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

Abstract

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 (BH 4), an essential cofactor of eNOS. Therefore, we examined whether an acute supplement of BH 4 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 (6 R)-5,6,7,8-tetrahydro-l-biopterin dihydrochloride (6R-BH 4; n = 10), the active cofactor of eNOS or its stereoisomer (6 S)-5,6,7,8-tetrahydro-l-biopterin sulfate (6S-BH 4; n = 10), which is inactive as a cofactor, was added 10 min (500 μg/min) before and during the 1-h postchallenge serotonin dose-response study. In vitro studies showed that 6R-BH 4 and 6S-BH 4 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-BH 4 but not by 6S-BH 4. 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 BH 4. Transient postprandial endothelial dysfunction may be partly explained by reduced bioavailability of BH 4 and NO.