BACKGROUND: Various organs including heart, kidneys, liver or brain respondto brief exposures to ischemia with an increased resistance to severe ischemia and this phenomenon iscalled 'preconditioning'. No study so for has been undertaken to check whether such short, repeated gastricischemic episodes protect gastric mucosa against the damage caused by subsequent prolonged ischemia-reperfusionor necrotizing substances.
MATERIAL AND METHODS: In this study, cyclooxygenase (COX)-1, COX-2, nitricoxide (NO) and adenosine receptors inhibitors were used to determine the possible involvement of endogenousprostaglandin, NO and adenosine in the mechanism of gastric preconditioning. This ischemic preconditioningwas induced by short episodes of occlusion of celiac artery from 1 to 5 times, for 5 min each applied30 min before prolonged (30 min) ischemia followed by 3 h of reperfusion (I/R) or 30 min before topicalapplication of strong mucosal irritants such as 100% ethanol, 25% NaCl or 80 mM taurocholate.
RESULTS:Exposure to regular I/R produced numerous gastric lesions and significant fall in the gastric blood flowand PGE2 generation. Short (5 min) ischemic episodes even induced several times (1-5 times) by itselffailed to cause any gastric lesions but significantly attenuated those produced by I/R and this protectiveeffect reached maximum with two 5 min ischemic episodes and this preconditioning was considered as standard.The protective effects of standard ischemic preconditioning against gastric lesions induced by I/R wasaccompanied by a reversal of the fall in the gastric blood flow and PGE2 generation and resembled thoseinduced by classic gastric mild irritants such as 20% ethanol, 5% NaCl and 5 mM taurocholate. These protectiveand hyperemic effects of standard preconditioning, lasted up to 6-8 h, and were significantly attenuatedby pretreatment with specific COX-1 and COX-2 inhibitors such as Vioxx (5 mg/kg i.g.) and resveratrol(10 mg/kg i.g.) that failed to affect PGE2 generation in intact gastric mucosa but attenuated significantlythat in preconditioned gastric mucosa. Non-specific COX-inhibitor indomethacin (5 mg/kg i.p.), that suppressedthe PGE2 generation by approximately 90% and non-specific NO synthase inhibitor L-NNA (20 mg/kg i. p.),that significantly suppressed NO production, significantly inhibited the protection and the rise in GBFinduced by standard preconditioning and these effects were restored by addition of 16,16 dm PGE2 (1 Kg/kgi.g.) or L-arginine (200 mg/kg i.g.), a substrate for NO-synthase, to indomethacin or L-NAME, respectively.Pretreatment with adenosine (10 mg/kg i.g.) also reduced the lesions induced by I/R and increased thegastric blood flow with the extent similar to that observed with standard ischemic preconditioning, whilean antagonist of adenosine receptors, 8-phenyl theophylline (SPT, 10 mg/kg i.g.) attenuated significantlythe gastroprotection afforded by the preconditioning. Gene expression of COX-1 but not COX-2 was detectedby RT-PCR in intact gastric mucosa and in that exposed to I/R with or without ischemic preconditioning,whereas COX-2 was overexpressed only in preconditioned mucosa.
CONCLUSIONS: 1) gastric ischemic preconditioningrepresents one of the most powerful protective intervention against the mucosal damage induced by severeI/R as well as by topical mucosal irritants in the stomach; 2) this protection, involving several mediatorssuch as PG derived from COX-1 and COX-2, NO originating from NO-synthase and adenosine, appear to playa key mechanism of gastric ischemic preconditioning.

Keywords: gastric preconditioning, gastroprotection, ischemia-reperfusion, mild irritants, gastric blood flow, Prostaglandins, cyclooxygenase, Nitric Oxide