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(Circulation. 1996;93:817-825.)
© 1996 American Heart Association, Inc.

Articles

Mechanism of Action of OPC-8490 in Human Ventricular Myocardium

Amelia Focaccio, MD; George Peeters, MD; Matthew Movsesian, MD; Robert Roden, MS; Yutaka Eki, MD; Judith Krall, BS; Michael R. Bristow, MD, PhD

From the University of Naples (Italy), Department of Cardiology (A.F.); the University of Utah Medical Center, Division of Cardiology, Salt Lake City (G.P., J.K.); the Departments of Internal Medicine (Cardiology) and Pharmacology, Salt Lake City (Utah) Veterans Affairs Medical Center and University of Utah School of Medicine, Salt Lake City (M.M.); the University of Colorado Health Sciences Center, Division of Cardiology, Denver (R.R., M.R.B.); and the National Defence Medical College, First Department, Tokaimura, Japan (Y.E.).

Correspondence to Michael R. Bristow, University of Colorado Health Sciences Center, Division of Cardiology, 4200 E 9th Ave, Denver, CO 80262. E-mail bristow_M@defiance.uchsc.edu.

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.

Methods and 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.

Key Words: inotropic agents • heart failure • drugs

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