title: Relation of positive inotropic and chronotropic effects of pimobendan, UD-CG 212 Cl, milrinone and other phosphodiesterase inhibitors to phosphodiesterase III inhibition in guinea-pig heart.
abstract: (1) This study was performed to elucidate the relation between positive inotropy and phosphodiesterase inhibition in the heart. Therefore, the influence on the activity of guinea-pig cardiac phosphodiesterase (PDE) I-III separated by DEAE-cellulose anion exchange chromatography was investigated for the new cardiotonic agents pimobendan, its metabolite UD-CG 212 Cl and milrinone. These effects were compared with those of various other PDE inhibitors such as IBMX, zaprinast, rolipram and AR-L 57 Cl. A selectivity factor (SF, mean of the IC50 values for PDE I and II inhibition divided by the IC50 for PDE III) was calculated for each drug. The greater this value the more selective was the PDE III inhibition. (2) UD-CG 212 Cl was the most potent (IC50 = 0.19 mumol/l) and most selective inhibitor of PDE III with a SF of 869. Also selective PDE III inhibitors were pimobendan (SF = 50.5) and milrinone (SF = 70.0) with slightly smaller potencies (IC50 = 2.40 and 1.52 mumol/l, respectively). Zaprinast and rolipram preferentially inhibited PDE I and II, respectively. IBMX and AR-L 57 Cl inhibited PDE I-III unselectively with similar potencies for all isoenzymes. (3) The PDE inhibitory effects of all substances were compared with their influence on force of contraction (electrically driven papillary muscles) and on frequency of beating (spontaneously beating right auricles) in guinea-pig hearts, thus in preparations of the same species. UD-CG 212 Cl and pimobendan resembled each other in their maximal positive inotropic effects with potencies (EC50) of 1.8 mumol/l and 6.0 mumol/l, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Abteilung Allgemeine Pharmakologie, Universitäts-Krankenhaus Eppendorf, Universität Hamburg, Federal Republic of Germany.
authors.forename: D
authors.initials: D
authors.lastname: Brunkhorst
authors.forename: H
authors.initials: H
authors.lastname: v der Leyen
authors.forename: W
authors.initials: W
authors.lastname: Meyer
authors.forename: R
authors.initials: R
authors.lastname: Nigbur
authors.forename: C
authors.initials: C
authors.lastname: Schmidt-Schumacher
authors.forename: H
authors.initials: H
authors.lastname: Scholz
mesh_terms: D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects*; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D020105:Milrinone; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000201:enzymology*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D011724:Pyridazines / Q000494:pharmacology; D011728:Pyridones / Q000494:pharmacology
chemical_list: D002316:Cardiotonic Agents; D007527:Isoenzymes; D010726:Phosphodiesterase Inhibitors; D011724:Pyridazines; D011728:Pyridones; C041648:pimobendan; C047936:UD CG 212 Cl; D010727:Phosphoric Diester Hydrolases; D020105:Milrinone