Positive inotropic effect of levosimendan is correlated to its stereoselective Ca2+-sensitizing effect but not to stereoselective phosphodiesterase inhibition

Petri Kaheinen, Piero Pollesello, Zita Hertelendi, A. Borbély, Szabolcs Szilágyi, I. Édes, Erkki Nissinen, Heimo Haikala, Z. Papp

Research output: Contribution to journalArticle

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Abstract

In order to clarify the mechanisms of the positive inotropic actions of levosimendan and its optical isomer, dextrosimendan, we compared their concentration-dependent effects in intact papillary muscles, permeabilized cardiomyocytes and in purified phosphodiesterase enzyme preparations of guinea-pig hearts. In papillary muscles twitch tension increased with EC 50 values of 60 nM and 2.8 μM for levosimendan and dextrosimendan, respectively. Hence, the two enantiomers exhibited a 47 times potency difference in their positive inotropic effects in a preparation where theoretically Ca2+-sensitization and phosphodiesterase inhibition could both contribute to the positive inotropic effects. In guinea-pig cardiomyocytes, levosimendan and dextrosimendan increased isometric force production (at pCa 6.2) due to Ca2+-sensitization with EC 50 values of 8.4 nM and 0.64 μM, respectively, with a similar relative potency difference of 76. A major difference appeared in their relative pharmacological potencies, however, when the inhibitory effects of the two enantiomers were assayed on phosphodiesterase III, purified from guinea pig left ventricle (i.e. the phosphodiesterase isoenzyme which is dominant in that tissue). Levosimendan was a 427 times more potent phosphodiesterase inhibitor than dextrosimendan, with IC50 values of 7.5 nM, and 3.2 μM, respectively. Taken together, our data support the hypothesis that levosimendan and dextrosimendan exert their positive inotropic effects via a stereoselective Ca2+-sensitizing mechanism and not via stereoselective inhibition of phosphodiesterase III in the myocardium.

Original languageEnglish
Pages (from-to)74-78
Number of pages5
JournalBasic and Clinical Pharmacology and Toxicology
Volume98
Issue number1
DOIs
Publication statusPublished - Jan 2006

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Phosphoric Diester Hydrolases
Type 3 Cyclic Nucleotide Phosphodiesterases
Guinea Pigs
Enantiomers
Papillary Muscles
Cardiac Myocytes
Muscle
simendan
Muscle Tonus
Phosphodiesterase Inhibitors
Isomers
Isoenzymes
Inhibitory Concentration 50
Heart Ventricles
Myocardium
Pharmacology
Tissue

ASJC Scopus subject areas

  • Pharmacology
  • Toxicology

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Positive inotropic effect of levosimendan is correlated to its stereoselective Ca2+-sensitizing effect but not to stereoselective phosphodiesterase inhibition. / Kaheinen, Petri; Pollesello, Piero; Hertelendi, Zita; Borbély, A.; Szilágyi, Szabolcs; Édes, I.; Nissinen, Erkki; Haikala, Heimo; Papp, Z.

In: Basic and Clinical Pharmacology and Toxicology, Vol. 98, No. 1, 01.2006, p. 74-78.

Research output: Contribution to journalArticle

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AU - Borbély, A.

AU - Szilágyi, Szabolcs

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