Torsades de pointes is a potentially life-threatening form of polymorphic
ventricular tachyarrhythmia typically seen in the presence of repolarization-prolonging agents. We investigated this particular form of
tachyarrhythmia in the isolated, perfused rabbit heart. The experimental model was designed to reproduce conditions that are clinically known to be associated with an increased propensity to the development of
torsades de pointes. The class III agent
clofilium (1 microM) and d,l-
sotalol (10 microM), as well as the
antibiotic erythromycin (30-150 microM) were infused in the presence of either normal (5.88 mM) or low (1.5 mM)
potassium concentration in sinus-driven or atrioventricular (AV)-blocked hearts.
Ventricular tachyarrhythmias spontaneously emerged in the
clofilium-, d,l-
sotalol-, and
erythromycin-treated AV-blocked hearts. The episodes showed typical features of
torsades de pointes found in humans. They developed within 4-12 min after the onset of infusion, were normally nonsustained, and only rarely degenerated into
ventricular fibrillation. Electrical stimulation at cycle lengths <600 ms and perfusion with MgSO4 suppressed arrhythmic activity. In the d,l-
sotalol- and
erythromycin-treated hearts,
torsades de pointes occurred only in the presence of
hypokalemia and
bradycardia, whereas, in the presence of
clofilium,
bradycardia alone caused
torsades de pointes. Monophasic action-potential recordings demonstrated early afterdepolarizations in endocardial and epicardial recordings. Thus the isolated AV-blocked rabbit heart represents a model for studying
drug-related
torsades de pointes and its mechanism.