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(Circulation Research. 2004;95:1019.)
© 2004 American Heart Association, Inc.

Integrative Physiology

Angiotensin II Impairs Neurovascular Coupling in Neocortex Through NADPH Oxidase–Derived Radicals

Ken Kazama, Josef Anrather, Ping Zhou, Helene Girouard, Kelly Frys, Teresa A. Milner, Costantino Iadecola

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

Correspondence to C. Iadecola, MD, Division of Neurobiology, 411 E 69th St, Room KB410, New York, NY 10021. E-mail coi2001{at}med.cornell.edu

Angiotensin II (Ang II) exerts detrimental effects on cerebral circulation, the mechanisms of which have not been elucidated. In particular, Ang II impairs the increase in cerebral blood flow (CBF) produced by neural activity, a critical mechanism that matches substrate delivery with energy demands in brain. We investigated whether Ang II exerts its deleterious actions by activating Ang II type 1 (AT₁) receptors on cerebral blood vessels and producing reactive oxygen species (ROS) through NADPH oxidase. Somatosensory cortex CBF was monitored in anesthetized mice by laser-Doppler flowmetry. Ang II (0.25 µg/kg per minute IV) attenuated the CBF increase produced by mechanical stimulation of the vibrissae. The effect was blocked by the AT₁ antagonist losartan and by ROS scavenger superoxide dismutase or tiron and was not observed in mice lacking the gp91^phox subunit of NADPH oxidase or in wild-type mice treated with the NADPH oxidase peptide inhibitor gp91ds-tat. Ang II increased ROS production in cerebral microvessels, an effect blocked by the ROS scavenger Mn(III)tetrakis (4-benzoic acid) porphyrin and by the NADPH oxidase assembly inhibitor apocynin. Ang II did not increase ROS production in gp91-null mice. Double-label immunoelectron microscopy demonstrated that AT₁ and gp91^phox immunoreactivities were present in endothelium and adventitia of neocortical arterioles. Collectively, these findings suggest that Ang II impairs functional hyperemia by activating AT₁ receptors and inducing ROS production via a gp91^phox containing NADPH oxidase. The data provide the mechanistic basis for the cerebrovascular dysregulation induced by Ang II and suggest novel therapeutic strategies to counteract the effects of hypertension on the brain.

Key Words: cerebral circulation • hypertension • somatosensory activation • gp91-null mice • laser-Doppler flowmetry

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