Selective inhibition by a class III antiarrhythmic agent, E-4031, of the negative chronotropic response to parasympathetic stimulation in anesthetized dogs

To investigate the influence of a class III antiarrhythmic agent, E-4031, on the vagus control of the heart, we studied the effects of E-4031 on the chronotropic, dromotropic and inotropic responses to parasympathetic stimulation in the autonomically decentralized hearts of the open-chest, anesthetized dogs. E-4031 (0.01-3 mumol/kg i.v.) decreased heart rate dose-dependently without affecting atrioventricular (AV) conduction time, first derivative of "a" wave component of the right atrial pressure (RA dP/dt), maximum rate of the right ventricular pressure development (RV +dP/dt) and arterial blood pressure. When cervical vagus stimulation decreased the heart rate, RA dP/dt and RV +dP/dt and prolonged the AV conduction time, E-4031 antagonized the negative chronotropic response in a dose-dependent manner but affected neither dromotropic nor atrial inotropic responses. E-4031 at a high dose of 3 mumol/kg i.v. attenuated the ventricular inotropic response. ID50 for the chronotropism was 0.20 +/- 0.05 mumol/kg. Stimulation of the selective intracardiac parasympathetic nerves to the sinoatrial nodal area decreased the heart rate and RA dP/dt without a dromotropic response. E-4031 antagonized the negative chronotropic response to the stimulation but not the inotropic response. Stimulation of the selective intracardiac parasympathetic nerves to the AV nodal area prolonged the AV conduction time without a chronotropic response. E-4031 at a high dose of 3 mumol/kg i.v. attenuated the negative dromotropic response to the stimulation by 35 +/- 10%. These results suggest that E-4031 preferentially blocks the negative chronotropic response to vagus stimulation without significantly affecting other cardiac responses at a site distal to the muscarinic receptor in the heart in situ.