A BRADYCARDIAC AGENT, UL-FS 49, INCREASES ATRIAL FORCE AND DECREASES VENTRICULAR FORCE IN ISOLATED, PERFUSED HEART PREPARATIONS OF DOGS

We investigated the effects of a bradycardic agent, UL-FS 49 11,3,4,5- tetrahydro-7,8-dimethoxy-3[3-f [2-(3,4-dimethoxyphenyl) ethyl]methylim ino]propyl]-2H-3-benzazepin-2-on hydrochloride}, on the sinus rate and atrial contractile force and the ventricular force in the isolated, b lood-perfused right atrial and left ventricular preparations of the do g and the inhibition by UL-FS 49 of the negative cardiac responses to acetylcholine, adenosine and cromakalim. UL-FS 49 (0.003-3 mumol) decr eased sinus rate, increased atrial force and decreased ventricular for ce in a dose-dependent manner. The threshold doses of UL-FS 49 (0.03 m umol) for atrial responses were smaller than that (1 mumol) for a vent ricular response. The duration of bradycardia induced by UL-FS 49 was longer than the inotropic one. Propranolol and atropine did not block the positive inotropic and negative chronotropic responses to UL-FS 49 , respectively, in isolated atria. UL-FS 49 (0.1-3 mumol) dose-depende ntly inhibited the negative chronotropic and inotropic responses to pa rasympathetic nerve stimulation and acetylcholine exogenously administ ered. UL-FS 49 at higher doses (1 and 3 mumol) attenuated the negative inotropic but not chronotropic responses to adenosine and cromakalim. UL-FS 49 did not attenuate the negative cardiac responses to verapami l. These results suggest that UL-FS 49 differentiates the sinoatrial n odal pacemaker activity, atrial contractility and ventricular contract ility due to other mechanisms in addition to inhibition of hyperpolari zation-activated current and L-type calcium current reported previousl y and at higher doses blocks muscarinic receptors and inhibits the Kchannel-related inotropic responses in the dog heart.