This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 27/2/303    most recent 01.ATV.0000253885.41509.25v1 Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Girouard, H. Articles by Iadecola, C. Search for Related Content PubMed PubMed Citation Articles by Girouard, H. Articles by Iadecola, C.

(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

This article has been cited by other articles:

				C. Capone, J. Anrather, T. A. Milner, and C. Iadecola Estrous Cycle-Dependent Neurovascular Dysfunction Induced by Angiotensin II in the Mouse Neocortex Hypertension, August 1, 2009; 54(2): 302 - 307. [Abstract] [Full Text] [PDF]

				N. Toda, K. Ayajiki, and T. Okamura Cerebral Blood Flow Regulation by Nitric Oxide: Recent Advances Pharmacol. Rev., March 1, 2009; 61(1): 62 - 97. [Abstract] [Full Text] [PDF]

				H. Girouard, G. Wang, E. F. Gallo, J. Anrather, P. Zhou, V. M. Pickel, and C. Iadecola NMDA Receptor Activation Increases Free Radical Production through Nitric Oxide and NOX2 J. Neurosci., February 25, 2009; 29(8): 2545 - 2552. [Abstract] [Full Text] [PDF]

				H. Iida, M. Iida, M. Takenaka, N. Fukuoka, and S. Dohi Rho-kinase inhibitor and Nicotinamide Adenine Dinucleotide PHosphate oxidase inhibitor prevent impairment of endothelium-dependent cerebral vasodilation by acute cigarette smoking in rats Journal of Renin-Angiotensin-Aldosterone System, June 1, 2008; 9(2): 89 - 94. [Abstract] [PDF]

				H. Girouard, A. Lessard, C. Capone, T. A. Milner, and C. Iadecola The neurovascular dysfunction induced by angiotensin II in the mouse neocortex is sexually dimorphic Am J Physiol Heart Circ Physiol, January 1, 2008; 294(1): H156 - H163. [Abstract] [Full Text] [PDF]

				M. Orio, A. Kunz, T. Kawano, J. Anrather, P. Zhou, and C. Iadecola Lipopolysaccharide Induces Early Tolerance to Excitotoxicity via Nitric Oxide and cGMP Stroke, October 1, 2007; 38(10): 2812 - 2817. [Abstract] [Full Text] [PDF]

				G. Peluffo and R. Radi Biochemistry of protein tyrosine nitration in cardiovascular pathology Cardiovasc Res, July 15, 2007; 75(2): 291 - 302. [Abstract] [Full Text] [PDF]

				A. Kunz, L. Park, T. Abe, E. F. Gallo, J. Anrather, P. Zhou, and C. Iadecola Neurovascular Protection by Ischemic Tolerance: Role of Nitric Oxide and Reactive Oxygen Species J. Neurosci., July 4, 2007; 27(27): 7083 - 7093. [Abstract] [Full Text] [PDF]