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 approximate to20% 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 AT(1) 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 AT(2) receptor stimulation has a protective effect on ischemic brain lesions, at least partly through the modulation of cerebral blood flow and superoxide production.