Effects of gastrointestinal prokinetic agents, TKS159 and cisapride, on the in situ canine heart assessed by cardiohemodynamic and electrophysiological monitoring.
Effects of a novel 5-HT4 receptor agonist TKS159 on the cardiovascular system were assessed in comparison with cisapride using an in vivo canine model. TKS159 in doses of 0.1, 1.0, and 10 mg/kg (n = 6) or cisapride in 1/10 doses of 0.01, 0.1, and 1.0 mg/kg (n = 6) was cumulatively infused over 10 min with a pause of 20 min. The doses of the drugs were determined according to the previous knowledge of their pharmacokinetics. Clinically effective plasma concentrations as a gastrointestinal prokinetic drug were obtained after the infusion of 0.1 mg/kg of the respective drugs. In TKS159-administered animals, no significant change was induced in each cardiovascular parameter by an infusion of 0.1 mg/kg. The blood pressure was decreased, and the effective refractory period and repolarization phase of the ventricle were prolonged after 1.0 mg/kg. The heart rate was decreased, and the atrioventricular, as well as intraventricular, conduction were suppressed after 10 mg/kg, while no significant changes were observed in the cardiac output and the ventricular contraction and the relative refractory period of the ventricle during the study. Meanwhile, in cisapride-administered animals, the repolarization phase and the effective refractory period were prolonged after 0.01 mg/kg. The heart rate and the blood pressure were decreased after 0.1 mg/kg. The cardiac output, the ventricular contraction, and the atrioventricular conduction were suppressed, the relative refractory period was prolonged, and early afterdepolarization was detected after 1.0 mg/kg, while no significant change was observed in the intraventricular conduction during the study. Thus, TKS159 may have a safer cardiovascular profile than cisapride.
Department of Pharmacology, Yamanashi Medical University, Tamaho-cho, Nakakoma-gun, Yamanashi, 409-3898, Japan.
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Sugiyama
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Hashimoto
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D020117:Cisapride / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D004285:Dogs; D004562:Electrocardiography; D005260:Female; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D006329:Heart Conduction System / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D009206:Myocardium; D011759:Pyrrolidines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D012032:Refractory Period, Electrophysiological / Q000187:drug effects / Q000502:physiology; D017366:Serotonin Receptor Agonists / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D016277:Ventricular Function, Left / Q000187:drug effects* / Q000502:physiology
D011759:Pyrrolidines; D017366:Serotonin Receptor Agonists; C098494:TKS 159; D020117:Cisapride