Electrophysiological mechanisms in a canine model of erythromycin-associated long QT syndrome.
BACKGROUND
Erythromycin is known to prolong ventricular repolarization and has been associated with the occurrence of torsades de pointes. In this study, we have investigated potential mechanisms in vivo and in vitro for induction of an acquired long QT syndrome by erythromycin.


RESULTS
Ventricular electrograms and endocardial monophasic action potentials were recorded in anesthetized open-chest dogs before and after administration of 40 to 120 mg/kg of erythromycin lactobionate. Conventional microelectrode techniques were used to record transmembrane action potentials in isolated dog Purkinje fibers and papillary muscles. Erythromycin at concentrations > 20 mg/L prolonged action potential duration. At higher concentrations (100 to 200 mg/L), erythromycin induced phase 2 and phase 3 early afterdepolarizations (EADs) both in vivo and in vitro. The effects of erythromycin on repolarization were more marked in Purkinje fibers than in papillary muscle. Pretreatment of Purkinje fibers with erythromycin antagonized the effects of dofetilide, a selective delayed-rectifier potassium channel (IK) blocker. Pretreatment with prazosin or tetrodotoxin had no effect on erythromycin-induced changes in action potential duration.


CONCLUSIONS
These pharmacological studies suggest that erythromycin prolongs repolarization to a large extent by block of IK. In turn, prolongation of action potential duration resulting from erythromycin's actions on IK may promote the development of EADs. The induction of ventricular arrhythmias observed clinically after exposure to erythromycin may be related to the development of EADs. The rarity of occurrence of ventricular arrhythmias suggests that other predisposing factors contribute to the acquired long QT syndrome associated with erythromycin.
Rubart
M
M
Krannert Institute of Cardiology, Indiana University School of Medicine, Indianapolis 46202-4800.
Pressler
M L
ML
Pride
H P
HP
Zipes
D P
DP
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D004285:Dogs; D004562:Electrocardiography; D004917:Erythromycin / Q000009:adverse effects*; D066298:In Vitro Techniques; D008133:Long QT Syndrome / Q000139:chemically induced* / Q000503:physiopathology*; D010210:Papillary Muscles / Q000187:drug effects*; D015221:Potassium Channels / Q000187:drug effects; D011690:Purkinje Fibers / Q000187:drug effects*; D015222:Sodium Channels / Q000187:drug effects
D015221:Potassium Channels; D015222:Sodium Channels; D004917:Erythromycin