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. (C) 1998 Academic Press.