Effects of 5-HT4-receptor agonists, cisapride, mosapride citrate, and zacopride, on cardiac action potentials in guinea pig isolated papillary muscles.
The purpose of this study was to examine the effects of 5-HT4-receptor agonists cisapride, mosapride citrate (mosapride), and zacopride on action potentials (APs) in guinea pig isolated papillary muscles. Cisapride (0.1-3 microM) concentration-relatedly prolonged the duration of APs (APD) without affecting the other AP parameters. Mosapride and its main metabolite M1 (des-4-fluoro-benzyl-mosapride) did not affect APs at 10 microM. Zacopride at 10 microM shortened APD, and the APD-shortening effect was not affect by GR113808 (10 microM), a 5-HT4-receptor antagonist. The cisapride (1 microM)-induced prolongation of APD was not affected by GR113808 (10 microM), ritanserin (10 microM), a 5-HT2A/2C-receptor antagonist, or prazosin (10 microM), an alpha 1-receptor antagonist. The same concentrations of GR113808, ritanserin, and prazosin did not affect APD. Clofilium, a class III antiarrhythmic agent, prolonged APD; the effect was more pronounced at a stimulus frequency of 0.3 Hz than at 2.0 Hz. Cisapride did not exert such reverse use dependence, suggesting that its mechanism of action is different from that of clofilium. These results suggest that cisapride prolongs APD without involvement of 5-HT2, 5-HT4, or alpha 1 receptors. Mosapride is unlikely to induce the prolongation of electrocardiographic QT intervals correlated with the prolongation of APD in isolated ventricular muscles.
Kii
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Department of Toxicology and Pharmacology, Dainippon Pharmaceutical Co. Ltd., Suita/Osaka, Japan.
Ito
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D000200:Action Potentials / Q000187:drug effects; D058669:Adrenergic alpha-2 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D001549:Benzamides / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D020117:Cisapride; D004558:Electric Stimulation; D004562:Electrocardiography / Q000187:drug effects; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects / Q000502:physiology*; D066298:In Vitro Techniques; D008297:Male; D008839:Microelectrodes; D009025:Morpholines / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000294:innervation / Q000502:physiology*; D010210:Papillary Muscles / Q000187:drug effects / Q000502:physiology; D010880:Piperidines / Q000494:pharmacology; D011224:Prazosin / Q000494:pharmacology; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D013564:Sympathetic Nervous System / Q000187:drug effects* / Q000502:physiology*
D058669:Adrenergic alpha-2 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists; D000889:Anti-Arrhythmia Agents; D001549:Benzamides; D019086:Bridged Bicyclo Compounds, Heterocyclic; D009025:Morpholines; D010880:Piperidines; D000644:Quaternary Ammonium Compounds; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; C022799:clofilium; C055971:zacopride; C062720:mosapride; D020117:Cisapride; D011224:Prazosin