title: Anti-Inflammatory Profile of Levosimendan in Cecal Ligation-Induced Septic Mice and in Lipopolysaccharide-Stimulated Macrophages.
abstract: OBJECTIVE
  The calcium sensitizer levosimendan is used in treatment of decompensated heart failure and may also exhibit anti-inflammatory properties. We examined whether treatment with levosimendan is substantially beneficial in mice with cecal ligation and puncture-induced polymicrobial sepsis, and its arbitration mechanism was explored in the mouse macrophage cell line RAW264.7.
  
  
  METHODS
  Laboratory and animal/cell research.
  
  
  METHODS
  University research laboratory.
  
  
  METHODS
  BALB/c mice (8-10 wk old) and mouse macrophage cell line RAW264.7 cells.
  
  
  METHODS
  Levosimendan (0.5 μg/kg/min) was administered to mice through an osmotic pump that was implanted into the peritoneal cavity immediately following surgery. In RAW264.7 cells, levosimendan was added to the culture medium 30 minutes before lipopolysaccharide.
  
  
  RESULTS
  When levosimendan was continuously administered to cecal ligation and puncture-induced septic mice, a significant improvement of left ventricular function was found without any change in heart rate, and hypotension was significantly mitigated. Furthermore, levosimendan conferred substantial protection against sepsis-associated inflammation in mice, as indicated by reduced lung injury and decreased blood proinflammatory and chemotactic cytokine levels. These beneficial effects of levosimendan led to a significant improvement of survival in mice after cecal ligation and puncture. In endotoxin-stimulated RAW264.7 macrophages, treatment with levosimendan and pimobendan suppressed overproduction of proinflammatory and chemotactic cytokines. Levosimendan and pimobendan were without effect on activation of the nuclear factor-κB, mitogen-activated protein kinase, and Akt pathways. Instead, levosimendan and pimobendan prevented high mobility group box 1 release from the nucleus to the extracellular space in macrophages. This was associated with inhibition of the Rho kinase signaling pathway. The elevated serum high mobility group box 1 levels in cecal ligation and puncture-induced septic mice were also inhibited by continued administration of levosimendan and pimobendan.
  
  
  CONCLUSIONS
  We define a novel mechanism for the anti-inflammatory action of levosimendan and suggest that the pharmacological profiles of levosimendan as both an inotrope and an anti-inflammatory agent could contribute to its clinical benefit in patients with sepsis with heart problems.
authors.affiliation: 1Department of Molecular and Medical Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan. 2Department of Anesthesiology and Pain Relief Center, University of Tokyo Hospital, Tokyo, Japan. 3Department of Emergency and Critical Care Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Wang
authors.forename: Hiroki
authors.initials: H
authors.lastname: Yokoo
authors.forename: Michinori
authors.initials: M
authors.lastname: Takashina
authors.forename: Kimimasa
authors.initials: K
authors.lastname: Sakata
authors.forename: Wakana
authors.initials: W
authors.lastname: Ohashi
authors.forename: Lobna A
authors.initials: LA
authors.lastname: Abedelzaher
authors.forename: Takahiro
authors.initials: T
authors.lastname: Imaizumi
authors.forename: Takuya
authors.initials: T
authors.lastname: Sakamoto
authors.forename: Kohshi
authors.initials: K
authors.lastname: Hattori
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Matsuda
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Hattori
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001707:Biopsy, Needle; D015153:Blotting, Western; D002432:Cecum / Q000601:surgery; D002478:Cells, Cultured; D016207:Cytokines / Q000187:drug effects / Q000378:metabolism*; D004195:Disease Models, Animal; D004452:Echocardiography / Q000379:methods; D004797:Enzyme-Linked Immunosorbent Assay; D006835:Hydrazones / Q000494:pharmacology*; D007150:Immunohistochemistry; D007275:Injections, Intravenous; D008026:Ligation / Q000379:methods; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D011724:Pyridazines / Q000494:pharmacology*; D011897:Random Allocation; D060888:Real-Time Polymerase Chain Reaction; D012016:Reference Values; D018805:Sepsis / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology*; D000077464:Simendan; D018709:Statistics, Nonparametric; D015996:Survival Rate
chemical_list: D000893:Anti-Inflammatory Agents; D016207:Cytokines; D006835:Hydrazones; D008070:Lipopolysaccharides; D011724:Pyridazines; D000077464:Simendan