The cardiovascular properties of
MS-857 [4-acetyl-1-methyl-7-(4-pyridyl)-5,6,7,8-tetrahydro-3(2H)-isoquinolinone ], a novel
cardiotonic agent, were investigated in anesthetized and conscious dogs.
MS-857 (1-100 micrograms/kg i.v.) produced a significant and dose-dependent increase in cardiac contractility with relatively small changes in heart rate and blood pressure. This indicates a sizable separation between positive inotropic and other effects of
MS-857.
Oral administration of
MS-857 to conscious dogs (0.1-1 mg/kg) also produced a sustained increase in cardiac contractility in a dose-dependent manner. The total duration of action was longer than 7 h at a dose of 1 mg/kg p.o. There occurred no arrhythmias and no changes in animal behavior. After chronic
oral administration,
MS-857 completely retained its activities, indicating the lack of tachyphylaxis. In the acute
heart failure models induced by either
propranolol or
pentobarbital,
MS-857 reversed the
cardiac depressant effects of these drugs. Moreover,
MS-857 also significantly improved the
pentobarbital-induced
heart failure in the heart-lung preparation.
MS-857 did not inhibit the Na+, K+-
ATPase, but inhibited the
phosphodiesterase (PDE) III selectively, both of which were prepared from the dog ventricular muscle. Thus,
MS-857 can be characterized as a potent nonsympathomimetic, nonglycoside
cardiotonic drug with a selective inhibitory activity on PDE III. The cardiovascular properties revealed by this study strongly suggest that
MS-857 will exert a beneficial effect in the treatment of
congestive heart failure.