Tetrahydrobiopterin restores endothelial function in long-term smokers.
OBJECTIVE
We sought to test whether tetrahydrobiopterin (BH4) supplementation improves nitric oxide (NO) bioactivity in smokers.


BACKGROUND
In smokers, endothelium-derived NO bioactivity is impaired. BH4 is an essential cofactor of NO synthase, and its deficiency decreases NO bioactivity.


METHODS
Sapropterin hydrochloride, an active analogue of BH4 (2 mg/kg body weight), was administered orally to healthy male smokers and age-matched nonsmokers. Before and 3 and 24 h after sapropterin, we measured plasma levels of BH4 and examined flow-mediated vasodilation (FMV) of the brachial artery by high resolution ultrasonography, a noninvasive test of endothelial function.


RESULTS
Basal plasma levels of BH4 were not different between smokers and nonsmokers. Sapropterin administration increased plasma levels of BH4 by threefold at 3 h, which returned to the baseline at 24 h. Before sapropterin, FMV was significantly smaller in smokers (p = 0.0002). Sapropterin significantly augmented endothelium-dependent vasodilation in smokers, but did not affect it in nonsmokers (p = 0.001 by analysis of variance [ANOVA]). Coadministration of N(G)-monomethyl-L-arginine (L-NMMA), an NO synthase inhibitor (20 micromol), into the brachial artery completely abolished the vasodilatory effects of sapropterin (p = 0.002 by ANOVA). Endothelium-independent vasodilation by glyceryl trinitrate was not different between smokers and nonsmokers and was not altered by BH4.


CONCLUSIONS
We demonstrated that BH4 supplementation improved bioactivity of endothelium-derived NO in smokers. These observations strongly suggest that decreased NO-dependent vasodilation in smokers could be related to reduced bioactivity of BH4.
Ueda
S
S
Department of Internal Medicine III, and the Cardiovascular Research Institute, Kurume University School of Medicine, Fukuoka, Japan.
Matsuoka
H
H
Miyazaki
H
H
Usui
M
M
Okuda
S
S
Imaizumi
T
T
D000284:Administration, Oral; D000328:Adult; D000975:Antioxidants / Q000008:administration & dosage* / Q000378:metabolism; D001708:Biopterins / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood; D001916:Brachial Artery / Q000187:drug effects / Q000502:physiology; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000503:physiopathology; D006801:Humans; D008297:Male; D009569:Nitric Oxide / Q000502:physiology*; D012907:Smoking / Q000503:physiopathology*; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology
D000975:Antioxidants; D001708:Biopterins; D009569:Nitric Oxide; C003402:sapropterin