EFFECTS OF CYCLOOXYGENASE-2 SELECTIVE AND NITRIC OXIDE-RELEASING NONSTEROIDAL ANTIINFLAMMATORY DRUGS ON MUCOSAL ULCEROGENIC AND HEALING RESPONSES OF THE STOMACH

Effects of selective cyclooxygenase-2 (COX-2) inhibitors (NS-398) and nitric oxide (NO) -releasing aspirin (NO-ASA) on gastric ulcerogenic a nd healing responses were examined in comparison with nonselective COX inhibitors such as indomethacin and aspirin (ASA). Hypothermic stress (28-30 degrees C, 4 hr) induced gastric lesions in anesthetized rats with an increase of acid secretion. The lesions induced by hypothermic stress were markedly worsened by subcutaneous administration of both indomethacin and ASA but were not affected by either NS-398 or NO-ASA, although the increased acid secretion during hypothermia was not affe cted by any of the drugs. On the other hand, the healing of gastric ul cers induced in mice by thermal cauterization (70 degrees C, 15 sec) w as significantly delayed by daily subcutaneous administration of indom ethacin and ASA as well as NS-398, but not by NO-ASA, COX-2 mRNA was n ot detected in the intact mucosa but was positively expressed in the u lcerated mucosa, most potently on day 3 after ulceration. Prostaglandi n contents in the intact mouse stomach were reduced by indomethacin, A SA, and NO-ASA, while the increased prostaglandin generation in the ul cerated mucosa was inhibited by all drugs including NS-398. After subc utaneous administration of NO-ASA to pylorus-ligated rats and mice, hi gh amounts of NO, were detected in both the gastric contents and serum . Tn addition, both NS-398 and NO-ASA showed an equipotent antiinflamm atory effect against carrageenan-induced paw edema in rats as compared with indomethacin and ASA. These results suggest that both indomethac in and ASA not only increased the mucosal ulcerogenic response to stre ss but impaired the healing response of gastric ulcers as well. The fo rmer action was due to inhibition of COX-1, while the latter effect wa s accounted for by inhibition of COX-2 and was mimicked by the COX-2-s elective inhibitor NS-398. NO-ASA, although it inhibited both COX-1 an d COX-2 activity, had no deleterious effects on gastric ulcerogenic an d healing responses.