Angiotensin - (1-7) The Therapeutic Effect On Cerebral Ischemic Injury

Neuroprotective effect of angiotensin-(1-7) on focal cerebral ischemic- reperfusion injury in ratsPurpose To investigate the protective effects of Ang-(1-7) on the focal cerebral ischemic-reperfusion injury in rats. Methods The middle cerebral artery occlusion (MCAO) and sham-operation models were prepared, administrated with Ang-(1-7) (100pmol/0.5μl/h) or aCSF (0.5μl/h) by implanted Alzet osmotic minipumps into lateral cerebral ventricle at 24h and 48h after reperfusion in SD rats, and thus were divided into sham group (sham+aCSF), Ang-(1-7) group [MCAO+Ang-(1-7)] and aCSF group (MCAO+aCSF). In all experimental rats, their neurological function scores, the brain edema at 48h after reperfusion and the cerebral infarct size were evaluated at 24h after reperfusion. The MDA content and SOD activity in the ischemic cerebral tissue at 24h and 48h after reperfusion were also determined. The number of neuronal apoptosis within the tissue around the infarct at 48h after reperfusion were detected by the way of staining with terminal deoxynucleotidyl transferase-mediated dUTP-biotin in situ nick-end labeling (TUNEL) assay. Results In the treatment of MCAO rats, Ang-(1-7) can significantly ameliorated their neurological function score (P<0.05), reduced the infarct size (P<0.05), decreased the tissue MDA content (P<0.05), increased the tissue SOD activity (P<0.05). It was also shown to reduce markedly the number of apoptosis around the infarct (P<0.01), but had no the role to affect the water content in the brain. Conclusions Ang-(1-7) can play the role of amelioration on cerebral ischemic -reperfusion injury and neuroprotection, perhaps by the mechanism of its anti-oxidation stress and prevention of apoptosis. Effects of intracerebroventricular infusion of angiotensin-(1-7) on bradykinin formation and the kinin receptor expression after focal cerebral ischemia-reperfusion in ratsBACKGROUND AND PURPOSE: Accumulating evidence suggests that the angiotensin-(1-7) [Ang-(1-7)], is an active member of the brain renin-angiotensin system (RAS). We evaluated the possibility that intracerebroventricular (ICV, lateral ventricle) infusion of exogenous Ang-(1-7) could participate in the potentiation of bradykinin (BK) release and the kinin receptor expression in ischemic brain parenchyma after focal cerebral ischemia-reperfusion in rats. METHODS AND RESULTS: The middle cerebral artery occlusion (MCAO) and sham-operation models were prepared, continuous administrated with Ang-(1-7) or artificial cerebrospinal fluid (aCSF) by implanted Alzet osmotic minipumps into lateral cerebral ventricle after reperfusion in male Sprague-Dawley (SD) rats. Experimental animals were divided into sham-operated group (sham operation + aCSF), aCSF treatment group (MCAO+aCSF) and Ang-(1-7) treatment groups [MCAO + Ang-(1-7)] at low (1pmol/0.5μl/h), medium (100pmol/0.5μl/h) or high (10nmol/0.5μl/h) dose levels. Cerebral infarction resulted in a significant increase of BK formation from 3h to 6h compared with sham-operated group after reperfusion, whereas medium- and high-dose Ang-(1-7) infusion markedly enhanced BK levels from 3h to 48h after reperfusion. Medium-and high-dose Ang-(1-7) infusion markedly increased kinin B₂ receptor mRNA and protein expression, whereas only high-dose Ang-(1-7) infusion induced upregulating the expression of B₁ receptor. Low-dose Ang-(1-7) infusion did not modify both the kinin B₁ and B₂ receptors expression compared with aCSF treatment group after focal cerebral ischemia-reperfusion at each time point. CONCLUSIONS: Differential dose of Ang-(1-7) differentially regulates expression of the kinin B₁ and B₂ receptors and excess Ang-(1-7) in high doses upregulates expression of the B₁ receptor. The finding might indicate complex interactions between Ang-(1-7) and kallikrein-kinin system in the CNS after focal cerebral ischemia-reperfusion in rats. Central administration of angiotensin-(1-7) stimulates nitric oxide release and upregulates the endothelial nitric oxide synthase expression following focal cerebral ischemia/ reperfusion in rats.BACKGROUND AND PURPOSE: Angiotensin-(1-7) [Ang-(1-7)] is an endogenous peptide of the renin-angiotensin system with several beneficial effects that are often opposite to those attributed to Ang II. Since there are no data available so far on the role of Ang-(1-7) after cerebral ischemia/reperfusion, in this paper, we investigated the central administration of Ang-(1-7) modulates in vivo the nitric oxide(NO) release and the endothelial NO synthase (eNOS) expression following focal cerebral ischemia/reperfusion in rats. METHODS AND RESULTS: Cerebral ischemia/reperfusion injury was induced by intraluminal thread occlusion of middle cerebral artery in the adult male rats. The levels of NO in ischemic tissues were measured by NO detection kits. Reverse transcription(RT)-PCR and western blotting were used to determine messenger RNA (mRNA) and protein level of the eNOS in ischemic tissues. The cerebral ischemic lesion resulted in a significant increase of NO release at 3 and 6 hours after reperfusion compared with sham operation group in our model, whereas medium and high-dose Ang-(1-7) markedly enhanced NO levels compared with aCSF treatment group at 3～24 hours and 3～72 hours after reperfusion, respectively. In addition, NO release increased was significantly induced by high-dose Ang-(1-7) compared with medium-dose Ang-(1-7) at 24～72 hours after reperfusion. Medium and high-dose Ang-(1-7) significantly stimulated eNOS activation when compared with aCSF treatment group at 3～48 hours after reperfusion, however, no significant changes in eNOS expression were found between medium and high-dose Ang-(1-7) at different times after the ischemic insult. CONCLUSIONS: These findings indicate that medium and high-dose Ang-(1-7) stimulate NO release and upregulate eNOS expression in ischemic tissues following focal cerebral ischemia/reperfusion in rats.