Chemical synthesis and microvascular effects of new nitric oxide donors in humans.
Chemical synthesis and microvascular effects of new nitric oxide donors in humans.
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人类新一氧化氮供体的化学合成和微血管效应。
DOI：
10.1042/cs20030144
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发表时间：
2003
期刊：
影响因子：
6
通讯作者：
A. Butler
中科院分区：
文献类型：
--
作者：
F. Khan;R. Pearson;D. Newton;J. Belch;A. Butler
一氧化氮(NO)是由血管内皮细胞持续产生的一种物质，在调节血管张力中起着关键作用。目前许多通过产生NO来增加血流量的治疗药物都必须口服，而且可能会产生严重的副作用。我们现在报道一些新的非供体药物，基于自发产生NO的硫糖。从合成的化合物范围来看，D-SNAG(S-亚硝基-1-硫代-2，3，4，6-四-O-乙酰基-β-D-吡喃葡萄糖苷)是与其他化合物一样有效的血管扩张剂，而且由于它是最容易合成的，所以我们进行了更详细的评价，以了解其血管扩张作用的化学和作用方式。从化学动力学数据中我们发现，NO的释放主要是通过热分解发生的，在19-37℃之间，分解速率增加了20倍。在8名正常男性受试者的前臂上，我们发现D-SNAG产生了显著的剂量依赖的血管扩张效应(P=0.001)，重复测试的重复性良好(19%)。我们认为，NO从D-SNAG到前臂皮肤微血管的传递很可能是通过跨表皮扩散发生的。由于这些化合物在局部应用后以非酶的方式释放NO，它们可能会产生一种有吸引力的局部NO释放的治疗来源，而不会引起全身副作用。
Nitric oxide (NO) is produced continuously from the endothelium and plays a pivotal role in the control of vascular tone. Many of the current therapeutic agents that increase blood flow through production of NO have to be taken orally and can produce significant adverse side effects. We now report on some novel NO-donor drugs, based on thiosugars that generate NO spontaneously. From the range of compounds synthesized, D-SNAG ( S -nitroso-1-thio-2,3,4,6-tetra- O -acetyl-beta-D-glucopyranose) was as effective a vasodilator as any other and, as it was the easiest to synthesize, we undertook a more detailed evaluation to understand the chemistry and mode of action of its vasodilator effect. From the chemical kinetic data, we found that NO release occurred predominantly by thermal decomposition, with a 20-fold increase in decomposition rate between 19 and 37 degrees C. In the forearm of eight normal male subjects, we found that D-SNAG produced a significant dose-dependent vasodilator effect ( P =0.001) with good reproducibility (19%) on repeated testing. We propose that delivery of NO from D-SNAG to the forearm skin microvessels most probably occurs by diffusion across the epidermis. Since such compounds release NO in a non-enzymic manner following topical application, they might produce an attractive therapeutic source of localized NO delivery without inducing systemic side effects.
DOI：
10.1073/pnas.95.24.14100
发表时间：
1998-11-24
影响因子：
11.1
作者：
Hausladen, A;Gow, AJ;Stamler, JS
通讯作者：
Stamler, JS