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Intensive Care Medicine
Published in: Intensive Care Medicine 8/2011

01-08-2011 | Experimental

Levosimendan attenuates pulmonary vascular remodeling

Authors: M. Revermann, M. Schloss, A. Mieth, A. Babelova, K. Schröder, S. Neofitidou, J. Buerkl, T. Kirschning, R. T. Schermuly, C. Hofstetter, R. P. Brandes

Published in: Intensive Care Medicine | Issue 8/2011

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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.
Appendix
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Metadata
Title
Levosimendan attenuates pulmonary vascular remodeling
Authors
M. Revermann
M. Schloss
A. Mieth
A. Babelova
K. Schröder
S. Neofitidou
J. Buerkl
T. Kirschning
R. T. Schermuly
C. Hofstetter
R. P. Brandes
Publication date
01-08-2011
Publisher
Springer-Verlag
Published in
Intensive Care Medicine / Issue 8/2011
Print ISSN: 0342-4642
Electronic ISSN: 1432-1238
DOI
https://doi.org/10.1007/s00134-011-2254-9

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