The cerebrovascular dysfunction induced by slow pressor doses of angiotensin II precedes the development of hypertension.
Hypertension alters cerebrovascular regulation and increases the brain's susceptibility to stroke and dementia. We investigated the temporal relationships between the arterial pressure (AP) elevation induced by "slow pressor" angiotensin II (ANG II) infusion, which recapitulates key features of human hypertension, and the resulting cerebrovascular dysfunction. Minipumps delivering saline or ANG II for 14 days were implanted subcutaneously in C57BL/6 mice (n = 5/group). Cerebral blood flow was assessed by laser-Doppler flowmetry in anesthetized mice equipped with a cranial window. With ANG II (600 ng · kg(-1) · min(-1)), AP started to rise after 9 days (P < 0.05 vs. saline), remained elevated at 11-17 days, and returned to baseline at 21 days (P > 0.05). ANG II attenuated the cerebral blood flow increase induced by neural activity (whisker stimulation) or endothelium-dependent vasodilators, an effect observed before the AP elevation (7 days), as well as after the hypertension subsided (21 days). Nonpressor doses of ANG II (200 ng · kg(-1) · min(-1)) induced cerebrovascular dysfunction and oxidative stress without elevating AP (P > 0.05 vs. saline), whereas phenylephrine elevated AP without inducing cerebrovascular effects. ANG II (600 ng · kg(-1) · min(-1)) augmented neocortical reactive oxygen species (ROS) with a time course similar to that of the cerebrovascular dysfunction. Neocortical application of the ROS scavenger manganic(I-II)meso-tetrakis(4-benzoic acid)porphyrin or the NADPH oxidase peptide inhibitor gp91ds-tat attenuated ROS and cerebrovascular dysfunction. We conclude that the alterations in neurovascular regulation induced by slow pressor ANG II develop before hypertension and persist beyond AP normalization but are not permanent. The findings unveil a striking susceptibility of cerebrovascular function to the deleterious effects of ANG II and raise the possibility that cerebrovascular dysregulation precedes the elevation in AP also in patients with ANG II-dependent hypertension.
Division of Neurobiology, Department of Neurology and Neuroscience, Weill Cornell Medical College, New York, New York, USA.
Carmen
C
Capone
Giuseppe
G
Faraco
Laibaik
L
Park
Xian
X
Cao
Robin L
RL
Davisson
Costantino
C
Iadecola
D000704:Analysis of Variance; D000804:Angiotensin II / Q000008:administration & dosage* / Q000378:metabolism; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D002560:Cerebrovascular Circulation / Q000187:drug effects* / Q000502:physiology; D004594:Electrophysiology; D005071:Evoked Potentials / Q000187:drug effects; D006973:Hypertension / Q000139:chemically induced* / Q000378:metabolism; D007150:Immunohistochemistry; D007260:Infusion Pumps; D017078:Laser-Doppler Flowmetry; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D013686:Telemetry; D013997:Time Factors; D014662:Vasoconstrictor Agents / Q000008:administration & dosage / Q000378:metabolism; D014738:Vibrissae / Q000502:physiology
D017382:Reactive Oxygen Species; D014662:Vasoconstrictor Agents; D000804:Angiotensin II