ORM-3819 promotes cardiac contractility through Ca sensitization in combination with selective PDE III inhibition, a novel approach to inotropy
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...
Elmentve itt :
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| Dokumentumtípus: | Cikk |
| Megjelent: |
2016
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| Sorozat: | EUROPEAN JOURNAL OF PHARMACOLOGY
775 |
| doi: | 10.1016/j.ejphar.2016.02.028 |
| mtmt: | 3023740 |
| Online Access: | http://publicatio.bibl.u-szeged.hu/15899 |
| Tartalmi kivonat: | 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. This dual mechanism of action results in the concentration-dependent augmentation of the contractile performance under control conditions and in the postischemic failing myocardium. |
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| Terjedelem/Fizikai jellemzők: | 120-129 |
| ISSN: | 0014-2999 |