Angiotensin II produces superoxide-mediated impairment of endothelial function in cerebral arterioles.
OBJECTIVE
Angiotensin II (Ang II) produces oxidative stress in vascular cells in culture and in extracranial conduit arteries. The goal of this study was to examine the hypothesis that Ang II produces superoxide-mediated impairment of endothelial function in cerebral microvessels.


METHODS
Diameter of cerebral arterioles (baseline diameter=104+/-3 microm) was measured with the use of a closed cranial window in anesthetized rabbits. Topical application of Ang II was used to avoid effects on arterial pressure.


RESULTS
Ang II (0.1 to 1 micromol/L for 2 hours) had no effect on baseline diameter (change in diameter of -3+/-2% in response to 1 micromol/L Ang II) but produced concentration-dependent inhibition of vasodilatation to the endothelium-dependent agonist bradykinin. For example, 1 micromol/L Ang II inhibited responses to 1 nmol/L bradykinin by almost 80%. These inhibitory effects of Ang II were prevented by the superoxide scavenger 4,5-dihydroxy-1,3-benzene-disulfonic acid (Tiron; 10 mmol/L) or diphenylene iodonium (DPI; 3 micromol/L), an inhibitor of NAD(P)H oxidase. Ang II did not inhibit vasodilatation in response to nitroprusside, an endothelium-independent vasodilator.


CONCLUSIONS
These findings are the first evidence that local Ang II produces superoxide-mediated vascular dysfunction in cerebral microvessels. The results with DPI suggest that the source of superoxide may be an NAD(P)H oxidase.
Didion
Sean P
SP
Department of Internal Medicine, Cardiovascular Center, University of Iowa Carver College of Medicine, Iowa City, IA 52242-1081, USA.
Faraci
Frank M
FM
D014013:1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt / Q000494:pharmacology; D000287:Administration, Topical; D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001160:Arterioles / Q000187:drug effects* / Q000502:physiology; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D001920:Bradykinin / Q000037:antagonists & inhibitors / Q000494:pharmacology; D002540:Cerebral Cortex / Q000098:blood supply* / Q000187:drug effects / Q000502:physiology; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000494:pharmacology; D008833:Microcirculation / Q000187:drug effects / Q000502:physiology; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors; D020030:Nitric Oxide Donors / Q000494:pharmacology; D010841:Pia Mater / Q000098:blood supply; D011817:Rabbits; D013481:Superoxides / Q000378:metabolism*; D014654:Vascular Patency / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects
D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D020030:Nitric Oxide Donors; D013481:Superoxides; D000804:Angiotensin II; D014013:1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt; D019255:NADPH Oxidases; D001920:Bradykinin