title: Functionally selective AT(1) receptor activation reduces ischemia reperfusion injury.
abstract: Angiotensin II (AngII) is a key peptide in cardiovascular homeostasis and is a ligand for the Angiotensin II type 1 and 2 seven transmembrane receptors (AT(1)R and AT(2)R). The AT(1) receptor is a seven-transmembrane (7TM) G protein-coupled receptor (GPCR) mediating the majority of the physiological functions of AngII. The AT(1)R mediates its effects through both G protein-dependent and independent signaling, which can be separated by functionally selective agonists. In the present study we investigate the effect of AngII and the β-arrestin biased agonist [SII]AngII on ischemia-reperfusion injury in rat hearts. Isolated hearts mounted in a Langendorff perfused rat heart preparations showed that preconditioning with [SII]AngII reduced the infarct size induced by global ischemia from 46±8.4% to 22±3.4%. In contrast, neither preconditioning with AngII nor postconditioning with AngII or [SII]AngII had a protective effect. Together these results demonstrate a cardioprotective effect of simultaneous blockade of G protein signaling and activation of G protein independent signaling through AT(1) receptors.
authors.affiliation: Danish Arrhythmia Research Centre, Department of Biomedical Sciences, Faculty of Health, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Anders
authors.initials: A
authors.lastname: Hostrup
authors.forename: Gitte Lund
authors.initials: GL
authors.lastname: Christensen
authors.forename: Bo Hjort
authors.initials: BH
authors.lastname: Bentzen
authors.forename: Bo
authors.initials: B
authors.lastname: Liang
authors.forename: Mark
authors.initials: M
authors.lastname: Aplin
authors.forename: Morten
authors.initials: M
authors.lastname: Grunnet
authors.forename: Jakob Lerche
authors.initials: JL
authors.lastname: Hansen
authors.forename: Thomas
authors.initials: T
authors.lastname: Jespersen
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D019390:Arrestins / Q000494:pharmacology; D002316:Cardiotonic Agents / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000378:metabolism; D006339:Heart Rate / Q000187:drug effects; D006352:Heart Ventricles / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D011312:Pressure; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D015427:Reperfusion Injury / Q000378:metabolism* / Q000503:physiopathology; D000071557:beta-Arrestins
chemical_list: D019390:Arrestins; D002316:Cardiotonic Agents; D044140:Receptor, Angiotensin, Type 1; D000071557:beta-Arrestins; D000804:Angiotensin II; D019204:GTP-Binding Proteins