The inotropic effect of the active metabolite of levosimendan, OR-1896, is mediated through inhibition of PDE3 in rat ventricular myocardium

PloS One
Øivind ØrstavikKurt A Krobert

Abstract

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. 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. 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 extrace...Continue Reading

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Citations

Jan 29, 2020·Antioxidants & Redox Signaling·Valentina SalaAlessandra Ghigo
Oct 9, 2018·European Heart Journal·Christoph MaackAlexandre Mebazaa
Nov 7, 2019·European Heart Journal. Cardiovascular Pharmacotherapy·Nicola CosentinoGiancarlo Marenzi
Nov 9, 2019·Communications Biology·Gaia CalameraKjetil Wessel Andressen
Nov 14, 2020·Anesthesia and Analgesia·Carolin TorregrozaRagnar Huhn
Jan 12, 2020·Communications Biology·Gaia CalameraKjetil Wessel Andressen
Apr 4, 2021·International Journal of Molecular Sciences·Sebastian RothRagnar Huhn
Feb 17, 2021·Pediatric Critical Care Medicine : a Journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies·Lukas SchroederFlorian Kipfmueller

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Methods Mentioned

BETA
chip
FRET
NMR

Software Mentioned

Offline Analysis
ARRIVE

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