Electrophysiological and antiarrhythmic effects of the atrial selective 5-HT4 receptor antagonist RS-100302 in experimental atrial flutter and fibrillation

Background-Stimulation of 5-HT4 receptors increases atrial chronotropic and inotropic responses. Whether other electrophysiological effects are produc ed is unknown. In humans and swine, 5-HT4 receptors are present only in atr ium. Therefore, the effects of a novel 5-HT4 receptor antagonist, RS-100302 , and the partial agonist cisapride on atrial flutter and fibrillation indu ced in swine were studied to delineate the role of the 5-HT4 receptor in mo dulating atrial electrophysiological properties and the antiarrhythmic pote ntial of RS-100302. Methods and Results-In 17 anesthetized, open-chest, juvenile pigs, atrial f lutter or fibrillation was induced by rapid right atrial pacing with or wit hout a right: atrial free wall crush injury, respectively. Atrial effective refractory period (ERP), conduction velocity, wavelength, and dispersion o f refractoriness were determined during programmed stimulation via a 56-ele ctrode mapping plaque sutured to the right atrial Free wall. Ventricular el ectrophysiological parameters were also measured. All electrophysiological parameters were measured at baseline and after infusion of RS-100302 and ci sapride. In the atrium, RS-100302 prolonged mean ERP (115 +/- 8 versus 146 +/- 7 ms, P < 0.01) and wavelength (8.3 +/- 0.9 versus 9.9 +/- 0.8 cm, P < 0.01), reduced dispersion of ERP (15 +/- 5 versus 8 +/- 1 ms, P < 0.01), an d minimally slowed conduction velocity (72 +/- 4 versus 67 +/- 5 cm/s, P < 0.01). These effects were all partially reversed by cisapride. RS-100302 pr oduced no ventricular electrophysiological effects. RS-100302 terminated at rial flutter in 6 of 8 animals and atrial fibrillation in 8 of 9 animals an d prevented reinduction of sustained tachycardia in all animals. Conclusions-The electrophysiological profile of RS-100302 suggests that it may have atrial antiarrhythmic potential without producing ventricular proa rrhythmic effects.