{ "labelLang" : "hun", "responseDate" : "2024-03-28 23:13", "content" : { "otype" : "JournalArticle", "mtid" : 3023740, "status" : "VALIDATED", "published" : true, "comment" : "Megjegyzés-25819113\nN1 Funding Details: OTKA, Országos Tudományos Kutatási Alapprogramok\nN1 Funding Details: K 109083, OTKA, Országos Tudományos Kutatási Alapprogramok\nDivision of Clinical Physiology, Institute of Cardiology, Research Centre for Molecular Medicine, Faculty of Medicine, University of Debrecen, Hungary Móricz Zs. krt. 22 Hungary, Debrecen, 4032, Hungary \n Orion Pharma, Drug Discovery and Pharmacology, Espoo, Finland \n Department of Pharmacology and Pharmacotherapy, University of Szeged, Szeged, Hungary \n MTA-SZTE Research Group of Cardiovascular Pharmacology, Hungarian Academy of Sciences, Szeged, Hungary \n Export Date: 3 October 2019 \n CODEN: EJPHA \n Correspondence Address: Papp, Z.; Division of Clinical Physiology, Institute of Cardiology, Research Centre for Molecular Medicine, Faculty of Medicine, University of Debrecen, Hungary Móricz Zs. krt. 22 Hungary, Hungary; email: pappz@med.unideb.hu \n Chemicals/CAS: calcium ion, 14127-61-8; troponin C, 56094-11-2; calcium, 7440-70-2, 14092-94-5; Calcium; Cardiotonic Agents; Hydrazones; ORM-3819; Phosphodiesterase 3 Inhibitors; Pyridazines; Troponin C \n Tradenames: orm 3819\nDivision of Clinical Physiology, Institute of Cardiology, Research Centre for Molecular Medicine, Faculty of Medicine, University of Debrecen, Hungary Móricz Zs. krt. 22 Hungary, Debrecen, 4032, Hungary \n Orion Pharma, Drug Discovery and Pharmacology, Espoo, Finland \n Department of Pharmacology and Pharmacotherapy, University of Szeged, Szeged, Hungary \n MTA-SZTE Research Group of Cardiovascular Pharmacology, Hungarian Academy of Sciences, Szeged, Hungary \n Export Date: 24 February 2020 \n CODEN: EJPHA \n Correspondence Address: Papp, Z.; Division of Clinical Physiology, Institute of Cardiology, Research Centre for Molecular Medicine, Faculty of Medicine, University of Debrecen, Hungary Móricz Zs. krt. 22 Hungary, Hungary; email: pappz@med.unideb.hu \n Chemicals/CAS: calcium ion, 14127-61-8; troponin C, 56094-11-2; calcium, 7440-70-2, 14092-94-5; Calcium; Cardiotonic Agents; Hydrazones; ORM-3819; Phosphodiesterase 3 Inhibitors; Pyridazines; Troponin C \n Tradenames: orm 3819\n236101\nDivision of Clinical Physiology, Institute of Cardiology, Research Centre for Molecular Medicine, Faculty of Medicine, University of Debrecen, Hungary Móricz Zs. krt. 22 Hungary, Debrecen, 4032, Hungary \n Orion Pharma, Drug Discovery and Pharmacology, Espoo, Finland \n Department of Pharmacology and Pharmacotherapy, University of Szeged, Szeged, Hungary \n MTA-SZTE Research Group of Cardiovascular Pharmacology, Hungarian Academy of Sciences, Szeged, Hungary \n Cited By :2 \n Export Date: 31 May 2021 \n CODEN: EJPHA \n Correspondence Address: Papp, Z.; Division of Clinical Physiology, Hungary Móricz Zs. krt. 22 Hungary, Hungary; email: 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"snippet" : true }, "oaType" : "GREEN", "oaFree" : true, "validState" : "IDENTICAL", "idValue" : "15899", "realUrl" : "http://publicatio.bibl.u-szeged.hu/15899", "published" : false, "snippet" : true } ], "journal" : { "otype" : "Journal", "mtid" : 1517, "link" : "/api/journal/1517", "label" : "EUROPEAN JOURNAL OF PHARMACOLOGY 0014-2999 1879-0712", "pIssn" : "0014-2999", "eIssn" : "1879-0712", "reviewType" : "REVIEWED", "noIF" : false, "sciIndexed" : true, "scopusIndexed" : true, "lang" : "FOREIGN", "hungarian" : false, "published" : true, "oldId" : 1517, "snippet" : true }, "volume" : "775", "firstPage" : "120", "lastPage" : "129", "firstPageOrInternalIdForSort" : "120", "pageLength" : 10, "publishedYear" : 2016, "abstractText" : "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+/-0.3nM) was revealed during in vitro enzyme assays. The Ca2+-sensitizing effect of ORM-3819 was demonstrated in vitro in permeabilized myocyte-sized preparations from left ventricles (LV) of guinea pig hearts (DeltapCa50=0.12+/-0.01; EC50=2.88+/-0.14microM). ORM-3819 increased the maximal rate of LV pressure development (+dP/dtmax) (EC50=8.9+/-1.7nM) and LV systolic pressure (EC50=7.63+/-1.74nM) in Langendorff-perfused guinea pig hearts. Intravenous administration of ORM-3819 increased LV+dP/dtmax (EC50=0.13+/-0.05microM/kg) and improved the rate of LV pressure decrease (-dP/dtmax); (EC50=0.03+/-0.02microM/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 Ca2+-sensitizing mechanism in combination with the selective inhibition of the PDE III isozyme. 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