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Pàgina inicial > Articles > Articles publicats > Peroxynitrite formed during a transient episode of brain ischemia increases endothelium-derived hyperpolarization-type dilations in thromboxane/prostaglandin receptor-stimulated rat cerebral arteries |
Data: | 2016 |
Resum: | 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. |
Ajuts: | Ministerio de Ciencia e Innovación SAF2010-19282 Ministerio de Ciencia e Innovación SAF2014-56111-R Agència de Gestió d'Ajuts Universitaris i de Recerca 2014/SGR-574 Instituto de Salud Carlos III FIS/PI13/0091 Instituto de Salud Carlos III RIC/RD12/0042/0006 |
Drets: | Tots els drets reservats. |
Llengua: | Anglès |
Document: | Article ; recerca ; Versió acceptada per publicar |
Matèria: | SKC a ; KCa2.3 ; Actin ; Calcium-activated potassium channels ; Ischaemia/reperfusion ; Stroke ; Thromboxane |
Publicat a: | Acta Physiologica, Vol. 220, no. 1 (September 2016) , p. 150-166, ISSN 1748-1716 |
Post-print 39 p, 2.5 MB |
Taules i Figures 8 p, 604.4 KB |