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(Stroke. 2005;36:1077.)
© 2005 American Heart Association, Inc.

Original Contributions

Critical Role of Angiotensin II in Excess Salt-Induced Brain Oxidative Stress of Stroke-Prone Spontaneously Hypertensive Rats

Shokei Kim-Mitsuyama; Eiichiro Yamamoto; Tomoko Tanaka; Yumei Zhan; Yasukatsu Izumi; Yasuhiro Izumiya; Takeshi Ioroi; Hideki Wanibuchi Hiroshi Iwao

From the Department of Pharmacology and Molecular Therapeutics (S.K.-M., E.Y., T.T.), Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan; and Departments of Pharmacology (Y.Z., Y. Izumi, Y. Izumiya, T.I., H.I.) and Pathology (H.W.), Osaka City University Graduate School of Medical Science, Osaka, Japan.

Correspondence to Shokei Kim-Mitsuyama, MD, PhD, Department of Pharmacology and Molecular Therapeutics, Kumamoto University Graduate School of Medical Sciences, 1-1-1 Honjyo, Kumamoto 860-8556, Japan. E-mail kimmitsu{at}gpo.kumamoto-u.ac.jp

Background and Purpose— The detailed role of angiotensin II in salt-exacerbated stroke is unclear. We examined the role of angiotensin II in salt-accelerated stroke of stroke-prone spontaneously hypertensive rats (SHRSP).

Methods— Salt-loaded SHRSP were orally given the angiotensin II type 1 (AT1) receptor blocker candesartan (0.3 to 3 mg/kg per day) and calcium channel blocker amlodipine (1 mg/kg per day), and the effects on stroke (n=61) and brain superoxide were compared between them. We also examined the effect of angiotensin II infusion (200 ng/kg per min) on brain superoxide production and blood–brain barrier.

Results— Despite the comparable hypotensive effect between candesartan and amlodipine, candesartan prolonged survival of salt-loaded SHRSP much more than amlodipine (P<0.01), being associated with more improvement of cerebral arteriolar thickening, cerebral arteriolar cell proliferation, and hippocampal CA1 neuronal cell reduction (1024.9±20.6 versus 724.9±22.8 cells/mm²; P<0.01; n=7 to 10 in each group) in SHRSP by candesartan (P<0.05) than amlodipine. Salt loading increased superoxide and NADPH oxidase activity in brain cortex and hippocampus of SHRSP, and this increase was prevented by candesartan (P<0.01) but not amlodipine. Angiotensin II infusion, via AT1 receptor, directly increased brain superoxide by 1.8-fold (P<0.05; n=6 to 7 in each group) and impaired blood–brain barrier in salt-loaded SHRSP by 1.7-fold (P<0.05), and this increase in brain superoxide and blood–brain barrier impairment was prevented by tempol as well as candesartan.

Conclusion— Excess salt, via oxidative stress, accelerates stroke, and angiotensin II, via AT1 receptor, plays a pivotal role in brain superoxide production of SHRSP by excess salt.

Key Words: angiotensins • blood–brain barrier • stroke

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