(6R)-5,6,7,8-tetrahydro-L-biopterin and its stereoisomer prevent ischemia reperfusion injury in human forearm
(6R)-5,6,7,8-tetrahydro-L-biopterin and its stereoisomer prevent ischemia reperfusion injury in human forearm
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DOI：
10.1161/atvbaha.107.142257
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发表时间：
2007-06-01
影响因子：
8.7
通讯作者：
Hingorani, Aroon D.
中科院分区：
文献类型：
--
作者：
Mayahi, Lila;Heales, Simon;Hingorani, Aroon D.
目的- 6R-5,6,7,8-四氢-L-生物蝶呤 (6R-BH4) 是内皮一氧化氮合酶的辅助因子，但也具有抗氧化特性。其立体异构体6S-5,6,7,8-四氢-L-生物蝶呤(6S-BH4)和结构相似的蝶呤6R,S-5,6,7,8-四氢-D-新蝶呤(NH4)也是抗氧化剂，但没有辅因子功能。当内皮一氧化氮合酶 6R-BH4 耗尽时，它会合成超氧化物而不是一氧化氮。由于与活性氧相互作用而降低一氧化氮的生物利用度与内皮功能障碍 (ED) 有关。 6R-BH4 可纠正缺血再灌注损伤 (IRI) 动物模型和有心血管风险的患者中的 ED。目前还不确定外源性 6R-BH4 对 ED 的影响是通过其辅助因子还是抗氧化作用。 方法和结果 - 在健康志愿者中，在 IRI 前后动脉内输注内皮依赖性血管舒张剂乙酰胆碱或内皮非依赖性血管舒张剂三硝酸甘油期间，通过静脉阻塞体积描记法测量前臂血流量。 IRI 降低血浆总抗氧化状态（P=0.03）并损害乙酰胆碱的血管舒张（P=0.01），但不影响三硝酸甘油的血管舒张（P=0.3）。动脉内输注大约等摩尔浓度的 6R-BH4、6S-BH4 和 NH4 可预防 IRI。结论 -IRI 导致 ED，其与氧化应激增加有关，而氧化应激增加可通过 6R-BH4、6S-BH4 和 NH4 来预防，这种作用可能是由抗氧化剂而不是辅因子功能介导的。无论机制如何，6R-BH4、6S-BH4 或 NH4 都可以减少临床 IRI 综合征期间的组织损伤。
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.