Two inotropes with different mechanisms of action

Contractile, PDE-inhibitory and direct myofibrillar effects of levosimendan and enoximone

Szabolcs Szilágyi, Piero Pollesello, Jouko Levijoki, Heimo Haikala, I. Bak, A. Tósaki, A. Borbély, I. Édes, Z. Papp

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

We characterized the Ca2+-sensitizing and phosphodiesterase (PDE)-inhibitory potentials of levosimendan and enoximone to assess their contributions to the positive inotropic effects of these drugs. In guinea pig hearts perfused in the working-heart mode, the maximal increase in cardiac output (55%, P <0.05) was attained at 50 nM levosimendan. The corresponding value for enoximone (36%) was significantly smaller (P <0.05) and was observed at a higher concentration (500 nM). In permeabilized myocyte-sized preparations levosimendan evoked a maximal increase of 55.8 ± 8% (mean ± SEM) in isometric force production via Ca2+ sensitization (pCa 6.2, EC50 8.4 nM). Enoximone up to a concentration of 10 μM failed to influence the isometric force. The PDE-inhibitory effects were probed on the PDE III and PDE IV isoforms. Levosimendan proved to be a 1300-fold more potent and a 90-fold more selective PDE III inhibitor (IC50 for PDE III 1.4 nM, and IC50 for PDE IV 11 μM, selectivity factor ∼8000) than enoximone (IC50 for PDE III 1.8 μM, and IC 50 for PDE IV 160 μM, selectivity factor ∼90). Hence, our data support the hypothesis that levosimendan exerts positive inotropy via a Ca 2+-sensitizing mechanism, whereas enoximone does so via PDE inhibition with a limited PDE III versus PDE IV selectivity.

Original languageEnglish
Pages (from-to)369-376
Number of pages8
JournalJournal of Cardiovascular Pharmacology
Volume46
Issue number3
DOIs
Publication statusPublished - Sep 2005

Fingerprint

Enoximone
Type 3 Cyclic Nucleotide Phosphodiesterases
Type 4 Cyclic Nucleotide Phosphodiesterase
Phosphoric Diester Hydrolases
Inhibitory Concentration 50
Phosphodiesterase Inhibitors
Cardiac Output
Muscle Cells
Protein Isoforms
Guinea Pigs
simendan
Pharmaceutical Preparations

Keywords

  • Ca sensitization
  • Enoximone
  • Levosimendan
  • Phosphodiesterase inhibition
  • Phosphodiesterase subtypes
  • Positive inotropy

ASJC Scopus subject areas

  • Pharmacology
  • Cardiology and Cardiovascular Medicine

Cite this

Two inotropes with different mechanisms of action : Contractile, PDE-inhibitory and direct myofibrillar effects of levosimendan and enoximone. / Szilágyi, Szabolcs; Pollesello, Piero; Levijoki, Jouko; Haikala, Heimo; Bak, I.; Tósaki, A.; Borbély, A.; Édes, I.; Papp, Z.

In: Journal of Cardiovascular Pharmacology, Vol. 46, No. 3, 09.2005, p. 369-376.

Research output: Contribution to journalArticle

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abstract = "We characterized the Ca2+-sensitizing and phosphodiesterase (PDE)-inhibitory potentials of levosimendan and enoximone to assess their contributions to the positive inotropic effects of these drugs. In guinea pig hearts perfused in the working-heart mode, the maximal increase in cardiac output (55{\%}, P <0.05) was attained at 50 nM levosimendan. The corresponding value for enoximone (36{\%}) was significantly smaller (P <0.05) and was observed at a higher concentration (500 nM). In permeabilized myocyte-sized preparations levosimendan evoked a maximal increase of 55.8 ± 8{\%} (mean ± SEM) in isometric force production via Ca2+ sensitization (pCa 6.2, EC50 8.4 nM). Enoximone up to a concentration of 10 μM failed to influence the isometric force. The PDE-inhibitory effects were probed on the PDE III and PDE IV isoforms. Levosimendan proved to be a 1300-fold more potent and a 90-fold more selective PDE III inhibitor (IC50 for PDE III 1.4 nM, and IC50 for PDE IV 11 μM, selectivity factor ∼8000) than enoximone (IC50 for PDE III 1.8 μM, and IC 50 for PDE IV 160 μM, selectivity factor ∼90). Hence, our data support the hypothesis that levosimendan exerts positive inotropy via a Ca 2+-sensitizing mechanism, whereas enoximone does so via PDE inhibition with a limited PDE III versus PDE IV selectivity.",
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AU - Édes, I.

AU - Papp, Z.

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