Published online before print January 22, 2004, doi: 10.1161/01.STR.0000112974.37028.58
(Stroke. 2004;35:584.)
© 2004 American Heart Association, Inc.
Original Contributions |
Increased NADPH-Oxidase Activity and Nox4 Expression During Chronic Hypertension Is Associated With Enhanced Cerebral Vasodilatation to NADPH In Vivo
From the Department of Pharmacology (T.M.P., S.C., C.G.S.) and Howard Florey Institute (T.M.P., G.R.D.), University of Melbourne, Parkville, Victoria, Australia.
Correspondence to Christopher G. Sobey, PhD, Department of Pharmacology, University of Melbourne, Parkville, Victoria 3010, Australia. E-mail cgsobey{at}unimelb.edu.au
Background and Purpose— We examined the importance of NADPH-oxidase in reactive oxygen species production in cerebral arteries and its effect on vascular tone in vivo. Furthermore, we investigated whether chronic hypertension affects function or expression of this enzyme in cerebral vessels.
Methods— Superoxide generation was detected in isolated rat basilar arteries with the use of lucigenin-enhanced chemiluminescence. mRNA expression of NADPH-oxidase subunits was assessed by real-time polymerase chain reaction. Basilar artery diameter was measured with the use of a cranial window preparation in anesthetized rats.
Results— NADPH-stimulated superoxide production was 2.3-fold higher in arteries from spontaneously hypertensive rats (SHR) versus normotensive Wistar-Kyoto rats (WKY) and could be blocked by the NADPH-oxidase inhibitor diphenyleneiodonium. Higher NADPH-oxidase activity was also reflected at the molecular level as mRNA expression of the NADPH-oxidase subunit Nox4 was 4.1-fold higher in basilar arteries from SHR versus WKY. In contrast, expression of Nox1, gp91phox, p22phox, and p47phox did not differ between strains. Application of NADPH to basilar arteries caused larger vasodilatation in SHR than WKY. Vasodilatation to NADPH could be attenuated by diphenyleneiodonium, as well as diethyldithiocarbamate (Cu2+/Zn2+–superoxide dismutase inhibitor), catalase (H2O2 scavenger), or tetraethylammonium (BKCa channel inhibitor).
Conclusions— Activation of NADPH-oxidase in cerebral arteries generates superoxide, which is dismutated by Cu2+/Zn2+–superoxide dismutase to H2O2. H2O2 then elicits vasodilatation via activation of BKCa channels. Upregulation of Nox4 during chronic hypertension is associated with elevated cerebral artery NADPH-oxidase activity.
Key Words: cerebrovascular disorders • hypertension • pharmacology • potassium channels • vasodilation
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