Clarke Zoe L, Moat Stuart J, Miller Alastair L, Randall Michael D, Lewis Malcolm J, Lang Derek
Wales Heart Research Institute, Wales College of Medicine, Cardiff University, Heath Park Campus, Cardiff, CF14 4XN, United Kingdom.
Eur J Pharmacol. 2006 Dec 3;551(1-3):92-7. doi: 10.1016/j.ejphar.2006.08.085. Epub 2006 Sep 12.
The exact mechanism(s) by which hyperhomocysteinaemia promotes vascular disease remains unclear. Moreover, recent evidence suggests that the beneficial effect of folic acid on endothelial function is independent of homocysteine-lowering. In the present study the effect of a low (400 microg/70 kg/day) and high (5 mg/70 kg/day) dose folic acid supplement on endothelium-dependent relaxation in the isolated perfused mesenteric bed of heterozygous cystathionine beta-synthase deficient mice was investigated. Elevated total plasma homocysteine and impaired relaxation responses to methacholine were observed in heterozygous mice. In the presence of N(G)-nitro-L-arginine methyl ester relaxation responses in wild-type tissues were reduced, but in heterozygous tissues were abolished. Clotrimazole and 18alpha-glycyrrhetinic acid, both inhibitors of non-nitric oxide/non-prostanoid-induced endothelium-dependent relaxation, reduced responses to methacholine in wild-type but not heterozygous tissues. The combination of N(G)-nitro-L-arginine methyl ester and either clotrimazole or 18alpha-glycyrrhetinic acid completely inhibited relaxation responses in wild-type tissues. Both low and high dose folic acid increased plasma folate, reduced total plasma homocysteine and reversed endothelial dysfunction in heterozygous mice. A greater increase in plasma folate in the high dose group was accompanied by a more significant effect on endothelial function. In the presence of N(G)-nitro-L-arginine methyl ester, a significant residual relaxation response was evident in tissues from low and high dose folic acid treated heterozygous mice. These data suggest that the impaired mesenteric relaxation in heterozygous mice is largely due to loss of the non-nitric oxide/non-prostanoid component. While low dose folic acid may restore this response in a homocysteine-dependent manner, the higher dose has an additional effect on nitric oxide-mediated relaxation that would appear to be independent of homocysteine lowering.
高同型半胱氨酸血症促进血管疾病的确切机制仍不清楚。此外，最近的证据表明，叶酸对内皮功能的有益作用独立于降低同型半胱氨酸。在本研究中，研究了低剂量（400微克/70千克/天）和高剂量（5毫克/70千克/天）叶酸补充剂对杂合型胱硫醚β-合酶缺陷小鼠离体灌注肠系膜床中内皮依赖性舒张的影响。杂合型小鼠血浆总同型半胱氨酸升高，对乙酰甲胆碱的舒张反应受损。在存在N（G）-硝基-L-精氨酸甲酯的情况下，野生型组织中的舒张反应降低，但杂合型组织中的舒张反应消失。克霉唑和18α-甘草次酸，这两种非一氧化氮/非前列腺素诱导的内皮依赖性舒张的抑制剂，降低了野生型组织对乙酰甲胆碱的反应，但对杂合型组织没有影响。N（G）-硝基-L-精氨酸甲酯与克霉唑或18α-甘草次酸的组合完全抑制了野生型组织中的舒张反应。低剂量和高剂量叶酸均增加了血浆叶酸，降低了血浆总同型半胱氨酸，并逆转了杂合型小鼠的内皮功能障碍。高剂量组血浆叶酸的更大增加伴随着对内皮功能更显著的影响。在存在N（G）-硝基-L-精氨酸甲酯的情况下，低剂量和高剂量叶酸处理的杂合型小鼠组织中明显存在显著的残余舒张反应。这些数据表明，杂合型小鼠肠系膜舒张受损主要是由于非一氧化氮/非前列腺素成分的丧失。虽然低剂量叶酸可能以同型半胱氨酸依赖性方式恢复这种反应，但高剂量对一氧化氮介导的舒张有额外的作用，这似乎独立于降低同型半胱氨酸。
