title: Nitrite supplementation reverses vascular endothelial dysfunction and large elastic artery stiffness with aging.
abstract: We tested the hypothesis that short-term nitrite therapy reverses vascular endothelial dysfunction and large elastic artery stiffening with aging, and reduces arterial oxidative stress and inflammation. Nitrite concentrations were lower (P < 0.05) in arteries, heart, and plasma of old (26-28 month) male C57BL6 control mice, and 3 weeks of sodium nitrite (50 mg L(-1) in drinking water) restored nitrite levels to or above young (4-6 month) controls. Isolated carotid arteries of old control mice had lower acetylcholine (ACh)-induced endothelium-dependent dilation (EDD) (71.7 ± 6.1% vs. 93.0 ± 2.0%) mediated by reduced nitric oxide (NO) bioavailability (P < 0.05 vs. young), and sodium nitrite restored EDD (95.5 ± 1.6%) by increasing NO bioavailability. 4-Hydroxy-2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPOL), a superoxide dismutase (SOD) mimetic, apocynin, a nicotinamide adenine dinucleotide phosphate-oxidase (NADPH) inhibitor, and sepiapterin (exogenous tetrahydrobiopterin) each restored EDD to ACh in old control, but had no effect in old nitrite-supplemented mice. Old control mice had increased aortic pulse wave velocity (478 ± 16 vs. 332 ± 12 AU, P < 0.05 vs. young), which nitrite supplementation lowered (384 ± 27 AU). Nitrotyrosine, superoxide production, and expression of NADPH oxidase were ∼100-300% greater and SOD activity was ∼50% lower in old control mice (all P < 0.05 vs. young), but were ameliorated by sodium nitrite treatment. Inflammatory cytokines were markedly increased in old control mice (P < 0.05), but reduced to levels of young controls with nitrite supplementation. Short-term nitrite therapy reverses age-associated vascular endothelial dysfunction, large elastic artery stiffness, oxidative stress, and inflammation. Sodium nitrite may be a novel therapy for treating arterial aging in humans.
authors.affiliation: Department of Integrative Physiology, University of Colorado, Boulder, USA. amy.sindler@colorado.edu
authors.forename: Amy L
authors.initials: AL
authors.lastname: Sindler
authors.forename: Bradley S
authors.initials: BS
authors.lastname: Fleenor
authors.forename: John W
authors.initials: JW
authors.lastname: Calvert
authors.forename: Kurt D
authors.initials: KD
authors.lastname: Marshall
authors.forename: Melanie L
authors.initials: ML
authors.lastname: Zigler
authors.forename: David J
authors.initials: DJ
authors.lastname: Lefer
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Seals
mesh_terms: D000098:Acetophenones / Q000494:pharmacology; D000109:Acetylcholine / Q000494:pharmacology*; D000284:Administration, Oral; D000375:Aging; D000818:Animals; D001708:Biopterins / Q000031:analogs & derivatives / Q000494:pharmacology; D002339:Carotid Arteries / Q000502:physiology*; D003497:Cyclic N-Oxides / Q000494:pharmacology; D016207:Cytokines / Q000096:biosynthesis; D004548:Elasticity / Q000187:drug effects; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D009213:Myography; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009569:Nitric Oxide / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D012977:Sodium Nitrite / Q000378:metabolism / Q000494:pharmacology*; D013113:Spin Labels; D013482:Superoxide Dismutase / Q000378:metabolism / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: D000098:Acetophenones; D003497:Cyclic N-Oxides; D016207:Cytokines; D013113:Spin Labels; D014665:Vasodilator Agents; D001708:Biopterins; D009569:Nitric Oxide; C056165:acetovanillone; D013482:Superoxide Dismutase; D019255:NADPH Oxidases; C003402:sapropterin; D012977:Sodium Nitrite; D000109:Acetylcholine; C001803:tempol