Two inotropes with different mechanisms of action: contractile, PDE-inhibitory and direct myofibrillar effects of levosimendan and enoximone.
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 microM 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 microM, selectivity factor approximately 8000) than enoximone (IC50 for PDE III 1.8 microM, and IC50 for PDE IV 160 microM, selectivity factor approximately 90). Hence, our data support the hypothesis that levosimendan exerts positive inotropy via a Ca2+-sensitizing mechanism, whereas enoximone does so via PDE inhibition with a limited PDE III versus PDE IV selectivity.
Szilágyi
Szabolcs
S
Division of Clinical Physiology, Institute of Cardiology, University of Debrecen, Medical and Health Science Center, Faculty of Medicine, Debrecen, Hungary.
Pollesello
Piero
P
Levijoki
Jouko
J
Haikala
Heimo
H
Bak
István
I
Tósaki
Arpád
A
Borbély
Attila
A
Edes
István
I
Papp
Zoltán
Z
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000378:metabolism; D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D017335:Enoximone / Q000494:pharmacology*; D005260:Female; D006168:Guinea Pigs; D006835:Hydrazones / Q000494:pharmacology*; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000502:physiology; D007537:Isometric Contraction / Q000187:drug effects; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D032383:Myocytes, Cardiac / Q000187:drug effects; D009210:Myofibrils / Q000187:drug effects*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000502:physiology; D011724:Pyridazines / Q000494:pharmacology*; D000077464:Simendan; D013379:Substrate Specificity
D002316:Cardiotonic Agents; D006835:Hydrazones; D007527:Isoenzymes; D010726:Phosphodiesterase Inhibitors; D011724:Pyridazines; D000077464:Simendan; D017335:Enoximone; D010727:Phosphoric Diester Hydrolases; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4