title: Candesartan but not ramipril pretreatment improves outcome after stroke and stimulates neurotrophin BNDF/TrkB system in rats.
abstract: OBJECTIVE
  Drugs interfering with the renin-angiotensin system (RAS) have been shown to reduce the incidence of stroke in patients at risk and to afford neuroprotection in experimental brain ischemia. This study aimed to compare potential neuroprotective effects of systemic pretreatment with the angiotensin receptor blocker, candesartan, and the angiotensin-converting enzyme (ACE)-inhibitor, ramipril, in normotensive Wistar rats after focal cerebral ischemia, with special emphasis on the regulation of neurotrophins.
  
  
  METHODS
  Equipotent subcutaneous doses of candesartan and ramipril were determined via inhibition of pressor responses to intravenously injected angiotensin II (Ang II) or angiotensin I (Ang I), respectively. Accordingly, animals were treated with candesartan (0.1 mg/kg body weight, twice daily), ramipril (0.01 and 0.1 mg/kg body weight, twice daily) or vehicle (0.9% saline, twice daily), respectively, 5 days prior to middle cerebral artery occlusion (MCAO) with reperfusion. Severity of stroke was estimated via infarct size [magnetic resonance imaging (MRI) 48 h after MCAO] and neurological outcome (24 h, 48 h after MCAO). Measurements of neurotrophins/receptors in brain tissue were performed 48 h after MCAO.
  
  
  RESULTS
  Pretreatment with candesartan and ramipril (low dose) did not reduce blood pressure during MCAO, whereas ramipril high dose did. Candesartan, but not ramipril at any dose, significantly reduced stroke volume and improved neurological outcome. Poststroke mRNA and protein of the neurotrophin receptor, TrkB, were significantly elevated in animals treated with candesartan, but not ramipril.
  
  
  CONCLUSIONS
  Systemic pretreatment with a sub-hypotensive, RAS-blocking dose of candesartan affords neuroprotection after focal ischemia, associated with increased activity of the neurotrophin BDNF/TrkB system. Ramipril at sub-hypotensive and hypotensive, RAS-blocking doses showed no significant neuroprotective effects.
authors.affiliation: Center for Cardiovascular Research (CCR)/Institute of Pharmacology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Maxim
authors.initials: M
authors.lastname: Krikov
authors.forename: Christa
authors.initials: C
authors.lastname: Thone-Reineke
authors.forename: Susanne
authors.initials: S
authors.lastname: Müller
authors.forename: Arno
authors.initials: A
authors.lastname: Villringer
authors.forename: Thomas
authors.initials: T
authors.lastname: Unger
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001562:Benzimidazoles / Q000494:pharmacology*; D001713:Biphenyl Compounds; D002545:Brain Ischemia / Q000188:drug therapy*; D019208:Brain-Derived Neurotrophic Factor / Q000096:biosynthesis*; D004195:Disease Models, Animal; D015994:Incidence; D008297:Male; D010865:Pilot Projects; D017257:Ramipril / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D020813:Receptor, trkB / Q000378:metabolism*; D012084:Renin-Angiotensin System / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020521:Stroke / Q000517:prevention & control*; D013777:Tetrazoles / Q000494:pharmacology*
chemical_list: D000959:Antihypertensive Agents; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D019208:Brain-Derived Neurotrophic Factor; D013777:Tetrazoles; D020813:Receptor, trkB; D017257:Ramipril; C081643:candesartan