title: Positive inotropic activity of 5-amino-6-cyano-1,3-dimethyl-1,2,3,4-tetrahydropyrido[2,3-d]pyrim idine-2,4-dione in cardiac muscle from guinea-pig and man. Part 6: Compounds with positive inotropic activity.
abstract: In screening experiments, several 5-aminopyrido[2,3-d]-pyrimidine derivatives 1-14 were found to possess a positive inotropic action in guinea-pig left atria. The size of the effect varied between 10 and 60% of the maximum response to isoprenaline (3 x 10(-7) mol/l). Of these compounds, only 7 and 14 increased force of contraction also in papillary muscles. The latter effect was not accompanied by any changes in the shapes of the transmembrane action potentials and was reversible after addition of carbachol indicating that an increase in intracellular levels of cAMP might be involved. In Langendorff-perfused hearts of the guinea-pig 7 (10(-5) mol/l) increased force of contraction and spontaneous beating frequency like isoprenaline, but unlike isoprenaline, reduced perfusion pressure. Like 3-isobutyl-1-methylxanthine (IBMX) and milrinone, 7 also increased force of contraction of isolated right atrial trabeculae obtained from man during cardiac surgery. The influence of 7 on phosphodiesterase (PDE) activity was investigated in partially purified isoenzymes from guinea-pig ventricles. Compound 7 inhibited preferably PDE III with an IC50 value of 15.2 +/- 4.5 mumol/l. More than tenfold higher concentrations were needed to inhibit PDE II. The IC50 value was 198 +/- 91 mumol/l. PDE I and IV were inhibited by 7 only by a minor extent. At a drug concentration of 1 mmol/l PDE activity was reduced to 83 +/- 30 and 55 +/- 8% of control value, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Pharmaceutical Chemistry, University of Kiel.
authors.forename: D
authors.initials: D
authors.lastname: Heber
authors.forename: C
authors.initials: C
authors.lastname: Heers
authors.forename: U
authors.initials: U
authors.lastname: Ravens
mesh_terms: D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects*; D006801:Humans; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000378:metabolism; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D020105:Milrinone; D009200:Myocardial Contraction / Q000187:drug effects; D010210:Papillary Muscles / Q000187:drug effects; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D011728:Pyridones / Q000494:pharmacology; D011744:Pyrimidinones / Q000494:pharmacology*
chemical_list: D002316:Cardiotonic Agents; D007527:Isoenzymes; D010726:Phosphodiesterase Inhibitors; D011728:Pyridones; D011744:Pyrimidinones; C083554:5-amino-6-cyano-1,3-dimethyl-1,2,3,4-tetrahydropyrido(2,3-d)pyrimidine-2,4-dione; D010727:Phosphoric Diester Hydrolases; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D020105:Milrinone; D007545:Isoproterenol; D015056:1-Methyl-3-isobutylxanthine