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Positive Inotropic Effect of Levosimendan is Correlated to its Stereoselective Ca 2+ ‐Sensitizing Effect but not to Stereoselective Phosphodiesterase Inhibition
Author(s) -
Kaheinen Petri,
Pollesello Piero,
Hertelendi Zita,
Borbély Attila,
Szilágyi Szabolcs,
Nissinen Erkki,
Haikala Heimo,
Papp Zoltán
Publication year - 2006
Publication title -
basic and clinical pharmacology and toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.805
H-Index - 90
eISSN - 1742-7843
pISSN - 1742-7835
DOI - 10.1111/j.1742-7843.2006.pto_231.x
Subject(s) - levosimendan , inotrope , stereoselectivity , phosphodiesterase , chemistry , potency , enantiomer , guinea pig , phosphodiesterase inhibitor , milrinone , pharmacology , medicine , stereochemistry , endocrinology , enzyme , biochemistry , biology , in vitro , catalysis
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 Ca 2+ ‐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 Ca 2+ ‐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 IC 50 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 Ca 2+ ‐sensitizing mechanism and not via stereoselective inhibition of phosphodiesterase III in the myocardium.