Exploring the Pleiotropic Effects of Levosimendan– Impact on Systemic Inflammatory Parameters and Molecular Salvage Path-ways by Modulation of Cytokine Levels and Tissue Apoptosis Rate

Introduction: Although levosimendan is commonly used, recent clinical trials remain ambiguous. Extra-corporeal circulation induces Ischemia/Reperfusion Injury (IRI) and inflammation. Methods: In our study, male rats (400 - 500 g) were cannulated, intravenously treated with 12 μg/kg body weight levosimendan (n = 4) or vehicle solution (n = 5) and connected to a heart-lung machine. To induce IRI, 45 min circulatory arrest was performed. After reperfusion, rats were euthanized. Cytokines were analyzed by ELISA and salvage pathways and apoptosis by western blot. Results: After circulatory arrest, heart rate and blood pressure recovered faster in the levosimendan group. The need for buffering solution and catecholamines was 40% lower in the levosimendan group. Cytokines increased in both groups during the procedure but levosimendan diminished the increase of IL-6(- 44 %). Whereas activation of AKT did not differ between groups, p44-42 MAPK ( 29%) and p38 MAPK ( 17%) increased and STAT3 (- 55%) decreased in levosimendan heart samples. PARP-cleavage was 35% decreased in the levosimendan group indicating lower apoptosis. Conclusions: Application of levosimendan seems to affect salvage pathways, cytokines and apoptosis. Levosimendan treated rats recovered faster and showed beneficial changes. These findings may serve our understanding of levosimendan in the context of IRI, allowing better patient tailored drug application.