Abstract. – BACKGROUND AND OBJECTIVES: The present study was conducted to investigate the possible gastroprotective effect of sildenafil citrate, a selective inhibitor of cyclic guanosine monophosphate-specific phosphodiesterase, against indomethacin-induced gastric damage in rats. Further, the study was extended to investi- gate some possible mechanisms underlying this effect. MATERIALS AND METHODS: Forty rats were assigned to vehicle (saline), control (indomethacin, 30 mg/kg, p.o.), ranitidine (50 mg/kg, p.o.), silde- nafil (5 mg/kg, p.o.) and sildenafil (10 mg/kg, p.o.); the drugs were administered 30 minutes prior to indomethacin. Four hours after indomethacin ad- ministration, all rats were sacrificed and the gastric juices were collected. Then, each stomach was opened and macroscopically examined for gastric lesions and longitudinal sections were used for biochemical and histopathological analysis. RESULTS: Our results indicated that indome- thacin induced marked ulceration in the gastric mu- cosa, in addition to an increase in gastric acidity as compared to saline group (p ≤ 0.05). Further- more, indomethacin group showed lower concen- tration of mucin and reduced glutathione, whereas, lipid peroxides and tumor necrosis factor-α (TNF- α) were elevated in the stomach homogenate. Pre- treatment with sildenafil (5 mg/kg) significantly re- duced gastric acid secretion, ulcer score and lipid peroxides production without effect on mucin, TNF-α, or nitric oxide (NO). The higher dose of sildenafil (10 mg/kg) provided similar results with the exception of increasing tissue NO (p ≤ 0.05). CONCLUSIONS: We concluded that sildenafil can protect the gastric mucosa against the ag- gressive effect of indomethacin via increasing NO and inhibiting lipid peroxidation. Therefore, sildenafil might be helpful in preventing the gas- tric adverse effects of non-steroidal anti-inflam- matory drugs in a clinical setting. Key Words: Mucosal damage, Indomethacin, Sildenafil citrate, Ranitidine, Rats. Abbreviations cAMP = cyclic adenine monophosphate European Review for Medical and Pharmacological Sciences Sildenafil citrate protects against gastric mucosal damage induced by indomethacin in rats Y.M. MOUSTAFA, D.M. KHODER, E.E. EL-AWADY, S.A. ZAITONE Department of Pharmacology & Toxicology, Faculty of Pharmacy, Suez Canal University, Ismailia, Egypt Corresponding Author: Sawsan A. Zaitone, MD; e-mail: sawsan_zaytoon@pharm.suez.edu.eg 179 cGMP = cyclic guanosine monophosphate cNOS = constitutive nitric oxide synthase COX = cyclooxygenase GSH = reduced glutathione IL = interleukin iNOS = inducible nitric oxide synthase KATP = ATP sensitive potassium channel L-NAME = N (G)-nitro-L-arginine methyl ester LP = lipid peroxides NO = nitric oxide NSAIDs = nonsteroidal anti-inflammatory drugs ODQ = 1H-[1,2,4] oxadiazolo[4,3-a]quinoxalin-1-one PDE = phosphodiesterase PG = prostaglandins ROS = reactive oxygen species sGC = soluble guanylate cyclase TNF-α = tumor necrosis factor-α Introduction Gastric ulcers associated with the use of non- steroidal anti-inflammatory drugs (NSAIDs) re- main a major clinical problem and considered to cause a substantial socioeconomic burden and negatively impacts the quality of life 1 . NSAIDs are known to be aggressive agents and cause damage in the gastric mucosa. Although the in- hibition of cyclooxygenase (COX), which leads to depletion of endogenous prostaglandins (PGs), is a major pathogenic factor, it is unlike- ly that PG deficiency alone is sufficient to initi- ate the process that ultimately results in gastric ulceration 2 . Evidence has been produced that leukocyte adherence to the vascular endotheli- um 3 , superoxide radicals and protease liberation may be relevant pathogenic mechanisms in NSAIDs gastropathy 4 . In addition, diminished mucosal circulation has been blamed as one of the etiological factors in gastric ulcer formation. Like PGs, the L-argi- nine/nitric oxide (NO) pathway is a major protec- tive system in gastric mucosa 5 via relaxation of the arterial smooth muscles. Accumulating evi- 2013; 17: 179-188