The effects of levosimendan and OR-1896 on isolated hearts, myocyte-sized preparations and phosphodiesterase enzymes of the guinea pig

Szabolcs Szilágyi, Piero Pollesello, Jouko Levijoki, Petri Kaheinen, Heimo Haikala, István Édes, Zoltán Papp

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Abstract

The concentration dependences of the Ca2+-sensitizing and the phosphodiesterase-inhibitory effects of levosimendan (the (-) enantiomer of {[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]hydrazono} propanedinitrile) and its active metabolite, OR-1896 (the (-) enantiomer of N-[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl] acetamide), were compared with their positive inotropic effects to reveal their mechanisms of action in guinea pig hearts. In Langendorff-perfused hearts, left ventricular +dP/dtmax increased by 26±4% and 25±3% (mean±S.E.M.), with EC50 values of 15±2 and 25±1 nM for levosimendan and OR-1896, respectively. In permeabilized myocyte-sized preparations, levosimendan and OR-1896 both increased isometric force production via Ca2+ sensitization (at pCa 6.2), by 51±7% and 52±6%, with EC50 values of 8±1 and 36±7 nM (P<0.05), respectively. Thus, the two molecules could be defined as Ca2+ sensitizers and positive inotropes with very similar concentration dependences. However, major differences appeared when the phosphodiesterase-inhibitory effects of levosimendan and OR-1896 were probed on the two phosphodiesterase isoforms (phosphodiesterases III and IV) dominant in the left ventricular cardiac tissue. Levosimendan was a 40-fold more potent and a 3-fold more selective phosphodiesterase III inhibitor (IC50 for phosphodiesterase III=2.5 nM, and IC50 for phosphodiesterase IV=25 μM, selectivity factor ≈10000) than OR-1896 (IC50 for phosphodiesterase III=94 nM, and IC50 for phosphodiesterase IV=286 μM, selectivity factor ≈3000). Hence, our data support the hypothesis that levosimendan and OR-1896 both exert positive inotropy via a Ca 2+-sensitizing mechanism and not via simultaneous inhibition of the phosphodiesterases III and IV isozymes in the myocardium at their maximal free plasma concentrations.

Original languageEnglish
Pages (from-to)67-74
Number of pages8
JournalEuropean Journal of Pharmacology
Volume486
Issue number1
DOIs
Publication statusPublished - Feb 13 2004

Keywords

  • Ca-sensitization
  • Levosimendan
  • OR-1896
  • Phosphodiesterase inhibition
  • Phosphodiesterase subtype
  • Positive inotropy

ASJC Scopus subject areas

  • Pharmacology

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