Failure of acid suppression by H₂-receptor antagonists has been observed, and recently we have found a higher frequency of patients with inadequate antisecretory response among patients with cirrhosis of the liver. In the present study comprising 16 cirrhotics with inadequate antisecretory response to 300 mg of ranitidine, we tested the effect of 40 mg omeprazole. Nighttime intragastric pH was continuously monitored, and a rise in the intragastric pH above 4.0 for more than 6 h following the oral dose at 18.00 h was considered as response. The median pH profile during the omeprazole treatment was significantly higher than with ranitidine (p ≤ 0.001). In contrast to 300 mg ranitidine, which despite sufficient plasma levels 2 and 4 h after intake (762 ± 431 and 802 ± 668 ng/ml) resulted in a rise in the nighttime intragastric pH above 4 only for 1.8 ± 1.7 h, after omeprazole for at least 5 days, the intragastric pH was for 10.1 ± 2.4 of 12 h above 4 during the night (p < 0.001). The omeprazole plasma levels were 611 ± 323 and 881 ± 533 ng/ml after 2 and 4 h. The data obtained with intragastric pH monitoring indicate that the H⁺K⁺-ATPase inhibitor omeprazole is able to overcome the H₂-blocker resistance in cirrhotics.

Human gastric mucosal cells were isolated by digestion of fundic biopsies with pronase and collagenase. The mean value of gastric cells per milligram biopsy specimen ± SEM was 59,000 ± 4,300 (n = 31) with a viability of 90 ± 5 %. With the cell yield of 1 patient a series of approximately 70 – 80 cyclic AMP measurements was possible. Histamine stimulated intracellular cyclic AMP production with an EC50 value of 35 ± 25 μmol/l (SEM; n = 4). In the presence of 100 μmol/l histamine the Ki values (μmol/l) for the histamine H2 receptor antagonists averaged 1.45 (cimetidine), 0.10 (ranitidine), and 0.02 (famotidine). No significant inhibition of histamine-induced cyclic AMP production was obtained with the histamine H₁ receptor antagonist triprolidine. With the new method histamine-induced cyclic AMP production can be measured in intact human gastric mucosal cells from fundic biopsy samples.

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In peptic ulcer patients with adequate (AR; N = 16) and inadequate response (IR; N = 20) to H2-receptor antagonists, the presence of parietal cell cAMP-stimulating autoantibodies was studied. Serum Ig fractions from these patients and 10 control subjects were examined to test whether they could stimulate cAMP production in a gastric cell line model. The human cell line HGT-1 was found to be a sensitive in vitro model for the cAMP stimulation assay as histamine (10 microM) increased by 11-fold the production of cAMP. Neither IgG (4 mg/ml) nor IgG-free Ig fractions (1 mg/ml) isolated from the blood of AR or IR affected cAMP production in the HGT-1 cells. The results obtained with the cAMP stimulation assay were confirmed by indirect immunofluorescence measurements based on frozen sections of rat stomach and kidney. No specific staining of rat parietal cells could be observed with patient sera. In addition, human gastric biopsies of the oxyntic mucosa from the same patients were studied for immunoreactive cell populations to assess organ-specific autoimmune processes. Biopsy specimens from AR and IR showed increased lymphocytic infiltrates, usually associated with gastritis. However, no significant differences in location of various cell populations between AR and IR could be observed. Our findings do not support a recent hypothesis that poor response to treatment with H2-receptor antagonists is due to the presence of autoantibodies.