Kipka Hannah, Schaflinger Rebecca, Tomasi Roland, Pogoda Kristin, Mannell Hanna
Doctoral Program Clinical Pharmacy, University Hospital, LMU Munich, 81377 Munich, Germany.
Institute of Cardiovascular Physiology and Pathophysiology, Biomedical Center, LMU Munich, 82152 Planegg, Germany.
Biomedicines. 2023 Mar 16;11(3):918. doi: 10.3390/biomedicines11030918.
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.
钙增敏剂左西孟旦用于治疗急性失代偿性心力衰竭。一小部分（4 - 7%）的左西孟旦通过无活性中间体OR - 1855代谢为具有药理活性的代谢产物OR - 1896。此外，左西孟旦已被证明在体外对内皮细胞具有积极作用，可拮抗血管功能障碍和炎症。然而，在此背景下左西孟旦代谢产物的功能仍不清楚。因此，在本研究中，我们调查了代谢产物OR - 1896和OR - 1855对体外内皮细胞炎症过程的影响。通过蛋白质印迹法、流式细胞术和定量逆转录聚合酶链反应评估，我们观察到左西孟旦处理后IL - 1β依赖性内皮细胞黏附分子ICAM - 1和VCAM - 1以及白细胞介素（IL）- 6表达降低，但用OR - 1855或OR - 1896处理后未出现这种情况。相反，这些代谢产物通过使丝裂原活化蛋白激酶p38、ERK1/2和JNK失活，损害了IL - 1β诱导的活性氧生成。我们的结果表明，左西孟旦代谢产物OR - 1896和OR - 1855具有一定的抗炎特性，部分不同于左西孟旦。重要的是，它们还表明中间代谢产物OR - 1855实际上在内皮细胞中具有药理作用。这很有趣，因为这些代谢产物是左西孟旦长期治疗效果的原因，而心力衰竭与血管功能障碍和炎症相关。
