title: The role of vasopressin V1A receptors in cytotoxic brain edema formation following brain injury.
abstract: BACKGROUND
  The hormone and neuropeptide arginine-vasopressin is designated to the maintenance of osmotic homoeostasis and blood pressure regulation. While experimental data show vasopressin V(1A) receptors to regulate aquaporin (AQP)4 water channel dependent brain water movement, the specific role in vasogenic and cytotoxic edema formation remains unclear. The present study was designed to quantify the V(1A) receptor mediated regional brain edema formation in two clinically relevant experimental models, brain injury combined with secondary insult and focal ischemia.
  
  
  METHODS
  Male Sprague-Dawley rats were randomly assigned to a continuous infusion of vehicle (1 % DMSO) or the selective non-peptide V(1A) antagonist SR49059 (83nM = 1 mg/kg) starting before controlled cortical impact (CCI) injury plus hypoxia and hypotension (HH, 30 min), or middle cerebral artery (MCA) occlusion (2 h + 2 h reperfusion).
  
  
  RESULTS
  A global analysis of brain water content by the wet/dry weight method allowed optimizing the SR49059 dosage, and demonstrated the down-regulation of brain AQP4 expression by immunoblotting. Microgravimetrical quantification in 64 one mm(3) samples per animal (n = 6 per group) from bregma +2.7 to -6.3 mm analysis demonstrated brain edema to be reduced at 4 h by SR49059 treatment in the injured and contralateral cortex following CCI + HH (p = 0.007, p < 0.001) and in the infarct area following MCA occlusion (p = 0.013, p = 0.002, p = 0.004).
  
  
  CONCLUSIONS
  Our findings demonstrate that an early cytotoxic brain edema component following brain injury plus secondary insult or focal ischemia results from a vasopressin V(1A) receptor mediated response, and occurs most likely through AQP4 up-regulation. The V(1A) antagonist SR49059 offers a new avenue in brain edema treatment and prompts further study into the role of vasopressin following brain injury.
authors.affiliation: Department of Neurosurgery, Virginia Commonwealth University, 1101 E. Marshall St., 23298, Richmond, VA, USA. andrea.kleindienst@uk-erlangen.de
authors.forename: Andrea
authors.initials: A
authors.lastname: Kleindienst
authors.forename: Jana G
authors.initials: JG
authors.lastname: Dunbar
authors.forename: Renee
authors.initials: R
authors.lastname: Glisson
authors.forename: Anthony
authors.initials: A
authors.lastname: Marmarou
mesh_terms: D000818:Animals; D065092:Antidiuretic Hormone Receptor Antagonists; D051401:Aquaporin 4 / Q000378:metabolism; D001929:Brain Edema / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D001930:Brain Injuries / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D006727:Hormone Antagonists / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D020244:Infarction, Middle Cerebral Artery / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D008297:Male; D011759:Pyrrolidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017483:Receptors, Vasopressin / Q000502:physiology*
chemical_list: D065092:Antidiuretic Hormone Receptor Antagonists; D051401:Aquaporin 4; D006727:Hormone Antagonists; D007211:Indoles; D011759:Pyrrolidines; D017483:Receptors, Vasopressin; C082134:relcovaptan