Elsevier

Atherosclerosis

Volume 186, Issue 2, June 2006, Pages 390-395
Atherosclerosis

Tetrahydrobiopterin improves aging-related impairment of endothelium-dependent vasodilation through increase in nitric oxide production

https://doi.org/10.1016/j.atherosclerosis.2005.07.025Get rights and content

Abstract

Deficiency of tetrahydrobiopterin (BH4), an essential cofactor for nitric oxide (NO) synthase, decreases NO production and increases reactive oxygen species. The purpose of this study was to elucidate the effects of aging on endothelial function and to determine whether the degree of BH4 deficiency is related to aging and oxidative stress. We evaluated forearm blood flow (FBF) responses to acetylcholine (ACh), an endothelium-dependent vasodilator, and isosorbide dinitrate (ISDN), an endothelium-independent vasodilator, before and after co-infusion of BH4 (500 mg/min) in 37 healthy men (mean age, 41 ± 18 yr; range, 19–81 yr). FBF was measured using strain-gauge plethysmograph. Urinary 8-hydroxy-2′-deoxyguanosine (8-OHdG) and serum malondialdehyde-modified low-density lipoprotein (MDA-LDL) were measured as indices of oxidative stress. Both ACh and ISDN increased the FBF in a dose-dependent manner in all subjects. Co-infusion of BH4 resulted in a significant increase in ACh-induced vasodilation (from 22.3 ± 6.7 to 30.1 ± 7.5 mL/min/100 mL tissue, P < 0.05). Aging was found to be significantly correlated with ACh-induced vasodilation (r = −0.47, P = 0.006), urinary 8-OHdG (r = 0.38, P = 0.02), serum MDA-LDL (r = 0.36, P = 0.02), and the change in ACh-induced vasodilation after co-infusion of BH4 (r = 0.45, P = 0.007). The FBF response to ISDN did not correlate with any parameters. Infusion of NG-monomethyl-l-arginine, an NO synthase inhibitor, abolished the BH4-induced enhancement of forearm vasorelaxation evoked by ACh. The increase in FBF after ISDN was not altered by BH4. These findings suggest that a deficiency of BH4 may be involved in the pathogenesis of disturbances in endothelium-dependent vasodilation related to aging through decrease in NO production and increase in oxidative stress.

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Subjects

Thirty-seven healthy men (mean age, 41 ± 18 yr; range, 19–81 yr) were enrolled in this study. Subjects with a history of cardiovascular or cerebrovascular disease, hypertension, hypercholesterolemia, diabetes mellitus, liver disease, renal disease, or a smoking habit were excluded. The study protocol was approved by the Ethical Committee of the Hiroshima University School of Medicine. Informed consent for participation in this study was obtained from all subjects.

Study protocol: effects of BH4 on endothelium-dependent and -independent vasodilation

Forearm vascular responses to ACh

Clinical characteristics

The baseline clinical characteristics of the 37 healthy male subjects are shown in Table 1.

Effects of co-infusion of BH4 and ACh or ISDN on forearm hemodynamics

Intra-arterial infusions of ACh and ISDN significantly increased FBF in dose-dependent manners (Fig. 1, Fig. 2). The FBF response to ACh increased significantly with co-infusion of BH4 (Fig. 1). The increase in FBF during infusion of ISDN was not altered by co-infusion of BH4 (Fig. 2). No significant change was observed in arterial blood pressure or heart rate after intra-arterial infusion of either ACh

Discussion

The present findings demonstrate that BH4 augments ACh-induced vasodilation but not ISDN-induced vasodilation and that aging significantly correlated with FBF response to ACh, urinary excretion of 8-OHdG, serum concentration of MDA-LDL, and the augmentation of FBF response to ACH in combination with BH4. The infusion of l-NMMA completely abolished the enhancement of ACh-induced vasodilation by BH4.

In the present study, ACh-induced vasodilation was progressively more impaired with advance of

Acknowledgments

This study was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science, and Culture of Japan, Japan Heart Foundation Grant for Research on Hypertension and Metabolism, and a Grant for Research Foundation for Community Medicine.

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