Cerebrovascular nitrosative stress mediates neurovascular and endothelial dysfunction induced by angiotensin II.
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.


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 microg/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.
Girouard
Helene
H
Division of Neurobiology, Weill Medical College of Cornell University, New York, NY 10021, USA.
Park
Laibaik
L
Anrather
Josef
J
Zhou
Ping
P
Iadecola
Costantino
C
D000109:Acetylcholine / Q000494:pharmacology; D000241:Adenosine / Q000494:pharmacology; D000804:Angiotensin II / Q000502:physiology*; D000818:Animals; D002560:Cerebrovascular Circulation / Q000187:drug effects / Q000502:physiology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009566:Nitrates / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D015538:Nitrosation; D030421:Peroxynitrous Acid / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D014665:Vasodilator Agents / Q000494:pharmacology; D014738:Vibrissae / Q000502:physiology
D009566:Nitrates; D017382:Reactive Oxygen Species; D014665:Vasodilator Agents; D013481:Superoxides; D000804:Angiotensin II; D030421:Peroxynitrous Acid; D009569:Nitric Oxide; C002744:3-nitrotyrosine; D014443:Tyrosine; D019001:Nitric Oxide Synthase; D000241:Adenosine; D000109:Acetylcholine