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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:303.)
© 2007 American Heart Association, Inc.

Vascular Biology

Cerebrovascular Nitrosative Stress Mediates Neurovascular and Endothelial Dysfunction Induced by Angiotensin II

Helene Girouard; Laibaik Park; Josef Anrather; Ping Zhou; Costantino Iadecola

From the Division of Neurobiology, Department of Neurology & Neuroscience, Weill Medical College of Cornell University, New York.

Correspondence to Dr Costantino Iadecola, Division of Neurobiology, Weill Medical College of Cornell University, 411 East 69^th Street, KB-410, New York, NY 10021. E-mail coi2001{at}med.cornell.edu

Objective— Angiotensin II (AngII) disrupts the regulation of the cerebral circulation through superoxide, a reactive oxygen species (ROS) generated by a nox2-containing NADPH oxidase. We tested the hypothesis that AngII-derived superoxide reacts with nitric oxide (NO) to form peroxynitrite, which, in turn, contributes to the vascular dysfunction.

Methods and Results— Cerebral blood flow (CBF) was monitored by laser Doppler flowmetry in the neocortex of anesthetized mice equipped with a cranial window. AngII (0.25±0.02 µg/kg/min; intravenous for 30 to 45 minutes) attenuated the cerebral blood flow (CBF) increase produced by topical application of the endothelium-dependent vasodilator acetylcholine (–43±1%) and by whisker stimulation (–47±1%). AngII also increased the nitration marker 3-nitrotyrosine (3-NT) in cerebral blood vessels, an effect dependent on NO and nox2-derived ROS. Both the cerebrovascular effects of AngII and the nitration were attenuated by pharmacological inhibition or genetic inactivation of NO synthase. The nitration inhibitor uric acid or the peroxynitrite decomposition catalyst FeTPPS abolished AngII-induced cerebrovascular nitration and prevented the cerebrovascular effects of AngII.

Conclusions— These findings provide evidence that peroxynitrite, formed from NO and nox2-derived superoxide, contributes to the deleterious cerebrovascular effects of AngII. Inhibitors of peroxynitrite action may be valuable tools to counteract the deleterious cerebrovascular effects of AngII-induced hypertension.

Angiotensin II attenuates the increase in cerebral blood flow produced by acetylcholine or whisker stimulation. We found that these effects require nitric oxide and nox2-derived radicals, and are prevented by peroxynitrite antagonists. The data point to the involvement of peroxynitrite in the cerebrovascular dysfunction induced by angiotensin II.

Key Words: 3-nitrotyrosine • cerebral blood flow • gp91^phox • laser Doppler flowmetry • NADPH oxidase • peroxynitrite • reactive oxygen species

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