Comparison of nitric oxide-releasing NSAID and vitamin C with classic NSAID in healing of chronic gastric ulcers; involvement of reactive oxygen species.

Background: Nonsteroidal anti-inflammatory drugs such as aspirin (ASA) are known to induce gastric mucosal damage including bleeding, ulceration and perforation in humans and experimental animals. These adverse effects of ASA were originally attributed to the inhibition of cyclooxygenase and the deficiency of endogenous prostaglandins induced by this drug but the role of reactive oxygen species (ROS), lipid peroxidation and antioxidizing mechanism in the pathogenesis of ASA damage has been little studied. New class of nitric oxide (NO)-releasing nonsteroidal anti-inflammatory drugs was shown to inhibit cyclooxygenase and prostaglandin generation without causing mucosal damage but it remains unknown 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 aspirin applied with or without vitamin C on the healing of acetic acid ulcers. The area of gastric ulcer was determined by planimetry, the gastric blood flow (GBF) at ulcer margin was measured by H2 gas clearance method and mucosal release of ROS was quantified by measuring the chemiluminescence before and after the treatment with ASA or NO-ASA alone and ASA combined with vitamin C. The plasma antiinflammatory cytokine such as IL-1b and oxygen radical-mediated lipid peroxidation was measured in the ulcerated gastric mucosa of ASA and NO-ASA-treated animals.

Results: ASA delayed significantly ulcer healing and this effect was accompanied by a marked increase in the chemiluminescence, lipid peroxidation and the fall in the GBF at ulcer margin. Vitamin C attenuated significantly both the ASA-induced gastric damage and accompanying fall in the GBF at ulcer margin and the rise in the chemiluminescence and reversed the ASA-induced lipid peroxidation. In contrast, NO-ASA failed to affect healing of gastric ulcers and failed to produce the rise in the plasma IL-1b levels and the increase of lipid peroxidation as compared to those recorded in ASA-treated animals.

Conclusions: 1) ROS-induced enhancement in lipid peroxidation plays an important role in the mechanism of gastric damage induced by ASA, 2) vitamin C attenuates the deleterious effect of ASA on ulcer healing due to its antioxidizing activity by mechanism involving preservation of gastric microcirculation and attenuation of lipid peroxidation and cytokine release and 3) coupling of NO to aspirin fails to delay the ulcer healing suggesting that NO might compensate for prostaglandin deficiency induced by NSAID.