Angiotensin II attenuates endothelium-dependent responses in the cerebral microcirculation through nox-2-derived radicals.
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.


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 microg/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 micromol/L), or by the NADPH oxidase peptide inhibitor gp91ds-tat (1 micromol/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.
Girouard
Helene
H
Division of Neurobiology, Department of Neurology and Neuroscience, Weill Medical College, Cornell University, New York, NY 10021, USA.
Park
Laibaik
L
Anrather
Josef
J
Zhou
Ping
P
Iadecola
Costantino
C
D000109:Acetylcholine / Q000494:pharmacology; D000804:Angiotensin II / Q000494:pharmacology / Q000502:physiology*; D000818:Animals; D001920:Bradykinin / Q000494:pharmacology; D000001:Calcimycin / Q000494:pharmacology; D002560:Cerebrovascular Circulation / Q000187:drug effects / Q000502:physiology*; D004730:Endothelium, Vascular / Q000502:physiology*; D006973:Hypertension / Q000503:physiopathology; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000378:metabolism; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism*; D044140:Receptor, Angiotensin, Type 1 / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects
D008562:Membrane Glycoproteins; D017382:Reactive Oxygen Species; D044140:Receptor, Angiotensin, Type 1; D000804:Angiotensin II; D000001:Calcimycin; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D000109:Acetylcholine; D001920:Bradykinin