Cellular and ionic mechanisms underlying erythromycin-induced long QT intervals and torsade de pointes

Objectives. This study sought to elucidate the cellular and ionic basis for erythromycin-induced long QT syndrome. Background. Erythromycin is known to produce long QTU intervals on the electrocardiogram (ECG) and to be associated with the development of torsade de pointes (TdP). The mechanisms responsible far the adverse effects of this widely used antibiotic are not well defined, Methods. The present study used microelectrode and whole-cell patch-damp techniques to assess the effects of erythromycin an epicardial, endocardial and M cells in transmural strips, arterially perfused wedges and single myocytes isolated from the canine left ventricle, Results. In isolated strips, erythromycin (10 to 100 mu g/ml) produced a much more pronounced prolongation of the action potential duration (APD) in M cells than in endocardial and epicardial cells, resulting in the development of a large dispersion of repolarization across the ventricular wall at slow stimulation rates, Erythromycin (50 to 100 mu g/ml) induced early afterdepolarizations (EADs) in cells in the M (20%) but not epicardial or endocardial regions in transmural strips of ventricular free wall, Erythromycin (100 mu g/ml) also caused APD prolongation and a transmural dispersion of repolarization, but not EADs, in intact arterially perfused wedges of canine left ventricle, These changes Here attended br the development of a long QT interval on the transmural ECG, A polymorphic ventricular tachycardia closely resembling TdP was readily and reproducibly induced after erythromycin but not before. Whole-cell patch-clamp techniques, used to examine the effects of erythromycin on myocytes isolated from the hf region, showed a potent effect of the drug to inhibit the rapidly activating component (I-Kr) but not the slowly activating component (I-Ks) of the delayed rectifier potassium current (I-K). The inward rectifier current (I-KI) Has unaffected, Conclusions. Our data demonstrate a preferential response of M cells to the class III actions of erythromycin, due principally to the effect of the drug to inhibit I-Kr in a population of cells largely devoid of I-Ks. Our findings indicate that erythromycin thus produces long QT intervals as well as a prominent dispersion of repolarization across the ventricular Hall, setting the stage for induction of TdP-like tachyarrhythmias displaying characteristics typical of reentry. (C) 1996 by the American College of Cardiology