985 Induced β-Pix Signaling by Polyamines Activates RAC1 and Stimulates Epithelial Restitution After Wounding

Abstract

BACKGROUND/AIM: Though antisecretory drugs such as histamine H2-receptor antagonists (H2-RAs) and proton pump inhibitors (PPIs) are commonly used for the treatment of upper gastrointestinal mucosal lesions induced by NSAIDs, it has recently been reported that these drugs exacerbated small intestinal lesions induced by NSAIDs in rats. However, there are few effective agents for the treatment of this complication. We examined the effect of various mucosal protective agents (MPAs) and mucin (MUC) on NSAID-induced intestinal lesions and the exacerbation of intestinal lesions caused by antisecretory drugs. Effect of drugs on intestinal motility was also examined. METHODS: Male Wistar rats (180-220 g, 7 rats/ group) were treated with diclofenac Na (DIC) with or without ranitidine (RAN) or omeprazole (OPZ) concomitantly. RAN or OPZ was administered p.o. 30 min before DIC. Each of MPAs (misoprostol, MIS; irsogladine, IRS; rebamipide, REB) and MUC was administered p.o. 30 min before RAN or OPZ. Intestinal lesions were examined 24 h after DIC administration. Intestinal motility was measured by using a balloon method under urethane anesthesia. RESULTS: 1) DIC (10 mg/kg, p.o.) produced many lesions in the middle and lower parts of the small intestine. The lesion index (LI, total length of individual lesions) in the vehicletreated group was 100.6±10.8 mm. Both MPAs (MIS: 0.03-0.3 mg/kg, IRS: 1-10 mg/kg, and REB: 30-300mg/kg) andMUC (30-300mg/kg) dose-dependently inhibited the formation of lesions. 2) Lower dose of DIC (3 mg/kg) or RAN (30 mg/kg) alone did not cause significant lesions in the small intestine, but marked lesions were observed following co-administration of RAN and DIC; the LI was 92.0±12.0 mm (P,0.001). The increase of lesions was prevented by the MPAs and MUC dose-dependently. 3) DIC (6 mg/kg) caused mild lesions in the small intestine, the LI in the vehicle-treated group was 38.3±4.5 mm. OPZ (100 mg/kg) did not cause lesions in the small intestine, but significantly increased the lesions caused by DIC; the LI was 78.5±10.9 mm (P,0.001). The increase of lesions was inhibited by the MPAs and MUC dose-dependently. 4) DIC (3-30 mg/kg, s.c.) increased the ileal motility dose-dependently. The increase of motility was inhibited by s.c. administration of MIS (0.1 mg/kg) and atropine (10 mg/kg), but was not affected by IRS (10 mg/kg) and REB (300 mg/kg). CONCLUSIONS: 1) Both RAN andOPZ enhanced the intestinal lesions caused by low (clinical) doses of DIC, supporting the previous findings that antisecretory drugs exacerbated intestinal lesions induced by NSAIDs; 2) MPAs as well as MUC prevented the formation of intestinal lesions induced by DIC alone and inhibited the exacerbation of intestinal lesions by RAN and OPZ, suggesting the usefulness of MPAs for the treatment of NSAID-induced small intestinal lesions with or without antisecretory drugs.