Tetrahydrobiopterin restores endothelial dysfunction induced by an oral glucose challenge in healthy subjects

被引:87
作者
Ihlemann, N
Rask-Madsen, C
Perner, A
Dominguez, H
Hermann, T
Kober, L
Torp-Pedersen, C
机构
[1] Bispebjerg Hosp, Dept Cardiol, DK-2400 Copenhagen, Denmark
[2] Joslin Diabet Ctr, Boston, MA 02215 USA
[3] Rigshosp, Dept Cardiol, DK-2100 Copenhagen, Denmark
[4] Herlev Hosp, Dept Med Gastroenterol, DK-2730 Herlev, Denmark
来源
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY | 2003年 / 285卷 / 02期
关键词
nitric oxide; postprandial; hyperglycemia;
D O I
10.1152/ajpheart.00008.2003
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
An oral glucose challenge causes transient impairment of endothelial function, probably because of increased oxidative stress. During oxidative stress, endothelial nitric oxide (NO) synthase (eNOS) becomes uncoupled because of decreased bioavailability of tetrahydrobiopterin (BH4), an essential cofactor of eNOS. Therefore, we examined whether an acute supplement of BH4 could restore endothelial dysfunction induced by an oral glucose challenge. Healthy subjects were examined in 53 experiments. Forearm blood flow was measured by venous occlusion plethysmography. Dose-response studies were obtained during intra-arterial infusion of serotonin to elicit endothelium-dependent, NO-specific vasodilation and during sodium nitroprusside ( SNP) infusion to elicit endothelium-independent vasodilation. Subjects were examined before (fasting) and 1 and 2 h after an oral glucose challenge (75 g) with serotonin (n = 10) and SNP (n = 8). On different days (6R)-5,6,7,8-tetrahydro-L-biopterin dihydrochloride (6R-BH4; n = 10), the active cofactor of eNOS or its stereoisomer (6S)-5,6,7,8-tetrahydro-L-biopterin sulfate (6S-BH4; n = 10), which is inactive as a cofactor, was added 10 min (500 mug/min) before and during the 1-h postchallenge serotonin dose-response study. In vitro studies showed that 6R-BH4 and 6S-BH4 were equipotent antioxidants. Serotonin response was reduced by 24 +/- 7% (at the highest dose) at 1 h postchallenge compared with fasting (P = 0.001) and was restored 2 h postchallenge. The reduction was reversed by the administration of 6R-BH4 but not by 6S-BH4. SNP responses were slightly increased 1 and 2 h postchallenge (increased by 15 +/- 13% at third dose 2 h postchallenge, P = 0.0001). An oral glucose challenge causes transient, NO-specific, endothelial dysfunction, which may be reversed by BH4. Transient postprandial endothelial dysfunction may be partly explained by reduced bioavailability of BH4 and NO.
引用
收藏
页码:H875 / H882
页数:8
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