title: Positive inotropic effect of levosimendan is correlated to its stereoselective Ca2+-sensitizing effect but not to stereoselective phosphodiesterase inhibition.
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 EC50 values of 60 nM and 2.8 microM 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 EC50 values of 8.4 nM and 0.64 microM, 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 microM, 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.
authors.affiliation: Orion Pharma, Cardiovascular Research, Espoo, Finland. petri.kaheinen@orionpharma.com
authors.forename: Petri
authors.initials: P
authors.lastname: Kaheinen
authors.forename: Piero
authors.initials: P
authors.lastname: Pollesello
authors.forename: Zita
authors.initials: Z
authors.lastname: Hertelendi
authors.forename: Attila
authors.initials: A
authors.lastname: Borbély
authors.forename: Szabolcs
authors.initials: S
authors.lastname: Szilágyi
authors.forename: Erkki
authors.initials: E
authors.lastname: Nissinen
authors.forename: Heimo
authors.initials: H
authors.lastname: Haikala
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Papp
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002316:Cardiotonic Agents / Q000737:chemistry / Q000494:pharmacology*; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D006835:Hydrazones / Q000737:chemistry / Q000494:pharmacology*; D066298:In Vitro Techniques; D007536:Isomerism; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology; D010210:Papillary Muscles / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D010726:Phosphodiesterase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D011724:Pyridazines / Q000737:chemistry / Q000494:pharmacology*; D000077464:Simendan
chemical_list: D002316:Cardiotonic Agents; D006835:Hydrazones; D010726:Phosphodiesterase Inhibitors; D011724:Pyridazines; D000077464:Simendan; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D002118:Calcium