Investigation of the positive inotropic action of 6,7-dimethoxy-3-cyano-3,4-dihydrocarbostyril.
6.7-Dimethoxy-3-cyano-3.4-dihydrocarbostyril (7A61, 1), a 2-quinolinone derivative, showed interesting cardiotonic properties in vitro. It exerted potent positive inotropic effects, without any change in heart rate, in guinea pig atrial preparations, and its effects were not dependent upon inhibition of phosphodiesterases, opening of Na+ channels, or inhibition of adenosine receptors. Notwithstanding its structural relationships with milrinone, vesnarinone, and other quinolinones endowed with cardiotonic activity, it appeared that 7A61 does not share any of the main mechanisms of action involved in the pharmacological activity of these compounds. Other experiments also excluded the involvement of other well known mechanisms of cardiac stimulation, such as adrenergic receptor activation or opening of Ca++ channels, the mode of action of 7A61 remaining unexplained. However, contrary to milrinone, 7A61 did not exert cardiotonic effects in human ventricular muscle preparations, thus discouraging further investigation. Although the lack of effect on human heart could not be predicted from the results obtained in several cardiac preparations commonly used in laboratory investigations, the scarce efficacy of 7A61 in comparison with milrinone in dog and cat papillary muscle and in guinea pig ventricular muscle suggests the utility of the latter preparations in laboratory experiments aimed at selecting new potential cardiotonic agents.
Ferrini
R
R
Research and Development Division, Bresso, Milan, Italy.
Miragoli
G
G
Calabi
M L
ML
Santangelo
F
F
Godfraind
T
T
Bravo
G
G
Casagrande
C
C
D000818:Animals; D002118:Calcium / Q000502:physiology; D002316:Cardiotonic Agents / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D002415:Cats; D002675:Child, Preschool; D004285:Dogs; D005260:Female; D006168:Guinea Pigs; D006325:Heart Atria / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D007223:Infant; D008297:Male; D008875:Middle Aged; D009200:Myocardial Contraction / Q000187:drug effects*; D009570:Nitriles / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D016627:Oxidopamine / Q000494:pharmacology; D010210:Papillary Muscles / Q000187:drug effects; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011433:Propranolol / Q000494:pharmacology; D015363:Quinolones / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D018047:Receptors, Purinergic P1 / Q000187:drug effects / Q000378:metabolism; D013565:Sympatholytics / Q000494:pharmacology; D013779:Tetrodotoxin / Q000494:pharmacology; D014700:Verapamil / Q000494:pharmacology
D002316:Cardiotonic Agents; D009570:Nitriles; D010726:Phosphodiesterase Inhibitors; D015363:Quinolones; D018047:Receptors, Purinergic P1; D013565:Sympatholytics; C102907:7A61 compound; D013779:Tetrodotoxin; D016627:Oxidopamine; D011433:Propranolol; D014700:Verapamil; D002118:Calcium