ELECTROPHYSIOLOGICAL MECHANISMS IN A CANINE MODEL OF ERYTHROMYCIN-ASSOCIATED LONG QT SYNDROME

Background. Erythromycin is known to prolong ventricular repolarizatio n and has been associated with the occurrence of torsades de pointes. In this study, we have investigated potential mechanisms in vivo and i n vitro for induction of an acquired long QT syndrome by erythromycin. Methods and Results. Ventricular electrograms and endocardial monopha sic action potentials were recorded in anesthetized open-chest dogs be fore and after administration of 40 to 120 mg/kg of erythromycin lacto bionate. Conventional microelectrode techniques were used to record tr ansmembrane action potentials in isolated dog Purkinje fibers and papi llary muscles. Erythromycin at concentrations >20 mg/L prolonged actio n potential duration. At higher concentrations (100 to 200 mg/L), eryt hromycin induced phase 2 and phase 3 early afterdepolarizations (EADs) both in vivo and in vitro. The effects of erythromycin on repolarizat ion were more marked in Purkinje fibers than in papillary muscle. Pret reatment of Purkinje fibers with erythromycin antagonized the effects of dofetilide, a selective delayed-rectifier potassium channel (I(K)) blocker. Pretreatment with prazosin or tetrodotoxin had no effect on e rythromycin-induced changes in action potential duration. Conclusions. These pharmacological studies suggest that erythromycin prolongs repo larization to a large extent by block of I(K). In turn, prolongation o f action potential duration resulting from erythromycin's actions on I (K) 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 ventri cular arrhythmias suggests that other predisposing factors contribute to the acquired long QT syndrome associated with erythromycin.