title: Neurokinin-1 receptor antagonism in a rat model of subarachnoid hemorrhage: prevention of upregulation of contractile ETB and 5-HT1B receptors and cerebral blood flow reduction.
abstract: OBJECTIVE
  Cerebral vasospasm following subarachnoid hemorrhage (SAH) leads to reduced cerebral blood flow (CBF) and to cerebral ischemia, in some cases even producing infarction and long-term disability. The goal of the present study was to investigate the hypothesis that inhibition of neurokinin-1 receptors (NK1Rs) by administration of L-822429 blunts the decrease in CBF as well as cerebrovascular receptor upregulation in an animal model of SAH.
  
  
  METHODS
  Subarachnoid hemorrhage was induced in rats by injection of 250 microl of blood into the prechiasmatic cistern. The NK1R inhibitor L-822429 was injected intracisternally 30 minutes and 24 hours after the induction of SAH. Two days after SAH induction, the basilar arteries were harvested, and contractile responses to endothelin-1 (ET-I, an ETA- and ETB-receptor agonist) and 5-carboxamidotryptamine (a 5-hydroxytryptamine- I1 [5-HT1]-receptor agonist) were investigated using sensitive myographs. To determine whether NKIR inhibition had an influence on local CBF after post-SAH, a quantitative autoradiographic technique was used. After SAH, the vascular receptor phenotype was changed in cerebral arteries through upregulation of contractile ET, and 5-HT1B receptors, while regional and total CBF were markedly reduced. Treatment with the selective NK1R inhibitor L-822429 prevented both the receptor upregulation and the reduction in regional and global CBF.
  
  
  CONCLUSIONS
  The data reveal the coregulation of vascular receptor changes and blood flow effects, and also show that interaction with a small-molecule NK1R antagonist is a promising area of focus for the development of specific treatments for SAH.
authors.affiliation: Department of Clinical Sciences, Division of Experimental Vascular Research, Lund University, Lund, Sweden.
authors.forename: Saema
authors.initials: S
authors.lastname: Ansar
authors.forename: Niels-Aage
authors.initials: NA
authors.lastname: Svendgaard
authors.forename: Lars
authors.initials: L
authors.lastname: Edvinsson
mesh_terms: D000818:Animals; D001345:Autoradiography; D001921:Brain / Q000098:blood supply; D002544:Cerebral Infarction / Q000503:physiopathology / Q000517:prevention & control; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D065131:Endothelin B Receptor Antagonists; D007276:Injections, Intraventricular; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D064729:Neurokinin-1 Receptor Antagonists; D051381:Rats; D017207:Rats, Sprague-Dawley; D044302:Receptor, Serotonin, 5-HT1B / Q000502:physiology; D018040:Receptors, Neurokinin-1 / Q000502:physiology; D012039:Regional Blood Flow / Q000187:drug effects / Q000502:physiology; D058829:Serotonin 5-HT1 Receptor Antagonists; D013345:Subarachnoid Hemorrhage / Q000188:drug therapy* / Q000503:physiopathology; D015854:Up-Regulation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology*; D020301:Vasospasm, Intracranial / Q000188:drug therapy* / Q000503:physiopathology
chemical_list: D065131:Endothelin B Receptor Antagonists; D064729:Neurokinin-1 Receptor Antagonists; D044302:Receptor, Serotonin, 5-HT1B; D018040:Receptors, Neurokinin-1; D058829:Serotonin 5-HT1 Receptor Antagonists; D014665:Vasodilator Agents