THIOL-MEDIATED GENERATION OF NITRIC-OXIDE ACCOUNTS FOR THE VASODILATOR ACTION OF FUROXANS
THIOL-MEDIATED GENERATION OF NITRIC-OXIDE ACCOUNTS FOR THE VASODILATOR ACTION OF FUROXANS
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DOI：
10.1016/0006-2952(92)90379-w
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发表时间：
1992-09-25
影响因子：
5.8
通讯作者：
NOACK, E
中科院分区：
文献类型：
--
作者：
FEELISCH, M;SCHONAFINGER, K;NOACK, E
呋咱（1，2，5-恶二唑-2-氧化物）作为合成各种杂环化合物的中间体广泛应用于有机化学中。尽管一些氧化呋咱已被发现具有显著的生物活性。迄今为止，还没有关于其作用方式的系统研究报道。本研究的目的是探讨氧化呋咱类药物的扩血管作用的分子模式。在离体工作大鼠心脏制备中，呋咱（而非相应的呋咱）浓度依赖性增加冠状动脉流量。这种作用在与亚甲蓝共输注后减弱。所有测试的氧化呋咱都被证明能有效地增加可溶性鸟苷酸环化酶的活性。酶的刺激被认为是介导的生成一氧化氮（NO）的氧化呋咱与巯基基团的低分子量硫醇和蛋白质的化学反应。因此，呋咱是通过形成NO增加环GMP水平的前药，因此可归类为硝基血管扩张剂。沿着NO的生成，亚硝酸根和硝酸根离子以及S-亚硝基硫醇也随之生成。然而，这些代谢产物的形成速率似乎与酶刺激无关。提出了一个符合实验数据的初步反应方案。最近报道的细胞毒性，致突变性，免疫抑制和抗癌作用的氧化呋咱进行了讨论，根据他们的能力，释放NO反应后与硫醇。
Furoxans (1,2,5-oxadiazole-2-oxides) are widely used in organic chemistry as intermediate compounds for the synthesis of various heterocycles. Despite the fact that some furoxans have been found to possess remarkable biological activities. up to now no systematic study on their mode of action has been reported. The aim of the present study was to investigate the molecular mode of the vasodilator action of furoxans. Furoxans, but not the corresponding furazans, concentration-dependently increased coronary flow in an isolated working rat heart preparation. This effect was blunted upon coinfusion with methylene blue. All tested furoxans were demonstrated to increase potently the activity of soluble guanylate cyclase. Enzyme stimulation was found to be mediated by the generation of nitric oxide (NO) following chemical reaction of the furoxans with sulfhydryl groups of low molecular weight thiols and proteins. Furoxans are thus prodrugs which increase the level of cyclic GMP via formation of NO and may therefore be classified as nitrovasodilators. Along with the generation of NO, nitrite and nitrate ions and S-nitrosothiols were formed. The rates of formation of these metabolites, however, did not appear to be related to enzyme stimulation. A tentative reaction scheme that fits the obtained experimental data is proposed. Recently reported cytotoxic, mutagenic, immunosuppressive and anticancer effects of furoxans are discussed in the light of their ability to release NO upon reaction with thiols.