title: CP-0597, a selective bradykinin B2 receptor antagonist, inhibits brain injury in a rat model of reversible middle cerebral artery occlusion.
abstract: OBJECTIVE
  Recent studies demonstrated a significant neuroprotective action of the selective peptide-based bradykinin B2 receptor antagonist CP-0597 after permanent middle cerebral artery (MCA) occlusion (MCAO) in the rat. We therefore evaluated the efficacy of this compound after reversible MCAO in the rat.
  
  
  METHODS
  Male Wistar rats underwent reversible MCAO by insertion of a nylon monofilament to the origin of the MCA. After 1 hour the filament was retracted and the ischemic tissue reperfused. Immediately after MCAO, primed miniosmotic pumps containing either vehicle or CP-0597 (300 ng/kg per minute) were implanted into the subcutaneous space (n = 14 per group). Twenty-four hours after surgery, animals were killed and brains fixed, and 4-micron sections were taken from five sequential tissue blocks labeled A through E and stained with hematoxylin and eosin. Clinical evaluation of rats was performed by neurological scoring and change in body weight.
  
  
  RESULTS
  Treatment with CP-0597 significantly reduced percent increase in hemisphere size of the ischemic hemisphere in all brain sections (C section: vehicle, 40.6 +/- 4.3% versus CP-0597, 20.8 +/- 5.3%; P < 0.001), total infarct volume (vehicle, 206.5 +/- 7.7 mm3 versus CP-0597, 94.0 +/- 19.2 mm3; P < .001), cortical infarct volume (vehicle, 145.5 +/- 4.5 mm3 versus CP-0597, 64.0 +/- 15.1 mm3; P < .001), subcortical infarct volume (vehicle, 55.8 +/- 4.1 mm3 versus CP-0597, 27.5 +/- 4.5 mm3; P < .001), and the number of necrotic neurons (vehicle 42.9 +/- 3.8 versus CP-0597, 23.6 +/- 4.7 per field; P < .01). Neurological score (vehicle, 2.78 +/- 0.36 versus CP-0597, 6.29 +/- 0.87 P < .01) and change in body weight (vehicle, -28.7 +/- 2.0 g versus CP-0597, -18.2 +/- 2.8 g; P < .01) were also significantly improved.
  
  
  CONCLUSIONS
  The present data demonstrate the significant overall efficacy profile of CP-0597 in a rat model of reversible MCAO and provide strong rationale for the use of such bradykinin B2 receptor antagonist in the treatment of stroke.
authors.affiliation: Cortech Inc., Denver, Colo. 80221, USA.
authors.forename: J K
authors.initials: JK
authors.lastname: Relton
authors.forename: V E
authors.initials: VE
authors.lastname: Beckey
authors.forename: W L
authors.initials: WL
authors.lastname: Hanson
authors.forename: E T
authors.initials: ET
authors.lastname: Whalley
mesh_terms: D000818:Animals; D001157:Arterial Occlusive Diseases / Q000188:drug therapy* / Q000378:metabolism; D001522:Behavior, Animal / Q000187:drug effects; D001831:Body Temperature; D001835:Body Weight; D065168:Bradykinin Receptor Antagonists; D001921:Brain / Q000098:blood supply*; D001923:Brain Chemistry / Q000502:physiology; D001929:Brain Edema / Q000188:drug therapy / Q000378:metabolism; D002545:Brain Ischemia / Q000188:drug therapy* / Q000378:metabolism; D002536:Cerebral Arteries; D002561:Cerebrovascular Disorders / Q000188:drug therapy / Q000378:metabolism; D004195:Disease Models, Animal; D008297:Male; D009842:Oligopeptides / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D043782:Receptor, Bradykinin B2; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism
chemical_list: D065168:Bradykinin Receptor Antagonists; C107323:CP 0597; D009842:Oligopeptides; D043782:Receptor, Bradykinin B2