title: Levosimendan: molecular mechanisms and clinical implications: consensus of experts on the mechanisms of action of levosimendan.
abstract: The molecular background of the Ca(2+)-sensitizing effect of levosimendan relates to its specific interaction with the Ca(2+)-sensor troponin C molecule in the cardiac myofilaments. Over the years, significant preclinical and clinical evidence has accumulated and revealed a variety of beneficial pleiotropic effects of levosimendan and of its long-lived metabolite, OR-1896. First of all, activation of ATP-sensitive sarcolemmal K(+) channels of smooth muscle cells appears as a powerful vasodilator mechanism. Additionally, activation of ATP-sensitive K(+) channels in the mitochondria potentially extends the range of cellular actions towards the modulation of mitochondrial ATP production and implicates a pharmacological mechanism for cardioprotection. Finally, it has become evident, that levosimendan possesses an isoform-selective phosphodiesterase-inhibitory effect. Interpretation of the complex mechanism of levosimendan action requires that all potential pharmacological interactions are analyzed carefully in the framework of the currently available evidence. These data indicate that the cardiovascular effects of levosimendan are exerted via more than an isolated drug-receptor interaction, and involve favorable energetic and neurohormonal changes that are unique in comparison to other types of inodilators.
authors.affiliation: Institute of Cardiology, Medical and Health Science Center, University of Debrecen, Mórics Zs krt 22, 4032 Debrecen, Hungary. pappz@med.unideb.hu
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Papp
authors.forename: István
authors.initials: I
authors.lastname: Édes
authors.forename: Sonja
authors.initials: S
authors.lastname: Fruhwald
authors.forename: Stefan G
authors.initials: SG
authors.lastname: De Hert
authors.forename: Markku
authors.initials: M
authors.lastname: Salmenperä
authors.forename: Heli
authors.initials: H
authors.lastname: Leppikangas
authors.forename: Alexandre
authors.initials: A
authors.lastname: Mebazaa
authors.forename: Giovanni
authors.initials: G
authors.lastname: Landoni
authors.forename: Elena
authors.initials: E
authors.lastname: Grossini
authors.forename: Philippe
authors.initials: P
authors.lastname: Caimmi
authors.forename: Andrea
authors.initials: A
authors.lastname: Morelli
authors.forename: Fabio
authors.initials: F
authors.lastname: Guarracino
authors.forename: Robert H G
authors.initials: RH
authors.lastname: Schwinger
authors.forename: Sven
authors.initials: S
authors.lastname: Meyer
authors.forename: Lars
authors.initials: L
authors.lastname: Algotsson
authors.forename: Bernt Gerhard
authors.initials: BG
authors.lastname: Wikström
authors.forename: Kirsten
authors.initials: K
authors.lastname: Jörgensen
authors.forename: Gerasimos
authors.initials: G
authors.lastname: Filippatos
authors.forename: John T
authors.initials: JT
authors.lastname: Parissis
authors.forename: Martín J García
authors.initials: MJ
authors.lastname: González
authors.forename: Alexander
authors.initials: A
authors.lastname: Parkhomenko
authors.forename: Mehmet Birhan
authors.initials: MB
authors.lastname: Yilmaz
authors.forename: Matti
authors.initials: M
authors.lastname: Kivikko
authors.forename: Piero
authors.initials: P
authors.lastname: Pollesello
authors.forename: Ferenc
authors.initials: F
authors.lastname: Follath
mesh_terms: D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002318:Cardiovascular Diseases / Q000188:drug therapy / Q000378:metabolism / Q000517:prevention & control; D002986:Clinical Trials as Topic / Q000379:methods; D006801:Humans; D006835:Hydrazones / Q000494:pharmacology / Q000627:therapeutic use*; D011724:Pyridazines / Q000494:pharmacology / Q000627:therapeutic use*; D000077464:Simendan; D014665:Vasodilator Agents / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D002316:Cardiotonic Agents; D006835:Hydrazones; D011724:Pyridazines; D014665:Vasodilator Agents; D000077464:Simendan