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 co mpounds that have no positive chronotropic effects. In subjects with h eart failure, the prototypic compound OPC-8212 may reduce morbidity an d mortality at low doses but increase mortality at high doses. Methods and Results To further characterize the inotropic mechanism(s) of act ion of these compounds, we investigated the effects of OPC-8490, a wat er-soluble quinolinone, on the inotropic response, inhibition of phosp hodiesterase (PDE), and action potential in human ventricular myocardi al preparations. In isolated right ventricular trabeculae and membrane s prepared from left ventricular myocardium, OPC-8490 produced dose-re lated positive inotropic effects, inhibited type III PDE activity, and prolonged action potential. Comparative experiments with other PDE in hibitors, sodium channel agonists, and potassium channel antagonists i ndicated 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 select ive positive inotropic effects because of type III PDE inhibition comb ined with ion channel effects, with the latter property inhibiting the positive chronotropic response usually associated with agents that in crease intracellular cAMP concentrations.