title: Protective effect of endothelin type A receptor antagonist on brain edema and injury after transient middle cerebral artery occlusion in rats.
abstract: OBJECTIVE
  Recent evidence strongly suggests that endothelins (ETs) play an important role in the regulation of blood-brain barrier (BBB) functions. The aim of the present study was to evaluate the role of ETs on edema formation and BBB permeability change after cerebral ischemia/reperfusion.
  
  
  METHODS
  We examined the brain tissue ET-1 content and evaluated the time and dose response of the therapeutic effects of the specific ET type A receptor (ET(A)) antagonist, S-0139, on brain edema formation, development of infarction, and disruption of BBB after 1 hour of middle cerebral artery occlusion (MCAO) in rats.
  
  
  RESULTS
  After 1-hour MCAO and reperfusion, the brain ET-1 content did not change during the first 3 hours, increased at 6 hours, and rose almost continuously over 48 hours in the ischemic region as well as in the ischemic rim. Rats infused with S-0139 (0.03 to 1.0 mg/kg per hour) during reperfusion showed dose-dependent and significant attenuation of the increase in brain water content 24 hours after reperfusion. When the infusion of S-0139 was begun after 10 minutes and 1 hour of reperfusion, the brain edema formation and infarct size were significantly attenuated. Furthermore, posttreatment with S-0139 significantly attenuated the increased Evans blue dye-quantified albumin extravasation and improved the mortality of animals after cerebral ischemia/reperfusion.
  
  
  CONCLUSIONS
  Our data demonstrate that infusion with S-0139, an ET(A) antagonist, results in significant reduction of brain injury and plasma extravasation after transient MCAO. Thus, ETs may contribute to cerebral ischemia/reperfusion injury at least partly by increasing the BBB permeability via ET(A)s.
authors.affiliation: Discovery Research Laboratories, Shionogi and Co, Ltd, Toyonaka, Osaka, Japan. yoshiyuki.matsuo@shionogi.co.jp
authors.forename: Y
authors.initials: Y
authors.lastname: Matsuo
authors.lastname: Mihara Si
authors.forename: M
authors.initials: M
authors.lastname: Ninomiya
authors.forename: M
authors.initials: M
authors.lastname: Fujimoto
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001923:Brain Chemistry; D001929:Brain Edema / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D002109:Caffeic Acids / Q000008:administration & dosage*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000378:metabolism; D016232:Endothelins / Q000378:metabolism / Q000494:pharmacology; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D002546:Ischemic Attack, Transient / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D009828:Oleanolic Acid / Q000008:administration & dosage* / Q000031:analogs & derivatives; D009195:Peroxidase / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D044022:Receptor, Endothelin A; D015427:Reperfusion Injury / Q000209:etiology / Q000517:prevention & control; D015996:Survival Rate; D013997:Time Factors; D014867:Water / Q000032:analysis / Q000378:metabolism
chemical_list: D002109:Caffeic Acids; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D016232:Endothelins; D018696:Neuroprotective Agents; D044022:Receptor, Endothelin A; C086421:S 0139; D014867:Water; D009828:Oleanolic Acid; D009195:Peroxidase