PHARMACOLOGICAL ACTIONS OF SDZ-218-135, A NOVEL POSITIVE INOTROPIC AGENT

The effects of the new inotropic agent, SDZ 218-135 methyl-1,2,4-triaz olo-[1,5-a]pyrimidin-7(4F)-one], were investigated using in vitro and in vivo techniques. In isolated rat atria, SDZ 218-135 elicited a dose -dependent increase in contractile force (+ 50% at 10 mu M), which was paralleled by an increase in functional refractory period. In anesthe tized rats SDZ 218-135 enhanced left ventricular (+)dP/dt(max) by 100% at 10 mg/kg without influencing heart rate, arterial blood pressure, and cardiac output. In contrast to its predecessor, DPI 201-106, cardi ac relaxation remained essentially unimpaired. The positive inotropic action was also maintained in a rabbit model of depressed heart functi on after myocardial infarction, where SDZ 218-135 increased peak accel eration of blood in the aorta. The prolongation of the effective refra ctory period in rat atria suggested possible antiarrhythmic effects. I ndeed, SDZ 218-135 showed a dose-dependent marked reduction in reperfu sion arrhythmias after coronary artery occlusion in rats. This effect was most likely due to a Class III action, since SDZ 218-135 significa ntly increased action potential duration (+10% at 10 mu M/1) of the is olated guinea pig papillary muscle. In conclusion, SDZ 218-135 is a no vel positive inotropic agent with an interesting profile of action. It does not impair cardiac relaxation and shows antiarrhythmic effects i n a model of reperfusion-induced arrhythmias. The in vivo and in vitro data are consistent with a mechanism of action via sodium channel ago nism.