Tetrahydrobiopterin ; Vasculoprotective Mechanisms and Its Therapeutic Application

在吸烟者中，内皮源性一氧化氮的生物活性受到损害。 BH4 是 NO 合酶的重要辅助因子，其缺乏会降低 NO 生物活性。本研究的目的是测试补充四氢生物蝶呤 (BH4) 是否可以改善吸烟者的一氧化氮 (NO) 生物活性。健康男性吸烟者和年龄匹配的非吸烟者口服沙丙蝶呤（BH4 的活性类似物）（2 毫克/千克）。在沙丙蝶呤治疗前以及治疗后 3 小时和 24 小时，我们测量了 BH4 的血浆水平，并通过高分辨率超声检查（一种内皮功能的非侵入性测试）检查了肱动脉的血流介导的血管舒张（FMD）。吸烟者和非吸烟者之间的 BH4 基础血浆水平没有差异。沙丙蝶呤给药 3 小时后 BH4 血浆水平增加 3 倍，并在 24 小时时恢复到基线。在使用沙丙蝶呤之前，吸烟者的 FMD 明显较小 (p=0.0002)。沙丙蝶呤显着增强吸烟者的内皮依赖性血管舒张，但对非吸烟者没有影响（方差分析，p=0.001）。将 NOS 抑制剂 N^G-单甲基-L-精氨酸 (L-NMMA)（20 μmol）共同给药至肱动脉，完全消除了沙丙蝶呤的血管舒张作用（方差分析 p=0.002）。三硝酸甘油的内皮依赖性血管舒张作用在吸烟者和非吸烟者之间没有差异，并且不会被 BH4 改变。我们证明补充 BH4 可以改善吸烟者内皮源性 NO 的生物活性。这些观察结果强烈表明，吸烟者中 NO 依赖性血管舒张的减少可能与 BH4 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.