Comparison of nitric oxide-releasing NSAID and vitamin C with classic NSAIDin healing of chronic gastric ulcers; involvement of reactive oxygen species.
Tomasz Brzozowski, Sławomir Kwiecień, Peter Christopher Konturek, Agata Ptak, Stanisław J Konturek, Małgorzata Mitis-Musiol, Aleksandra Duda, Władysław Bielański, Eckhart Georg Hahn
Med Sci Monit 2001; 7(4): BR592-599
BACKGROUND: Nonsteroidal anti-inflammatory drugs such as aspirin (ASA)are known to induce gastric mucosal damage including bleeding, ulceration and perforation in humans andexperimental animals. These adverse effects of ASA were originally attributed to the inhibition of cyclooxygenaseand the deficiency of endogenous prostaglandins induced by this drug but the role of reactive oxygenspecies (ROS), lipid peroxidation and antioxidizing mechanism in the pathogenesis of ASA damage has beenlittle studied. New class of nitric oxide (NO)-releasing nonsteroidal anti-inflammatory drugs was shownto inhibit cyclooxygenase and prostaglandin generation without causing mucosal damage but it remainsunknown whether these agents affect the healing process of chronic gastric ulcers. MATERIAL AND METHODS:In this study the effect of NO-releasing aspirin (NO-ASA) and was compared with that of native aspirinapplied with or without vitamin C on the healing of acetic acid ulcers. The area of gastric ulcer wasdetermined by planimetry, the gastric blood flow (GBF) at ulcer margin was measured by H2 gas clearancemethod and mucosal release of ROS was quantified by measuring the chemiluminescence before and afterthe treatment with ASA or NO-ASA alone and ASA combined with vitamin C. The plasma antiinflammatory cytokinesuch as IL-1b and oxygen radical-mediated lipid peroxidation was measured in the ulcerated gastric mucosaof ASA and NO-ASA-treated animals. RESULTS: ASA delayed significantly ulcer healing and this effect wasaccompanied by a marked increase in the chemiluminescence, lipid peroxidation and the fall in the GBFat ulcer margin. Vitamin C attenuated significantly both the ASA-induced gastric damage and accompanyingfall in the GBF at ulcer margin and the rise in the chemiluminescence and reversed the ASA-induced lipidperoxidation. In contrast, NO-ASA failed to affect healing of gastric ulcers and failed to produce therise in the plasma IL-1b levels and the increase of lipid peroxidation as compared to those recordedin ASA-treated animals. CONCLUSIONS: 1) ROS-induced enhancement in lipid peroxidation plays an importantrole in the mechanism of gastric damage induced by ASA, 2) vitamin C attenuates the deleterious effectof ASA on ulcer healing due to its antioxidizing activity by mechanism involving preservation of gastricmicrocirculation and attenuation of lipid peroxidation and cytokine release and 3) coupling of NO toaspirin fails to delay the ulcer healing suggesting that NO might compensate for prostaglandin deficiencyinduced by NSAID.
Keywords: Aspirin, Nitric Oxide, Ascorbic Acid, Vitamin C, Lipid Peroxidation, free oxygen metabolites, gastric blood flow, ulcer healing