Effects of 5-HT4 receptor agonists, cisapride and mosapride citrate on electrocardiogram in anaesthetized rats and guinea-pigs and conscious cats

The purpose of this study was to examine the arrhythmogenic potential of 5- HT4 receptor agonists, cisapride and mosapride citrate (mosapride) in vivo. In anaesthetized rats. cisapride at intravenous infusion of 10 and 30 mg/k g/hr for I hr prolonged the electrocardiographic RR and QT intervals, where as at 3 mg/kg/hr, it prolonged the RR interval without affecting the QT int erval. Mosapride at 30 mg/kg/hr for I hr slightly, but not significantly, p rolonged the QT interval. In anaesthetized guinea-pigs, cisapride at intrav enous infusion of 0.3, 1 and 3 mg/kg over 15 min. prolonged the RR interval (18-44%), QT interval (18-42%) and the corrected QT interval (QTc. 8-19%). Mosapride at 3, 10 and 30 mg/kg over 15 min. little affected the QTc altho ugh at 30 mg/kg, it slightly prolonged the RR and QT intervals. With repeat ed oral administrations of 30 mg/kg twice a day for 7 days, cisapride prolo nged the QT interval (11-35%) and QTc (11-32%) at the 3rd and 7th days in c onscious cats. In addition, cisapride depressed the ST segment in two out o f five cats. Mosapride at 60 mg/kg twice a day for 7 days did not affect th e QT interval or QTc in cats. The maximal plasma concentrations of mosaprid e and its main metabolite (a des-4-fluorobenzyl-mosapride) at the 7th day i n cats were 9.4 +/-2.8 muM and 2.5 +/-0.3 pM, respectively, being 100 and 3 0-60 times higher than those in man given therapeutic doses (Sakashita et a l. 1993a&b). These results indicate that mosapride has little arrhythmogeni c potential.