Published Online
on February 17, 2003

A more recent version of this article appeared on March 1, 2003

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Submitted on November 12, 2002
Revised on December 6, 2002

Vitamins Reverse Endothelial Dysfunction Through Regulation of eNOS and NAD(P)H Oxidase Activities

Sibel Ülker; Pascal P. McKeown; and Ulvi Bayraktutan^*

From the Department of Medicine, Institute of Clinical Science Block B, Queen's University Belfast, Belfast, United Kingdom.

^* To whom correspondence should be addressed. E-mail: u.bayraktutan{at}qub.ac.uk.

Abstract--Antioxidant vitamins C and E have protective properties in genetic hypertension associated with enhanced oxidative stress. This study investigated whether vitamins C and/or E modulate vascular function by regulating enzymatic activities of endothelial nitric oxide synthase (eNOS) and NAD(P)H oxidase using thoracic aortas of 20- to 22-week-old male spontaneously hypertensive rats (SHR) and their matched normotensive counterparts, Wistar-Kyoto rats (WKY). SHR aortas had impaired relaxant responses to acetylcholine but not to sodium nitroprusside, despite an 2-fold increase in eNOS activity and NO release. The levels of superoxide anion (O₂^-), a potent NO scavenger, and NAD(P)H oxidase activity were also 2-fold higher in SHR aortas. Mechanical but not pharmacological inactivation of endothelium (by rubbing and 100 µmol/L L-NAME, respectively) significantly abrogated O₂^- in both strains. Treatments of SHR aortas with NAD(P)H oxidase inhibitors, namely diphenyleneiodinium and apocynin, significantly diminished O₂^- production. The incubation of SHR aortas with different concentrations of vitamin C (10 to 100 µmol/L) and specifically with high concentrations of vitamin E (100 µmol/L) improved endothelial function, reduced superoxide production as well as NAD(P)H oxidase activity, and increased eNOS activity and NO generation in SHR aortas to the levels observed in vitamin C- and E-treated WKY aortas. Our results reveal endothelial NAD(P)H oxidase as the major source of vascular O₂^- in SHR and also show that vitamins C and E are critical in normalizing genetic endothelial dysfunction through regulation of eNOS and NAD(P)H oxidase activities.

Key words: nitric oxide • endothelium • enzymes • antioxidants • hypertension, experimental • vitamins

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