title: Adenosine receptors: regulatory players in the preservation of mitochondrial function induced by ischemic preconditioning of rat liver.
abstract: Although adenosine A1receptors (A1R) have been associated to ischemic preconditioning (IPC), direct evidence for their ability to preserve mitochondrial function upon hepatic preconditioning is still missing and could represent a novel strategy to boost the quality of liver transplants. We tested if the A1R antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) prevented IPC in the liver and if the A1R agonist 2-chloro-N6-cyclopentyladenosine (CCPA) might afford a pharmacological preconditioning. Livers underwent a 120 min of 70% warm ischemia and 16 h of reperfusion (I/R), and the IPC group underwent a 5-min ischemic episode followed by a 10-min period of reperfusion before I/R. DPCPX or CCPA was administered intraperitoneally 2 h before IPC or I/R. The control of mitochondrial function emerged as the central element affected by IPC and controlled by endogenous A1R activation. Thus, livers from IPC- or CCPA-treated rats displayed an improved oxidative phosphorylation with higher state 3 respiratory rate, higher respiratory control ratio, increased ATP content, and decreased lag phase. IPC and CCPA also prevented the I/R-induced susceptibility to calcium-induced mitochondrial permeability transition, the rate of reactive oxygen species (ROS) generation, and the decreased mitochondrial content of phospho-Ser9GSK-3β. DPCPX abrogated these effects of IPC. These implicate the control of GSK-3β activity by Akt-mediated Ser9-GSK-3β phosphorylation preserving the efficiency of oxidative phosphorylation and ROS-mediated cell death in the ability of A1R activation to mimic IPC in the liver. In conclusion, the parallel between IPC and A1R-mediated preconditioning also paves the way to consider a putative therapeutic use of the later in liver transplants.
authors.affiliation: CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504, Coimbra, Portugal.|Department of Life Sciences, Faculty of Sciences and Technology, University of Coimbra, 3000-504, Coimbra, Portugal.
authors.forename: Filipe V
authors.initials: FV
authors.lastname: Duarte
authors.affiliation: CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504, Coimbra, Portugal.
authors.forename: João A
authors.initials: JA
authors.lastname: Amorim
authors.affiliation: CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504, Coimbra, Portugal.|Department of Life Sciences, Faculty of Sciences and Technology, University of Coimbra, 3000-504, Coimbra, Portugal.
authors.forename: Ana T
authors.initials: AT
authors.lastname: Varela
authors.affiliation: CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504, Coimbra, Portugal.|Department of Life Sciences, Faculty of Sciences and Technology, University of Coimbra, 3000-504, Coimbra, Portugal.
authors.forename: João S
authors.initials: JS
authors.lastname: Teodoro
authors.affiliation: CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504, Coimbra, Portugal.|Department of Life Sciences, Faculty of Sciences and Technology, University of Coimbra, 3000-504, Coimbra, Portugal.
authors.forename: Ana P
authors.initials: AP
authors.lastname: Gomes
authors.affiliation: CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504, Coimbra, Portugal.|FMUC-Faculty of Medicine, University of Coimbra, 3004-504, Coimbra, Portugal.
authors.forename: Rodrigo A
authors.initials: RA
authors.lastname: Cunha
authors.affiliation: CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504, Coimbra, Portugal.|Department of Life Sciences, Faculty of Sciences and Technology, University of Coimbra, 3000-504, Coimbra, Portugal.
authors.forename: Carlos M
authors.initials: CM
authors.lastname: Palmeira
authors.affiliation: CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504, Coimbra, Portugal. anpiro@ci.uc.pt.|Department of Life Sciences, Faculty of Sciences and Technology, University of Coimbra, 3000-504, Coimbra, Portugal. anpiro@ci.uc.pt.
authors.forename: Anabela P
authors.initials: AP
authors.lastname: Rolo
mesh_terms: D058907:Adenosine A1 Receptor Agonists / Q000494:pharmacology; D058916:Adenosine A1 Receptor Antagonists / Q000494:pharmacology; D000818:Animals; D019194:Ischemic Preconditioning / Q000379:methods*; D008099:Liver / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D043682:Receptor, Adenosine A1 / Q000378:metabolism*
chemical_list: D058907:Adenosine A1 Receptor Agonists; D058916:Adenosine A1 Receptor Antagonists; D043682:Receptor, Adenosine A1
keywords: Adenosine A1 receptors; GSK-3β, glycogen synthase kinase 3β; Ischemic preconditioning; Liver; Mitochondrial permeability transition; Oxidative phosphorylation