title: Candesartan reduces the hemorrhage associated with delayed tissue plasminogen activator treatment in rat embolic stroke.
abstract: We have previously reported that angiotensin receptor blockade reduces reperfusion hemorrhage in a suture occlusion model of stroke, despite increasing matrix metalloproteinase (MMP-9) activity. We hypothesized that candesartan will also decrease hemorrhage associated with delayed (6 h) tissue plasminogen activator (tPA) administration after embolic stroke, widening the therapeutic time window of tPA. Adult male Wistar rats were subjected to embolic middle cerebral artery occlusion (eMCAO) and treated with either candesartan (1 mg/kg) alone early at 3 h, delayed tPA (10 mg/kg) alone at 6 h, the combination of candesartan and tPA, or vehicle control. Rats were sacrificed at 24 and 48 h post-eMCAO and brains perfused for evaluation of neurological deficits, cerebral hemorrhage in terms of hemoglobin content, occurrence rate of hemorrhage, infarct size, tissue MMP activity and protein expression. The combination therapy of candesartan and tPA after eMCAO reduced the brain hemorrhage, and improved neurological outcome compared with rats treated with tPA alone. Further, candesartan in combination with tPA increased activity of MMP-9 but decreased MMP-3, nuclear factor kappa-B and tumor necrosis factor-α expression and enhanced activation of endothelial nitric oxide synthase. An activation of MMP-9 alone is insufficient to cause increased hemorrhage in embolic stroke. Combination therapy with acute candesartan plus tPA may be beneficial in ameliorating tPA-induced hemorrhage after embolic stroke.
authors.affiliation: Charlie Norwood VA Medical Center, Augusta, GA, USA.
authors.forename: Tauheed
authors.initials: T
authors.lastname: Ishrat
authors.forename: Bindu
authors.initials: B
authors.lastname: Pillai
authors.forename: Adviye
authors.initials: A
authors.lastname: Ergul
authors.forename: Sherif
authors.initials: S
authors.lastname: Hafez
authors.forename: Susan C
authors.initials: SC
authors.lastname: Fagan
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000627:therapeutic use*; D000818:Animals; D001562:Benzimidazoles / Q000627:therapeutic use*; D001713:Biphenyl Compounds; D015153:Blotting, Western; D004617:Embolism / Q000150:complications*; D004789:Enzyme Activation; D008297:Male; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D020521:Stroke / Q000188:drug therapy* / Q000209:etiology; D013777:Tetrazoles / Q000627:therapeutic use*; D010959:Tissue Plasminogen Activator / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D016328:NF-kappa B; D013777:Tetrazoles; D014409:Tumor Necrosis Factor-alpha; D052250:Nitric Oxide Synthase Type III; D010959:Tissue Plasminogen Activator; D019278:Matrix Metalloproteinase 3; D020780:Matrix Metalloproteinase 9; C081643:candesartan