on May 13, 2004
Published online before print May 13, 2004, doi: 10.1161/01.STR.0000129788.26346.18
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Submitted on December 24, 2003
From the Section on Pharmacology, Division of Intramural Research Programs (H.A., J.Z., M.M., J.M.S.), National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, Bethesda, Md; and the Institute of Cell Biology (H.I.), University of Bern, Bern, Switzerland. * To whom correspondence should be addressed. E-mail: Saavedrj{at}intra.nimh.nih.gov.
Background and Purpose--The spontaneously hypertensive rat (SHR) is vulnerable to brain ischemia and stress and exhibits a chronically stimulated brain angiotensin II system, cerebrovascular hypertrophy, and inflammation. Pretreatment with angiotensin II type 1 (AT1) receptor antagonists protects from brain ischemia and from stress and prevents the development of stress-induced gastric ulcers in part by reducing inflammation in the gastric mucosa. We studied whether AT1 receptor antagonists could exert antiinflammatory effects in the brain vasculature as a mechanism for their protective effects against ischemia. Methods--Ten-week-old SHR and normotensive Wistar-Kyoto male rats received the AT1 receptor antagonist candesartan (0.3 mg/kg per day) or vehicle for 28 days via osmotic minipumps. We studied AT1 receptors, intercellular adhesion molecule-1 (ICAM-1), endothelial nitric oxide synthase (eNOS), and number of macrophages by immunohistochemistry and Western blots. Results--We found increased endothelial AT1 receptor expression of brain microvessels and middle cerebral artery of SHR. Brain AT1 receptor inhibition reversed the pathological vascular hypertrophy, increased and normalized eNOS expression, and decreased ICAM-1 expression and the number of adherent and infiltrating macrophages in cerebral vessels of SHR. Conclusions--The antiinflammatory effects of AT1 receptor antagonists may be an important mechanism in protecting against ischemia.
Revised on March 10, 2004
Accepted on March 17, 2004
Angiotensin II AT1 Receptor Blockade Reverses Pathological Hypertrophy and Inflammation in Brain Microvessels of Spontaneously Hypertensive Rats
Hiromichi Ando MD, PhD;
Key words: cerebral arteries • inflammation • intercellular adhesion molecule-1 • middle cerebral artery • cerebrovascular disorders
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