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1 Department of Cardiology, Bispebjerg University Hospital, Copenhagen, Denmark
2 Section on Vascular Cell Biology, Joslin Diabetes Center, Boston, MA, USA
3 Department of Gastroenterology, Herlev University Hospital, Copenhagen, Denmark
4 Department of Cardiology, Rigshospitalet, Copenhagen, Denmark
* To whom correspondence should be addressed. E-mail: nihl{at}heart.dk.
Background. An oral glucose challenge causes transient impairment of endothelial function, probably because of increased oxidative stress. During oxidative stress endothelial nitric oxide synthase (eNOS) becomes uncoupled due to 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. Methods. Healthy subjects were examined in a total of 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 sodium nitroprusside (SNP) to elicit endothelium-independent vasodilation. Subjects were examined before (fasting) and 1 and 2 hours after an oral glucose challenge (75-gram) with serotonin (n=10) and SNP (n=8). On different days 6R-BH4 (n=10), the active cofactor of eNOS or its stereoisomer 6S-BH4 (n=10), which is inactive as cofactor, was added 10 minutes (500 µg/minute) before and during the 1-hour post-challenge serotonin dose-response study. In vitro studies showed that 6R- and 6S-BH4 were equipotent antioxidants. Results. Serotonin response was reduced by 24±7%(at the highest dose) 1-hour post-challenge as compared to fasting (p=0.001) and restored 2 hours post-challenge. The reduction was reversed by the administration of 6R-BH4 but not by 6S-BH4. SNP-responses were slightly increased 1 and 2 hours post-challenge (increased by 15±13% at dose three 2 hours post-challenge, p=0.0001). Conclusions. 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.
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