Coruzzi G, Adami M, Morini G, Pozzoli C, Cena C, Bertinaria M, Gasco A
Institute of Pharmacology, University of Parma, Italy.
J Physiol Paris. 2000 Jan-Feb;94(1):5-10. doi: 10.1016/s0928-4257(99)00109-6.
In spite of the well recognized gastric antisecretory activity, the gastroprotective potential of histamine H2 receptor antagonists is controversial. Most clinical studies in fact indicate that these drugs do not substantially protect the gastric mucosa from aggressive factors. Nitric oxide (NO) has been recently recognized as a fundamental mediator in gastric defence mechanisms, due to its ability to increase gastric mucosal blood flow and mucus production and to inhibit neutrophils adherence to endothelial cells. The aim of this study was to investigate the gastroprotective and H2 receptor antagonistic activity of a series of lamtidine analogues which contain different NO-releasing moieties (furoxan, nitroxy and nitrosothiol). These compounds were tested, in comparison with related H2 antagonists devoid of NO-donor structures, in different H2 receptor assays and in the conscious rat against 0.6 N HCl-induced gastric lesions. All the compounds tested were able to antagonize histamine-mediated responses at cardiac and gastric H2 receptors; however, furoxan and nitroxy derivatives were 10-fold less potent than the analogues devoid of NO-donor properties. By contrast, NO-donor compounds were more active than reference H2 antagonists as gastroprotective agents against mucosal injury induced by 0.6 N HCl. Among the different NO-donor moieties, the furoxan group conferred to the H2 antagonist molecule the highest gastroprotective potential; this finding closely correlates with the characteristics of NO release. In conclusions, lamtidine-analogue H2 antagonists combined with NO-donor moieties are endowed with gastric antisecretory and protective activity and could be the prototypes of a new class of anti-ulcer drugs. Finally, the furoxan NO donor group seems to be the most favourable among the different moieties tested.
尽管组胺H2受体拮抗剂具有公认的胃抗分泌活性，但其胃保护潜力仍存在争议。事实上，大多数临床研究表明，这些药物并不能实质性地保护胃黏膜免受攻击因子的侵害。一氧化氮（NO）最近被认为是胃防御机制中的一种重要介质，因为它能够增加胃黏膜血流量和黏液分泌，并抑制中性粒细胞与内皮细胞的黏附。本研究的目的是研究一系列含有不同NO释放基团（呋咱、硝氧基和亚硝基硫醇）的雷尼替丁类似物的胃保护和H2受体拮抗活性。与不含NO供体结构的相关H2拮抗剂相比，这些化合物在不同的H2受体试验中以及在清醒大鼠中针对0.6N HCl诱导的胃损伤进行了测试。所有测试的化合物都能够拮抗组胺介导的心脏和胃H2受体反应；然而，呋咱和硝氧基衍生物的效力比不含NO供体特性的类似物低10倍。相比之下，作为针对0.6N HCl诱导的黏膜损伤的胃保护剂，NO供体化合物比参考H2拮抗剂更具活性。在不同的NO供体基团中，呋咱基团赋予H2拮抗剂分子最高的胃保护潜力；这一发现与NO释放的特性密切相关。总之，与NO供体基团结合的雷尼替丁类似物H2拮抗剂具有胃抗分泌和保护活性，可能成为一类新型抗溃疡药物的原型。最后，在测试的不同基团中，呋咱NO供体基团似乎是最有利的。
