title: Levosimendan attenuates pulmonary vascular remodeling.
abstract: OBJECTIVE
  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.
  
  
  RESULTS
  Animal subgroups received levosimendan, the K(+)-channel opener nicorandil, or levosimendan together with the K(+)-adenosine triphosphate (ATP)-sensitive potassium channel (K(ATP)) 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.
authors.affiliation: Institut für Kardiovaskuläre Physiologie, Fachbereich Medizin, Goethe-Universität Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany. revermann@zphys1.uni-frankfurt.de
authors.forename: M
authors.initials: M
authors.lastname: Revermann
authors.forename: M
authors.initials: M
authors.lastname: Schloss
authors.forename: A
authors.initials: A
authors.lastname: Mieth
authors.forename: A
authors.initials: A
authors.lastname: Babelova
authors.forename: K
authors.initials: K
authors.lastname: Schröder
authors.forename: S
authors.initials: S
authors.lastname: Neofitidou
authors.forename: J
authors.initials: J
authors.lastname: Buerkl
authors.forename: T
authors.initials: T
authors.lastname: Kirschning
authors.forename: R T
authors.initials: RT
authors.lastname: Schermuly
authors.forename: C
authors.initials: C
authors.lastname: Hofstetter
authors.forename: R P
authors.initials: RP
authors.lastname: Brandes
mesh_terms: D056151:Airway Remodeling / Q000187:drug effects*; D000818:Animals; D002316:Cardiotonic Agents / Q000008:administration & dosage / Q000494:pharmacology; D004195:Disease Models, Animal; D005858:Germany; D005905:Glyburide / Q000008:administration & dosage / Q000494:pharmacology; D006835:Hydrazones / Q000008:administration & dosage / Q000494:pharmacology*; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000188:drug therapy*; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000494:pharmacology; D009200:Myocardial Contraction / Q000187:drug effects; D020108:Nicorandil / Q000008:administration & dosage / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects; D011652:Pulmonary Circulation / Q000187:drug effects*; D011724:Pyridazines / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077464:Simendan; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000494:pharmacology
chemical_list: D002316:Cardiotonic Agents; D006835:Hydrazones; D007004:Hypoglycemic Agents; D015221:Potassium Channels; D011724:Pyridazines; D014665:Vasodilator Agents; D020108:Nicorandil; D000077464:Simendan; D005905:Glyburide