Systemic and vascular oxidation limits the efficacy of oral tetrahydrobiopterin treatment in patients with coronary artery disease.
BACKGROUND
The endothelial nitric oxide synthase cofactor tetrahydrobiopterin (BH4) plays a pivotal role in maintaining endothelial function in experimental vascular disease models and in humans. Augmentation of endogenous BH4 levels by oral BH4 treatment has been proposed as a potential therapeutic strategy in vascular disease states. We sought to determine the mechanisms relating exogenous BH4 to human vascular function and to determine oral BH4 pharmacokinetics in both plasma and vascular tissue in patients with coronary artery disease.


RESULTS
Forty-nine patients with coronary artery disease were randomized to receive low-dose (400 mg/d) or high-dose (700 mg/d) BH4 or placebo for 2 to 6 weeks before coronary artery bypass surgery. Vascular function was quantified by magnetic resonance imaging before and after treatment, along with plasma BH4 levels. Vascular superoxide, endothelial function, and BH4 levels were determined in segments of saphenous vein and internal mammary artery. Oral BH4 treatment significantly augmented BH4 levels in plasma and in saphenous vein (but not internal mammary artery) but also increased levels of the oxidation product dihydrobiopterin (BH2), which lacks endothelial nitric oxide synthase cofactor activity. There was no effect of BH4 treatment on vascular function or superoxide production. Supplementation of human vessels and blood with BH4 ex vivo revealed rapid oxidation of BH4 to BH2 with predominant BH2 uptake by vascular tissue.


CONCLUSIONS
Oral BH4 treatment augments total biopterin levels in patients with established coronary artery disease but has no net effect on vascular redox state or endothelial function owing to systemic and vascular oxidation of BH4. Alternative strategies are required to target BH4-dependent endothelial function in established vascular disease states.
Department of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.
Colin
C
Cunnington
Tim
T
Van Assche
Cheerag
C
Shirodaria
Ilias
I
Kylintireas
Alistair C
AC
Lindsay
Justin M
JM
Lee
Charalambos
C
Antoniades
Marios
M
Margaritis
Regent
R
Lee
Ruha
R
Cerrato
Mark J
MJ
Crabtree
Jane M
JM
Francis
Rana
R
Sayeed
Chandi
C
Ratnatunga
Ravi
R
Pillai
Robin P
RP
Choudhury
Stefan
S
Neubauer
Keith M
KM
Channon
D000284:Administration, Oral; D000368:Aged; D001708:Biopterins / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood; D003324:Coronary Artery Disease / Q000097:blood* / Q000188:drug therapy*; D004311:Double-Blind Method; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D010084:Oxidation-Reduction / Q000187:drug effects; D016896:Treatment Outcome
D001708:Biopterins; C003402:sapropterin