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

2007; Lippincott Williams & Wilkins; Volume: 27; Issue: 6 Linguagem: Inglês

10.1161/atvbaha.107.142257

1524-4636

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

Mitochondrial Function and Pathology

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.