Ischemic preconditioning, the most effective gastroprotective intervention: involvement of prostaglandins, nitric oxide, adenosine and sensory nerves

Various organs, including heart, kidneys, liver or brain, respond to brief exposures to ischemia with an increased resistance to severe ischemia/reper fusion and this phenomenon is called "preconditioning". No study so far has been undertaken to check whether such short, repeated gastric ischemic epi sodes protect gastric mucosa against severe damage caused by subsequent pro longed ischemia/reperfusion and, if so, what could be the mechanism of this phenomenon. The ischemic preconditioning was induced by short episodes of gastric ischemia (occlusion of celiac artery from one to five times, for 5 min each) applied 30 min before prolonged (30 min) ischemia followed by 3 h of reperfusion or 30 min before topical application of strong mucosal irri tants, such as 100% ethanol, 25% NaCl or 80 nim taurocholate. Exposure to r egular 30-min ischemia, followed by 3-h reperfusion, produced numerous seve re gastric lesions and significant fall in the gastric blood flow and prost aglandin E-2 generation. Short (5-min) ischemic episodes (1-5 times) by its elf failed to cause any gastric lesions, but significantly attenuated those produced by ischemia/reperfusion. This protection was accompanied by a rev ersal of the fall in the gastric blood flow and prostaglandin E2 generation and resembled that induced by classic gastric mild irritants. These protec tive and hyperemic effects of standard preconditioning were significantly a ttenuated by pretreatment with cyclooxygenase-2 and cyclooxygenase-1 inhibi tors, such as indomethacin, Vioxx, resveratrol and nitric oxide (NO)-syntha se inhibitor, N-G-nitro-L-arginine (L-NNA). The protective and hyperemic ef fects of standard preconditioning were restored by addition of 16,16 dm pro staglandin E. or L-arginine, a substrate for NO synthase, respectively. Gas troprotective and hyperemic actions of standard ischemic preconditioning we re abolished by pretreatment with capsaicin-inactivating sensory nerves, bu t restored by the administration of exogenous CGRP to capsaicin-treated ani mals. Gene and protein expression of cyclooxygenase-1, but not cyclooxygena se-2, were detected in intact gastric mucosa and in that exposed to ischemi a/reperfusion with or without ischemic preconditioning, whereas cyclooxygen ase-2 was overexpressed only in preconditioned mucosa. We conclude that: (1 ) gastric ischemic preconditioning represents one of the most powerful prot ective interventions against the mucosal damage induced by severe ischemia/ reperfusion as well as by topical mucosal irritants in the stomach; (2) gas tric ischemic preconditioning resembles the protective effect of "mild irri tants" against the damage by necrotizing substances in the stomach acting v ia "adaptive cytoprotection" and involves several mediators, such as prosta glandin derived from cyclooxygenase-1 and cyclooxygenase-2, NO originating from NO synthase and sensory nerves that appear to play a key mechanism of gastric ischemic preconditioning. (C) 2001 Elsevier Science BY. All rights reserved.