Effects of 5-HT(4) 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/kg/hr for 1 hr prolonged the electrocardiographic RR and QT intervals, whereas at 3 mg/kg/hr, it prolonged the RR interval without affecting the QT interval. Mosapride at 30 mg/kg/hr for 1 hr slightly, but not significantly, prolonged the QT interval. In anaesthetized guinea-pigs, cisapride at intravenous 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 although at 30 mg/kg, it slightly prolonged the RR and QT intervals. With repeated oral administrations of 30 mg/kg twice a day for 7 days, cisapride prolonged the QT interval (11-35%) and QTc (11-32%) at the 3rd and 7th days in conscious cats. In addition, cisapride depressed the ST segment in two out of five cats. Mosapride at 60 mg/kg twice a day for 7 days did not affect the QT interval or QTc in cats. The maximal plasma concentrations of mosapride and its main metabolite (a des-4-fluorobenzyl-mosapride) at the 7th day in cats were 9.4+/-2.8 microM and 2.5+/-0.3 microM , respectively, being 100 and 30-60 times higher than those in man given therapeutic doses (Sakashita et al. 1993a&b). These results indicate that mosapride has little arrhythmogenic potential.
Kii
Y
Y
Department of Safety Pharmacology, Developmental Research Laboratories, Dainippon Pharmaceutical Co. Ltd., 33-94 Enoki-cho, Suita/Osaka 564-0053, Japan. yoshihide-kii@dainippon-pharm.co.jp
Nakatsuji
K
K
Nose
I
I
Yabuuchi
M
M
Mizuki
Y
Y
Ito
T
T
D000758:Anesthesia; D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D002415:Cats; D020117:Cisapride / Q000494:pharmacology*; D003243:Consciousness; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography / Q000187:drug effects*; D005260:Female; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects; D006352:Heart Ventricles / Q000187:drug effects* / Q000503:physiopathology; D008133:Long QT Syndrome / Q000139:chemically induced; D008297:Male; D009025:Morpholines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*
D001549:Benzamides; D009025:Morpholines; D017366:Serotonin Receptor Agonists; C062720:mosapride; D020117:Cisapride