Feedback

The Effects of the Levosimendan Metabolites OR-1855 and OR-1896 on Endothelial Pro-Inflammatory Responses

ORCID
0000-0003-0968-8895
Affiliation
Doctoral Program Clinical Pharmacy, University Hospital, LMU Munich, 81377 Munich, Germany
Kipka, Hannah;
Affiliation
Doctoral Program Clinical Pharmacy, University Hospital, LMU Munich, 81377 Munich, Germany
Schaflinger, Rebecca;
ORCID
0000-0001-8484-0047
Affiliation
Department of Anaesthesiology, University Hospital, LMU Munich, 81377 Munich, Germany
Tomasi, Roland;
Affiliation
Institute of Cardiovascular Physiology and Pathophysiology, Biomedical Center, LMU Munich, 82152 Planegg, Germany
Pogoda, Kristin;
Affiliation
Doctoral Program Clinical Pharmacy, University Hospital, LMU Munich, 81377 Munich, Germany
Mannell, Hanna

The calcium sensitizer levosimendan is used for the treatment of acute decompensated heart failure. A small portion (4–7%) of levosimendan is metabolized to the pharmacologically active metabolite OR-1896 via the inactive intermediate OR-1855. In addition, levosimendan has been shown to exert positive effects on the endothelium in vitro antagonizing vascular dysfunction and inflammation. However, the function of the levosimendan metabolites within this context is still unknown. In this study, we thus investigated the impact of the metabolites OR-1896 and OR-1855 on endothelial inflammatory processes in vitro. We observed a reduction of IL-1β-dependent endothelial adhesion molecule ICAM-1 and VCAM-1 as well as interleukin (IL) -6 expression upon levosimendan treatment but not after treatment with OR-1855 or OR-1896, as assessed by western blotting, flow cytometry, and qRT-PCR. Instead, the metabolites impaired IL-1β-induced ROS formation via inactivation of the MAPK p38, ERK1/2, and JNK. Our results suggest that the levosimendan metabolites OR-1896 and OR-1855 have certain anti-inflammatory properties, partly other than levosimendan. Importantly, they additionally show that the intermediate metabolite OR-1855 does, in fact, have pharmacological effects in the endothelium. This is interesting, as the metabolites are responsible for the long-term therapeutic effects of levosimendan, and heart failure is associated with vascular dysfunction and inflammation.

Cite

Citation style:
Could not load citation form.

Access Statistic

Total:
Downloads:
Abtractviews:
Last 12 Month:
Downloads:
Abtractviews:

Rights

License Holder: © 2023 by the authors.

Use and reproduction: