Two Inotropes With Different Mechanisms of Action: Contractile, PDE-Inhibitory and Direct Myofibrillar Effects of Levosimendan and Enoximone


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Abstract

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 μM 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 μM, selectivity factor ∼8000) than enoximone (IC50 for PDE III 1.8 μM, and IC50 for PDE IV 160 μM, selectivity factor ∼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.

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