Cardiovascular effects of cisapride and prucalopride on human 5-HT 4 receptors in transgenic mice

Cisapride and prucalopride act as 5-HT4 receptor agonists. As a part of our ongoing effort to study the utility of a transgenic (TG) mouse model overexpressing cardiac 5-HT4 receptors, we assessed the extent to which we could recapitulate cisapride and prucalopride agonists. Contractile studies were performed using isolated left and right atrial preparations of TG mice showing cardiac-specific human 5-HT4a receptor expression and those of their wild-type (WT) littermates. 5-Hydroxytryptamine (5-HT), cisapride, and prucalopride exerted concentration-dependent positive inotropic effects in the left atrial preparations of TG mice. Moreover, 5-HT induced concentration-dependent arrhythmias in the right atrial preparations of TG mice starting from 10-nM concentration. However, cisapride induced arrhythmias not only in the right atrial preparations of TG mice but also in the right atrial preparations of WT mice. For instance, 10 μM cisapride induced arrhythmias in the right atrial preparations of TG and WT mice to the same extent. Prucalopride did not exert concentration-dependent proarrhythmic effects in the isolated atrial preparations (left or right, WT or TG). Furthermore, cisapride and prucalopride increased the contractility and beating rate in vivo in TG mice, as assessed by performing echocardiography and surface electrocardiography. In summary, our results indicate that cisapride and prucalopride increase contractility and beating rate in the isolated atrial preparations of TG mice or in intact TG mice. Moreover, 5-HT induced arrhythmias in the isolated right atrial preparations of TG mice in a concentration-dependent manner. Furthermore, cisapride induced arrhythmias in the isolated right atrial preparations of both TG and WT mice. In contrast, prucalopride did not induce arrhythmias in the atrial preparations (left or right) of both WT and TG mice. We suggest that the present TG mouse model might be useful to predict at least some important cardiac effects of 5-HT4 receptor agonists in the human heart.