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 occu rrence of the polymorphic ventricular arrhythmia torsades de pointes in pat ients. Therefore, it was of interest to study the actions of some of these drugs such as imipramine, amitriptyline, doxepin, chlorpromazine, trifluope razine and thioridazine in isolated, spontaneously beating Purkinje fibers of guinea-pig hearts using the intracellular microelectrode technique becau se experimentally induced early afterdepolarizations (EADs) may be associat ed with this special type of arrhythmia. If the extracellular K+ concentrat ion was 2.7 mM none of these drugs could elicit EADs. For that reason the K + concentration was lowered to 1.35 mM and EADs were evoked by imipramine ( 2 and 5 mu M). Amitriptyline (2 and 5 mu M) and doxepin (2 mu M) did not in duce EADs. Only a concentration of 5 mu M doxepin elicited EADs. Among the neuroleptic drugs, chlorpromazine at a concentration of 2 and 5 mu M was re sponsible for the occurrence of EADs as well as thioridazine in the same co ncentrations. When trifluoperazine (2 and 5 mu M) was applied no EADs could be observed. Tetrodotoxin (0.21 mu M) abolished thiorictazine-induced EADs . Several membrane depolarizing currents may participate in the initiation of these EADs. Our results demonstrate that in guinea-pig Purkinje fibers s ome tricyclic antidepressants and some neuroleptic drugs are responsible fo r the rare occurrence of EADs under hypokalemic conditions. (C) 1998 Elsevi er Science B.V. All rights reserved.