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(Stroke. 2006;37:1271.)
© 2006 American Heart Association, Inc.

Original Contributions

AT₁ Receptor Blockade Regulates the Local Angiotensin II System in Cerebral Microvessels From Spontaneously Hypertensive Rats

Jin Zhou, MD, PhD; Jaroslav Pavel, PhD; Miroslava Macova, PhD; Zu-Xi Yu, MD, PhD; Hans Imboden, PhD; Linna Ge, BSc; Tsuyoshi Nishioku, PhD; Jingtao Dou, MD, PhD; Elizabeth Delgiacco, BSc Juan M. Saavedra, MD

From the Section on Pharmacology (J.Z., J.P., M.M., L.G., T.N., J.D., E.D., J.M.S.), Division of Intramural Research Programs, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, Bethesda, Md; Pathology Core (Z.-X.Y.), National Heart, Lung and Blood Institute, Bethesda, Md; and Institute of Cell Biology (H.I.), University of Bern, Bern, Switzerland.

Correspondence and reprint requests to Jin Zhou, MD, PhD, Section on Pharmacology, Division of Intramural Research Programs, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892, USA. E-mail jinzhou{at}mail.nih.gov

Background and Purpose— Blockade of angiotensin II AT₁ 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 AT₁ receptors were localized to the endothelium. There was no evidence of AT₂ receptor localization in the microvascular endothelium. In SHR, (pro)renin receptor mRNA and AT₁ receptor mRNA and protein expression were higher, whereas Aogen, ACE mRNA and AT₂ receptor mRNA and protein expression were lower than in WKY rats. Candesartan treatment increased Aogen, ACE and AT₂ receptor in SHR, and increased ACE and decreased Aogen in WKY rats, without affecting the (pro)renin and AT₁ receptors.

Conclusions— Increased (pro)renin and AT₁ receptor expression in SHR substantiates the importance of the local RAS overdrive in the cerebrovascular pathophysiology in hypertension. AT₁ receptor blockade and increased AT₂ receptor stimulation after administration of candesartan may contribute to the protection against brain ischemia and inflammation.

Key Words: circulation • endothelial cells • hypertension • renin-angiotensin system

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