ABSTRACT
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.
Subject(s)
Cardiotonic Agents/pharmacology , Heart/drug effects , Piperazines/pharmacology , Quinolones/pharmacology , 3',5'-Cyclic-AMP Phosphodiesterases/antagonists & inhibitors , Action Potentials/drug effects , Adult , Azetidines/pharmacology , Cyclic Nucleotide Phosphodiesterases, Type 3 , Enoximone/pharmacology , Heart/physiology , Heart Failure/physiopathology , Heart Ventricles/drug effects , Humans , In Vitro Techniques , Ion Channels/drug effects , Middle Aged , Milrinone , Myocardial Contraction/drug effects , Phosphodiesterase Inhibitors/pharmacology , Pyridones/pharmacology , Sotalol/pharmacology , Ventricular Function , Veratridine/pharmacologyABSTRACT
The study of adult human ventricular cells has been limited by tissue availability. In this study we describe techniques for the isolation of Ca(2+)-tolerant adult human ventricular cells from both transvenous endomyocardial and epicardial biopsies. Ca(2+)-tolerant cells were obtained from 80% of the biopsies processed. Although the yield of Ca(2+)-tolerant myocytes from either type of biopsy was low (1-5%), myocytes with normal resting potentials and action potentials can be obtained from single biopsy specimens, providing a source of normal human myocytes for electrophysiological study. Resting potentials (Vrest) were recorded in 41 isolated right ventricular endomyocardial cells at 37 degrees C. Sixteen cells were depolarized (Vrest = -26 +/- 13 mV), and 25 cells had normal resting potentials (Vrest = -84 +/- 6 mV). Action potentials were recorded in 16 cells. At a pacing cycle length of 1 s, 4 cells had prolonged action potential duration at 90% (APD90, 718 +/- 26 ms) and 10 cells had normal APD90 (381 +/- 94 ms) compared with those recorded from intact right ventricular septal trabeculae from explanted hearts. Voltage-clamp studies of isolated human ventricular myocytes obtained from these biopsies document the presence of currents previously reported from cells isolated from explanted hearts.
