title: Early events triggering delayed vasoconstrictor receptor upregulation and cerebral ischemia after subarachnoid hemorrhage.
abstract: BACKGROUND
  Upregulation of vasoconstrictor receptors in cerebral arteries, including endothelin B (ETB) and 5-hydroxytryptamine 1B (5-HT(1B)) receptors, has been suggested to contribute to delayed cerebral ischemia, a feared complication after subarachnoid hemorrhage (SAH). This receptor upregulation has been shown to be mediated by intracellular signalling via the mitogen activated protein kinase kinase (MEK1/2)--extracellular regulated kinase 1/2 (ERK1/2) pathway. However, it is not known what event(s) that trigger MEK-ERK1/2 activation and vasoconstrictor receptor upregulation after SAH.We hypothesise that the drop in cerebral blood flow (CBF) and wall tension experienced by cerebral arteries in acute SAH is a key triggering event. We here investigate the importance of the duration of this acute CBF drop in a rat SAH model in which a fixed amount of blood is injected into the prechiasmatic cistern either at a high rate resulting in a short acute CBF drop or at a slower rate resulting in a prolonged acute CBF drop.
  
  
  RESULTS
  We demonstrate that the duration of the acute CBF drop is determining for a) degree of early ERK1/2 activation in cerebral arteries, b) delayed upregulation of vasoconstrictor receptors in cerebral arteries and c) delayed CBF reduction, neurological deficits and mortality. Moreover, treatment with an inhibitor of MEK-ERK1/2 signalling during an early time window from 6 to 24 h after SAH was sufficient to completely prevent delayed vasoconstrictor receptor upregulation and improve neurological outcome several days after the SAH.
  
  
  CONCLUSIONS
  Our findings suggest a series of events where 1) the acute CBF drop triggers early MEK-ERK1/2 activation, which 2) triggers the transcriptional upregulation of vasoconstrictor receptors in cerebral arteries during the following days, where 3) the resulting enhanced cerebrovascular contractility contribute to delayed cerebral ischemia.
authors.affiliation: Department of Clinical Experimental Research, Glostrup Research Institute, Glostrup University Hospital, Nordre Ringvej 69, Glostrup DK 2600, Denmark. grklpo01@glo.regionh.dk
authors.forename: Gro Klitgaard
authors.initials: GK
authors.lastname: Povlsen
authors.forename: Sara Ellinor
authors.initials: SE
authors.lastname: Johansson
authors.forename: Carl Christian
authors.initials: CC
authors.lastname: Larsen
authors.forename: Ajoy Kumar
authors.initials: AK
authors.lastname: Samraj
authors.forename: Lars
authors.initials: L
authors.lastname: Edvinsson
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000983:Antipyrine / Q000031:analogs & derivatives; D019540:Area Under Curve; D001794:Blood Pressure / Q000502:physiology; D002545:Brain Ischemia / Q000209:etiology* / Q000378:metabolism* / Q000401:mortality; D002070:Butadienes / Q000494:pharmacology; D002247:Carbon Isotopes; D002536:Cerebral Arteries / Q000378:metabolism; D002560:Cerebrovascular Circulation / Q000502:physiology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D017078:Laser-Doppler Flowmetry; D020935:MAP Kinase Signaling System / Q000502:physiology; D008297:Male; D009043:Motor Activity / Q000502:physiology; D009422:Nervous System Diseases / Q000209:etiology / Q000517:prevention & control; D009570:Nitriles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044023:Receptor, Endothelin B / Q000235:genetics / Q000378:metabolism*; D044302:Receptor, Serotonin, 5-HT1B / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013345:Subarachnoid Hemorrhage / Q000150:complications*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology*
chemical_list: D002070:Butadienes; D002247:Carbon Isotopes; D004791:Enzyme Inhibitors; D009570:Nitriles; D044023:Receptor, Endothelin B; D044302:Receptor, Serotonin, 5-HT1B; C113580:U 0126; D000983:Antipyrine; C008135:iodoantipyrine