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

L. Nagy, Piero Pollesello, Heimo Haikala, A. Végh, Tia Sorsa, Jouko Levijoki, Szabolcs Szilágyi, I. Édes, Attila Tóth, Z. Papp, J. Papp

Research output: Contribution to journalArticle

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-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/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 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.

Original languageEnglish
Pages (from-to)120-129
Number of pages10
JournalEuropean Journal of Pharmacology
Volume775
DOIs
Publication statusPublished - Mar 15 2016

Fingerprint

Heart Ventricles
Troponin C
Cardiotonic Agents
Guinea Pigs
Isoenzymes
Type 3 Cyclic Nucleotide Phosphodiesterases
Myocardial Stunning
Pressure
Enzyme Assays
Intravenous Administration
Muscle Cells
Inhibitory Concentration 50
Reperfusion
Myocardium
Magnetic Resonance Spectroscopy
Ischemia
Pharmacology
Dogs
Blood Pressure
In Vitro Techniques

Keywords

  • Ca sensitization
  • Levosimendan
  • Myocardial stunning
  • ORM-3819
  • Phosphodiesterase III inhibition
  • Positive inotropic agent

ASJC Scopus subject areas

  • Pharmacology

Cite this

ORM-3819 promotes cardiac contractility through Ca2+ sensitization in combination with selective PDE III inhibition, a novel approach to inotropy. / Nagy, L.; Pollesello, Piero; Haikala, Heimo; Végh, A.; Sorsa, Tia; Levijoki, Jouko; Szilágyi, Szabolcs; Édes, I.; Tóth, Attila; Papp, Z.; Papp, J.

In: European Journal of Pharmacology, Vol. 775, 15.03.2016, p. 120-129.

Research output: Contribution to journalArticle

@article{f33c78f72a3c4e5998f79eacce0056a3,
title = "ORM-3819 promotes cardiac contractility through Ca2+ 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-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/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 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.",
keywords = "Ca sensitization, Levosimendan, Myocardial stunning, ORM-3819, Phosphodiesterase III inhibition, Positive inotropic agent",
author = "L. Nagy and Piero Pollesello and Heimo Haikala and A. V{\'e}gh and Tia Sorsa and Jouko Levijoki and Szabolcs Szil{\'a}gyi and I. {\'E}des and Attila T{\'o}th and Z. Papp and J. Papp",
year = "2016",
month = "3",
day = "15",
doi = "10.1016/j.ejphar.2016.02.028",
language = "English",
volume = "775",
pages = "120--129",
journal = "European Journal of Pharmacology",
issn = "0014-2999",
publisher = "Elsevier",

}

TY - JOUR

T1 - ORM-3819 promotes cardiac contractility through Ca2+ sensitization in combination with selective PDE III inhibition, a novel approach to inotropy

AU - Nagy, L.

AU - Pollesello, Piero

AU - Haikala, Heimo

AU - Végh, A.

AU - Sorsa, Tia

AU - Levijoki, Jouko

AU - Szilágyi, Szabolcs

AU - Édes, I.

AU - Tóth, Attila

AU - Papp, Z.

AU - Papp, J.

PY - 2016/3/15

Y1 - 2016/3/15

N2 - 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/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 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.

AB - 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/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 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.

KW - Ca sensitization

KW - Levosimendan

KW - Myocardial stunning

KW - ORM-3819

KW - Phosphodiesterase III inhibition

KW - Positive inotropic agent

UR - http://www.scopus.com/inward/record.url?scp=84959568901&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84959568901&partnerID=8YFLogxK

U2 - 10.1016/j.ejphar.2016.02.028

DO - 10.1016/j.ejphar.2016.02.028

M3 - Article

C2 - 26872993

AN - SCOPUS:84959568901

VL - 775

SP - 120

EP - 129

JO - European Journal of Pharmacology

JF - European Journal of Pharmacology

SN - 0014-2999

ER -