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Eur J Pharmacol. 2011 Mar 25;655(1-3):59-66. doi: 10.1016/j.ejphar.2010.12.035. Epub 2011 Jan 13.

Levosimendan preserves the contractile responsiveness of hypoxic human myocardium via mitochondrial K(ATP) channel and potential pERK 1/2 activation.

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1
Cardiovascular Therapeutics Unit, Department of Pharmacology, University of Melbourne, Parkville, Australia. paulsoeding@bigpond.com.au

Abstract

This study investigated the role of levosimendan, a mitochondrial K(ATP) channel opener, during hypoxia-reoxygenation injury in human isolated tissue. The activation of preconditioning pathways, and the release of mitochondrial cytochrome c were determined. Human right atrial trabeculae were mounted in an organ bath, electrically paced and contractile force measured. Tissue was subjected to hypoxia-reoxygenation, and isoproterenol concentration-response experiments were performed as an index of contractile viability. The intracellular activities of Akt, ERK 1/2, P38, caspase 3, and cytochrome c were assayed by western blot. Following hypoxia-reoxygenation, the maximal contractile response of trabeculae to isoproterenol was significantly increased with levosimendan pretreatment compared to the hypoxia-reoxygenation control (0.88±0.02 versus 0.60±0.01g, P<0.01). This enhanced response was blocked by 5-hydroxydecoanate (0.54±0.09g, P<0.01). A significant increase in both phosphorylated and total ERK 1/2 and P38 occurred at 60min reoxygenation, compared to control tissue. No difference was observed in phosphorylated or total Akt, though there was a trend for increased levels in hypoxic tissue. Cytochrome c was detected at 60min post reoxygenation, in both levosimendan treated and untreated tissue. No increase in cleaved-caspase 3 activity was observed. Our findings suggest that levosimendan preserves the contractile force to isoproterenol after hypoxia-reoxygenation, a response mediated via mK(ATP) channel activation. The significant increase in the activity of prosurvival mediators ERK 1/2 and P38 following hypoxia indicates a potential mechanism of action for levosimendan-induced cardioprotection.

PMID:
21237146
DOI:
10.1016/j.ejphar.2010.12.035
[Indexed for MEDLINE]

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