Document Detail

Postconditioning with levosimendan reduces the infarct size involving the PI3K pathway and KATP-channel activation but is independent of PDE-III inhibition.
MedLine Citation:
PMID:  19842009     Owner:  NLM     Status:  MEDLINE    
Reperfusion injury is strongly involved in the loss of functional heart tissue in patients after acute myocardial infarction. Various signal transduction pathways to reduce infarct size during reperfusion have been characterized. However, so far in the clinical setting no standard therapies are applied due to the lack of suitable drugs. Levosimendan, a calcium sensitizer, has been shown to improve survival in cardiogenic shock after infarction. Focus of the present study was to address the question, whether a bolus application of levosimendan prior to reperfusion is able to reduce the infarct size. A well-characterized model, the in vivo rat model, was used and levosimendan applied 5 min prior to reperfusion after 30-min occlusion of the left coronary artery followed by a 30-min reperfusion period. This pharmacological postconditioning was compared to the ischemic postconditioning with three times occlusion/reperfusion periods of 30 s each. To further address the question if in this in vivo model the phosphatidylinositol 3-kinase (PI3K) pathway may be involved, the PDE-III inhibiting property of levosimendan was compared to the PDE-III inhibitor enoximone. Ischemic postconditioning significantly reduced the infarct size from 48 +/- 2 to 32 +/- 1% of the area at risk (P < 0.05). Similarly, levosimendan decreased infarct size down to 29 +/- 3%. The combination of ischemic postconditioning and pharmacological postconditioning using levosimendan did not result in a further reduction of the infarct size. Both, the mitochondrial KATP-channel blocker 5-hydroxydecanoate (5-HD) and the PI3K inhibitor wortmannin abolished the protection afforded by levosimendan completely, while the inhibitors alone did not influence the infarct size in control hearts. Pharmacological postconditioning with enoximone did not result in any infarct size reduction. Postconditioning with levosimendan significantly increased the phosphorylation of protein kinase B (Akt) and glycogen synthase kinase-3beta (GSK-3beta) at 5 min of reperfusion, an effect which could be blocked completely by the additional administration of wortmannin. In conclusion, levosimendan applied prior to reperfusion in acute myocardial infarction significantly reduces the infarct size in an in vivo rat model. This protection involves the PI3K pathway and the activation of mitochondrial KATP-channels, but is independent of PDE-III inhibition. This finding may open new possibilities for the treatment of patients with acute myocardial infarction using levosimendan, which is an already established therapy in cardiogenic shock. Whether the reduction of mortality in cardiogenic shock by levosimendan may in part be based on this postconditioning effect remains to be elucidated in clinical setting.
Antje H?nisch; Norman Theuring; Bernd Ebner; Claudia Wagner; Ruth H Strasser; Christof Weinbrenner
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2009-10-16
Journal Detail:
Title:  Basic research in cardiology     Volume:  105     ISSN:  1435-1803     ISO Abbreviation:  Basic Res. Cardiol.     Publication Date:  2010 Mar 
Date Detail:
Created Date:  2010-01-21     Completed Date:  2010-03-31     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0360342     Medline TA:  Basic Res Cardiol     Country:  Germany    
Other Details:
Languages:  eng     Pagination:  155-67     Citation Subset:  IM    
Department of Medicine and Cardiology, Heart Center Dresden University Hospital, University of Technology Dresden, Fetscherstr. 74, 01307 Dresden, Germany.
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MeSH Terms
1-Phosphatidylinositol 3-Kinase / metabolism*
Cardiotonic Agents / therapeutic use*
Cyclic Nucleotide Phosphodiesterases, Type 3 / antagonists & inhibitors
Hydrazones / therapeutic use*
KATP Channels / metabolism*
Myocardial Reperfusion Injury / metabolism,  pathology,  prevention & control*
Myocardium / pathology
Phosphodiesterase Inhibitors
Pyridazines / therapeutic use*
Rats, Wistar
Signal Transduction
Reg. No./Substance:
0/Cardiotonic Agents; 0/Hydrazones; 0/KATP Channels; 0/Phosphodiesterase Inhibitors; 0/Pyridazines; 131741-08-7/simendan; 77671-31-9/Enoximone; EC 3-Kinase; EC Nucleotide Phosphodiesterases, Type 3

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