Published Online
on August 2, 2004

A more recent version of this article appeared on August 17, 2004

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Submitted on September 9, 2003
Revised on April 1, 2004
Accepted on April 4, 2004

Possible Inhibition of Focal Cerebral Ischemia by Angiotensin II Type 2 Receptor Stimulation

Masaru Iwai MD, PhD, Hong-Wei Liu MD, Rui Chen MD, Ayumi Ide BS, Shoko Okamoto BS, Ryuji Hata MD, PhD, Masahiro Sakanaka MD, PhD, Tetsuya Shiuchi MD, PhD, and Masatsugu Horiuchi MD, PhD^*

From the Departments of Medical Biochemistry (M.I., H.-W.L., R.C., A.I., S.O., T.S., M.H.) and Anatomy (R.H., M.S.), Ehime University School of Medicine, Shigenobu, Onsen-gun, Ehime, Japan.

^* To whom correspondence should be addressed. E-mail: horiuchi{at}m.ehime-u.ac.jp.

Background--The role of angiotensin II receptor subtypes was investigated in focal brain ischemia induced by middle cerebral artery (MCA) occlusion.

Methods and Results--In Agtr2⁺ (wild-type) mice, MCA occlusion induced focal ischemia of 20% to 30% of the total area in coronal section of the brain. The ischemic area was significantly larger in angiotensin II type 2 receptor-deficient (Agtr2^-) mice than in Agtr2⁺ mice. The neurological deficit after MCA occlusion was also greater in Agtr2^- mice than in Agtr2⁺ mice. The decrease in surface cerebral blood flow after MCA occlusion was significantly exaggerated in the peripheral region of the MCA territory in Agtr2^- mice. Superoxide production and NADPH oxidase activity were enhanced in the ischemic area of the brain in Agtr2^- mice. An AT₁ receptor blocker, valsartan, at a nonhypotensive dose significantly inhibited the ischemic area, neurological deficit, and reduction of cerebral blood flow as well as superoxide production and NADPH oxidase activity in Agtr2⁺ mice. These inhibitory actions of valsartan were weaker in Agtr2^- mice.

Conclusions--These results suggest that AT₂ receptor stimulation has a protective effect on ischemic brain lesions, at least partly through the modulation of cerebral blood flow and superoxide production.

Key words: stroke • angiotensin • ischemia • receptors • stress

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