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The mucosal changes by which duodenogastric reflux may predispose to gastric cancer have not been fully clarified. In this study in rats, duodenal fluid was directed into the stomach through a gastroenterostomy (jejunal reflux, N = 29) or through the pylorus (pyloric reflux, N = 30) and compared with 30 controls. Twenty-four weeks later the stomach was exposed to N-[3H]methyl-N-nitro-N-nitrosoguanidine ([3H]MNNG). The corpus mucosa was examined for proliferating cells (bromodeoxyuridine labeled) and cells at risk of methyl-N-nitro-N-nitrosoguanidine-induced carcinogenesis (cells labeled with bromodeoxyuridine and [3H]MNNG). The number of double-labeled cells increased from 0.8 +/- 0.1/mm mucosa in the control group to 5.2 +/- 0.9 in the jejunal reflux group (P < 0.05) and 2.7 +/- 0.5 in the pyloric reflux group (P < 0.05). An erosion or ulcer appeared at the gastroenterostomy in 52% of animals with jejunal reflux and 17% of those with pyloric reflux (P < 0.006). Within erosions the mean number of double-labeled cells was 9.6 +/- 2.2 in the jejunal reflux group and 7.7 +/- 4.8 in the pyloric reflux group, and significantly higher than in the nonlesion area of the mucosa (0.6 +/- 0.2 and 0.8 +/- 0.3). In erosions the distance between the gastric lumen and the proliferating cells was significantly shorter and the cell proliferation significantly higher than in the nonlesion area of the mucosa. We conclude that duodenogastric reflux increases the penetration of [3H]MNNG into the corpus mucosa of rats and also induces mucosa lesions, which further increase the penetration of [3H]MNNG into the corpus mucosa.

Glutathione plays a role in gastric mucosal protection and the glutathione level is elevated in some forms of gastritis. We studied the relevance of glutathione for the penetration of N-methyl-N-nitro-N-nitrosoguanidine in the glandular mucosa of the stomach. Male Wistar rats were treated with glutathione (0.5 mmol/kg intravenously), N-acetylcysteine (0.5 mmol/kg intravenously), or L-buthionine-[S,R,]-sulfoximine (BSO, 2 mmol/kg intraperitoneally), before the gastric mucosa was exposed to N-[3H]methyl-N-nitro-N-nitrosoguanidine for 10 min. Penetration of the carcinogen was evaluated by light microscopic identification of cells labeled with bromodeoxyuridine and N-[3H]methyl-N-nitro-N-nitrosoguanidine (double-labeled cells). Thiol substances were quantified by reversed-phase ion-pair liquid chromatography and fluorescence detection. The percentage double-labeled cells was higher in antrum mucosa (11.7 +/- 3.1%) than in corpus mucosa (1.1 +/- 0.2%) (P < 0.05). Total glutathione level was 1853 +/- 101 nmol/g in antrum and 1560 +/- 76 nmol/g in corpus mucosa. BSO administration reduced the amount of glutathione in antrum to 495 +/- 14 nmol/g (P < 0.05) and reduced the percentage double-labeled cells in antrum mucosa to 6.1 +/- 1.3% (P < 0.05). A positive correlation was found between the percentage of double-labeled cells in the antrum mucosa and the total amount of glutathione (r = 0.451, P = 0.002), and the amount of reduced glutathione (r = 0.449, P = 0.002). Glutathione modulation effects the penetration of N-[3H]methyl-N-nitro-N-nitrosoguanidine in the antrum but not in the corpus mucosa. Thiols do not explain the different penetration of carcinogen in antrum and corpus mucosa.

Clinical conditions with low gastric acid secretion have been associated with increased risk of gastric cancer. There has also been concern about gastric acid inhibition and N-nitroso compound formation in the stomach. This study investigates the effect of gastric acid secretion on the penetration of N-3H-methyl-N-nitro-N-nitrosoguanidine, an N-nitroso compound and gastric carcinogen, into the gastric mucosa of rats. Gastric acid secretion was stimulated by pentagastrin (40 microg/kg/hr) and inhibited by omeprazole (40 micromol/kg) before mucosal exposure to N-3H-methyl-N-nitro-N-nitrosoguanidine. Penetration of the carcinogen was evaluated by light microscopic identification of cells in the S-phase labeled with N-3H-methyl-N-nitro-N-nitrosoguanidine. This population of double-labeled cells is considered at risk from N-methyl-N-nitro-N-nitrosoguanidine-induced carcinogenesis. The percentage of double-labeled cells was significantly higher in antrum than in corpus mucosa (P < 0.0001). Stimulation or inhibition of gastric acid secretion did not affect the penetration of N-3H-methyl-N-nitro-N-nitrosoguanidine in antrum or corpus mucosa. We conclude that modulation of gastric acid secretion does not affect the penetration of the carcinogen into the gastric mucosa nor does it explain the different penetration of the carcinogen into corpus and antrum mucosa.

Glutathione has been studied as a possible mediator in gastric mucosal protection and healing, but its extracellular function is not fully understood. This study evaluates blood flow changes in normal gastric mucosa secondary to glutathione modulation under stable central hemodynamic conditions. Thiol substances were quantified by reverse-phase ion-pair liquid chromatography and fluorescence detection. Central hemodynamics remained stable when glutathione and N-acetylcysteine were administered in a dose of 0.5 mmol/kg. Higher doses than 0.5 mmol/kg of glutathione and N-acetylcysteine caused unstable hemodynamics. Glutathione (0.5 mmol/kg intravenously) and N-acetylcysteine (0.5 mmol/kg intravenously) reduced corpus mucosal blood flow by 28% and 26% (P < 0.0005), respectively, and glutathione reduced antral mucosa blood flow by 22% (P < 0.01). L-Buthionine-[S,R]-sulfoximine (2 mmol/kg intravenously) did not effect gastric mucosal blood flow. Cysteine content in mucosa and plasma increased while mucosal glutathione levels were largely unchanged after administration of reduced glutathione and N-acetylcysteine. Plasma glutathione only increased after injection of glutathione. L-Buthionine-[S,R]-sulfoximine reduced the glutathione level in both plasma and mucosa. We conclude that glutathione and N-acetylcysteine reduce gastric mucosal blood flow and that the effect may be related to increased cysteine levels in plasma or mucosa.

The effects of intragastric capsaicin and gastric artery ligation on the penetration of the gastric carcinogen N[methyl-3H]-N'-nitro-N-nitrosoguanidine ([3H]MNNG) to proliferative cells were studied in normal and healing rat gastric mucosa. The percentage of S-phase cells labeled with [3H]MNNG in normal corpus mucosa was higher (7.0 +/- 2.0%) after gastric artery ligation than in controls with intact blood flow (2.7 +/- 1.0%) and in animals treated with capsaicin (1.8 +/- 0.5%). Corpus mucosal blood flow was correlated with the percentage of S-phase cells labeled with [3H] MNNG in normal controls and in capsaicin-treated animals. In healing corpus mucosa and in the antrum, capsaicin or gastric artery ligation did not affect carcinogen penetration. We conclude that blood flow protects against penetration of carcinogens to proliferative cells in normal corpus mucosa but not in the antrum. Low mucosal blood flow in the corpus could be a risk factor for initiation of gastric carcinogenesis.

This study was undertaken to examine the role of prostaglandins and histamine in the hyperemic response to gastric mucosal damage followed by H+ back-diffusion. Cat stomachs were exposed to 2 mol/liter NaCl for 10 min followed by luminal perfusion at pH 1. Hypertonic saline caused extensive (microscopic) damage to the surface epithelium, increased gastric mucosal blood flow, and increased release of histamine, PGE2, and 6-keto PGF1 alpha (prostacyclin) into portal venous blood. The effect of indomethacin and histamine blockers (H1 + H2) on the hyperemic response to acid back-diffusion was related to the depth of the mucosal injury and the region of the stomach. In the corpus, indomethacin enhanced mucosal injury. In areas with superficial damage, the hyperemia was inhibited by indomethacin and antihistamines and eliminated by the combination of both. In corpus areas with indomethacin-induced deep lesions, the blood flow was very high, and this hyperemia was partly inhibited by antihistamines. In the antrum the hyperemic response was reduced by antihistamines. Indomethacin increased the release of histamine into portal venous blood (baseline recordings) and reduced basal gastric mucosal blood flow.

In this study we tested the influence of blood flow and the mucoid cap on the penetration of carcinogens to the proliferative cells in the injures rat gastric mucosa. Ten minutes after mucosal exposure to 4.5 mol/liter NaCl, N-[3H]methyl-N'-nitro-N-nitrosoguanidine was instilled intragastrically. Hypertonic saline caused superficial mucosal damage, formation of a mucoid cap, high gastric mucosal blood flow, and a large flux of fluid into the gastric lumen. The mean percentage of S-phase cells labeled with carcinogen (the cell population at risk for N-methyl-N'nitro-N-nitrosoguanidine-induced carcinogenesis) in the antrum and corpus was 0.2 and 0.2, respectively, in the injury control group, 10.1 and 2.0 after removal of the mucoid cap, 1.5 and 9.8 after celiac artery ligation, and 28.2 and 21.9 after removal of the mucoid cap and celiac artery ligation. These results show that both the mucoid cap and gastric mucosal blood flow protect against penetration of carcinogens into the superficially injured gastric mucosa.

Dimethyl sulfoxide applied intragastrically for 10 min in rats caused extensive mucosal damage. In concentrations of 5%, 10%, or 100%, dimethyl sulfoxide caused superficial damage to 33%, 36%, and 97%, respectively, of the corpus mucosa, and 28%, 44%, and 96%, respectively, of the antral mucosa. Concentrated dimethyl sulfoxide also caused damage to the pits and glands in some areas of the mucosa. The amount of fluid in the stomach increased by 0.24 ml, 0.48 ml, and 2.07 ml during application of 5%, 10%, and 100% dimethyl sulfoxide. The 10% dimethyl sulfoxide increased mucosal blood flow by 0.57 ml/min/g in the antrum, and 100% dimethyl sulfoxide increased mucosal blood flow by 2.21 ml/min/g in the antrum and by 1.17 ml/min/g in the corpus. We conclude that dimethyl sulfoxide is a gastric irritant, which should be considered when it is used as an oxygen radical scavenger, as a drug or carcinogen vehicle, or as oral medication in patients. The protective effect of intragastric dimethyl sulfoxide against stress and various drug-induced gastric injury may be due to "adaptive cytoprotection" rather than an oxyradical scavenger effect.