Cardiovascular effects of NSP-804 and NSP-805, novel cardiotonic agents with vasodilator properties

The cardiovascular properties of NSP-804 (4,5-dihydro-6-[4-[(2-methyl-3-oxo-1-cyclopentenyl)-amino] phenyl]-3(2H)-pyridazinone) and NSP-805 (4,5-dihydro-5-methyl-6-[4-[(2-methyl-3-oxo-1-cyclopentenyl) amino]phenyl]-3(2H)-pyridazinone), novel cardiotonic agents, were investigated in vitro and in vivo in comparison with those of other cardiotonic agents. In isolated guinea pig left atria, the positive inotropic EC50 values (microM) in order of potency were about 0.18 (NSP-805), 0.39 (indolidan), 1.1 (MCI-154), 1.7 (NSP-804, milrinone), 2.0 (denopamine), 4.0 (papaverine), 4.4 3-isobutyl-1-methylxanthine, IBMX, 6.5 (imazodan), and 27 (amrinone). In anesthetized dogs, intravenous (i.v.) injection of NSP-804 and NSP-805 produced dose-dependent increases in left ventricular VVdp/dtmax and decreases in aortic blood pressure (ABP) with relatively small increases in heart rate (HR). The ED50 values (micrograms/kg) for LVdP/dtmax of NSP-804, NSP-805, denopamine, milrinone, MCI-154, and indolidan were 15, 12, 22, 23, 15, and 7.3, respectively. When the drugs were administered intraduodenally to anesthetized dogs, the ED50 values (micrograms/kg) for LVdP/dtmax of NSP-804, NSP-805, milrinone and indolidan were approximately 30, 10, 200, and 25 respectively. In the propranolol-induced heart failure model, NSP-804 and NSP-805 completely improved the hemodynamic state of heart failure to normal levels. The in vitro positive inotropic effects of NSP-804 and NSP-805 were accompanied by increases in tissue cyclic AMP and abolished by carbachol. NSP-805 was the most potent and selective inhibitor of guinea pig cardiac phosphodiesterase (PDE) III among the agents examined, and NSP-804 was a potent and selective inhibitor of PDE III similar to indolidan. The cardiovascular properties determined in this study suggest that both NSP-804 and NSP-805 may have beneficial effects for treatment of congestive heart failure (CHF).