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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:1334.)
© 2007 American Heart Association, Inc.

Vascular Biology

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

Lila Mayahi; Simon Heales; David Owen; Juan P. Casas; Joanne Harris; Raymond J. MacAllister; Aroon D. Hingorani

From Centre for Clinical Pharmacology (L.M., D.O., J.P.C., J.H., R.J.M., A.D.H.), University College London, London, UK; Neurometabolic Unit (S.H.), Hospital for Neurology and Neurosurgery (UCLH Foundation Trust), Queen Square, London, UK.

Correspondence to Dr Lila Mayahi, Centre for Clinical Pharmacology, BHF laboratories, Department of Medicine, UCL, 5 University Street, London, UK, WC1E 6JJ. E-mail l.mayahi{at}ucl.ac.uk

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.

6R-BH4, the NOS cofactor, corrected ischemia reperfusion injury in the human forearm arterioles, an effect shared by 6S-BH4 and NH4. This may be a result of radical scavenging action rather than NOS catalysis.

This study shows that insulin and angiotensin II have a major role in HDL metabolism in vivo. These hormones induce redistribution of SR-BI to the plasma membrane in adipose tissue. This will then lead to an increase in LXR binding activity in an insulin and angiotensin II dependent fashion.

Key Words: 6R-5,6,7,8-tetrahydro-L-biopterin • antioxidant • endothelial dysfunction • ischemia • reperfusion

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