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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
250 g
tMCAO
90 min
24 h recovery
Irbesartan
i.c.v infusion or injection
0.5, 2.0, 5 nmol injection or 2 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
200 g
tMCAO
90 min
3 or 7 days recovery
Irbesartan
i.c.v infusion
2 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]
  1. Studies involved either transient middle cerebral artery (tMCAO) or permanent middle cerebral artery occlusion (pMCAO). Unless specified, tMCAO was performed via intraluminal filament model
  2. 8-OHdG 8-hydroxy-2′-deoxyguanosine, Ang II angiotensin II, AT 1 R angiotensin II type I receptor, BDNF brain derived neurotrophic factor, BHT behavioural testing, BP blood pressure, CBF cerebral blood flow, COX-2 cyclooxygenase 2, dMCAO distal middle cerebral artery occlusion model, ED-1 anti cluster differentiation 68 antibody, eNOS endothelial nitric oxide synthase, ET-1 endothelin-1, GAP-43 growth associated protein 43, Glut-1 glucose transporter 1, HIF-α hypoxia inducible factor alpha, i.c.v intracerebroventricular, IkB IkappaB, i.p intraperitoneal, i.v intravenous, MAP-2 microtubule-associated protein 2, MCA middle cerebral artery, MCP-1 macrophage chemokine protein 1, MMP matrix metalloproteinase type 2, MMP-9 matrix metalloproteinase type 9, MRI magnetic resonance imaging, MT1-MMP membrane type 1 matrix metalloproteinase, NO nitric oxide, NS neurological score, PARP poly(ADP-ribose) polymerase, PECAM-1 platelet endothelial cell adhesion molecule 1, SHR spontaneously hypertensive rats, TNF-α tumor necrosis factor alpha, s.c subcutaneous, TrkB tropomyosin receptor kinase B, TTC 2,3,5-triphenyltetrazolium chloride staining, TUNEL terminal deoxynucleotidyl transferase dUTP nick end labelling