Role of gastric acid secretion in progression of acute gastric erosions induced by ischemia-reperfusion into gastric ulcers

Ischemia followed by reperfusion is known to produce gastric lesions due to oxidative stress, but the role of gastric H+ secretion in the formation of this mucosal injury remains unknown. We studied alterations in gastric aci d secretion and gastric histamine content, as well as the expression of his tidine-decarboxylase and interleukin-1 beta during the mucosal recovery fro m ischemia-reperfusion erosions. Gastric secretion was studied in rats (ser ies A) with gastric fistula before, during and after the ischemia induced b y clamping of celiac artery for 0.5 h followed by reperfusion in animals pr etreated with vehicle (saline), omeprazole, a proton pump inhibitor, or ran itidine, a histamine (H-2) receptor antagonist. In series B, the animals we re submitted to 0.5 h of ischemia followed by 1 h of reperfusion and then a nesthetized at 0, 3, 12 and 24 h or 3, 5, 10 or 15 days after the end of is chemia-reperfusion to determine gastric blood flow by H-2-gas clearance tec hnique, area of gastric lesions. plasma gastrin and interleukin-1 beta leve ls, histamine content by radioimmunoassay (RIA) and expression of histidine -decarboxylase and interleukin-1 beta mRNA by reverse transcription polymer ase chain reaction. Clamping of celiac artery caused cessation of gastric b lood flow and almost complete suppression of basal gastric acid secretion ( series A) that returned gradually to the control value at day 3 after ische mia-reperfusion, accompanied by the rise in plasma gastrin levels, pronounc ed expression of histidine-decarboxylase mRNA and increased mucosal histami ne content. Ischemia, followed by 1 h of reperfusion, produced gastric eros ions (series B) that reached maximum at 12 h, but then declined at 24 h. Th ese erosions progressed at day 3 into deeper ulcers whose area declined pro gressively within the next 5-15 days. The gastric blood ceased to flow (ser ies B) during 30 min of clamping and was reduced throughout the period of h ealing of acute erosions, bring accompanied by a gradual rise in mucosal in terleukin-1 beta mRNA content and in plasma interleukin-1 beta levels. Trea tment with omeprazole or ranitidine. which completely suppressed gastric ac id secretion and significantly raised plasma gastrin level, greatly reduced the formation of erosive lesions preventing nn the progression of these le sions to chronic gastric ulcers, and this was accompanied by the rise in ga stric blood flow and plasma gastrin levels and the significant attenuation of plasma interleukin-1 beta levels. The ranitidine and omeprazole-induced suppression of ischemia-reperfusion erosions were abolished by the instilla tion of exogenous 0.2 N HCl into the stomach of these rats. The histidine-d ecarboxylase was faintly expressed in the intact gastric mucosa, but strong ly upregulated during mucosal recovery from the damage induced by ischemia- reperfusion. We conclude that following ischemia-reperfusion: (1) gastric a cid secretion, gastric microcirculation and histamine production markedly d ecline, while interleukin-1 beta release significantly increases, probably playing an important role in the progression of acute lesions into chronic gastric ulcerations; (2) the suppression of gastric acid secretion by omepr azole and ranitidine, that induces hypergastrinemia, prevents the progressi on of gastric erosions into ulcers; and (3) the addition of exogenous acid restores the progression of the acute lesions into gastric ulcers, indicati ng that gastric acid plays a key role in ulcerogenesis induced by ischemia- reperfusion. (C) 2000 Elsevier Science B.V. All rights reserved.