Tetrahydrobiopterin improves aging-related impairment of endothelium-dependent vasodilation through increase in nitric oxide production
Tetrahydrobiopterin improves aging-related impairment of endothelium-dependent vasodilation through increase in nitric oxide production
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DOI：
10.1016/j.atherosclerosis.2005.07.025
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发表时间：
2006-06-01
期刊：
影响因子：
5.3
通讯作者：
Yoshizumi, Masao
中科院分区：
文献类型：
--
作者：
Higashi, Yukihito;Sasaki, Shota;Yoshizumi, Masao
缺乏四氢生物蝶呤（BH4），一氧化氮（NO）合成酶的重要辅助因子，减少NO的产生和增加活性氧。本研究的目的是阐明衰老对内皮功能的影响，并确定BH4缺乏程度是否与衰老和氧化应激有关。我们评估了37名健康男性（平均年龄41 +/- 18岁，范围19-81岁）在联合输注BH4 （500 mg/min）前后对乙酰胆碱（ACh）（内皮依赖性血管扩张剂）和硝酸异山梨酯（ISDN）（内皮依赖性血管扩张剂）的前臂血流（FBF）反应。FBF采用应变式容积描记仪测量。测定尿8-羟基-2'-脱氧鸟苷（8-OHdG）和血清丙二醛修饰低密度脂蛋白（MDA-LDL）作为氧化应激指标。在所有受试者中，乙酰胆碱和ISDN均以剂量依赖的方式增加FBF。联合输注BH4可显著增加乙酰胆碱诱导的血管舒张（从22.3 +/- 6.7 mL/min增加到30.1 +/- 7.5 mL/min/100 mL组织，P < 0.05）。发现衰老与乙酰胆碱诱导的血管舒张（r= -0.47, P = 0.006）、尿8-OHdG （r= 0.38, P = 0.02）、血清MDA-LDL （r= 0.36, P = 0.02）以及共输BH4后乙酰胆碱诱导的血管舒张变化（r= 0.45, P = 0.007）显著相关。FBF对ISDN的响应与任何参数无关。输注NO合成酶抑制剂ng -单甲基- l-精氨酸，可消除乙酰胆碱引起的bh4诱导的前臂血管松弛增强。ISDN后FBF的增加不受BH4的影响。这些发现表明，BH4的缺乏可能通过减少NO的产生和增加氧化应激参与了与衰老相关的内皮依赖性血管舒张紊乱的发病机制。2005爱思唯尔爱尔兰有限公司版权所有。
Deficiency of tetrahydrobiopterin (BH4), an essential cofactor for nitric oxide (NO) synthase, decreases NO production and increases reactive oxygen species. The purpose of this study was to elucidate the effects of aging on endothelial function and to determine whether the degree of BH4 deficiency is related to aging and oxidative stress. We evaluated forearm blood flow (FBF) responses to acetylcholine (ACh), an endothelium-dependent vasodilator, and isosorbide dinitrate (ISDN), an endothelium-independent vasodilator, before and after co-infusion of BH4 (500 mg/min) in 37 healthy men (mean age, 41 +/- 18 yr; range, 19-81 yr). FBF was measured using strain-gauge plethysmograph. Urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) and serum malondialdehyde-modified low-density lipoprotein (MDA-LDL) were measured as indices of oxidative stress. Both ACh and ISDN increased the FBF in a dose-dependent manner in all subjects. Co-infusion of BH4 resulted in a significant increase in ACh-induced vasodilation (from 22.3 +/- 6.7 to 30.1 +/- 7.5 mL/min/100 mL tissue, P < 0.05). Aging was found to be significantly correlated with ACh-induced vasodilation (r= -0.47, P = 0.006), urinary 8-OHdG (r= 0.38, P = 0.02), serum MDA-LDL (r = 0.36, P = 0.02), and the change in ACh-induced vasodilation after co-infusion of BH4 (r= 0.45, P = 0.007). The FBF response to ISDN did not correlate with any parameters. Infusion of NG-monomethyl-L-arginine, an NO synthase inhibitor, abolished the BH4-induced enhancement of forearm vasorelaxation evoked by ACh. The increase in FBF after ISDN was not altered by BH4. These findings suggest that a deficiency of BH4 may be involved in the pathogenesis of disturbances in endothelium-dependent vasodilation related to aging through decrease in NO production and increase in oxidative stress. (c) 2005 Elsevier Ireland Ltd. All rights reserved.