Tetrahydrobiopterin restores endothelial function in long-term smokers

• Published in: Journal of the American College of Cardiology Vol. 35; no. 1; pp. 71 - 75
• Main Authors: Ueda, Seiji, Matsuoka, Hidehiro, Miyazaki, Hiroshi, Usui, Michiaki, Okuda, Seiya, Imaizumi, Tsutomu
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01.01.2000; Elsevier Science
• Subjects: Administration, Oral; Adult; Antioxidants - administration & dosage; Antioxidants - metabolism; Biological and medical sciences; Biopterins - administration & dosage; Biopterins - analogs & derivatives; Biopterins - blood; Blood and lymphatic vessels; Brachial Artery - drug effects; Brachial Artery - physiology; Cardiology. Vascular system; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Endothelium, Vascular - drug effects; Endothelium, Vascular - physiopathology; Humans; Male; Medical sciences; Nitric Oxide - physiology; Smoking - physiopathology; Vasodilation - drug effects; Vasodilation - physiology; GTN; HDL; NO; NOS; ANOVA; LDL; HbA1c; FMV; l-NMMA; BH4; Human; Prevention; Tetrahydrobiopterin; Toxicity; Defective operation; Tobacco smoking; Cardiovascular disease; Complication; Male; Supplementation; Endothelium
• ISSN: 0735-1097; 1558-3597
• DOI: 10.1016/S0735-1097(99)00523-9

OBJECTIVES 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 NG-monomethyl-l-arginine (L-NMMA), an NO synthase inhibitor (20 μmol), 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.