Levosimendan induces NO production through p38 MAPK, ERK and Akt in porcine coronary endothelial cells: Role for mitochondrial K ATP channel

E. Grossini, C. Molinari, P. P. Caimmi, F. Uberti, G. Vacca

Research output: Contribution to journalArticlepeer-review

Abstract

Background and purpose: Levosimendan acts as a vasodilator through the opening of ATP-sensitive K + channels (K ATP) channels. Moreover, the coronary vasodilatation caused by levosimendan in anaesthetized pigs has recently been found to be abolished by the nitric oxide synthase (NOS) inhibitor N ω-nitro-L-arginine methyl ester, indicating that nitric oxide (NO) has a role in the vascular effects of levosimendan. However, the intracellular pathway leading to NO production caused by levosimendan has not yet been investigated. Thus, the purpose of the present study was to examine the effects of levosimendan on NO production and to evaluate the intracellular signalling pathway involved. Experimental approach: In porcine coronary endothelial cells (CEC), the release of NO in response to levosimendan was examined in the presence and absence of N ω-nitro-L-arginine methyl ester, an adenylyl cyclase inhibitor, K ATP channel agonists and antagonists, and inhibitors of intracellular protein kinases. In addition, the role of Akt, ERK, p38 and eNOS was investigated through Western blot analysis. Key results: Levosimendan caused a concentration-dependent and K +-related increase of NO production. This effect was amplified by the mitochondrial K ATP channel agonist, but not by the selective plasma membrane K ATP channel agonist. The response of CEC to levosimendan was prevented by the K ATP channel blockers, the adenylyl cyclase inhibitor and the Akt, ERK, p38 inhibitors. Western blot analysis showed that phosphorylation of the above kinases lead to eNOS activation. Conclusions and implications: In CEC levosimendan induced eNOS-dependent NO production through Akt, ERK and p38. This intracellular pathway is associated with the opening of mitochondrial K ATP channels and involves cAMP. Mandarin translation of abstract.

Original languageEnglish
Pages (from-to)250-261
Number of pages12
JournalBritish Journal of Pharmacology
Volume156
Issue number2
DOIs
Publication statusPublished - Jan 2009
Externally publishedYes

Keywords

  • Akt involvement
  • Coronary endothelial cells
  • ERK
  • K channel
  • Levosimendan
  • Nitric oxide production
  • P38

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