In vitro electrophysiological detection of iatrogenic arrhythmogenicity

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Abstract
Summary— Cardiac arrhythmias and sudden death have been associated with both therapeutic and toxic doses of a number of cardiotropic and non‐cardiac drugs. Generally the drug‐induced electrocardiographic (ECG) alterations have been well described, whereas corresponding cellular electrophysiological effects are poorly documented or lacking. Taking into account the recent advances in the understanding of the mechanisms underlying arrhythmias and antiarrhythmic effects, suitable relationships can be established between ECG alterations and drug effects on cardiac action potential. Thus, a decrease in maximal upstroke velocity (Vmax) and membrane depolarisation leading to cellular inexcitability may slow conduction, prolong QRS interval duration and result in incessant wide QRS ventricular tachycardia. On the other hand, lengthening of the repolarisation phase and early afterdepolarisations (EADs) have been proposed as a mechanism for prolonged QT interval and subsequent Torsades de Pointes. A representative study aimed at detecting the arrhythmogenic potentiality of a drug is given, by examining carefully the concentration‐ and frequency‐dependent effects of four neuroleptics (sultopride, droperidol, thioridazine and clozapine) on Purkinje fibers and comparing them with the reported iatrogenic arrhythmias. The results showed that 10 to 100 μM sultopride and 0.01 to 1 μM droperidol exerted “pure” class III effects. In addition, higher concentrations (3 to 30 μM) of droperidol reversed the prolonging effect on repolarisation concomitantly with a dose‐ and frequency‐dependent decrease in Vmax, action potential amplitude and resting membrane potential (class I effects) resulting in cellular inexcitability at 30 μM. Similar class I effects were induced by thioridazine and clozapine concomitantly with a slight prolonging effect on final repolarisation (class la effects). In the presence of sultopride (30 and 100 μM) and droperidol (0.3 to 3 μM), EADs developed at plateau level. Their incidence, amplitude and number were influenced by extracellular K or Mg concentration, stimulation frequency, modification of Ca entry (by nifedipine or isoproterenol). These experimental results fit well with clinical data although they need further development to precise underlying ionic mechanisms. Therefore, in vitro studies should be considered before clinical prospects for future drug development.