Therapeutic potential of the renin angiotensin system in ischaemic stroke

Mariana Moreira Coutinho Arroja; Emma Reid; Christopher McCabe

doi:10.1186/s13231-016-0022-1

Experimental & Translational Stroke Medicine

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]

Studies involved either transient middle cerebral artery (tMCAO) or permanent middle cerebral artery occlusion (pMCAO). Unless specified, tMCAO was performed via intraluminal filament model
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

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