(6R)-5,6,7,8-tetrahydro-L-biopterin and its stereoisomer prevent ischemia reperfusion injury in human forearm.
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.


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.


CONCLUSIONS
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.
Mayahi
Lila
L
Centre for Clinical Pharmacology, BHF laboratories, Department of Medicine, UCL, 5 University Street, London, UK, WC1E 6JJ. l.mayahi@ucl.ac.uk
Heales
Simon
S
Owen
David
D
Casas
Juan P
JP
Harris
Joanne
J
MacAllister
Raymond J
RJ
Hingorani
Aroon D
AD
D000109:Acetylcholine / Q000494:pharmacology; D000328:Adult; D000975:Antioxidants / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D001708:Biopterins / Q000031:analogs & derivatives* / Q000097:blood / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D003067:Coenzymes / Q000097:blood / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D005260:Female; D005542:Forearm / Q000098:blood supply*; D006801:Humans; D008297:Male; D009569:Nitric Oxide / Q000097:blood; D019001:Nitric Oxide Synthase / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D012039:Regional Blood Flow / Q000187:drug effects; D015427:Reperfusion Injury / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D013237:Stereoisomerism; D013997:Time Factors; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology
D000975:Antioxidants; D003067:Coenzymes; D014665:Vasodilator Agents; D001708:Biopterins; C023455:tetrahydroneopterin; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; C003402:sapropterin; D000109:Acetylcholine