Comparative effects on cardiac repolarization of cisapride, erythromycin, tegaserod and its metabolite in isolated rabbit hearts

Gastro-prokinetic drugs cisapride (C) and erythromycin (E) have been reported to cause acquired Long QT syndrome, Torsades de Pointes and sudden death in predisposed patients. The underlying mechanism is most likely a prolongation of the action potential secondary to a blockade of the delayed rectifier I_K. Tegaserod (T) being a new drug developed for gastrointestinal prokinesis, we aimed to compare the effects of C, E, T and its metabolite (M) on the QT interval of isolated rabbit hearts (QT). Methods: The hearts of NZ rabbits were cannulated, perfused (Langendorff) and paced (cycle length:400 ms), while increasing concentrations C, E, T and M [0.1 to 100 μM] were perfused to determine their effect on the QT interval. Results: C increased the QT interval from 13 ± 3% at 100 nM up to > 70% at 50 μM. E also increased the QT values from 2 ± 3% at 1 μM up to 11 ± 2 % at 100 nM (p<0.001, n=5). During T perfusion, the QT intervals remained unchanged up to 10 μM. A 12 ± 4% increase (p<0.01, n=4) was observed at the concentration of 50 μ.M (500 to 1000 fold the therapeutic concentrations). No change in the QT duration was observed during M perfusion, at any of the concentrations tested. Conclusion: i) gastro-prokinetic drugs can act directly on the heart to slow cardiac repolarization and ii) the lower potency of tegaserod with respect to QT prolongation suggests that it may represent a safer alternative to cisapride as a gastrointestinal prokinetic agent.