Larger anastomoses in angiotensinogen-knockout mice attenuate early metabolic disturbances after middle cerebral artery occlusion

Abnormalities in the homeostasis of the renin-angiotensin system have been implicated in the pathogenesis of vascular disorders, including stroke. The authors investigated whether angiotensinogen (AGN) knockout mice exhibit d ifferences in brain susceptibility to focal ischemia, and whether such diff erences can be related to special features of the collateral circulation. W ild-type and AGN-knockout mice were submitted to permanent suture occlusion of the middle cerebral artery (MCA). The collateral vascular system was vi sualized by systemic latex infusion, and the ischemic lesions were identifi ed by cresyl-violet staining. The core and penumbra of the evolving infarct were differentiated by bioluminescence and autoradiographic imaging of ATP and protein biosynthesis, respectively. In wild-type mice, mean arterial b lood pressure was 95.0 +/- 8.6 mm Hg, and the diameter of fully relaxed ana stomotic vessels between the peripheral branches of the anterior and middle cerebral arteries 26.6 +/- 4.0 mu m. In AGN knockouts, mean arterial blood pressure was significantly lower, 71.5 +/- 8.5 mm Hg (P < .01), and the an astomotic vessels were significantly larger, 29.4 +/- 4.6 mu m (P < .01), O ne hour after MCA occlusion, AGN-knockout mice exhibited a smaller ischemic core (defined as the region of ATP depletion) bur a larger penumbra (the a rea of disturbed protein synthesis with preserved ATP). At 24 hours after M CA occlusion, this difference disappeared, and histologically visible lesio ns were of similar size in both strains. The observations show that in AGN- knockout mice the more efficient collateral blood supply delays ischemic in jury despite the lower blood pressure. Pharmacologic suppression of angiote nsin formation may prolong the therapeutic window for treatment of infarcts .