methylatropine and tiotidine

Although oxyntic cell secretion can be studied at many organisation levels between isolated cell suspensions and non-invasive techniques in animals, the isolated, lumen-perfused, stomach preparation of the mouse represents a hierarchical level which eliminates extrinsic regulatory influences but retains all the cellular architecture known to be necessary for physiological responses and so can be defined as the physiological unit of acid secretion. The feeding pattern before and the distending pressure during an experiment have been identified as the main determinants of basal secretion: the combination of an intragastric pressure of 12 cmH2O and the fasted state generated a stable basal secretion over 2 h providing a satisfactory basis for bioassays. Basal acid secretion was lowered by treatment with omeprazole and sodium thiocyanate but not with tetrodotoxin, N-methylatropine or tiotidine, suggesting that basal secretion does not involve nervous stimulation or the local release of histamine under these experimental conditions. The improved assay permitted the full characterization of cumulative agonist concentration-effect curves in single stomach preparations to histamine, 5-methylfurmethide, pentagastrin and isobutyl-methylxanthine. Interestingly, pentagastrin produced sustained stimulation of gastric acid secretion under conditions when there was no pharmacological evidence that histamine secretion was taking place. This finding is discussed in relation to the role of histamine in the control of gastric acid secretion.

Topics: 1-Methyl-3-isobutylxanthine; Animals; Atropine Derivatives; Benzimidazoles; Cimetidine; Fasting; Gastric Acid; Gastric Mucosa; Histamine; Histamine H2 Antagonists; Hydrogen-Ion Concentration; In Vitro Techniques; Male; Mice; Muscarine; Omeprazole; Pentagastrin; Pressure; Tetrodotoxin; Thiocyanates

In the light of recent attempts to subclassify muscarinic receptors, agonist-antagonist interactions at muscarinic receptors have been re-examined using improved techniques, on the mouse, isolated, lumen-perfused stomach gastric acid assay. Using 5-methylfurmethide as the muscarinic agonist, the pKB estimated for atropine was significantly lower on the stomach assay (7.78) than on the guinea-pig trachea (8.93). However pKB values for N-methylatropine, the quaternary ammonium derivative of atropine, at concentrations producing dose-ratios above 20 on the stomach assay (pKB = 9.67), and over the full concentration range studied on the trachea (pKB = 9.69) were not significantly different. The deviation from simple competitive behaviour at low dose-ratios with N-methylatropine in the stomach assay is consistent with the effects of a saturable uptake mechanism for quaternary ammonium compounds. The pKB values for pirenzepine on the stomach (6.67) and the trachea (6.87) were not significantly different suggesting that pirenzepine behaves more like N-methylatropine in terms of expressed affinity. We conclude that the oxyntic cell muscarinic receptors are homogeneous with those in the guinea-pig trachea. An initial exploration suggests that there is a relationship between the lipophilicity (log P) of the antagonists and the degree of apparent underestimation of antagonist affinity in the stomach assay. This supports the hypothesis that the underestimation of antagonist affinity is due to the loss of antagonist into the gastric secretion from the receptor compartment. Apparently, relatively selective inhibition of acid secretion, compared to atropine, could be explained without the need to postulate heterogeneity of muscarinic receptor populations.

Topics: Animals; Atropine; Atropine Derivatives; Benzodiazepinones; Binding, Competitive; Cimetidine; Guinea Pigs; Histamine H2 Antagonists; In Vitro Techniques; Mice; Muscarine; Muscle Contraction; Muscle, Smooth; Parasympatholytics; Parietal Cells, Gastric; Pirenzepine; Receptors, Muscarinic; Trachea