Table 1 Experimental stroke studies using AT1 receptor antagonists
From: Therapeutic potential of the renin angiotensin system in ischaemic stroke
Animals Gender Strain Weight | Stroke model | Treatment profile AT1R blocker Administration Dose Time point | In vivo measures and methods | Treatment outcome | Proposed underlying mechanism | Reference |
|---|---|---|---|---|---|---|
Male Wistar rats 250Â g | tMCAO 90Â min 24Â h recovery | Irbesartan i.c.v infusion or injection 0.5, 2.0, 5Â nmol injection or 2Â nmol/h infusion Pre and post treatment | BP: pressure transducer NS: Bederson score Drinking response | Low dose treatment Did not affect BP Improved NS Abolished Ang II induced drinking response | Decreased c-Fos and c-Jun protein expression in ipsilateral cerebral cortex | Dai et al. [46] |
Male Wistar rats 200Â g | tMCAO 90Â min 3 or 7Â days recovery | Irbesartan i.c.v infusion 2Â nmol/h Pre and post treatment | BP: pressure transducer NS: Bederson and Garcia scores CBF: laser Doppler Infarct volume: cresyl violet staining and quantitative histopathology | Did not affect BP Did not affect CBF Improved NS Decreased infarct volume | Anti-inflammatory and anti-apoptotic Decrease in TUNEL, PARP positive cells and activated microglia (ED-1 marker) in cortical peri-infarct areas | Lou et al. [47] |
Male Wistar rats 280–305 g | tMCAO 3 h 24 h recovery | Candesartan i.v bolus 1 mg/kg Post treatment | BP: telemetry method NS: Bederson score Infarct volume: TTC Cerebral oedema: hemisphere volume analysis Haemoglobin content | Improved NS Decreased BP Decreased infarct volume Decreased cerebral oedema Decreased haemoglobin content | Not discussed | Fagan et al. [48] |
Male Wistar rats 120–130 g | tMCAO 2 h 24 h recovery | Candesartan 0.5 or 1 mg/kg i.p bolus Pre-treatment | BP: telemetry method Infarct volume: TTC | Decreased BP Decreased infarct volume | Anti-oxidant and pro-regenerative Decrease in HIF-α and 8-OHdG positive cells and upregulation of eNOS and growth associated proteins, MAP-2, GAP-43 and cyclin D1 | Liu et al. [49] |
Male Wistar rats 160–200 g | tMCAO 90 min 48 h recovery | Candesartan s.c bolus 0.1 mg/kg Pre-treatment | BP: pressure transducer NS: Garcia score CBF: laser-Doppler Infarct volume: MRI T2 scan | Did not affect BP Did not affect CBF Improved NS Decreased infarct volume | Activation of BDNF/TrkB signalling pathway Upregulation of BDNF gene expression and TrkB neurotrophin receptor protein levels in infarct and penumbral areas | Krikov et al. [50] |
Male Sprague–Dawley rats 180–250 g | tMCAO 2 h 7 day recovery | Olmesartan i.p infusion 0.001, 0.01, 0.1 or 1 μmol/kg/h Post treatment | BP: tail cuff method NS: 34 point score Infarct volume: TTC Cerebral oedema: microgravimetry | Treatment at low dose Did not affect BP Improved NS Decreased infarct volume Decreased cerebral oedema | Downregulation of Ang II, MMP-2, MMP-9 and MT1-MMP protein levels in ischaemic area | Hosomi et al. [51] |
Male Sprague–Dawley rats 250–275 g | tMCAO ET-1 induced MCAO 48 h recovery | Candesartan s.c infusion 0.2/mg/kg per day Pre-treatment | BP: telemetry method NS: Bederson and Garcia scores Behavioural testing (BHT): seed eating test Infarct volume: TTC | Did not affect BP Improved motor function Improved NS Decreased infarct volume | Not discussed | Mecca et al. [52] |
Male Sprague–Dawley rats 200–220 g | tMCAO 60 min Up to 28 days recovery | Fimasartan Oral administration 0.5, 1 or 3 mg/kg Pretreatment | BP: CODA noninvasive BP system BHT: limb placing test Infarct volume: Nissl staining and TTC | Treatment at low dose Did not affect BP Improved functional recovery Decreased infarct volume | Anti-inflammatory Attenuation of activated microglia (Ox6 staining), IκB degradation and COX-2 expression in peri infarct areas | Kim et al. [53] |
Male SHR 270–306 g | tMCAO 60–120 min 24 h recovery | Candesartan s.c infusion 0.5 mg/kg per day Pre-treatment | BP: tail cuff method CBF: laser-Doppler Infarct volume: TTC Cerebral oedema | Did not affect BP compared to WKY rats Improved CBF Decreased infarct volume Decreased cerebral oedema | Normalised autoregulation Decrease in AT1R protein expression in the nucleus of the solitary tract and area postrema | Nishimura et al. [54] |
Male SHR 190–240 g | pMCAO dMCAO model 24 h recovery | Candesartan s.c infusion 0.1 or 0.3 mg/kg per day Pretreatment | BP: tail cuff method CBF: autoradiography Infarct volume: TTC Cerebral oedema | Improved CBF Decreased BP Decreased infarct volume Decreased cerebral oedema | Normalised autoregulation Attenuation of MCA media thickness | Ito et al. [55] |
Male C57BL/6 mice 20 g | pMCAO 24 h recovery | Valsartan i.p infusion 3 mg/kg per day Pre-treatment | BP: method not specified NS: Bederson score CBF: laser-Doppler Infarct volume: TTC | Did not affect BP Improved NS Improved CBF Decreased infarct volume | Anti-oxidant and pro-angiogenic Decrease in MCP-1, TNF-α gene expression and superoxide levels and an increase in eNOS, NO and capillary density markers (PECAM-1; Glut-1) | Li et al. [56] |