Mechanism of action of OPC-8490 in human ventricular myocardium.
BACKGROUND
The quinolinone compounds OPC-8212 (vesnarinone), OPC-18790, and OPC-8490 are members of a family of unique positive inotropic compounds that have no positive chronotropic effects. In subjects with heart failure, the prototypic compound OPC-8212 may reduce morbidity and mortality at low doses but increase mortality at high doses.


RESULTS
To further characterize the inotropic mechanism(s) of action of these compounds, we investigated the effects of OPC-8490, a water-soluble quinolinone, on the inotropic response, inhibition of phosphodiesterase (PDE), and action potential in human ventricular myocardial preparations. In isolated right ventricular trabeculae and membranes prepared from left ventricular myocardium, OPC-8490 produced dose-related positive inotropic effects, inhibited type III PDE activity, and prolonged action potential. Comparative experiments with other PDE inhibitors, sodium channel agonists, and potassium channel antagonists indicated that the positive inotropic effects are due to PDE inhibition, whereas the action potential effects of OPC-8490 are due to effects on ion channels.


CONCLUSIONS
We conclude that OPC-8490 produces selective positive inotropic effects because of type III PDE inhibition combined with ion channel effects, with the latter property inhibiting the positive chronotropic response usually associated with agents that increase intracellular cAMP concentrations.
Focaccio
A
A
Department of Cardiology, University of Naples, Italy.
Peeters
G
G
Movsesian
M
M
Roden
R
R
Eki
Y
Y
Krall
J
J
Bristow
M R
MR
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors; D000200:Action Potentials / Q000187:drug effects; D000328:Adult; D001384:Azetidines / Q000494:pharmacology; D002316:Cardiotonic Agents / Q000494:pharmacology*; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D017335:Enoximone / Q000494:pharmacology; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D006333:Heart Failure / Q000503:physiopathology; D006352:Heart Ventricles / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D007473:Ion Channels / Q000187:drug effects; D008875:Middle Aged; D020105:Milrinone; D009200:Myocardial Contraction / Q000187:drug effects; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology*; D011728:Pyridones / Q000494:pharmacology; D015363:Quinolones / Q000494:pharmacology*; D013015:Sotalol / Q000494:pharmacology; D016276:Ventricular Function; D014701:Veratridine / Q000494:pharmacology
D001384:Azetidines; D002316:Cardiotonic Agents; D007473:Ion Channels; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011728:Pyridones; D015363:Quinolones; C071117:BDF 9148; C061380:OPC 8490; D014701:Veratridine; D013015:Sotalol; D017335:Enoximone; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D020105:Milrinone