Cellular and Ionic Mechanisms Underlying Erythromycin-Induced Long QT Intervals and Torsade de Pointes

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• 作者：Charles Antzelevitch ; Zhuo-Qian Sun ; Zi-Qing Zhang ; Gan-Xin Yan
• 刊名：Journal of the American College of Cardiology
• 出版年：1996
• 出版时间：December 1996
• 年：1996
• 卷：28
• 期：7
• 页码：1836-1848
• 全文大小：503 K

文摘

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 for the adverse effects of this widely used antibiotic are not well defined.

Methods

The present study used microelectrode and whole-cell patch-clamp techniques to assess the effects of erythromycin on 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 Mg/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 Mg/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 Mg/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 were attended by 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 M 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_K1) was 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 wall, setting the stage for induction of TdP-like tachyarrhythmias displaying characteristics typical of reentry.