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1Departments of Anesthesia Research and Molecular Pharmacology and Experimental Therapeutics and 2Division of Nephrology and Hypertension, Mayo Clinic College of Medicine, Rochester, Minnesota 55905
Submitted 19 March 2004 ; accepted in final form 29 June 2004
Oxidative stress has been implicated as an important mechanism of vascular endothelial dysfunction induced by aging. Previous studies suggested that tetrahydrobiopterin (BH4), an essential cofactor of endothelial NO synthase, could be a molecular target for oxidation. We tested the hypothesis that oxidative stress, in particular oxidation of BH4, may contribute to attenuation of endothelium-dependent relaxation in aged mice. Vasomotor function of isolated carotid arteries was studied using a video dimension analyzer. Vascular levels of BH4 and its oxidation products were measured via HPLC. In aged mice (age, 95 ± 2 wk), endothelium-dependent relaxation to ACh (10–5 to 10–9 M) as well as endothelium-independent relaxation to the NO donor diethylammonium (Z)-1-(N,N-diethylamino)diazen-1-ium-1,2-diolate (DEA-NONOate, 10–5 to 10–9 M) were significantly reduced compared with relaxation detected in young mice (age, 23 ± 0.5 wk). Incubation of aged mouse carotid arteries with the cell-permeable SOD mimetic Mn(III)tetra(4-benzoic acid)porphyrin chloride normalized relaxation to ACh and DEA-NONOate. Furthermore, production of superoxide anion in aorta and serum levels of amyloid P component, which is the murine analog of C-reactive protein, was increased in old mice. In aorta, neither the concentration of BH4 nor the ratio of reduced BH4 to the oxidation products were different between young and aged mice. Our results demonstrate that in mice, aging impairs relaxation mediated by NO most likely by increased formation of superoxide anion. Oxidation of BH4 does not appear to be an important mechanism underlying vasomotor dysfunction in aged mouse arteries.
endothelial dysfunction; nitric oxide; superoxide anion; reactive oxygen species; C-reactive protein
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