STUDIES ON THE MECHANISM OF THE CARDIOTONIC ACTIVITY OF MDL-19205 - EFFECTS ON SEVERAL BIOCHEMICAL SYSTEMS

  • 1 January 1984
    • journal article
    • research article
    • Vol. 6  (1) , 50-55
Abstract
MDL 19205, 4-ethyl-1,3-dihydro-5-(4-pyridinyl-carbonyl)-2H-imidazol-2-one, is a new drug with cardiotonic properties. Its effects on several biochemical systems considered to be important in myocardial contraction were investigated. Cyclic nucleotide phosphodiesterases (PDE) from dog hearts were separated into 3 isoenzymes, FI, F II and F III, and the effect of the drug on these enzymes was tested. MDL 19205 inhibited F III PDE specifically and produced little or no inhibition of F I and F II PDE. The IC50 [median inhibitory concentration] for inhibition of F III PDE was 8.6 .mu.M when 0.5 .mu.M cAMP was used, whereas no >10% inhibition of F I and 18% of F II PDE occurred at drug concentrations up to 200 .mu.M when 1 .mu.M cAMP was used. Concentrations of MDL 19205 up to 100 .mu.M had no effect on Ca2+-ATPase or Ca2+ uptake by dog cardiac sarcoplasmic reticulum. At 100 .mu.M, the drug produced a weak (18%) inhibition of Na+, K+-ATPase. Inhibition of F III PDE may be the primary mechanism by which MDL 19205 produces its cardiotonic effect. Inhibition of Na+, K+-ATPase may also be involved at very high concentrations of this drug.