Inhibitory effect of erythromycin on potassium currents in rat ventricular myocytes in comparison with disopyramide.
Disopyramide, a class Ia antiarrhythmic agent, has been reported to induce torsades de pointes (TdP) associated with excessive QT prolongation in electrocardiogram (ECG), especially when concomitantly administered with erythromycin, a macrolide antibiotic agent. In this study, we have evaluated the effects of erythromycin on action potential duration (APD) and potassium currents in rat ventricular myocytes in comparison with disopyramide. We have evaluated the relationship between in-vitro potassium current inhibition and in-vivo QT prolongation observed in a previous study. Action potentials and membrane potassium currents, including delayed rectifier current (I(K)) and transient outward current (I(to)), were recorded using a whole-cell patch clamp method in enzymatically-dissociated ventricular cells. Erythromycin and disopyramide prolonged APD in a concentration-dependent manner. Disopyramide (10-100 microM) and erythromycin (100 microM) led to increases in the APD at 90% repolarization level. Disopyramide reduced I(K) (IC50 = 37.2 +/- 0.17 microM) and I(to) (IC50 = 20.9 +/- 0.13 microM) while erythromycin reduced I(K) (IC50 = 60.1 +/- 0.29 microM) but not I(to). The observed prolongation of APD might be ascribed to the inhibition of potassium currents. Erythromycin produced the prolongation of APD and the inhibition of potassium currents with a lag time after addition of the drugs, which suggested that erythromycin might not reach potassium channels from outside the ventricular cells. The potency of disopyramide was almost equivalent under in-vitro and in-vivo conditions. However, potency of erythromycin in-vitro was far weaker than that in-vivo reported in a previous study, presumably due to a difference in the uptake of erythromycin into ventricular myocytes between in-vivo and in-vitro conditions. Therefore, when drug-induced risks of QT prolongation are to be evaluated, the difference of potencies between in-vitro and in-vivo should be taken into consideration.
Hanada
Erika
E
Department of Pharmacy, University of Tokyo Hospital, Faculty of Medicine, University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
Ohtani
Hisakazu
H
Hirota
Michiko
M
Uemura
Noriko
N
Nakaya
Haruaki
H
Kotaki
Hajime
H
Sato
Hitoshi
H
Yamada
Yasuhiko
Y
Iga
Tatsuji
T
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D051668:Delayed Rectifier Potassium Channels; D004206:Disopyramide / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004917:Erythromycin / Q000494:pharmacology*; D066298:In Vitro Techniques; D008133:Long QT Syndrome / Q000139:chemically induced; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000502:physiology; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000187:drug effects*; D024642:Potassium Channels, Voltage-Gated; D051381:Rats; D017207:Rats, Sprague-Dawley
D000889:Anti-Arrhythmia Agents; D000900:Anti-Bacterial Agents; D051668:Delayed Rectifier Potassium Channels; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D004917:Erythromycin; D004206:Disopyramide