Tetrahydrobiopterin ; Vasculoprotective Mechanisms and Its Therapeutic Application

在吸烟者中，内皮衍生的NO生物活性受损。BH4是一氧化氮合酶的重要辅因子，它的缺乏降低了一氧化氮合酶的生物活性。本研究的目的是测试补充四氢生物蝶呤(BH4)是否能改善吸烟者的一氧化氮(NO)生物活性。给健康男性吸烟者和年龄匹配的非吸烟者口服盐酸腐普妥，这是一种BH4的活性类似物(2 mg/kg)。分别于治疗前、治疗后3小时和24小时测定血浆BH4水平，并用高分辨率超声(一种无创血管内皮功能检测方法)检测肱动脉血流介导的血管扩张功能。吸烟者和非吸烟者基础血浆BH4水平无差异。给药后3小时血浆BH4水平增加3倍，24小时恢复到基线水平。在服用腐胺喋呤之前，吸烟者的FMD值明显较小(p=0.0002)。在吸烟者中，腐胺蝶呤显著增强内皮依赖性血管扩张，而在非吸烟者中则不受影响(经方差分析p=0.001)。一氧化氮合酶抑制剂L(N^G-单甲基-L-精氨酸，N^G-单甲基-L-精氨酸，20μ摩尔)可完全阻断腐胺喋呤的血管扩张作用(P=0.002)。在吸烟者和非吸烟者中，硝酸甘油的非内皮依赖性血管扩张作用没有差别，BH4也没有改变。我们证明，补充BH4可以改善吸烟者内皮源性NO的生物活性。这些观察有力地表明，吸烟者对NO依赖的血管扩张功能的降低可能与BH4的生物活性降低有关。

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.