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Diethyldithiocarbamate (DDC), an inhibitor of superoxide dismutase, produced ulceration in the proximal duodenum of rats, and erosions or ulcers in the stomach. DDC given s. c. at 1.5 g/kg increased duodenal and gastric vascular permeability, and reduced blood flow. The decrease in gastric blood flow caused by DDC was attenuated by pretreatment with superoxide dismutase, and significantly inhibited by a xanthine oxidase inhibitor, allopurinol. It is suggested that the superoxide and other radicals damage the mucosal vasculature, and play a role in the pathogenesis of gastric and duodenal mucosal lesions.

The interrelationships of core body temperature, blood viscosity, gastric mucosal blood flow, surface pH of the corpus mucosa, and acute gastric mucosal lesions in rats after up to 3 h of hypothermic stress were investigated. Three groups of rats were studied: (a) control rats restrained at room temperature, (b) conscious rats under restraint and varying degrees of hypothermia, and (c) anesthetized rats under hypothermia. Under hypothermic stress both restrained and anesthetized rats manifested a sharp decline in core temperature, a marked increase in blood viscosity with a mirror-image decrease in gastric mucosal blood flow, a significant decline in gastric mucosal surface pH, and similar frequencies and severities of acute gastric mucosal lesions. In the control group, neither mucosal lesions nor changes in physiologic measurements were observed, except for a decline in mucosal surface pH. An increase in blood viscosity identical to that in rats subjected to hypothermia was observed in vitro when blood temperature was lowered in the viscometer. These findings indicate that hypothermia but not restraint led to an increase in blood viscosity, which in turn resulted in a decrease in mucosal blood flow and the development of gastric mucosal lesions. Also, hyperacidity was found to be a permissive factor in the pathogenesis of mucosal lesions.

We studied the effect of plasmin inhibitor on ethanol and ammonia-induced gastric mucosal lesions in rats using an ex vivo chamber. Tranexamic acid and aminocaproic acid significantly inhibited macroscopic gastric hemorrhagic necrosis and attenuated the decrease of gastric transmucosal potential difference induced by 50% ethanol and 1% ammonia. The protection of gastric mucosa afforded by tranexamic acid and aminocaproic acid was not affected by pretreatment with indomethacin (5 mg/kg). These results suggest that plasmin inhibitor plays an important role in the prevention of gastric deep necrosis following exposure of the stomach to a damaging agent.

The effect of necrotizing agents, such as ammonia and ethanol, on the gastric mucosa was compared. Intragastric administration of ammonia (0.6-1.0%) and ethanol (60-100%) produced hemorrhagic necrosis of gastric mucosa in a concentration-dependent manner. In the anesthetized rat, the macroscopic lesions induced by ethanol were significantly inhibited by pretreatment with 3 or 10 micrograms/kg of 16,16-dmPGE2, but the lesions induced by ammonia were not inhibited by either 3 or 10 micrograms/kg of 16,16-dmPGE2 in the anesthetized rat. The decrease of gastric transmucosal potential difference and mucosal blood flow produced by ethanol (100%) were significantly attenuated by 16,16-dmPGE2; however, those produced by ammonia (1%) were not inhibited by 16,16-dmPGE2 in the anesthetized rat. In conscious rats, ammonia-induced lesions were not inhibited by pretreatment with 3 micrograms/kg of 16,16-dmPGE2 but they were significantly reduced by the pretreatment of 10 micrograms/kg of 16,16-dmPGE2. These results show that 16,16-dmPGE2 afforded little protection against ammonia-induced gastric lesions in the anesthetized rat and suggest that a different mechanism is involved in the development of gastric mucosal lesions between those induced by ethanol and those induced by ammonia.

We examined the effect of ammonia on the gastric mucosal barrier by measuring the changes in transmucosal fluxes of H+, Na+ and K+. In rats, ammonia at concentrations of 0.1 to 0.5% increased the H+ loss from the lumen and 0.2 to 0.5% concentrations of ammonia increased both Na+ and K+ influxes into the lumen. In dogs, in an exactly similar manner to rats, ammonia at concentrations of 0.1 to 0.5% increased H+ loss, and ammonia at concentration of 0.5% increased both Na+ and K+ influxes into the lumen. These results suggest that ammonia breaks the gastric mucosal barrier.

We examined the protective effect of plasmin inhibitors on gastric mucosal vascular permeability in rats. Tranexamic acid and aminocaproic acid significantly inhibited the increase in vascular permeability and macroscopic gastric mucosal lesions induced by 50% ethanol and 1% ammonia. The protective effect afforded by plasmin inhibitors was not affected by pretreatment with indomethacin. Our results show that plasmin inhibitors inhibit the increase in gastric vascular permeability and suggest that plasmin may play an important role in the pathogenesis of gastric mucosal damage.

We examined the role of gastric ammonia in the development of gastric lesions in rats. Exposure of the gastric mucosa to ammonia (30 mM) produced microscopic injury, but no macroscopic lesion was observed. However, exposure of the stomach to ammonia in rats subjected to ischemia resulted in macroscopic gastric lesions. The macroscopic lesions were markedly inhibited by pretreatment with taurine, a scavenger of hypochlorous acid (HOCI) and monochloramine (NH2Cl). These results indicate that ammonia is deleterious to gastric mucosa, and monochloramine may be involved in the pathogenesis of ammonia-induced mucosal lesions.

The hydrogen clearance rate of the nucosa of the glandular stomach of the anesthetized rat was obtained with the platinum electrode in contact with the surface of the gastric mucosa (Contact Electrode Method). By using two indicator electrodes, the gastric blood flow was measured simultaneously with one electrode in contact with the mucosal surface (Contact Electrode Method), and with the other electrode inserted into the gastric wall (Inserted Electrode Method). Pentagastrin produced increase in blood flow by both contact and inserted electrode methods. Isoproterenol stimulated blood flow as determined by the contact electrode method, but when the flow was determined by the inserted electrode method it reduced the blood flow. The combination of these two methods is useful in the determination of the blood flow in the different layers of the stomach.

We examined the pathophysiological roles of the urea-urease-ammonia system in gastric ulcer disease using rats. Exposure of the stomach to ammonia (0.01-1.0%) decreased the transmucosal potential difference (PD) and histological injury in a concentration-dependent manner. Exposure of the stomach for 20 min to urea (0.025-0.2%) together with urease (100 IU) produced a decrease in PD and microscopic injury similarly, and the lesion was closely associated with the amount of ammonia produced. Urea and urease alone had no effect on the gastric mucosa. These results suggested the pathophysiological importance of urea, urease and ammonia in gastric ulcer disease.