Background

Non-steroidal anti-inflammatory drugs (NSAIDs) are a major cause of upper gastro-intestinal (GI) ulceration and bleeding as well as cardiovascular (CV) diseases (e.g., myocardial infarction and stroke). A feature common to both these adverse events is a variety of vascular reactions. One approach to overcome these side effects has been the development of nitric-oxide (NO)-donating NSAIDs. The NO is considered to overcome some of these vascular reactions caused by NSAIDs. Unfortunately, the NO-NSAIDs developed so far have not had the expected benefits compared with NSAIDs alone.

Objectives

Using in vitro preparations it is hoped to gain insight into the vascular and smooth muscle reactions induced by NO-NSAIDs compared with NSAIDs as a basis for improving the protective responses attributed to the NO-donating properties of these drugs.

Methods

A range of NO-NSAIDs was synthesized based on the esterification of NSAIDs with the nitro-butoxylate as a prototype of an NO-donor. These compounds, as well as NO-donor agents and NSAIDS, were examined for their possible effects on isolated segments of digital arteries of fallow deer, which provide a robust model for determining the effects of vasodilator and vasoconstrictor activities, in comparison with those of standard pharmacological agents.

Results

The NO-NSAIDs were found to antagonise the smooth muscle contractions produced by 5-hydroxytryptamine (serotonin, 5-HT). However, while almost all their parent NSAIDs had little or no effect, with the exception of the R-(−)-isomers of both ibuprofen and flurbiprofen, which caused vasodilatation, all the NO-NSAIDs tested antagonised the increase in tension produced by 5-HT.

Conclusions

R-(−)-ibuprofen and R-(−)-flurbiprofen, along with the nitro-butoxyl esters of the NSAIDs examined, produce relaxation of segments of deer digital artery smooth muscle in vitro. The evidence presented suggests that their mechanism involves the release of NO or its products.

中文翻译：

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与母体化合物相比，非甾体抗炎药的硝基丁氧基酯和丁酯对小鹿（Dama dama）指动脉平滑肌收缩力的影响

背景

非甾体抗炎药 (NSAID) 是上消化道 (GI) 溃疡和出血以及心血管 (CV) 疾病（例如心肌梗塞和中风）的主要原因。这两种不良事件的共同特征是各种血管反应。克服这些副作用的一种方法是开发提供一氧化氮 (NO) 的非甾体抗炎药。NO被认为可以克服由非甾体抗炎药引起的一些血管反应。不幸的是，与单独使用非甾体抗炎药相比，迄今为止开发的非非甾体抗炎药并没有预期的好处。

目标

使用体外制剂，希望深入了解 NO-NSAID 与 NSAID 相比诱导的血管和平滑肌反应，以此作为改善归因于这些药物的 NO 供体特性的保护反应的基础。

方法

基于 NSAIDs 与作为 NO 供体原型的硝基丁氧基化物的酯化反应，合成了一系列 NO-NSAIDs。研究了这些化合物以及 NO 供体剂和 NSAIDS 对小鹿指状动脉孤立段的可能影响，与标准相比，这为确定血管扩张剂和血管收缩剂活动的影响提供了一个稳健的模型药剂。

结果

发现 NO-NSAID 可拮抗由 5-羟色胺（5-羟色胺，5-HT）产生的平滑肌收缩。然而，尽管几乎所有的母体 NSAID 几乎没有或没有效果，除了布洛芬和氟比洛芬的 R-(-)-异构体引起血管舒张外，所有测试的 NO-NSAID 都拮抗了由 5 产生的张力增加。 -H T。

结论

R-(-)-布洛芬和 R-(-)-氟比洛芬，连同所检查的 NSAID 的硝基丁氧基酯，在体外产生鹿指动脉平滑肌节段的松弛。所提供的证据表明，它们的机制涉及 NO 或其产物的释放。