on January 26, 2006
Published online before print January 26, 2006, doi: 10.1161/01.ATV.0000205849.22807.6e
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Submitted on October 14, 2005
Accepted on January 13, 2006
Angiotensin II Attenuates Endothelium-Dependent Responses in the Cerebral Microcirculation Through Nox-2-Derived Radicals
Helene Girouard ;
From the Division of Neurobiology, Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, NY.
* To whom correspondence should be addressed. E-mail: coi2001{at}med.cornell.edu.
Objective--Angiotensin II (Ang II) exerts deleterious effect on the cerebral circulation through production of reactive oxygen species (ROS). However, the enzymatic source of the ROS has not been defined. We tested the hypothesis that Ang II impairs endothelium-dependent responses in the cerebral microcirculation through ROS generated in cerebrovascular cells by the enzyme NADPH oxidase.
Methods and Results--Cerebral blood flow (CBF) was monitored by laser Doppler flowmetry in anesthetized mice equipped with a cranial window. Ang II (0.25±0.02 µg/kg per minute for 30 to 45 minutes) attenuated the CBF increase produced by the endothelium-dependent vasodilators acetylcholine (-42±5%; P<0.05), bradykinin (-53±5%; P<0.05), and A23187 (-43±4%; P<0.05), and induced cerebrovascular ROS production, assessed by hydroethidine fluoromicrography. These actions of Ang II were prevented by losartan, by the ROS scavenger Mn(III) tetrakis (4-benzoic acid) porphyrin chloride (100 µmol/L), or by the NADPH oxidase peptide inhibitor gp91ds-tat (1 µmol/L), and were not observed in mice lacking the NADPH oxidase subunit gp91phox (nox-2).
Conclusions--Ang II impairs the endothelial regulation of the cerebral microcirculation through AT1 receptor-mediated cerebrovascular oxidative stress. The source of the ROS is a nox-2-containing NADPH oxidase. These effects of Ang II could threaten the cerebral blood supply and contribute to the increased susceptibility to stroke and dementia associated with hypertension.
Key words: cerebral blood flow • gp91phox • laser Doppler flowmetry • NADPH oxidase • reactive oxygen species
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