title: Effects of the new phosphodiesterase-III inhibitor R80122 on contractility and calcium current in human cardiac tissue.
abstract: The selective phosphodiesterase III (PDE-III) inhibitor R80122 ((E)-N-cyclohexal-N-methyl-2-[[[phenyl-(1,2,3,5- tetrahydro-2-oxoimidazo-[2,1b]-quinazolin-7-yl)-methylene]-a mino]-oxy]-acetamide) has been reported to possess greater cardiotonic potency and less side effects than the standard compounds milrinone or enoximone. To characterize this new compound further, we investigated the effects of R80122 on force of contraction (Fc) and calcium current (ICa) in human right atrium (HRA) and human left ventricle (HLV) with reference to the nonselective PDE-inhibitor IBMX (3-isobutyl-1-methylxanthine). With "late" exposure (300- to 330-min equilibration) of human atrial trabeculae, R80122 (3 microM) increased Fc by 60 +/- 11%; log EC50 was -6.2 +/- 0.1. R80122 (3 microM) induced a relative leftward shift of forskolin concentration-response curves by 0.34 log units; the respective value for IBMX (20 microM) was 0.46. A positive inotropic effect of R80122 was also shown in guinea pig papillary muscles. ICa was measured in voltage-clamped isolated myocytes of human right atrial and left ventricular (LV) tissue, and, for comparison, guinea pig ventricle. With clamp steps from -40 to +5 mV, R80122 (3 microM) increased peak ICa from 3.1 +/- 0.2 to 5.4 +/- 0.3 pA/pF in HRA cells, from 2.9 +/- 0.4 to 5.1 +/- 0.6 pA/pF in HLV cells, and from 4.4 +/- 0.3 to 6.6 +/- 0.5 pA/pF in guinea pig myocytes. IBMX 20 microM increased ICa to a greater extent. Washout or addition of carbachol 10 microM partially reversed the effect of R80122. Voltage dependence, inactivation time course, and steady-state inactivation of ICa were little changed by either compound. Stimulation of Ca2+ influx by L-type Ca2+ channels contributes to the positive inotropic effect of the selective PDE-III inhibitor R80122.
authors.affiliation: Institut für Pharmakologie, Universitätsklinikum Essen, Germany.
authors.forename: Q
authors.initials: Q
authors.lastname: Li
authors.forename: H M
authors.initials: HM
authors.lastname: Himmel
authors.forename: U
authors.initials: U
authors.lastname: Ravens
mesh_terms: D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002316:Cardiotonic Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D006325:Heart Atria / Q000187:drug effects / Q000378:metabolism; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D066298:In Vitro Techniques; D009200:Myocardial Contraction / Q000187:drug effects*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*
chemical_list: D002316:Cardiotonic Agents; D007093:Imidazoles; D010726:Phosphodiesterase Inhibitors; D011799:Quinazolines; C076518:R 80122; D002118:Calcium; D015056:1-Methyl-3-isobutylxanthine