title: Dexmedetomidine protects the heart against ischemia-reperfusion injury by an endothelial eNOS/NO dependent mechanism.
abstract: The alpha2-adrenergic receptor agonist Dexmedetomidine (Dex) is a sedative medication used by anesthesiologists. Dex protects the heart against ischemia-reperfusion (IR) and can also act as a preconditioning mimetic. The mechanisms involved in Dex-dependent cardiac preconditioning, and whether this action occurs directly or indirectly on cardiomyocytes, still remain unclear. The endothelial nitric oxide synthase (eNOS)/nitric oxide (NO) signaling pathway and endothelial cells are known to play key roles in cardioprotection against IR injury. Therefore, the aims of this work were to evaluate whether the eNOS/NO pathway mediates the pharmacological cardiac effect of Dex, and whether endothelial cells are required in this cardioprotective action. Isolated adult rat hearts were treated with Dex (10nM) for 25min and the dimerization of eNOS and production of NO were measured. Hearts were then subjected to global IR (30/120min) and the role of the eNOS/NO pathway was evaluated. Dex promoted the activation of eNOS and production of NO. Dex reduced the infarct size and improved the left ventricle function recovery, but this effect was reversed when Dex was co-administered with inhibitors of the eNOS/NO/PKG pathway. In addition, Dex was unable to reduce cell death in isolated adult rat cardiomyocytes subjected to simulated IR. Cardiomyocyte death was attenuated by co-culturing them with endothelial cells pre-treated with Dex. In summary, our results show that Dex triggers cardiac protection by activating the eNOS/NO signaling pathway. This pharmacological effect of Dex requires its interaction with the endothelium.
authors.affiliation: Advanced Center for Chronic Disease (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas & Facultad de Medicina, Universidad de Chile, Santiago, Chile.
authors.forename: Jaime A
authors.initials: JA
authors.lastname: Riquelme
authors.affiliation: Advanced Center for Chronic Disease (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas & Facultad de Medicina, Universidad de Chile, Santiago, Chile.
authors.forename: Francisco
authors.initials: F
authors.lastname: Westermeier
authors.affiliation: The Hatter Cardiovascular Institute, University College London, London, United Kingdom.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Hall
authors.affiliation: The Hatter Cardiovascular Institute, University College London, London, United Kingdom.
authors.forename: José Miguel
authors.initials: JM
authors.lastname: Vicencio
authors.affiliation: Advanced Center for Chronic Disease (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas & Facultad de Medicina, Universidad de Chile, Santiago, Chile; Instituto de Ciencias Biomédicas (ICBM), Facultad de Medicina, Universidad de Chile, Santiago, Chile.
authors.forename: Zully
authors.initials: Z
authors.lastname: Pedrozo
authors.affiliation: División de Anestesiología. Facultad Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Mauricio
authors.initials: M
authors.lastname: Ibacache
authors.affiliation: Cellular and Molecular Physiology Laboratory (CMPL), Division of Obstetrics and Gynaecology, School of Medicine, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Bárbara
authors.initials: B
authors.lastname: Fuenzalida
authors.affiliation: Cellular and Molecular Physiology Laboratory (CMPL), Division of Obstetrics and Gynaecology, School of Medicine, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile; University of Queensland Centre for Clinical Research (UQCCR), Faculty of Medicine and Biomedical Sciences, University of Queensland, Herston, Queensland, Australia; Department of Physiology, Faculty of Pharmacy, Universidad de Sevilla, Seville, Spain.
authors.forename: Luis
authors.initials: L
authors.lastname: Sobrevia
authors.affiliation: The Hatter Cardiovascular Institute, University College London, London, United Kingdom.
authors.forename: Sean M
authors.initials: SM
authors.lastname: Davidson
authors.affiliation: The Hatter Cardiovascular Institute, University College London, London, United Kingdom.
authors.forename: Derek M
authors.initials: DM
authors.lastname: Yellon
authors.affiliation: Instituto de Ciencias Biomédicas (ICBM), Facultad de Medicina, Universidad de Chile, Santiago, Chile. Electronic address: gisanchez@med.uchile.cl.
authors.forename: Gina
authors.initials: G
authors.lastname: Sánchez
authors.affiliation: Advanced Center for Chronic Disease (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas & Facultad de Medicina, Universidad de Chile, Santiago, Chile; Instituto de Ciencias Biomédicas (ICBM), Facultad de Medicina, Universidad de Chile, Santiago, Chile; Department of Internal Medicine (Cardiology Division), University of Texas Southwestern Medical Center, Dallas, Texas, USA. Electronic address: slavander@uchile.cl.
authors.forename: Sergio
authors.initials: S
authors.lastname: Lavandero
mesh_terms: D058647:Adrenergic alpha-2 Receptor Agonists / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002478:Cells, Cultured; D018920:Coculture Techniques; D020927:Dexmedetomidine / Q000494:pharmacology* / Q000627:therapeutic use; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D006801:Humans; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects; D009569:Nitric Oxide / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D017207:Rats, Sprague-Dawley
chemical_list: D058647:Adrenergic alpha-2 Receptor Agonists; D002316:Cardiotonic Agents; D009569:Nitric Oxide; D020927:Dexmedetomidine; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat
keywords: Dexmedetomidine; Endothelium; Heart; Ischemia-reperfusion; Preconditioning; eNOS