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).