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Divergent Proarrhythmic Potential of Macrolide Antibiotics Despite Similar QT Prolongation: Fast Phase 3 Repolarization Prevents Early Afterdepolarizations and Torsade de Pointes
Macrolide antibiotics are known to have a different proarrhythmic potential in the presence of comparable QT prolongation in the surface ECG. Because the extent of QT prolongation has been used as a surrogate marker for cardiotoxicity, we aimed to study the different electrophysiological effects of...
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Published in: | The Journal of pharmacology and experimental therapeutics 2002-10, Vol.303 (1), p.218-225 |
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Main Authors: | , , , , , , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
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Summary: | Macrolide antibiotics are known to have a different proarrhythmic potential in the presence of comparable QT prolongation
in the surface ECG. Because the extent of QT prolongation has been used as a surrogate marker for cardiotoxicity, we aimed
to study the different electrophysiological effects of the macrolide antibiotics erythromycin, clarithromycin, and azithromycin
in a previously developed experimental model of proarrhythmia. In 37 Langendorff-perfused rabbit hearts, erythromycin (150â300
μM, n = 13) clarithromycin (150â300 μM, n = 13), and azithromycin (150â300 μM, n = 11) led to similar increases in QT interval and monophasic action potential (MAP) duration. In bradycardic (atrioventricular-blocked)
hearts, eight simultaneously recorded epi- and endocardial MAPs demonstrated increased dispersion of repolarization in the
presence of all three antibiotics. Erythromycin and clarithromycin led to early afterdepolarizations (EADs) and torsade de
pointes (TdP) after lowering of potassium concentration. In the presence of azithromycin, no EAD or TdP occurred. Erythromycin
and clarithromycin changed the MAP configuration to a triangular pattern, whereas azithromycin caused a rectangular pattern
of MAP prolongation. In 13 additional hearts, 150 μM azithromycin was administered after previous treatment with 300 μM erythromycin
and suppressed TdP provoked by erythromycin. In conclusion, macrolide antibiotics lead to similar prolongation of repolarization
but show a different proarrhythmic potential (erythromycin > clarithromycin > azithromycin). In the presence of azithromycin,
neither EAD nor TdP occur. This effect may be related to a rectangular pattern of action potential prolongation, whereas erythromycin
and clarithromycin cause triangular action potential prolongation and induce TdP. |
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ISSN: | 0022-3565 1521-0103 |
DOI: | 10.1124/jpet.102.037911 |