Table 1.
Summary of studies utilising Mas receptor agonism in experimental stroke. Abbreviations: AVE0991: Mas antagonist; BBB: blood brain barrier, BP: blood pressure, CBF: cerebral blood flow, COX-2: cyclooxygenase-2; DIZE: diminazene aceturate; eNOS: endothelial nitric oxide synthase ET-1: endothelin-1 injection, HPβCP-Ang-(1–7): Ang-(1–7) complexed with hydroxypropyl-β-cyclodextrins; ICV: intracerebroventricular, IL-1α/1β/6: interleukin-1α/1β/6; iNOS: inducible nitric oxide synthase; IP: intraperitoneal, IV: intravenous; MDA: malondialdehyde; NFκB: nuclear factor κ-light-chain-enhancer of activated B cells; NO: nitric oxide; NOX1: NADPH oxidase 1; SD: Sprague Dawley, SOD: superoxide dismutase; t/pMCAO: transient/permanent middle cerebral artery occlusion, TNF-α: tumor necrosis factor-α; VEGF: vascular endothelial growth factor.
| Animal. | Drug delivery dose, route & timing | Stroke model | Outcome | Mechanistic insight (if any) | Reference |
|---|---|---|---|---|---|
| Male SD rats | Ang-(1–7) 1.1 nM/0.5 μL/h or DIZE 5 μg/ 5 μL/h (ACE2 activator) ICV minipump infusion 7 days prior & 3 days post | ET-1 | Ang-(1–7): No effect BP No effect CBF ↓ infarct volume at 3 days ↑ neurological score & fine motor function at 3 days DIZE: ↓ BP with 7 days of treatment ↓ infarct volume at 3 days ↑ neurological score at 3 days |
Positive stroke outcomes blocked by Mas inhibition. Ang-(1–7) attenuated stroke induced increase in iNOS expression |
244 |
| Male SD rats | Ang-(1–7) 1.11 nM/1 μL/h ICV minipump infusion 48 h prior & 24 h post | Filament pMCAO | No effect CBF ↓ infarct volume at 24 h ↑ neurological score at 24 h |
Reduced oxidative stress (reduced MDA & increased SOD levels) Reduced NFκB activation Reduced expression of pro-inflammatory cytokines (TNF-α and IL-1β) and COX-2 Effects blocked by Mas inhibition but not AT2R inhibition |
246 |
| Male SD rats | Ang-(1–7) 1.1 nM/0.5 μL/h ICV minipump infusion 7 days prior & post until sacrifice | ET-1 | ↓ infarct volume at 24 h | Reduced expression of iNOS Blunting inflammatory response - reduced expression pro-inflammatory cytokines IL-1α & IL-6, & chemokine receptors CXCL12 & CXCR4, reduced expression of CD11b (marker of macrophage/microglial activation) In vitro evidence of reduction of NO production in glia, prevented by Mas inhibition |
248 |
| Male SD rats | Ang-(1–7) 1.1 nM/0.25 μL/h ICV minipump infusion 4 weeks prior to | Filament pMCAO | No effect BP prior to stroke ↑ peripheral CBF ↓ infarct volume at 24 h ↑ neurological score at 24 h |
Increased eNOS activation, NO production, VEGF levels and angiogenesis Positive stroke outcomes and signalling effects abolished by Mas or eNOS inhibition |
247 |
| Male C57BL6/J mice, 8 week old | AVE0991 10 mg/kg or 20 mg/kg IP at reperfusion & 4 h post | Filament tMCAO 60 min | No effect CBF No effect neurological deficit, or locomotor and motor coordination at 24 h No effect infarct volume at 24 h |
Reduced glucose deprivation induced neuronal death in vitro | 252 |
| Male SD rats, 9–13 weeks | HPβCP-Ang-(1–7) 125 μg/kg orally at 90 min, 4 h, 24 h & 48 h post hydroxypropyl-β-cyclodextrins, | ET-1 | ↓ infarct volume at 3 days ↑ neurological function at 3 days No effect CBF No effect BP |
Not investigated | 250 |
| Male Wistar rats | Ang-(1–7) 1.1 nmol/μL/h ICV minipump infusion post-reperfusion | Filament tMCAO, 90 min | ↑ tissue salvage at 7 days No effect infarct volume at 7 days No effect neurological score at 7 days No effect BP |
Upregulation of NOX1 Prevention of ‘steal phenomenon’ in contralateral hemisphere perfusion No effect on BBB permeability, microglia activation or inflammatory markers |
249 |