokalemic conditions.