Sydow Karsten, Schwedhelm Edzard, Arakawa Naoshi, Bode-Böger Stefanie M, Tsikas Dimitrios, Hornig Burkhard, Frölich Jürgen C, Böger Rainer H
Department of Cardiology, University Hospital Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany.
Cardiovasc Res. 2003 Jan;57(1):244-52. doi: 10.1016/s0008-6363(02)00617-x.
Hyperhomocyst(e)inemia is a risk factor for atherosclerotic vascular disease, and it is associated with endothelial dysfunction. Mechanisms responsible for endothelial dysfunction in hyperhomocyst(e)inemia may involve impaired bioavailability of NO, possibly secondary to accumulation of the endogenous NO synthase inhibitor asymmetric dimethylarginine (ADMA) and increased oxidative stress. We investigated whether oral treatment with B vitamins or L-arginine normalizes endothelium-dependent, flow-dependent vasodilation (FDD) in patients with peripheral arterial occlusive disease (PAOD) and hyperhomocyst(e)inemia.
27 patients with PAOD and hyperhomocyst(e)inemia were assigned to oral treatment with combined B vitamins (folate, 10 mg; vitamin B-12, 200 microg; vitamin B-6, 20 mg/day), L-arginine (24 g/day) or placebo, for 8 weeks in a double-blind fashion. FDD was determined by high-resolution ultrasound in the radial artery.
Vitamin B supplementation significantly lowered plasma homocyst(e)ine concentration from 15.8+/-1.8 to 8.7+/-1.1 micromol/l (P<0.01). However, B vitamins had no significant effect on FDD (baseline, 7.8+/-0.7%, B vitamins, 8.3+/-0.9%, placebo 8.9+/-0.7%; P=n.s.). In contrast, L-arginine treatment did not affect homocyst(e)ine levels, but significantly improved FDD (10.2+/-0.2%), probably by antagonizing the impact of elevated ADMA concentration (3.8+/-0.3 micromol/l) and reducing the oxidative stress by lowering urinary 8-iso-prostaglandin F(2alpha) (baseline, 76.3+/-7.1 vs. 62.7+/-8.3 pmol/mmol creatinine after 8 weeks).
Oral supplementation with combined B vitamins during 8 weeks does not improve endothelium-dependent vasodilation in PAOD patients with hyperhomocyst(e)inemia, whereas L-arginine significantly improved endothelial function in these patients. Thus, accumulation of ADMA and increased oxidative stress may underlie endothelial dysfunction under hyperhomocyst(e)inemic conditions. These findings may have importance for evaluation of homocyst(e)ine-lowering therapy.
高同型半胱氨酸血症是动脉粥样硬化性血管疾病的危险因素，且与内皮功能障碍相关。高同型半胱氨酸血症中导致内皮功能障碍的机制可能涉及一氧化氮（NO）生物利用度受损，这可能继发于内源性NO合酶抑制剂不对称二甲基精氨酸（ADMA）的蓄积以及氧化应激增加。我们研究了口服B族维生素或L-精氨酸是否能使外周动脉闭塞性疾病（PAOD）合并高同型半胱氨酸血症患者的内皮依赖性、流量依赖性血管舒张（FDD）恢复正常。
27例PAOD合并高同型半胱氨酸血症患者被随机分配接受口服复合B族维生素（叶酸10mg；维生素B12 200μg；维生素B6 20mg/天）、L-精氨酸（24g/天）或安慰剂治疗，为期8周，采用双盲方式。通过高分辨率超声测定桡动脉的FDD。
补充B族维生素可使血浆同型半胱氨酸浓度从15.8±1.8显著降至8.7±1.1μmol/L（P<0.01）。然而，B族维生素对FDD无显著影响（基线时为7.8±0.7%，B族维生素组为8.3±0.9%，安慰剂组为8.9±0.7%；P无统计学意义）。相比之下，L-精氨酸治疗对同型半胱氨酸水平无影响，但显著改善了FDD（达到10.2±0.2%），这可能是通过拮抗升高的ADMA浓度（3.8±0.3μmol/L）的影响以及通过降低尿8-异前列腺素F2α来减轻氧化应激（基线时为76.3±7.1，8周后为62.7±8.3pmol/mmol肌酐）。
在8周内口服复合B族维生素并不能改善PAOD合并高同型半胱氨酸血症患者的内皮依赖性血管舒张，而L-精氨酸可显著改善这些患者的内皮功能。因此，ADMA的蓄积和氧化应激增加可能是高同型半胱氨酸血症状态下内皮功能障碍的基础。这些发现可能对评估降低同型半胱氨酸的治疗具有重要意义。
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