title: High selectivity for inhibition of phosphodiesterase III and positive inotropic effects of MCI-154 in guinea pig myocardium.
abstract: MCI-154 (0.3-100 microM) exerted a concentration-dependent positive inotropic effect in isolated guinea pig papillary muscles (EC50 0.8 microM). The efficacy of MCI-154 (253% of predrug value) was 1.7-fold higher than that of saterinone but comparable to that of milrinone. Carbachol markedly reduced the increase in force of contraction (FOC) of MCI-154. In intact contracting papillary muscles, the positive inotropic effect was accompanied by an increase in cyclic AMP content to 0.78 +/- 0.09 pmol/mg wet weight (n = 10), corresponding to 150% of the basal value (0.51 +/- 0.05 pmol/mg wet weight, n = 21) in the presence of submaximal cyclic AMP phosphodiesterase (PDE) isoenzyme III inhibiting concentrations of MCI-154 (30 microM). MCI-154 (1-1,000 microM) concentration-dependently inhibited the activity of PDE III from homogenates of guinea pig myocardium. The IC50 was 3.8 microM. PDE I, II, and IV were not significantly affected up to 100 microM (PDE I and IV) and up to 1,000 microM (PDE II). In comparison, milrinone and saterinone were PDE III/IV-selective PDE inhibitors. Rolipram inhibited PDE IV only. IBMX and theophylline were nonselective PDE inhibitors. MCI-154 had only a marginal positive chronotropic effect. The frequency of spontaneously beating right auricles from guinea pig heart was increased by 8.7% at most (n = 5). MCI-154 increased Ca2+ sensitivity in chemically skinned porcine ventricular muscle fibers.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Abteilung Allgemeine Pharmakologie, Universitäts-Krankenhaus Eppendorf, Hamburg, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Bethke
authors.forename: W
authors.initials: W
authors.lastname: Meyer
authors.forename: W
authors.initials: W
authors.lastname: Schmitz
authors.forename: H
authors.initials: H
authors.lastname: Scholz
authors.forename: H
authors.initials: H
authors.lastname: Wenzlaff
authors.forename: B I
authors.initials: BI
authors.lastname: Armah
authors.forename: R
authors.initials: R
authors.lastname: Brückner
authors.forename: A
authors.initials: A
authors.lastname: Raap
mesh_terms: D000818:Animals; D002118:Calcium / Q000494:pharmacology; D002316:Cardiotonic Agents / Q000494:pharmacology*; D003285:Contractile Proteins / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism; D004558:Electric Stimulation; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000378:metabolism; D007700:Kinetics; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000201:enzymology*; D010210:Papillary Muscles / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011724:Pyridazines / Q000494:pharmacology*
chemical_list: D002316:Cardiotonic Agents; D003285:Contractile Proteins; D007527:Isoenzymes; D010726:Phosphodiesterase Inhibitors; D011724:Pyridazines; C052228:MCI 154; D000242:Cyclic AMP; D002118:Calcium