Levosimendan: a cardiovascular drug to prevent liver ischemia-reperfusion injury?

PLoS One. 2013 Sep 11;8(9):e73758. doi: 10.1371/journal.pone.0073758. eCollection 2013.

Abstract

Introduction: Temporary occlusion of the hepatoduodenal ligament leads to an ischemic-reperfusion (IR) injury in the liver. Levosimendan is a new positive inotropic drug, which induces preconditioning-like adaptive mechanisms due to opening of mitochondrial KATP channels. The aim of this study was to examine possible protective effects of levosimendan in a rat model of hepatic IR injury.

Material and methods: Levosimendan was administered to male Wistar rats 1 hour (early pretreatment) or 24 hours (late pretreatment) before induction of 60-minute segmental liver ischemia. Microcirculation of the liver was monitored by laser Doppler flowmeter. After 24 hours of reperfusion, liver and blood samples were taken for histology, immuno- and enzyme-histochemistry (TUNEL; PARP; NADH-TR) as well as for laboratory tests. Furthermore, liver antioxidant status was assessed and HSP72 expression was measured.

Results: In both groups pretreated with levosimendan, significantly better hepatic microcirculation was observed compared to respective IR control groups. Similarly, histological damage was also reduced after levosimendan administration. This observation was supported by significantly lower activities of serum ALT (p early = 0.02; p late = 0.005), AST (p early = 0.02; p late = 0.004) and less DNA damage by TUNEL test (p early = 0.05; p late = 0.034) and PAR positivity (p early = 0.02; p late = 0.04). Levosimendan pretreatment resulted in significant improvement of liver redox homeostasis. Further, significantly better mitochondrial function was detected in animals receiving late pretreatment. Finally, HSP72 expression was increased by IR injury, but it was not affected by levosimendan pretreatment.

Conclusion: Levosimendan pretreatment can be hepatoprotective and it could be useful before extensive liver resection.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alanine Transaminase / blood
  • Animals
  • Aspartate Aminotransferases / blood
  • Blotting, Western
  • Cardiotonic Agents / pharmacology*
  • DNA Damage / drug effects
  • HSP72 Heat-Shock Proteins / metabolism
  • Hydrazones / pharmacology*
  • Immunohistochemistry
  • Liver / blood supply*
  • Liver / metabolism
  • Male
  • Microcirculation / drug effects
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Oxidation-Reduction / drug effects
  • Poly(ADP-ribose) Polymerases / metabolism
  • Pyridazines / pharmacology*
  • Rats
  • Rats, Wistar
  • Reperfusion Injury / blood
  • Reperfusion Injury / physiopathology
  • Reperfusion Injury / prevention & control*
  • Simendan
  • Time Factors
  • Treatment Outcome

Substances

  • Cardiotonic Agents
  • HSP72 Heat-Shock Proteins
  • Hydrazones
  • Pyridazines
  • Simendan
  • Poly(ADP-ribose) Polymerases
  • Aspartate Aminotransferases
  • Alanine Transaminase

Grant support

The authors thank Orion Pharma for covering the publication fee. Orion Pharma had no influence on this study and publication. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.