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


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

1988-12

AUTHORS

S. T. Rapundalo, D. A. Lathrop, S. A. Harrison, J. A. Beavos, A. Schwartz

ABSTRACT

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-Km, 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. More... »

PAGES

692-698

References to SciGraph publications

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  • 1973-09. Adrenaline-like Effects of Intracellular Iontophoresis of Cyclic AMP in Cardiac Purkinje Fibres in NATURE
  • 1987-02. Removal of inactivation and blockade of cardiac Na+ channels by DPI 201-106 different voltage-dependencies of the drug actions in NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY
  • 1985-05. DPI 201-106, a novel cardioactive agent. Combination of cAMP-independent positive inotropic, negative chronotropic, action potential prolonging and coronary dilatory properties in NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY
  • 1987-08. Bronchoconstrictor and hypotensive effects in relation to pharmacokinetics of tachykinins in the guinea-pig —evidence for extraneuronal cleavage of neuropeptide K to neurokinin A in NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY
  • 1980. Effects of Beta- and Alpha-Adrenoceptor Activators and Adrenergic Transmitter Releasing Agents on the Mechanical Activity of the Heart in ADRENERGIC ACTIVATORS AND INHIBITORS
  • 1986-02. Negative inotropic effects of tetrodotoxin and seven class 1 antiarrhythmic drugs in relation to sodium channel blockade in NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY
  • 1984-03. UD-CG 115 — a cardiotonic pyridazinone which elevates cyclic AMP and prolongs the action potential in guinea-pig papillary muscle in NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY
  • 1982. Cardioactive substances that prolong the open state of sodium channels in REVIEWS OF PHYSIOLOGY, BIOCHEMISTRY AND PHARMACOLOGY, VOLUME 86
  • 1973-12. Ionic mechanism of inotropic effect of veratrine on frog heart in PFLÜGERS ARCHIV - EUROPEAN JOURNAL OF PHYSIOLOGY
  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1007/bf00165636

    DOI

    http://dx.doi.org/10.1007/bf00165636

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1017853869

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/2854217


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