Antisecretory and gastroprotective activities of compounds endowed with H-2 antagonistic and nitric oxide (NO) donor properties

In spite of the well recognized gastric antisecretory activity, the gastrop rotective potential of histamine H-2 receptor antagonists is controversial. Most clinical studies in fact indicate that these drugs do not substantial ly protect the gastric mucosa from aggressive factors. Nitric oxide (NO) ha s been recently recognized as a fundamental mediator in gastric defence mec hanisms, due to its ability to increase gastric mucosal blood flow and mucu s production and to inhibit neutrophils adherence to endothelial cells. The aim of this study was to investigate the gastroprotective and H-2 receptor antagonistic activity of a series of lamtidine analogues which contain dif ferent NO-releasing moieties (furoxan, nitroxy and nitrosothioI). These com pounds were tested, in comparison with related H-2 antagonists devoid of NO -donor structures, in different H-2 receptor assays and in the conscious ra t against 0.6 N HCl-induced gastric lesions. All the compounds tested were able to antagonize histamine-mediated responses at cardiac and gastric H-2 receptors; however, furoxan and nitroxy derivatives were 10-fold less poten t than the analogues devoid of NO-donor properties. By contrast, NO-donor c ompounds were more active than reference Il, antagonists as gastroprotectiv e agents against mucosal injury induced by 0.6 N HCl. Among the different N O-donor moieties, the furoxan group conferred to the H-2 antagonist molecul e the highest gastroprotective potential; this finding closely correlates w ith the characteristics of NO release. In conclusions, lamtidine-analogue H -2 antagonists combined with NO-donor moieties are endowed with gastric ant isecretory and protective activity and could be the prototypes of a new cla ss of anti-ulcer drugs. Finally, the furoxan NO donor group seems to be the most favourable among the different moieties tested. (C) 2000 Elsevier Sci ence Ltd. Published by Editions scientifiques et medicales Elsevier SAS.