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Peroxynitrite formed during a transient episode of brain ischemia increases endothelium-derived hyperpolarization-type dilations in thromboxane/prostaglandin receptor-stimulated rat cerebral arteries
Onetti Vilalta, Yara (Universitat Autònoma de Barcelona. Institut de Neurociències)
Dantas, Ana P. (Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS))
Pérez Fernández, Belén (Universitat Autònoma de Barcelona. Institut de Neurociències)
McNeish, Alister J. (University of Reading. Reading School of Pharmacy)
Vila Calsina, Elisabet (Universitat Autònoma de Barcelona. Institut de Neurociències)
Jiménez Altayó, Francesc (Universitat Autònoma de Barcelona. Institut de Neurociències)

Date: 2016
Abstract: AIM: Increased thromboxane A2 and peroxynitrite are hallmarks of cerebral ischaemia/reperfusion (I/R). Stimulation of thromboxane/prostaglandin receptors (TP) attenuates endothelium-derived hyperpolarization (EDH). We investigated whether EDH-type middle cerebral artery (MCA) relaxations following TP stimulation are altered after I/R and the influence of peroxynitrite. METHODS: Vascular function was determined by wire myography after TP stimulation with the thromboxane A2 mimetic 9,11-dideoxy-9α, 11α -methano-epoxy prostaglandin F2α (U46619) in MCA of Sprague Dawley rats subjected to MCA occlusion (90 min)/reperfusion (24 h) or sham operation, and in non-operated (control) rats. Some rats were treated with saline or the peroxynitrite decomposition catalyst 5,10,15,20-tetrakis(4-sulfonatophenyl)porphyrinato iron (III) (20 mg kg-1 ). Protein expression was evaluated in MCA and in human microvascular endothelial cells submitted to hypoxia (overnight)/reoxygenation (24 h) (H/R) using immunofluorescence and immunoblotting. RESULTS: In U46619-pre-constricted MCA, EDH-type relaxation by the proteinase-activated receptor 2 agonist serine-leucine-isoleucine-glycine-arginine-leucine-NH2 (SLIGRL) was greater in I/R than sham rats due to an increased contribution of small-conductance calcium-activated potassium channels (SKCa ), which was confirmed by the enlarged relaxation to the SKCa activator N-cyclohexyl-N-2-(3,5-dimethyl-pyrazol-1-yl)-6-methyl-4-pyrimidinamine. I/R and H/R induced endothelial protein tyrosine nitration and filamentous-actin disruption. In control MCA, either cytochalasin D or peroxynitrite disrupted endothelial filamentous-actin and augmented EDH-type relaxation. Furthermore, peroxynitrite decomposition during I/R prevented the increase in EDH-type responses. CONCLUSION: Following TP stimulation in MCA, EDH-type relaxation to SLIGRL is greater after I/R due to endothelial filamentous-actin disruption by peroxynitrite, which prevents TP-induced block of SKCa input to EDH. These results reveal a novel mechanism whereby peroxynitrite could promote post-ischaemic brain injury.
Note: Número d'acord de subvenció MICINN/SAF2010-19282
Note: Número d'acord de subvenció MICINN/SAF2014-56111-R
Note: Número d'acord de subvenció AGAUR/2014/SGR-574
Note: Número d'acord de subvenció ISCIII/FIS/PI13/0091
Note: Número d'acord de subvenció ISCIII/RIC/RD12/0042/0006
Rights: Tots els drets reservats
Language: Anglès.
Document: article ; recerca ; acceptedVersion
Subject: SKC a ; KCa2.3 ; Actin ; Calcium-activated potassium channels ; Ischaemia/reperfusion ; Stroke ; Thromboxane
Published in: Acta Physiologica, Vol. 220, no. 1 (September 2016) , p. 150-166, ISSN 1748-1708

DOI: 10.1111/apha.12809

39 p, 2.5 MB

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8 p, 604.4 KB

The record appears in these collections:
Research literature > UAB research groups literature > Research Centres and Groups (scientific output) > Health sciences and biosciences > Institut de Neurociències (INc)
Articles > Research articles
Articles > Published articles

 Record created 2017-01-24, last modified 2019-02-08

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