title: ORM-3819 promotes cardiac contractility through Ca(2+) sensitization in combination with selective PDE III inhibition, a novel approach to inotropy.
abstract: This study is the first pharmacological characterization of the novel chemical entity, ORM-3819 (L-6-{4-[N'-(4-Hydroxi-3-methoxy-2-nitro-benzylidene)-hydrazino]-phenyl}-5-methyl-4,5-dihydro-2H-pyridazin-3-one), focusing primarily on its cardiotonic effects. ORM-3819 binding to cardiac troponin C (cTnC) was confirmed by nuclear magnetic resonance spectroscopy, and a selective inhibition of the phosphodiesterase III (PDE III) isozyme (IC50=3.88±0.3 nM) was revealed during in vitro enzyme assays. The Ca(2+)-sensitizing effect of ORM-3819 was demonstrated in vitro in permeabilized myocyte-sized preparations from left ventricles (LV) of guinea pig hearts (ΔpCa50=0.12±0.01; EC50=2.88±0.14 µM). ORM-3819 increased the maximal rate of LV pressure development (+dP/dtmax) (EC50=8.9±1.7 nM) and LV systolic pressure (EC50=7.63±1.74 nM) in Langendorff-perfused guinea pig hearts. Intravenous administration of ORM-3819 increased LV+dP/dtmax (EC50=0.13±0.05 µM/kg) and improved the rate of LV pressure decrease (-dP/dtmax); (EC50=0.03±0.02 µM/kg) in healthy guinea pigs. In an in vivo dog model of myocardial stunning, ORM-3819 restored the depressed LV+dP/dtmax and improved % segmental shortening (%SS) in the ischemic area (to 18.8±3), which was reduced after the ischaemia-reperfusion insult (from 24.1±2.1 to 11.0±2.4). Our data demonstrate ORM-3819 as a potent positive inotropic agent exerting its cardiotonic effect by a cTnC-dependent Ca(2+)-sensitizing mechanism in combination with the selective inhibition of the PDE III isozyme. This dual mechanism of action results in the concentration-dependent augmentation of the contractile performance under control conditions and in the postischemic failing myocardium.
authors.affiliation: Division of Clinical Physiology, Institute of Cardiology, Research Centre for Molecular Medicine, Faculty of Medicine, University of Debrecen, Hungary Móricz Zs. krt. 22 Hungary, 4032 Debrecen, Hungary.
authors.forename: László
authors.initials: L
authors.lastname: Nagy
authors.affiliation: Orion Pharma, Drug Discovery and Pharmacology, Espoo, Finland.
authors.forename: Piero
authors.initials: P
authors.lastname: Pollesello
authors.affiliation: Orion Pharma, Drug Discovery and Pharmacology, Espoo, Finland.
authors.forename: Heimo
authors.initials: H
authors.lastname: Haikala
authors.affiliation: Department of Pharmacology and Pharmacotherapy, University of Szeged, Szeged, Hungary.
authors.forename: Ágnes
authors.initials: Á
authors.lastname: Végh
authors.affiliation: Orion Pharma, Drug Discovery and Pharmacology, Espoo, Finland.
authors.forename: Tia
authors.initials: T
authors.lastname: Sorsa
authors.affiliation: Orion Pharma, Drug Discovery and Pharmacology, Espoo, Finland.
authors.forename: Jouko
authors.initials: J
authors.lastname: Levijoki
authors.affiliation: Division of Clinical Physiology, Institute of Cardiology, Research Centre for Molecular Medicine, Faculty of Medicine, University of Debrecen, Hungary Móricz Zs. krt. 22 Hungary, 4032 Debrecen, Hungary.
authors.forename: Szabolcs
authors.initials: S
authors.lastname: Szilágyi
authors.affiliation: Division of Clinical Physiology, Institute of Cardiology, Research Centre for Molecular Medicine, Faculty of Medicine, University of Debrecen, Hungary Móricz Zs. krt. 22 Hungary, 4032 Debrecen, Hungary.
authors.forename: István
authors.initials: I
authors.lastname: Édes
authors.affiliation: Division of Clinical Physiology, Institute of Cardiology, Research Centre for Molecular Medicine, Faculty of Medicine, University of Debrecen, Hungary Móricz Zs. krt. 22 Hungary, 4032 Debrecen, Hungary.
authors.forename: Attila
authors.initials: A
authors.lastname: Tóth
authors.affiliation: Division of Clinical Physiology, Institute of Cardiology, Research Centre for Molecular Medicine, Faculty of Medicine, University of Debrecen, Hungary Móricz Zs. krt. 22 Hungary, 4032 Debrecen, Hungary. Electronic address: pappz@med.unideb.hu.
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Papp
authors.affiliation: MTA-SZTE Research Group of Cardiovascular Pharmacology, Hungarian Academy of Sciences, Szeged, Hungary.
authors.forename: Julius Gy
authors.initials: JG
authors.lastname: Papp
mesh_terms: D000818:Animals; D002118:Calcium / Q000502:physiology; D002316:Cardiotonic Agents / Q000494:pharmacology*; D004285:Dogs; D005260:Female; D006168:Guinea Pigs; D006352:Heart Ventricles / Q000166:cytology; D006835:Hydrazones / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology; D058987:Phosphodiesterase 3 Inhibitors / Q000494:pharmacology*; D011724:Pyridazines / Q000494:pharmacology*; D019209:Troponin C / Q000378:metabolism; D016277:Ventricular Function, Left / Q000187:drug effects
chemical_list: D002316:Cardiotonic Agents; D006835:Hydrazones; C000612829:ORM-3819; D058987:Phosphodiesterase 3 Inhibitors; D011724:Pyridazines; D019209:Troponin C; D002118:Calcium
keywords: Ca(2+) sensitization; Levosimendan; Myocardial stunning; ORM-3819; Phosphodiesterase III inhibition; Positive inotropic agent