Cardiovascular pharmacology of RS-1893, an orally active cardiotonic agent with arterial and venous vasodilator actions. 1988

S Miyake, and H Shiga, and H Koike, and H Mizuno, and R Yorikane, and T Oda, and Y Iijima, and S Kumakura, and Y Morisawa
Research Laboratories, Sankyo Co., Ltd., Tokyo, Japan.

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.

UI MeSH Term Description Entries
D007275 Injections, Intravenous Injections made into a vein for therapeutic or experimental purposes. Intravenous Injections,Injection, Intravenous,Intravenous Injection
D008297 Male Males
D009025 Morpholines Tetrahydro-1,4-Oxazines,Tetrahydro 1,4 Oxazines
D009206 Myocardium The muscle tissue of the HEART. It is composed of striated, involuntary muscle cells (MYOCYTES, CARDIAC) connected to form the contractile pump to generate blood flow. Muscle, Cardiac,Muscle, Heart,Cardiac Muscle,Myocardia,Cardiac Muscles,Heart Muscle,Heart Muscles,Muscles, Cardiac,Muscles, Heart
D010727 Phosphoric Diester Hydrolases A class of enzymes that catalyze the hydrolysis of one of the two ester bonds in a phosphodiester compound. EC 3.1.4. Phosphodiesterase,Phosphodiesterases,Hydrolases, Phosphoric Diester
D011724 Pyridazines Six-membered rings with two adjacent nitrogen atoms also called 1,2-diazine.
D002316 Cardiotonic Agents Agents that have a strengthening effect on the heart or that can increase cardiac output. They may be CARDIAC GLYCOSIDES; SYMPATHOMIMETICS; or other drugs. They are used after MYOCARDIAL INFARCT; CARDIAC SURGICAL PROCEDURES; in SHOCK; or in congestive heart failure (HEART FAILURE). Cardiac Stimulant,Cardiac Stimulants,Cardioprotective Agent,Cardioprotective Agents,Cardiotonic,Cardiotonic Agent,Cardiotonic Drug,Inotropic Agents, Positive Cardiac,Myocardial Stimulant,Myocardial Stimulants,Cardiotonic Drugs,Cardiotonics,Agent, Cardioprotective,Agent, Cardiotonic,Drug, Cardiotonic,Stimulant, Cardiac,Stimulant, Myocardial
D004285 Dogs The domestic dog, Canis familiaris, comprising about 400 breeds, of the carnivore family CANIDAE. They are worldwide in distribution and live in association with people. (Walker's Mammals of the World, 5th ed, p1065) Canis familiaris,Dog
D005260 Female Females
D006333 Heart Failure A heterogeneous condition in which the heart is unable to pump out sufficient blood to meet the metabolic need of the body. Heart failure can be caused by structural defects, functional abnormalities (VENTRICULAR DYSFUNCTION), or a sudden overload beyond its capacity. Chronic heart failure is more common than acute heart failure which results from sudden insult to cardiac function, such as MYOCARDIAL INFARCTION. Cardiac Failure,Heart Decompensation,Congestive Heart Failure,Heart Failure, Congestive,Heart Failure, Left-Sided,Heart Failure, Right-Sided,Left-Sided Heart Failure,Myocardial Failure,Right-Sided Heart Failure,Decompensation, Heart,Heart Failure, Left Sided,Heart Failure, Right Sided,Left Sided Heart Failure,Right Sided Heart Failure

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