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

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 approximately 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.