Key result
OR-1896 evoked a maximum positive inotropic response of 33% above basal at 1 μM in rat ventricular strips, which was mediated through PDE3 inhibition rather than calcium sensitization.
The positive inotropic effect of OR-1896, the active metabolite of levosimendan, is mediated primarily through PDE3 inhibition rather than calcium sensitization in rat myocardium.
Challenges calcium sensitization mechanism for levosimendan metabolite; animal data leaves open human translation.
AIMS: We recently published that the positive inotropic response (PIR) to levosimendan can be fully accounted for by phosphodiesterase (PDE) inhibition in both failing human heart and normal rat heart. To determine if the PIR of the active metabolite OR-1896, an important mediator of the long-term clinical effects of levosimendan, also results from PDE3 inhibition, we compared the effects of OR-1896, a representative Ca2+ sensitizer EMD57033 (EMD), levosimendan and other PDE inhibitors. METHODS: Contractile force was measured in rat ventricular strips. PDE assay was conducted on rat ventricular homogenate. cAMP was measured using RII_epac FRET-based sensors. RESULTS: OR-1896 evoked a maximum PIR of 33 ± 10% above basal at 1 μM. This response was amplified in the presence of the PDE4 inhibitor rolipram (89 ± 14%) and absent in the presence of the PDE3 inhibitors cilostamide (0.5 ± 5.3%) or milrinone (3.2 ± 4.4%). The PIR was accompanied by a lusitropic response, and both were reversed by muscarinic receptor stimulation with carbachol and absent in the presence of β-AR blockade with timolol. OR-1896 inhibited PDE activity and increased cAMP levels at concentrations giving PIRs. OR-1896 did not sensitize the concentration-response relationship to extracellular Ca2+. Levosimendan, OR-1896 and EMD all increased the sensitivity to β-AR stimulation. The combination of either EMD and levosimendan or EMD and OR-1896 further sensitized the response, indicating at least two different mechanisms responsible for the sensitization. Only EMD sensitized the α1-AR response. CONCLUSION: The observed PIR to OR-1896 in rat ventricular strips is mediated through PDE3 inhibition, enhancing cAMP-mediated effects. These results further reinforce our previous finding that Ca2+ sensitization does not play a significant role in the inotropic (and lusitropic) effect of levosimendan, nor of its main metabolite OR-1896.
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Ørstavik et al. (2015) studied Normal rat ventricular myocardium. OR-1896 vs. Basal / PDE3 inhibitors was evaluated on Positive inotropic response (increase in (dF/dt)max above basal). OR-1896 evoked a maximum positive inotropic response of 33% above basal at 1 μM in rat ventricular strips, which was mediated through PDE3 inhibition rather than calcium sensitization.
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