© 2000 American Heart Association, Inc.
Integrative Physiology |
Oral Administration of Tetrahydrobiopterin Prevents Endothelial Dysfunction and Vascular Oxidative Stress in the Aortas of Insulin-Resistant Rats
From the Third Department of Medicine (K.S., Y.N., H.M., H.K., R.K., A.K.) and Department of Pharmacology (T.O., N.T.), Shiga University of Medical Science, Otsu, Japan; and Laboratory of Biochemistry (Y.Y., M.M.), Faculty of Horticulture, Chiba University, Matsudo, Japan.
Correspondence to Dr Atsunori Kashiwagi, Third Department of Medicine, Shiga University of Medical Science, Tsukinowa-cho, Seta, Otsu, Shiga 520-2192, Japan. E-mail kasiwagi{at}belle.shiga-med.ac.jp
Abstract—We have reported that a
deficiency of tetrahydrobiopterin (BH4), an active cofactor
of endothelial NO synthase (eNOS), contributes to the
endothelial dysfunction through reduced eNOS activity
and increased superoxide anion (O2-)
generation in the insulin-resistant state. To further confirm
this hypothesis, we investigated the effects of dietary treatment with
BH4 on endothelium-dependent
arterial relaxation and vascular oxidative stress in the
aortas of insulin-resistant rats. Oral supplementation of
BH4 (10 mg · kg-1 ·
d-1) for 8 weeks significantly increased the
BH4 content in cardiovascular tissues of
rats fed high levels of fructose (fructose-fed rats). Impairment of
endothelium-dependent arterial relaxation
in the aortic strips of the fructose-fed rats was reversed with
BH4 treatment. The BH4 treatment was associated
with a 2-fold increase in eNOS activity as well as a 70% reduction in
endothelial O2-
production compared with those in fructose-fed rats. The
BH4 treatment also partially improved the insulin
sensitivity and blood pressure, as well as the serum
triglyceride concentration, in the fructose-fed rats.
Moreover, BH4 treatment of the fructose-fed rats markedly
reduced the lipid peroxide content of both aortic and cardiac tissues
and inhibited the activation of 2 redox-sensitive transcription
factors, nuclear factor-
B and activating protein-1, which were
increased in fructose-fed rats. The BH4 treatment of
control rats did not have any significant effects on these
parameters. These results indicate that BH4
augmentation is essential for the restoration of eNOS function and the
reduction of vascular oxidative stress in insulin-resistant rats.
Key Words: tetrahydrobiopterin • insulin • endothelium • free radicals
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