AT1 receptor blockade regulates the local angiotensin II system in cerebral microvessels from spontaneously hypertensive rats

Background and Purpose-Blockade of angiotensin II AT(1) receptors in cerebral microvessels protects against brain ischemia and inflammation. In this study, we tried to clarify the presence and regulation of the local renin-angiotensin system (RAS) in brain microvessels in hypertension. Methods-Spontaneously hypertensive rats (SHR) and Wistar Kyoto (WKY) controls were treated with an AT1 receptor antagonist (candesartan, 0.3 mg/ kg per day) via subcutaneous osmotic minipumps for 4 weeks. The expression and localization of RAS components and the effect of AT1 receptor blockade were assessed by Affymetrix microarray, qRT-PCR, Western blots, immunohistochemistry and immunofluorescence. Results-We found transcripts of most of RAS components in our microarray database, and confirmed their expression by qRT-PCR. Angiotensinogen (Aogen), angiotensin-converting enzyme (ACE) and AT(1) receptors were localized to the endothelium. There was no evidence of AT(2) receptor localization in the microvascular endothelium. In SHR, (pro) renin receptor mRNA and AT(1) receptor mRNA and protein expression were higher, whereas Aogen, ACE mRNA and AT(2) receptor mRNA and protein expression were lower than in WKY rats. Candesartan treatment increased Aogen, ACE and AT(2) receptor in SHR, and increased ACE and decreased Aogen in WKY rats, without affecting the (pro) renin and AT(1) receptors. Conclusions-Increased (pro) renin and AT(1) receptor expression in SHR substantiates the importance of the local RAS overdrive in the cerebrovascular pathophysiology in hypertension. AT(1) receptor blockade and increased AT(2) receptor stimulation after administration of candesartan may contribute to the protection against brain ischemia and inflammation.