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The factors that determine which Helicobacter pylori infected subjects develop duodenal ulcer (DU) are unclear. This study tested the hypothesis that infection density and urease activity are higher in DU than non-DU subjects. Fifty five DU and 55 age and sex matched non-DU subjects were studied. Quantitative methods were used for measuring infection density (viable organism count) and urease activity (Berthelot reaction). DU subjects had a greater antral infection density (geometric mean of colony forming units/mg biopsy protein; 10.5 x 10(5) v 1.3 x 10(5), p < 0.001). They also had higher biopsy urease activity (geometric mean of NH3 nmol/min-1/mg protein-1; 103 v 25, p < 0.001). Urease activity per organism, however, was similar in the two groups showing that high antral urease activity in DU was a reflection of organism density. DU was not present in subjects with an antral infection density less than 10(5) colony forming units/mg protein. A correlation was present between H pylori viable counts and the severity and activity of gastritis. Both severity and activity of gastritis were greater in the antrum of DU compared with non-DU subjects but there was no difference in the body between the two groups. It is concluded that antral H pylori infection density is probably an important determinant of DU development, and that there is a baseline of infection density that is necessary for ulcer formation.

Nitric oxide, the product of nitric oxide synthase in inflammatory cells, may have a role in tissue injury through its oxidative metabolism. Nitric oxide may have a role in the pathogenesis of duodenal ulcer and may be one of the mechanisms responsible for the association between gastric infection with Helicobacter pylori and peptic disease. In this study, calcium independent nitric oxide synthase activity was detected in human gastric mucosa suggesting expression of the inducible isoform. In 17 duodenal ulcer patients gastric antral and fundic nitric oxide synthase activity was found to be two and 1.5-fold respectively higher than its activity in the antrum and fundus of 14 normal subjects (p < 0.05). H pylori was detected in the antrum of 15 of 17 duodenal ulcer patients and only in 7 of 14 of the control subjects. Antral nitric oxide synthase activity in H pylori positive duodenal ulcer patients was twofold higher than in H pylori positive normal subjects (p < 0.05). In duodenal ulcer patients antral and fundic nitric oxide synthase activity resumed normal values after induction of ulcer healing with ranitidine. Eradication of H pylori did not further affect gastric nitric oxide synthase activity. These findings suggest that in duodenal ulcer patients stimulated gastric mucosal nitric oxide synthase activity, though independent of the H pylori state, may contribute to the pathogenesis of the disease.

The gastroduodenal mucosa has a rich blood supply. An active fibrinolytic system is presumably required to maintain vascular patency, and impairment may result in reduced blood flow, focal tissue necrosis, and peptic ulcerogenesis. Tissue type and urokinase type plasminogen activator activity (expressed as mIU/mg protein) and plasminogen activator inhibitor type-1 antigen were assayed in homogenates of gastric and duodenal biopsy specimens taken from patients with: normal endoscopy (controls) (n = 14); active duodenal ulcer (n = 21); healed duodenal ulcer (n = 12); and active benign gastric ulcer (n = 15). In controls mean duodenal tissue type plasminogen activator activity was 4110 and urokinase type plasminogen activator activity 150; gastric tissue type plasminogen activator was 2760 and urokinase type plasminogen activator 170; plasminogen activator inhibitor type-1 was generally undetectable. At the edge of active duodenal ulcers tissue type plasminogen activator was considerably reduced, 2220 (p < 0.001) whereas urokinase type plasminogen activator was raised, 290 (p < 0.01). At the edge of active benign gastric ulcers tissue type plasminogen activator was substantially reduced, 1160 (p < 0.001) but urokinase type plasminogen activator was unchanged. At the scar of healed duodenal ulcers tissue type plasminogen activator was slightly reduced, 3290, but urokinase type plasminogen activator was increased, 308 (p < 0.05). H2 receptor antagonist treatment had little effect on tissue type or urokinase type plasminogen activator activity. Plasminogen activator inhibitor type-1 was increased at the edge of active ulcers (p < 0.05) especially when tissue type plasminogen activity was low (r = -0.61, p < 0.05). These findings are consistent with the hypothesis that impaired fibrinolytic activity may be implicated in peptic ulcerogenesis.

To investigate the relation of the serum group I pepsinogen (PG I) concentration to the location of gastric ulcers and chronicity of peptic ulcers, ulcer patients (n = 322) were compared with endoscopically normal subjects (n = 174). The mean PG I concentration was significantly higher in male control subjects (n = 90) than in female control subjects (n = 84). In male patients with ulcers in the duodenum (n = 69), antrum (n = 34), or angulus portion (the lower third of the body; n = 83), the mean serum PG I concentration was significantly higher than in the control subjects but in patients with an ulcer in the upper body (n = 49) it was similar to control values. Men with active or healing ulcers (n = 149) showed a significantly higher serum PG I concentration than those with scarred lesions (n = 86) when the abnormality was located in either the upper body or in the angulus portion. For female patients (n = 87), the results were similar. These results suggest that serum PG I concentrations reflect the stages of activity of peptic ulcer.

Gastric mucosal concentrations of histamine and of its metabolic enzyme, histamine methyltransferase activity, were measured in patients with duodenal ulcer disease and patients with an apparently normal stomach and duodenum. Patients with duodenal ulcer had significantly less (p less than 0.05) mucosal histamine (median 204 nmol/g) than control subjects (median 252 nmol/g). There was no significant difference between the two groups in their histamine methyltransferase activity values. Omeprazole therapy did not significantly change mucosal histamine (+23%), histamine methyltransferase activity (+5%), histamine release before (+5%) or during (+7%) pentagastrin infusion. It significantly decreased acid secretion during pentagastrin stimulation (median -73%, p less than 0.001). Omeprazole, like cimetidine, does not stop histamine release during pentagastrin stimulation.

The relationship between the secretion of pepsin 1 (the most electronegative of the pepsins), and the smoking habits of 219 patients has been investigated. Significantly more cigarette smokers with peptic ulceration (72.5%) secreted pepsin 1 in greater than trace amounts after pentagastrin or histamine than did non-smokers with ulceration (51.2%). Differences of a similar order were found for men with duodenal ulcer, women with duodenal ulcer, and all patients with gastric ulcer, but the difference was statistically significant only for men with duodenal ulcer. Significantly more patients with peptic ulcer smoking six to 15 cigarettes/day secreted moderate or high concentrations of pepsin 1 than did heavier smokers or non-smokers. There was no significant association between cigarette smoking and pepsin 1 secretion among 74 patients without ulceration. Maximal acid output was not significantly related to smoking in any group studied. The findings add to the increasing body of evidence linking pepsins and pepsin 1 with the pathogenesis of peptic ulceration.

Histamine and histamine methyltransferase (HMT) have been measured in gastric mucosa from 110 patients with duodenal ulcer and 62 control subjects. Both antral and fundic mucosa had similar levels of HMT activity despite antral mucosa containing significantly less histamine. Patients with duodenal ulcer had significantly lower levels of fundic mucosal HMT activity and lower concentrations of fundic mucosal histamine than control subjects. An additional finding was that men who were cigarette smokers had significantly lower concentrations of fundic mucosal histamine (but not HMT) than non-smokers and, as there was an excess of cigarette smokers among patients with duodenal ulcer, this may be the explanation for the reduced concentrations of fundic mucosal histamine in these patients.

Plasminogen activator activity has been localized in gastric and duodenal tissue using a histological technique. This activity could be separated from proteolytic activity by incorporating in-aminocaproic acid into the fibrin substrate or by heat treatment. Plasminogen activator activity was found in relation to mucosal and submucosal blood vessels in the tissues studied. Proteolytic activity was identified in the surface epithelium, the gastric antral and fundal glands, and in the antral submucosal fat. Proximal duodenal tissue contained proteolytic activity in relation to Brunner's glands.

The interrelationships of proteolytic enzymes and amylase have been studied in the duodenal aspirate obtained from subjects with normal and abnormal pancreatic function during stimulation with secretin and pancreozymin. While the relationship of trypsin to chymotrypsin was independent of stimulus and presence of pancreatic disease the ratio of proteolytic enzymes to amylase rose when the degree of stimulation of the pancreas was increased. Patients with recent acute pancreatitis and with chronic pancreatitis tended to have more severe impairment of secretion of proteolytic enzymes than of amylase. In routine tests of pancreatic function both proteolytic and non-proteolytic enzymes should be measured, both because an abnormal ratio may be of diagnostic significance and because the two different groups of enzymes provide mutual checks of the secretory capacity of pancreatic enzymes.