Pharmacological analysis of the pentagastrin-tiotidine interaction in the mouse isolated stomach

The pentagastrin-tiotidine interaction has been analysed, using improved techniques, in the mouse isolated, lumen-perfused, stomach assay. For comparison and quantification of the H2-receptor blocking activity of tiotidine, histamine-tiotidine interactions have also been analysed in the mouse stomach and guinea-pig isolated right atrial preparation. Tiotidine behaved as a competitive antagonist of histamine both in the guinea-pig right atrium (pKB 7.57) and mouse stomach (pKB 6.96). The difference in pKB was attributed to the loss of tiotidine into the gastric secretion. On the stomach assay, pentagastrin concentration-effect curves were significantly flatter with lower maximal responses than those obtained to histamine. In addition the profile of inhibition observed with tiotidine was different in that the pentagastrin curve maxima were depressed with only a small concomitant dextrad shift. A mathematical model has been developed which accounts for the differences in agonist concentration-effect curves and describes in a quantitative manner the expectations for the competitive antagonism of endogenous histamine assumed to be released by pentagastrin. Fitting of the pentagastrin-tiotidine data to this model provided a reasonable goodness-of-fit. The results are discussed in terms of the role of endogenous histamine in gastrin-stimulated acid secretion. We conclude that the results are consistent with the hypothesis that pentagastrin stimulates acid secretion via the release of endogenous histamine under the present experimental conditions.