title: Therapeutic effects of postischemic treatment with hypotensive doses of an angiotensin II receptor blocker on transient focal cerebral ischemia.
abstract: BACKGROUND
  Neurovascular protection against cerebral ischemia is not consistently observed with a postischemia hypotensive dose of candesartan. The aim of this study was to determine the levels of brain angiotensin II after reperfusion and the efficacy and therapeutic time window of postischemic treatments with hypotensive doses of candesartan for the treatment of cerebral ischemia.
  
  
  METHODS
  Occlusions of the right middle cerebral artery (60 min) followed by reperfusion were performed using the thread method under halothane anesthesia in Sprague-Dawley (SD) rats. Protein levels of brain angiotensin II and mRNA levels of renin-angiotensin system components were evaluated following reperfusion (n=184 in total). Low-dose or high-dose treatments with candesartan cilexetil (1 or 10 mg/kg per day, respectively) were administered orally immediately following reperfusion once daily for 4 or 7 days (n = 119 in total). An additional group was treated with low-dose candesartan cilexetil after a 12-h delay based on the brain angiotensin II levels (n = 14).
  
  
  RESULTS
  Levels of brain angiotensin II transiently increased 4-12 h after reperfusion, which followed an increase in angiotensinogen mRNA. Candesartan cilexetil treatments significantly reduced blood pressure (BP) in rats administered the high dose and moderately in rats receiving the low dose. A low dose of candesartan cilexetil reduced the infarct size, cerebral edema, and neurological deficits, whereas the high-dose treatments showed limited reductions. Furthermore, oxidative stress following reperfusion was reduced with the low-dose treatments. The therapeutic time window was open for at least 12 h after reperfusion when brain angiotensin II levels had peaked.
  
  
  CONCLUSIONS
  Postischemic treatments using low hypotensive doses of candesartan cilexetil provided protection against cerebral ischemic injury and may have a clinically relevant therapeutic time window.
authors.affiliation: Department of Cardiorenal and Cerebrovascular Medicine, Kagawa University School of Medicine, Kagawa, Japan.
authors.forename: Hua
authors.initials: H
authors.lastname: Fu
authors.forename: Naohisa
authors.initials: N
authors.lastname: Hosomi
authors.forename: Nicolas
authors.initials: N
authors.lastname: Pelisch
authors.forename: Daisuke
authors.initials: D
authors.lastname: Nakano
authors.forename: Gang
authors.initials: G
authors.lastname: Liu
authors.forename: Masaki
authors.initials: M
authors.lastname: Ueno
authors.forename: Takanori
authors.initials: T
authors.lastname: Miki
authors.forename: Hisashi
authors.initials: H
authors.lastname: Masugata
authors.forename: Yoshimasa
authors.initials: Y
authors.lastname: Sueda
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Itano
authors.forename: Masayasu
authors.initials: M
authors.lastname: Matsumoto
authors.forename: Akira
authors.initials: A
authors.lastname: Nishiyama
authors.forename: Masakazu
authors.initials: M
authors.lastname: Kohno
mesh_terms: D000804:Angiotensin II / Q000097:blood; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000808:Angiotensinogen / Q000378:metabolism; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000494:pharmacology; D001794:Blood Pressure; D001921:Brain / Q000378:metabolism / Q000473:pathology; D001929:Brain Edema / Q000473:pathology; D002545:Brain Ischemia / Q000188:drug therapy* / Q000473:pathology*; D007022:Hypotension; D007511:Ischemia / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013777:Tetrazoles / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D013777:Tetrazoles; D000808:Angiotensinogen; D000804:Angiotensin II; C077793:candesartan cilexetil; C081643:candesartan