Cellular and ionic mechanisms underlying erythromycin-induced long QT intervals and torsade de pointes.
OBJECTIVE
This study sought to elucidate the cellular and ionic basts 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 micrograms/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 micrograms/ml) induced early after depolarizations (EADs) in cells in the M (20%) but not epicardial or endocardial regions in transmural strips of ventricular free wall. Erythromycin (100 micrograms/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 (IK(r)) but not the slowly activating component (IKs) of the delayed rectifier potassium current (IK). The inward rectifier current (IK1) 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 IK(r) in a population of cells largely devoid of IKs. 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.
Antzelevitch
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Masonic Medical Research Laboratory Utica, New York 13501, USA. ca@mmrl.edu
Sun
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Zhang
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Yan
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D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000900:Anti-Bacterial Agents / Q000633:toxicity*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography; D004594:Electrophysiology; D004699:Endocardium / Q000503:physiopathology; D004917:Erythromycin / Q000633:toxicity*; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D006352:Heart Ventricles / Q000503:physiopathology; D066298:In Vitro Techniques; D008133:Long QT Syndrome / Q000139:chemically induced / Q000503:physiopathology*; D008297:Male; D008839:Microelectrodes; D009206:Myocardium / Q000473:pathology; D018408:Patch-Clamp Techniques; D010496:Pericardium / Q000503:physiopathology; D015221:Potassium Channels / Q000502:physiology*; D016171:Torsades de Pointes / Q000139:chemically induced / Q000503:physiopathology*
D000900:Anti-Bacterial Agents; D015221:Potassium Channels; D004917:Erythromycin