ERYTHROMYCIN BLOCKS THE RAPID COMPONENT OF THE DELAYED RECTIFIER POTASSIUM CURRENT AND LENGTHENS REPOLARIZATION OF GUINEA-PIG VENTRICULAR MYOCYTES

Background Administration of erythromycin to humans has been associate d with lengthening of cardiac repolarization and even proarrhythmia. T he objectives of our study were to describe effects of erythromycin on repolarization of isolated hearts and to determine effects of the dru g on major K+ currents involved in cardiac repolarization. Methods and Results A first set of experiments was conducted in isolated, buffer- perfused guinea pig hearts electrically stimulated at a basic cycle le ngth of 250 ms. In this model, erythromycin 10(-4) mol/L increased mon ophasic action potential duration measured at 90% repolarization (MAPD (90)) by 40 +/- 7 ms. Increase in MAPD(90) was reproducibly observed i n seven hearts studied. To study the mechanism of these effects on car diac repolarization, a second set of experiments was performed in isol ated guinea pig ventricular myocytes using the whole cell configuratio n of the patch-clamp technique. In these cells, erythromycin 10(-4) mo l/L decreased by about 40% (P<.05 versus baseline) the time-dependent outward K+ current elicited by short depolarizations (250 ms) to low d epolarizing voltages (-20 to 0 mV). In contrast, the drug was without significant effects on the time-dependent K+ current elicited by long pulses (5000 ms) to high depolarizing voltages (+10 to +50 mV), on the time-independent background current (mostly I-K1), and on the slow in ward calcium current. Conclusions The outward time-dependent K+ curren t blocked by erythromycin in isolated guinea pig ventricular myocytes had characteristics similar to those described for I-Kr. Selective blo ck of this component of I-K gives an explanation for the effects of er ythromycin on cardiac repolarization. These effects were observed at c linically relevant concentrations reached after intravenous administra tion of the drug and warn for potential interactions with other action potential-lengthening drugs.