Cardiovascular pharmacology of RS-1893, an orally active cardiotonic agent with arterial and venous vasodilator actions.
RS-1893, 2-[2-chloro-4-(2,3,4,5-tetrahydro-3-oxo-6-pyridazinyl)]-phenoxy-N- (2-(2-morpholinoethyl)-acetamide, is a newly synthesized compound whose structure is different from that of cardiac glycosides and beta-stimulants. The in vitro cardiotonic action of RS-1893 was about 3 times more potent than that of milrinone. This action is most likely due to inhibition of phosphodiesterase-III, as has been suggested for many other cardiotonic agents. In pentobarbital anesthetized dogs, RS-1893 (1-30 micrograms/kg, i.v.) produced dose dependent increases in left ventricular dP/dtmax and cardiac output and caused decreases in blood pressure and total peripheral resistance with a relatively small increase in heart rate. Central venous pressure decreased markedly, suggesting venous vasodilation. The in vivo cardiotonic action of RS-1893 was 3 times more potent than that of milrinone and was not affected in the presence of a large dose of propranolol. Oral administration of RS-1893 (0.03 and 0.1 mg/kg) also produced a dose-related increase in cardiac contractility in conscious beagles. The increase in LVdP/dtmax reached a maximum in 1-3 hr after administration and lasted for more than 8 hr. Thus, RS-1893 appeared to be an orally active cardiotonic agent with vasodilator properties, probably acting on both arterioles and veins.
Miyake
S
S
Research Laboratories, Sankyo Co., Ltd., Tokyo, Japan.
Shiga
H
H
Koike
H
H
Mizuno
H
H
Yorikane
R
R
Oda
T
T
Iijima
Y
Y
Kumakura
S
S
Morisawa
Y
Y
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000284:Administration, Oral; D000758:Anesthesia; D000818:Animals; D002316:Cardiotonic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D004285:Dogs; D005260:Female; D006333:Heart Failure / Q000139:chemically induced / Q000503:physiopathology; D006439:Hemodynamics / Q000187:drug effects*; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D008297:Male; D009025:Morpholines / Q000008:administration & dosage / Q000494:pharmacology*; D009206:Myocardium / Q000201:enzymology; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D011724:Pyridazines / Q000008:administration & dosage / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000494:pharmacology*
D002316:Cardiotonic Agents; D009025:Morpholines; D011724:Pyridazines; D014665:Vasodilator Agents; C058563:RS 1893; D010727:Phosphoric Diester Hydrolases; D015105:3',5'-Cyclic-AMP Phosphodiesterases