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Intensive Care Medicine

, Volume 37, Issue 8, pp 1368–1377 | Cite as

Levosimendan attenuates pulmonary vascular remodeling

  • M. RevermannEmail author
  • M. Schloss
  • A. Mieth
  • A. Babelova
  • K. Schröder
  • S. Neofitidou
  • J. Buerkl
  • T. Kirschning
  • R. T. Schermuly
  • C. Hofstetter
  • R. P. Brandes
Experimental

Abstract

Purpose

The calcium-sensitizing drug levosimendan increases myocardial contractility and, by activating K+-channels, dilates pulmonary vessels. In the acute setting, levosimendan is clinically used to treat right heart failure in pulmonary hypertension. As K+-channel activation elicits several beneficial effects in the vascular system, we hypothesized that levosimendan also attenuates the remodeling process in the monocrotaline model of rat pulmonary hypertension.

Methods and results

Animal subgroups received levosimendan, the K+-channel opener nicorandil, or levosimendan together with the K+-adenosine triphosphate (ATP)-sensitive potassium channel (KATP) blocker glibenclamide. Morphometric analyses revealed that levosimendan and nicorandil attenuated the increased pulmonary vascular medial wall thickness after monocrotaline challenge. Accordingly, in vivo BrdU assays revealed that levosimendan significantly diminished proliferation of pulmonary arterial smooth muscle cells (PASMCs), and this effect was attenuated by glibenclamide. Levosimendan also reduced right ventricular hypertrophy, but this effect was not glibenclamide sensitive and not recapitulated by nicorandil. In cell culture, levosimendan had a direct inhibitory effect on the platelet-derived growth factor (PDGF)-induced proliferation of PASMCs, which however required high concentrations of the compound, pointing towards an endothelial effect. Indeed, levosimendan increased cyclic guanosine monophosphate (cGMP) in human umbilical vein endothelial cells (HUVECs) and impaired the tumor necrosis factor-α (TNF-α)-induced inflammatory expression of E-selectin, intercellular adhesion molecule-1 (ICAM-1), cyclooxygenase-2 (COX-2), and monocyte chemotactic protein-1 (MCP-1). In luciferase reporter gene assays in HUVECs, levosimendan dose-dependently attenuated the TNF-α-stimulated increase of proinflammatory transcription factors activator protein 1 (AP1), hypoxia-inducible factor-1α (HIF-1α), and nuclear factor-κB (NF-κB).

Conclusions

Levosimendan attenuates pulmonary vascular remodeling, presumably by an antiproliferative and anti-inflammatory effect which is mediated by cellular hyperpolarization. The compound also has a direct inhibitory effect on cardiac hypertrophy, which is however K+-channel independent.

Keywords

Levosimendan Pulmonary arterial hypertension Potassium channel Vascular remodeling 

Notes

Acknowledgments

The study was supported by the Deutsche Forschungsgemeinschaft (FOG 784), DGP-Excellence Clusters Cardio-Pulmonary System (ECCPS), and the B. Braun-Stiftung (M.R.). The authors are grateful for the excellent technical support of Susanne Schütz, Katalin Wandzioch, Isabella Schlöffel, and Sina Bätz.

Supplementary material

134_2011_2254_MOESM1_ESM.doc (56 kb)
Supplementary material 1 (DOC 55 kb)
134_2011_2254_MOESM2_ESM.doc (32 kb)
Supplementary material 2 (DOC 32 kb)
134_2011_2254_MOESM3_ESM.ppt (151 kb)
Supplementary material 3 (PPT 153 kb)

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Copyright information

© Copyright jointly held by Springer and ESICM 2011

Authors and Affiliations

  • M. Revermann
    • 1
    • 2
    Email author
  • M. Schloss
    • 1
  • A. Mieth
    • 1
  • A. Babelova
    • 1
  • K. Schröder
    • 1
  • S. Neofitidou
    • 1
  • J. Buerkl
    • 1
  • T. Kirschning
    • 2
  • R. T. Schermuly
    • 3
  • C. Hofstetter
    • 2
  • R. P. Brandes
    • 1
  1. 1.Institut für Kardiovaskuläre Physiologie, Fachbereich MedizinGoethe-Universität FrankfurtFrankfurt am MainGermany
  2. 2.Klinik für Anästhesiologie und Operative IntensivmedizinMedizinische Fakultät Mannheim der Universität HeidelbergMannheimGermany
  3. 3.Max-Planck-Institute for Heart and Lung ResearchBad NauheimGermany

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