Age-related alterations in reactivity of cerebral arterioles: role of oxidative stress.
OBJECTIVE
Our goal was to identify the role of oxidative stress via activation of NAD(P)H oxidase in cerebrovascular dysfunction in aged rats.


METHODS
We examined the reactivity of cerebral arterioles in adult and aged Fisher-344 rats to endothelial nitric oxide synthase (eNOS)-dependent (acetylcholine and adenosine diphosphate [ADP]) and-independent (nitroglycerin) agonists before and during application of tempol, apocynin, and diphenyleneiodonium chloride (DPI). We used Western blot to examine subunits of NAD(P)H oxidase, eNOS, and superoxide dismutase (SOD-1) in cerebral microvessels and parietal cortex. Finally, we measured superoxide production by cortex tissue in adult and aged rats.


RESULTS
Acetylcholine-and ADP-induced, but not nitroglycerin-induced, dilatation of cerebral arterioles was impaired in aged compared to adult rats. While tempol, apocynin, and DPI did not alter responses in adults, they alleviated impaired eNOS-dependent vasodilatation in aged rats, without influencing responses to nitroglycerin. eNOS and p67phox proteins were increased in cerebral microvessels from aged compared to adult rats. Further, p67phox and gp91phox proteins were increased, but SOD-1 protein was decreased, in cortex tissue of aged rats. Basal and agonist-induced production of superoxide was elevated in aged rats.


CONCLUSIONS
Aging impairs eNOS-dependent reactivity of cerebral arterioles via an increase in superoxide produced by activation of NAD(P)H oxidase.
Mayhan
William G
WG
Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, Nebraska 68198-5850, USA. wgmayhan@unmc.edu
Arrick
Denise M
DM
Sharpe
Glenda M
GM
Sun
Hong
H
D000109:Acetylcholine / Q000494:pharmacology; D000244:Adenosine Diphosphate / Q000494:pharmacology; D000375:Aging / Q000502:physiology*; D000818:Animals; D001160:Arterioles / Q000187:drug effects / Q000378:metabolism; D001921:Brain / Q000098:blood supply* / Q000378:metabolism*; D002560:Cerebrovascular Circulation / Q000187:drug effects / Q000502:physiology*; D008297:Male; D019255:NADPH Oxidases / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D005996:Nitroglycerin / Q000494:pharmacology; D018384:Oxidative Stress / Q000502:physiology*; D051381:Rats; D011916:Rats, Inbred F344; D013481:Superoxides / Q000378:metabolism; D014665:Vasodilator Agents / Q000494:pharmacology
D014665:Vasodilator Agents; D013481:Superoxides; D000244:Adenosine Diphosphate; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D019255:NADPH Oxidases; D005996:Nitroglycerin; D000109:Acetylcholine