The effects of levosimendan and OR-1896 on isolated hearts, myocyte-sized preparations and phosphodiesterase enzymes of the guinea pig.
The concentration dependences of the Ca(2+)-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/dt(max) increased by 26+/-4% and 25+/-3% (mean+/-S.E.M.), with EC(50) 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 Ca(2+) sensitization (at pCa 6.2), by 51+/-7% and 52+/-6%, with EC(50) values of 8+/-1 and 36+/-7 nM (P<0.05), respectively. Thus, the two molecules could be defined as Ca(2+) 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 (IC(50) for phosphodiesterase III=2.5 nM, and IC(50) for phosphodiesterase IV=25 microM, selectivity factor approximately 10000) than OR-1896 (IC(50) for phosphodiesterase III=94 nM, and IC(50) for phosphodiesterase IV=286 microM, selectivity factor approximately 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.
Szilágyi
Szabolcs
S
Division of Clinical Physiology, Faculty of Medicine, Medical and Health Science Center, Institute of Cardiology, University of Debrecen, P.O. BOX 1, H-4004 Debrecen, Hungary.
Pollesello
Piero
P
Levijoki
Jouko
J
Kaheinen
Petri
P
Haikala
Heimo
H
Edes
István
I
Papp
Zoltán
Z
D000081:Acetamides / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D002469:Cell Separation; D004305:Dose-Response Relationship, Drug; D005260:Female; D006168:Guinea Pigs; D006352:Heart Ventricles / Q000187:drug effects* / Q000201:enzymology; D006835:Hydrazones / Q000737:chemistry / Q000494:pharmacology*; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000201:enzymology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D011724:Pyridazines / Q000737:chemistry / Q000494:pharmacology*; D000077464:Simendan; D016276:Ventricular Function
D000081:Acetamides; D006835:Hydrazones; D007527:Isoenzymes; C414222:N-(4-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)acetamide; D010726:Phosphodiesterase Inhibitors; D011724:Pyridazines; D000077464:Simendan; D010727:Phosphoric Diester Hydrolases