(6R)-5,6,7,8-Tetrahydro-L-Biopterin and Its Stereoisomer Prevent Ischemia Reperfusion Injury in Human Forearm.

Mayahi, L; Heales, S; Owen, D; Casas, JP; Harris, J; Macallister, RJ; Hingorani, AD; (2007) (6R)-5,6,7,8-Tetrahydro-L-Biopterin and Its Stereoisomer Prevent Ischemia Reperfusion Injury in Human Forearm. Arteriosclerosis, thrombosis, and vascular biology, 27 (6). pp. 1334-9. ISSN 1079-5642 DOI: https://doi.org/10.1161/ATVBAHA.107.142257

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OBJECTIVE: 6R-5,6,7,8-tetrahydro-L-biopterin (6R-BH4) is a cofactor for endothelial nitric oxide synthase but also has antioxidant properties. Its stereo-isomer 6S-5,6,7,8-tetrahydro-L-biopterin (6S-BH4) and structurally similar pterin 6R,S-5,6,7,8-tetrahydro-D-neopterin (NH4) are also antioxidants but have no cofactor function. When endothelial nitric oxide synthase is 6R-BH4-deplete, it synthesizes superoxide rather than nitric oxide. Reduced nitric oxide bioavailability by interaction with reactive oxygen species is implicated in endothelial dysfunction (ED). 6R-BH4 corrects ED in animal models of ischemia reperfusion injury (IRI) and in patients with cardiovascular risks. It is uncertain whether the effect of exogenous 6R-BH4 on ED is through its cofactor or antioxidant action. METHODS AND RESULTS: In healthy volunteers, forearm blood flow was measured by venous occlusion plethysmography during intra-arterial infusion of the endothelium-dependent vasodilator acetylcholine, or the endothelium-independent vasodilator glyceryl trinitrate, before and after IRI. IRI reduced plasma total antioxidant status (P=0.03) and impaired vasodilatation to acetylcholine (P=0.01), but not to glyceryl trinitrate (P=0.3). Intra-arterial infusion of 6R-BH4, 6S-BH4 and NH4 at approximately equimolar concentrations prevented IRI. CONCLUSION: IRI causes ED associated with increased oxidative stress that is prevented by 6R-BH4, 6S-BH4, and NH4, an effect mediated perhaps by an antioxidant rather than cofactor function. Regardless of mechanism, 6R-BH4, 6S-BH4, or NH4 may reduce tissue injury during clinical IRI syndromes.

Item Type: Article
Faculty and Department: Faculty of Epidemiology and Population Health > Dept of Non-Communicable Disease Epidemiology
Research Centre: Centre for Global Non-Communicable Diseases (NCDs)
PubMed ID: 17413035
Web of Science ID: 246714600016
URI: http://researchonline.lshtm.ac.uk/id/eprint/10155


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