ArticlePloS one2015
The inotropic effect of the active metabolite of levosimendan, OR-1896, is mediated through inhibition of PDE3 in rat ventricular myocardium.
Article in PloS one, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 31 citations in OpenAlex.
- Serum concentrations of levosimendan and its metabolites OR-1855 and OR-1896 in cardiac surgery patients with cardiopulmonary bypass.Frontiers in cardiovascular medicine · 2024Article
- OR-1896 increases force of contraction in the isolated human atrium.Naunyn-Schmiedeberg's archives of pharmacology · 2023Article
- Evaluation of levosimendan as treatment option in a large case-series of preterm infants with cardiac dysfunction and pulmonary hypertension.European journal of pediatrics · 2023Article
- Levosimendan increases the phosphorylation state of phospholamban in the isolated human atrium.Naunyn-Schmiedeberg's archives of pharmacology · 2023Article
- The Effects of the Levosimendan Metabolites OR-1855 and OR-1896 on Endothelial Pro-Inflammatory Responses.Biomedicines · 2023Article
- Targeting the sarcomere in inherited cardiomyopathies.Nature reviews. Cardiology · 2022Review
- Drug Treatment of Heart Failure in Children: Gaps and Opportunities.Paediatric drugs · 2022Review
- Small Molecule RPI-194 Stabilizes Activated Troponin to Increase the Calcium Sensitivity of Striated Muscle Contraction.Frontiers in physiology · 2022Article
- [Perioperative cardioprotection - From bench to bedside : Current experimental evidence and possible reasons for the limited translation into the clinical setting].Der Anaesthesist · 2021Review
- Pharmacological Conditioning of the Heart: An Update on Experimental Developments and Clinical Implications.International journal of molecular sciences · 2021Review
- Recent and Upcoming Drug Therapies for Pediatric Heart Failure.Frontiers in pediatrics · 2021Review
- Treatments targeting inotropy.European heart journal · 2019Article
- FRET-based cyclic GMP biosensors measure low cGMP concentrations in cardiomyocytes and neurons.Communications biology · 2019Article
- Expression of Recombinant Phosphodiesterases 3A and 3B Using Baculovirus Expression System.Iranian journal of biotechnology · 2016Article
Corrections and comments
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
aimsWe 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.
methodsContractile force was measured in rat ventricular strips. PDE assay was conducted on rat ventricular homogenate. cAMP was measured using RII_epac FRET-based sensors.
resultsOR-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.
conclusionThe 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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