Effects of intracerebroventricular infusion of angiotensin-(1–7) on bradykinin formation and the kinin receptor expression after focal cerebral ischemia–reperfusion in rats

Abstract

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. The middle cerebral artery occlusion (MCAO) and sham-operated models were prepared, continuously 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 + aCSF), aCSF treatment group (MCAO + aCSF) and Ang-(1–7) treatment groups [MCAO + Ang-(1–7)] at low (1 pmol/0.5 µl/h), medium (100 pmol/0.5 µl/h) or high (10 nmol/0.5 µl/h) dose levels. Cerebral infarction resulted in a significant increase of BK formation from 3 h to 6 h compared with sham-operated group after reperfusion, whereas medium- and high-dose Ang-(1–7) infusion markedly enhanced BK levels from 6 h to 48 h after reperfusion. Medium- and high-dose Ang-(1–7) infusion markedly increased kinin B 2 receptor mRNA and protein expression, whereas only high-dose Ang-(1–7) infusion induced upregulating the expression of B 1 receptor. Low-dose Ang-(1–7) infusion did not modify both the kinin B 1 and B 2 receptor expression compared with aCSF treatment group after focal cerebral ischemia–reperfusion at each time point. The finding might indicate complex interactions between Ang-(1–7) and kallikrein–kinin system in the CNS after focal cerebral ischemia–reperfusion in rats.