Systemic and Vascular Oxidation Limits Efficacy of Oral Tetrahydrobiopterin Treatment in Patients with Coronary Artery Disease
Background—The endothelial nitric oxide synthase (eNOS) 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 determined oral BH4 pharmacokinetics in both plasma and vascular tissue in patients with coronary artery disease (CAD).
Methods and Results—Forty-nine patients with CAD were randomized to receive low-dose (400mg/d) or high-dose (700mg/d) BH4, or placebo, for two to six weeks prior to 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 (SV) and internal mammary artery (IMA). Oral BH4 treatment significantly augmented BH4 levels in plasma and in SV (but not IMA) but also increased levels of the oxidation product dihydrobiopterin (BH2), which lacks eNOS 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 CAD, but has no net effect on vascular redox state or endothelial function, due to systemic and vascular oxidation of BH4. Alternative strategies are required to target BH4-dependent endothelial function in established vascular disease states.
Clinical Trial Registration Information—clinicaltrials.gov; Identifier: NCT00423280.
- Received May 27, 2011.
- Accepted January 31, 2012.
- Copyright © 2012, American Heart Association, Inc. All rights reserved. Unauthorized use prohibited