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Cyclic AMP-dependent and cyclic AMP-independent actions of a novel cardiotonic agent, OPC-8212

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Summary

Possible cAMP-dependent and cAMP-independent mechanisms of action for the cardiac effects of OPC-8212, a novel piperazinyl-quinolinone derivative, were evaluated. OPC-8212 was tested for in vitro potency as an inhibitor of soluble bovine cardiac phosphodiesterases using a rapid isolation and assay method involving monoclonal antibodies that distinguish among isozymes. The drug was selective for a low-K m, cGMP-inhibited phosphodiesterase (CGI-PDE) with an IC50 (half-maximal inhibition concentration) of 7.4 μmol/l when measured at a substrate level of 0.35 μmol/l cAMP. Under the conditions used, sulfolane, the solvent for OPC-8212, did not affect CGI-PDE activity. In electrophysiological measurements, OPC-8212 prolonged the action potential duration in canine Purkinje strand preparations up to 148% (APD90) at 10 μmol/l. Concomitantly, OPC-8212 produced a 100% increase in developed force. Both prolongation of the action potential duration and the positive inotropic effect were readily reversed after exposure to tetrodotoxin, 3 μmol/l. Using Na-selective microelectrodes, intracellular Na+ ion activity increased 225% upon exposure to 10 μmol/l OPC-8212. OPC-8212 represents a novel type of positive inotropic agent, possessing both cAMP-dependent (selective PDE isozyme inhibition) and cAMP-independent (activation of intracellular Na+) mechanism of action.

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Authors and Affiliations

  1. Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, 45267-0575, Cincinnati, Ohio, USA

    S. T. Rapundalo, D. A. Lathrop & A. Schwartz

  2. Department of Pediatrics (Division of Cardiology), Children's Hospital Research Foundation, 45229, Cincinnati, Ohio, USA

    D. A. Lathrop

  3. Department of Pharmacology, SJ-30, School of Medicine, University of Washington, 98195, Seattle, Washington, USA

    S. A. Harrison & J. A. Beavos

Authors
  1. S. T. Rapundalo
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  2. D. A. Lathrop
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  3. S. A. Harrison
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  4. J. A. Beavos
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  5. A. Schwartz
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Rapundalo, S.T., Lathrop, D.A., Harrison, S.A. et al. Cyclic AMP-dependent and cyclic AMP-independent actions of a novel cardiotonic agent, OPC-8212. Naunyn-Schmiedeberg's Arch Pharmacol 338, 692–698 (1988). https://doi.org/10.1007/BF00165636

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  • DOI: https://doi.org/10.1007/BF00165636

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