title: Gastric preconditioning induced by short ischemia: the role of prostaglandins, nitric oxide and adenosine.
abstract: BACKGROUND
  Various organs including heart, kidneys, liver or brain respond to brief exposures to ischemia with an increased resistance to severe ischemia and this phenomenon is called 'preconditioning'. No study so for has been undertaken to check whether such short, repeated gastric ischemic episodes protect gastric mucosa against the damage caused by subsequent prolonged ischemia-reperfusion or necrotizing substances.
  
  
  METHODS
  In this study, cyclooxygenase (COX)-1, COX-2, nitric oxide (NO) and adenosine receptors inhibitors were used to determine the possible involvement of endogenous prostaglandin, NO and adenosine in the mechanism of gastric preconditioning. This ischemic preconditioning was induced by short episodes of occlusion of celiac artery from 1 to 5 times, for 5 min each applied 30 min before prolonged (30 min) ischemia followed by 3 h of reperfusion (I/R) or 30 min before topical application 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 flow and PGE2 generation. Short (5 min) ischemic episodes even induced several times (1-5 times) by itself failed to cause any gastric lesions but significantly attenuated those produced by I/R and this protective effect 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 was accompanied by a reversal of the fall in the gastric blood flow and PGE2 generation and resembled those induced by classic gastric mild irritants such as 20% ethanol, 5% NaCl and 5 mM taurocholate. These protective and hyperemic effects of standard preconditioning, lasted up to 6-8 h, and were significantly attenuated by 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 significantly that in preconditioned gastric mucosa. Non-specific COX-inhibitor indomethacin (5 mg/kg i.p.), that suppressed the 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 GBF induced by standard preconditioning and these effects were restored by addition of 16,16 dm PGE2 (1 Kg/kg i.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 the gastric blood flow with the extent similar to that observed with standard ischemic preconditioning, while an antagonist of adenosine receptors, 8-phenyl theophylline (SPT, 10 mg/kg i.g.) attenuated significantly the gastroprotection afforded by the preconditioning. Gene expression of COX-1 but not COX-2 was detected by 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 preconditioning represents one of the most powerful protective intervention against the mucosal damage induced by severe I/R as well as by topical mucosal irritants in the stomach; 2) this protection, involving several mediators such as PG derived from COX-1 and COX-2, NO originating from NO-synthase and adenosine, appear to play a key mechanism of gastric ischemic preconditioning.
authors: Department of Physiology, Jagiellonian University School of Medicine, Cracow, Poland. mpogonow@cyf-kr.edu.pl
authors: S J
authors: SJ
authors: Konturek
authors: T
authors: T
authors: Brzozowski
authors: R
authors: R
authors: Pajdo
authors: P C
authors: PC
authors: Konturek
authors: S
authors: S
authors: Kwiecień
authors: Z
authors: Z
authors: Sliwowski
authors: M
authors: M
authors: Pawlik
authors: A
authors: A
authors: Ptak
authors: D
authors: D
authors: Drozdowicz
authors: E G
authors: EG
authors: Hahn
mesh_terms: D000241:Adenosine / Q000502:physiology*; D000818:Animals; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000096:biosynthesis; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005753:Gastric Mucosa / Q000201:enzymology; D007511:Ischemia / Q000503:physiopathology*; D019194:Ischemic Preconditioning; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D019335:Nitroarginine / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics / Q000378:metabolism; D011453:Prostaglandins / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D012039:Regional Blood Flow; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013270:Stomach / Q000098:blood supply* / Q000187:drug effects; D013806:Theophylline / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D011453:Prostaglandins; D012333:RNA, Messenger; D019335:Nitroarginine; D009569:Nitric Oxide; D013806:Theophylline; C028322:8-phenyltheophylline; D019001:Nitric Oxide Synthase; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C496513:Ptgs1 protein, rat; D000241:Adenosine; D015232:Dinoprostone