Oral administration of tetrahydrobiopterin prevents endothelial dysfunction and vascular oxidative stress in the aortas of insulin-resistant rats

We have reported that a deficiency of tetrahydrobiopterin (BH,), an active cofactor of endothelial NO synthase (eNOS), contributes to the endothelial dysfunction through reduced eNOS activity and increased superoxide anion (O-2(-)) 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 O-2(-) 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-kappa 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.