Digestive Diseases and Sciences, Vol. 50, No. 9 (September 2005), pp. 1632–1640 ( C  2005) DOI: 10.1007/s10620-005-2908-y Nitro-Arginine Methyl Ester, a Non-Selective Inhibitor of Nitric Oxide Synthase Reduces Ibuprofen-Induced Gastric Mucosal Injury in the Rat PREMILA ABRAHAM, PhD,* INDIRANI K, PhD,† and DESIGAMANI K, MSc* Ibuprofen is a commonly used non-steroidal anti-inflammatory drug. Gastrointestinal adverse drug reactions from ibuprofen usage include gastric mucosal ulcers and bleeding. The mechanism by which ibuprofen induces gastric mucosal damage is not clear. The present study is an attempt to examine the role of nitric oxide in the pathogenesis of ibuprofen-induced gastric mucosal damage. Ibuprofen administered orally at the dose of 100 mg/kg body weight for 6 days to the rats resulted in gastric mucosal injury. Serum nitrite and nitrosothiol were increased significantly as compared with the controls, which were treated with the vehicle alone. In the gastric mucosa, lipid peroxidation and protein thiols were increased, and the activity of glyceraldehyde 3-phosphate dehydrogenase, a nitric oxide sensitive enzyme was decreased significantly. Pretreatment of the rats daily with nitric oxide synthase inhibitor, nitro-arginine methyl ester (30 mg/kg body weight) 1 hr before treatment with ibuprofen reduced the gastric mucosal injury. Biochemically, it prevented the rise in serum nitrite levels and the increase in lipid peroxidation and protein thiol levels and the loss of glyceraldehyde 3-phosphate dehydrogenase activity in the gastric mucosa. The results of the present study suggest that increased nitric oxide production may be one of the mechanisms by which ibuprofen produces gastric mucosal injury and that inhibition of nitric oxide synthase reduces gastric mucosal injury. KEY WORDS: ibuprofen; gastric mucosal injury; nitric oxide synthase; nitro-arginine methyl ester. Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used in the treatment of osteoarthiritis and rheuma- toid arthritis. Ibuprofen is a commonly used over-the- counter NSAID to treat pains of different origin. However, long-term use of this drug is limited by a high incidence of untoward effect on the gastrointestinal tract. Ibupro- fen produces gastric mucosal ulcer and bleeding in hu- mans (1–4) as well as experimental animals (5, 6). The Manuscript received December 01, 2004; accepted January 13, 2004. From the *Department of Biochemistry and †Department of Anatomy, Christian Medical College, Bagayam, Vellore 632002, India. Address for reprint requests: Premila Abraham, PhD, Christian Medical College, Bagayam, Vellore 632002, India; premilaabraham@ yahoo.com. mechanism by which ibuprofen produces gastric mucosal damage is not clear. Nitric oxide produced from L-arginine by nitric oxide synthase (NOS), under physiological condition plays role in maintaining mucosal integrity (7), blood flow (8) and gastrointestinal motility (9). Nitric oxide synthase is present in the gastric mucosa and blood vessel (10). How- ever, excessive production of nitric oxide has been shown to damage gastrointestinal tissues including mucosa and vasculature (11, 12). We hypothesise that gastric mucosal damage induced by ibuprofen may be mediated via increased production of nitric oxide. Free nitric oxide is highly reactive and unstable. Therefore it is difficult to measure nitric oxide. Nitric oxide reacts with oxygen to form nitrite and nitrate 1632 Digestive Diseases and Sciences, Vol. 50, No. 9 (September 2005) 0163-2116/05/0900-1632/0 C  2005 Springer Science+Business Media, Inc.