ORM-3819 promotes cardiac contractility through Ca²⁺ sensitization in combination with selective PDE III inhibition, a novel approach to inotropy

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• 作者：Lá ; szló ; Nagy^a ; Piero Pollesello^b ; Heimo Haikala^b ; Á ; gnes Vé ; gh^c ; Tia Sorsa^b ; Jouko Levijoki^b ; Szabolcs Szilá ; gyi^a ; Istvá ; n É ; des^a ; Attila Tó ; th^a ; Zoltá ; n Papp^a ; ¹ ; ^{pappz@med.unideb.hu" class="auth_mail" title="E-mail the corresponding author} ; Julius Gy. Papp^d ; ¹
• 关键词：Ca2+ ; calcium ion ; [Ca2+] ; calcium ion concentration ; cTnC ; cardiac troponin C ; cTnCcs ; recombinant chicken cTnC with mutation of cysteine-35 to serine ; DMSO ; dimethyl-sulfoxide ; DTT ; dithiothreitol ; Factive ; active force ; Fpassive ; passive force ; Fmax ; maximum force level ; Ftotal ; total force level ; HSQC ; heteronuclear single-quantum coherence ; LAD ; anterior descending branch of the left coronary artery ; LCX ; circumflex branch of the left coronary artery ; LV ; left ventricle ; nHill ; Hill coeffic
• 刊名：European Journal of Pharmacology
• 出版年：2016
• 出版时间：15 March 2016
• 年：2016
• 卷：775
• 期：Complete
• 页码：120-129
• 全文大小：735 K

文摘

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-2 H-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 Ca²⁺-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/dt_max) (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/dt_max (EC₅₀=0.13±0.05 µM/kg) and improved the rate of LV pressure decrease (−dP/dt_max); (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/dt_max 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.