Tetrahydrobiopterin ; Vasculoprotective Mechanisms and Its Therapeutic Application

在吸烟者中，内皮衍生的NO生物活性受损。BH 4是NO合成酶的一个重要辅因子，其缺乏会降低NO的生物活性。本研究的目的是测试四氢生物蝶呤（BH 4）补充剂是否改善吸烟者的一氧化氮（NO）生物活性。将BH 4的活性类似物盐酸沙丙蝶呤（2 mg/kg）经口给予健康男性吸烟者和年龄匹配的非吸烟者。在沙丙蝶呤给药前和给药后3小时和24小时，我们测量了血浆BH 4水平，并通过高分辨率超声检查（一种非侵入性内皮功能测试）检查了肱动脉的血流介导的血管舒张（FMD）。基础血浆BH 4水平在吸烟者和非吸烟者之间没有差异。沙丙蝶呤给药在3小时时使BH 4的血浆水平增加3倍，在24小时时恢复至基线。在沙丙蝶呤之前，吸烟者的FMD显著较小（p=0.0002）。沙丙蝶呤显著增强吸烟者的内皮依赖性血管舒张，但不影响非吸烟者（ANOVA，p=0.001）。将NOS抑制剂（20 μmol）N^G-单甲基-L-精氨酸（L-NMMA）共同给予肱动脉，可完全消除沙丙蝶呤的血管舒张作用（ANOVA，p=0.002）。三硝酸甘油引起的内皮非依赖性血管舒张在吸烟者和非吸烟者之间没有差异，也不受BH 4的影响。我们证明，BH 4补充改善了吸烟者内皮源性NO的生物活性。这些观察结果强烈表明，吸烟者NO依赖性血管舒张功能的降低可能与BH 4生物活性的降低有关。

In smokers, endothelium-derived NO bioactivity is impaired. BH4 is an essential co-factor of NO synthase, and its deficiency decreases NO bioactivity. The aim of this study was to test whether tetrahydrobiopterin (BH4) supplementation improves nitric oxide (NO) bioactivity in smokers. Sapropterin hydrochloride, an active analogue of BH4 (2 mg/kg), was administrated orally to healthy male smokers and age-matched non-smokers. Before and at 3- and 24-hours after sapropterin, we measured plasma levels of BH4 and examined flow-mediated vasodilation (FMD) of the brachial artery by high resolution ultrasonography, a non-invasive test of endothelial function. Basal plasma levels of BH4 were not different between smokers and non-smokers. Sapropterin administration increased plasma levels of BH4 by 3-fold at 3-hour, which returned to the baseline at 24-hour. Before sapropterin, FMD was significantly smaller in smokers (p=0.0002). Sapropterin significantly augmented endothelium-dependent vasodilation in smokers, but did not affect it in non-smokers (p=0.001 by ANOVA). Co-administration of N^G-monomethyl-L-arginine (L-NMMA), an NOS 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 non- smokers, and was not altered by BH4. We demonstrated that the 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.