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W Beil

Publications and source records attributed to W Beil.

At least 73 records · Page 4Linked to original sources
PubMed1989

Mast cell heterogeneity in the small intestine of normal, gnotobiotic and parasitized pigs.

A formalin fixative and a formalin-free fixative were used to study mast cells in the small intestine of conventional, gnotobiotic and parasitized pigs. Many more mast cells were identified after basic lead acetate fixation ('mucosal mast cells', MMC) than after routine formalin fixation ('connective tissue mast cells'). The MMC were preferentially localized in the lamina propria. There were no differences between conventional and gnotobiotic pigs. However, in parasitized animals, the number of mast cells was several times higher, mainly because there were more MMC. The heterogeneity of intestinal mast cells in the pig indicates that this might be an interesting model for functional studies on mast cell subsets.

Aging↗
PubMed1988

Omeprazole, SCH 28080 and doxepin differ in their characteristics to inhibit H+/K+-ATPase driven proton accumulation by parietal cell membrane vesicles.

The effects of omeprazole, SCH 28080 and doxepin were studied on H+/K+-ATPase mediated H+ accumulation in parietal cell membrane vesicles. Omeprazole had no effect on the initial rate of H+ accumulation and the initial steady state concentration of H+; an inhibition was found after the vesicles were acidified. This inhibition was counteracted by the SH reducing agent dithioerythritol. SCH 28080 inhibited the initial rate of H+ accumulation and the steady state H+ concentration. The inhibitory effect of SCH 28080 was counteracted by KCl. Doxepin (3-100 microM) reduced the initial steady state H+ concentration. Doxepin concentrations lower than 0.5 microM had no such effect but dissipated the proton gradient after the vesicles were fully acidified. This doxepin effect was partially counteracted by KCl and was also obtained in vesicles in which the pump reaction was stopped by EDTA. These data show that (i) omeprazole is an acid-activated compound which interferes with SH groups of the H+/K+-ATPase localized inside the vesicles; (ii) SCH 28080 interferes with the K+ site of the H+/K+-ATPase; and (iii) doxepin interacts by a K+ antagonistic activity at the H+/K+-ATPase site and in addition by intravesicular neutralization and/or a protonophoric mechanism with the process of H+ formation.

Adenosine Triphosphatases↗
PubMed1988

Studies on the mechanism of action of the omeprazole-derived cyclic sulphenamide.

The inhibitory effects of omeprazole and omeprazole-derived metabolites were studied on Escherichia coli glutaminase activity at pH 2.5 which might represent the conditions present at the target enzyme (K+/H+-ATPase) in the secretory membrane of the intact parietal cell. Omeprazole and the omeprazole-derived cyclic sulphenamide inhibited glutaminase at pH 2.5 with identical potency (IC50 36 microM). The substrate, glutamine as well as the mercaptane, dithiothreitol, protect the enzyme. Furthermore, dithioerythritol was found to reverse inhibition. This indicates that an SH-group localized in the substrate binding center of glutaminase is most likely involved in the reaction leading to enzyme inhibition. Glutaminase inhibition by both compounds was less pronounced at pH 5.0. Omeprazole radical, the metabolite generated from the cyclic sulphenamide at more neutral pH values, failed to affect the enzyme. These findings were in contrast with the properties of the omeprazole-derived cyclic sulphenamide and radical at the K+/H+-ATPase preparation. This enzyme was inhibited by both compounds at pH 7.5 with a high potency, and reversal experiments with dithiothreitol demonstrate that these agents interfere with SH-groups of the K+/H+-ATPase. From these data it is suggested that the cyclic sulphenamide and the radical interfere by different reaction pathways with enzymatic SH-groups.

Adenosine Triphosphatases↗
PubMed1988

Interaction of antidepressants and neuroleptics with histamine stimulated parietal cell adenylate cyclase and H+ secretion.

The tricyclic antidepressants trimipramine and doxepin, and the neuroleptic agents trifluoperazine and haloperidol were tested for their effect on histamine H2-receptor-mediated adenylate cyclase activity and H+ secretion in guinea-pig parietal cells. All compounds inhibited histamine-stimulated adenylate cyclase and H+ secretion in a concentration-dependent manner. The antisecretory potency was 1-2 orders of magnitude higher than that for adenylate cyclase inhibition. All drugs caused a rightward shift in the concentration-response curves of histamine-induced adenylate cyclase activation with Schild-plot lines having a slope significantly different from unity. Histamine-stimulated H+ secretion was inhibited by the drugs in a noncompetitive fashion. These results demonstrate that antidepressants and neuroleptics interfere noncompetitively with the parietal cell histamine H2-receptor and that this receptor blocking activity is not related to the antisecretory activity of the drugs.

Adenylyl Cyclases↗
PubMed1988

Comparative pharmacology of histamine H2-receptor antagonists.

There was no significant difference between the concentration-dependent inhibitory effects produced by roxatidine acetate, roxatidine and ranitidine on adenylate cyclase derived from isolated and enriched guinea-pig parietal cells. All the compounds shifted the concentration-response curve of histamine to the right and transformation of this data to Schild-plots produced straight lines with slopes greater than 1 but not significantly different from each other. The pA2 values characterising the potencies were roxatidine acetate 6.85 +/- 0.86, roxatidine 7.14 +/- 0.04, and ranitidine 6.92 +/- 0.01. Histamine-stimulated acid production from isolated guinea-pig parietal cells, measured by the 14C-aminopyrine accumulation technique, was similarly affected by the 3 compounds. Schild-plot slopes of roxatidine acetate and ranitidine were not significantly different from unity and pA2 values were similar to those of the adenylate cyclase inhibition, roxatidine acetate 7.15 +/- 0.09, roxatidine 7.03 +/- 0.02, and ranitidine 6.83 +/- 0.10. In conclusion, roxatidine acetate and its major metabolite roxatidine behave like competitive antagonists with potencies similar to ranitidine on H2-receptors on the guinea-pig parietal cell.

Histamine H2 Antagonists↗
PubMed1987

Protein kinase C and parietal cell function.

Ca2+-phospholipid dependent protein kinase activity and the effect of 12-O-tetradecanoylphorbol-13-acetate (TPA) on H+ secretion was studied in guinea-pig parietal cells. In resting parietal cells PK-C activity was distributed almost equally in both the cytosolic and particulate cell fraction. Exposure of the cells to TPA resulted in a loss of cytosolic PK-C activity which was not accompanied by a concomitant increase of particulate activity. Furthermore TPA inhibits the K+/H+-ATPase and dissipates H+ gradient in intact gastric vesicles by a protonophoric action. The role of these biochemical events for the antisecretory action of TPA found in the intact parietal cell are discussed.

Adenosine Triphosphatases↗
PubMed1987

SCH 28080 is a more selective inhibitor than SCH 32651 at the K+ site of gastric K+/H+-ATPase.

The anti-secretory agents SCH 32651 and SCH 28080 were compared for their potency to interact with the K+ site of guinea-pig parietal cell K+/H+-ATPase and dog kidney Na+/K+-ATPase. SCH 32651 and SCH 28080 had an inhibition constant of 9.0 and 0.02 mumol/l, respectively, for the K+/H+-ATPase. The Ki values for the Na+/K+-ATPase were 140 and 220 mumol/l. The data show that both drugs have a higher affinity to the K+ site of the K+/H+-ATPase than to that of the Na+/K+-ATPase and that the affinity ratio of SCH 28080 in favour of K+/H+-ATPase is much greater (11,000) than that of SCH 32651 (15).

Adenosine Triphosphatases↗
PubMed1987

Inhibition of gastric K+/H+-ATPase by acid-activated 2-((2-pyridylmethyl)sulphinyl)benzimidazole products.

The inhibitory effects of timoprazole- and omeprazole-derived metabolites were studied in different in vitro test systems in order to characterize the metabolites of substituted benzimidazoles originating from acid activation. Acidification of timoprazole and omeprazole to pH 1.0 markedly increased the inhibitory potency on gastric K+/H+-ATPase. The timoprazole-derived tetracyclic thiol and radical were found to be equally or more potent on the K+/H+-ATPase than the mother compounds dissolved at pH 1.0. Kinetic studies with omeprazole sulphide revealed a competitive inhibition of the K+/H+-ATPase with respect to K+. The mercaptan dithiothreitol reversed the inhibitory effect of omeprazole, acidified timoprazole and the timoprazole-derived radical in the parietal cell and K+/H+-ATPase preparation. In contrast, the inhibitory effect of omeprazole sulphide and the timoprazole-derived thiol could not be reversed by dithiothreitol. Wash-out experiments indicated that acidified timoprazole and the tetracyclic compounds interact irreversibly with the K+/H+-ATPase, which contrasts with the properties of timoprazole in the parietal cell preparation. It is concluded from these data that neither the tetracyclic compounds nor the sulphide act as the 'active principle' of substituted benzimidazoles in the parietal cell preparion.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed1987

The gastric proton pump, a target for neuroleptics and antidepressant drugs?

The antisecretory action of the antidepressant drugs trimipramine, doxepin and nortriptyline was studied in two different in-vitro test systems; the isolated and enriched guinea-pig parietal cell and the purified H+/K(+)-ATPase preparation. The effect of the antidepressants was compared with that of the neuroleptic agents chlorpromazine, triflupromazine, trifluperazine, haloperidol, fluspirilene and with that of the tricyclic anticholinergic agent pirenzepine. All neuroleptics and antidepressants inhibited acid formation in intact parietal cells with IC50 values in the nanomolar range. The inhibitory potency for each compound was identical regardless of whether histamine or db-cAMP was used as stimulant. Isolated H+/K(+)-ATPase, measured in the presence of 5 mmol litre-1 KCl, was inhibited by all psychotropic drugs with IC50 values in the micromolar range. EGTA did not affect the inhibitory potency at the H+/K(+)-ATPase, indicating that the action of the drugs does not depend on their calmodulin blocking activity. Pirenzepine was ineffective in both test systems. Kinetic studies done with nortriptyline, chlorpromazine and haloperidol showed a competitive type of inhibition with respect to K+ at low inhibitor concentrations. This competitive type was changed to a mixed type of inhibition with increasing inhibitor concentrations, demonstrating cooperative effects between drug binding and K+ activation of the enzyme. From these data it is suggested that antidepressants and neuroleptics act by an allosteric mechanism of action, and that the lipid solubility is a significant factor to establish enzyme inhibition.

Animals↗
PubMed1986

Mechanism of gastric antisecretory effect of SCH 28080.

The mechanism of the gastric antisecretory action of SCH 28080 has been studied utilizing two different in vitro test systems, isolated and enriched parietal cells from the guinea-pig and guinea-pig gastric membranes purified and enriched with K+/H+-ATPase. In guinea-pig isolated and enriched parietal cells SCH 28080 inhibited the acid response to histamine and high K+ concentrations with IC50 values not significantly different from each other. SCH 28080 inhibited the purified K+/H+-ATPase measured in the presence of 5 mM KCl with an IC50 value of 1.3 microM. Kinetic studies indicated a competitive inhibition of ATPase by SCH 28080 with respect to K+. Studies on Na+/K+-ATPase showed that this enzyme was only slightly depressed by SCH 28080. It is concluded that SCH 28080 acts with high selectivity on the parietal cell K%/H+-ATPase, establishing its antisecretory effect by a competitive interaction with the high affinity K+-site of the gastric ATPase.

4-Nitrophenylphosphatase↗
PubMed1986

The sulphoxide moiety of substituted benzimidazoles is essential for inhibition of parietal cell K+/H+-ATPase.

The antisecretory action of the benzimidazole sulphoxide derivative B 823-10, 2[(4-methoxy-3-methyl-2-pyridylmethyl)-sulphinyl]- 5-trifluoromethyl(1H)-benzimidazole, was compared with the effect of the corresponding sulphide B 823-08 in several in vivo and in vitro and in vitro test systems. The sulphide B 823-08 and the sulphoxide B 823-10 were found to be equipotent in the Shay rat. The sulphide was found to inhibit H+ secretion in intact rabbit gastric glands and enriched guinea-pig parietal cells with lower potency than the corresponding sulphoxide. The relative potency in antisecretory activity (sulphide/sulphoxide) decreased in the following rank order: Shay rat: gastric glands: parietal cells. Purified K+/H+-ATPase was not blocked by the sulphide, whereas the sulphoxide inhibited the overall as well as the partial reactions of this enzyme. In all in vitro systems tested, inhibition of H+ secretion and enzyme activity by the sulphoxide, but not by the sulphide, was antagonized by SH-compounds such as dithiothreitol. It is concluded that in vivo sulphoxidation of the sulphide plays an important role in acid inhibition. In vitro an additional inhibitory mechanism of the sulphide has to be considered.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed1985

The adenylate cyclase-cyclic AMP-protein kinase system in different cell populations of the guinea pig gastric mucosa.

In isolated guinea pig gastric mucous and enriched parietal cells it was tested whether or not cyclic AMP in response to histamine stimulation might reach concentrations sufficiently high to activate an intracellular cyclic AMP-dependent protein kinase and thereby mediate the acid response. Although histamine stimulated parietal cell adenylate cyclase to a greater extent than mucous cell adenylate cyclase, cyclic AMP levels in response to maximal histamine stimulation reached higher levels in mucous than in parietal cells. This had to be attributed to a five times higher phosphodiesterase activity in parietal cell than in mucous cell populations. In the absence of the phosphodiesterase inhibitor isobutylmethylxanthine exposure of the cells to histamine only in mucous cells produced an increase in cyclic AMP-dependent protein kinase activity ratio, but not in parietal cells. Dibutyryl-cyclic AMP induced cyclic AMP accumulation in parietal cell populations was compared to dibutyryl-cyclic AMP induced H+ secretion, as measured by 14C-aminopyrine uptake. A maximal acid response was associated with an intracellular cyclic AMP level of approximately 300 pmol/10(6) cells, which was never reached by maximal histamine stimulation even not in the presence of the phosphodiesterase inhibitor. It is concluded that activation of the parietal cell cyclic AMP-dependent protein kinase is one way for stimulating H+ secretion, but that the acid response elicited by histamine requires another intracellular pathway.

Adenylyl Cyclases↗
PubMed1984

Inhibition of partially purified K+/H+-ATPase from guinea-pig isolated and enriched parietal cells by substituted benzimidazoles.

The cellular and subcellular distributions of adenosinetriphosphatases (ATPases) were examined in guinea-pig gastric mucosal cells. All cell types displayed Mg2+-ATPase and bicarbonate (HCO3-)-stimulated ATPase activity. K+-ATPase was located only in fractions derived from parietal cells. Differential and density-gradient centrifugation of material prepared from parietal cells revealed that K+-ATPase activity was located in a tubulo-vesicular membrane fraction. Enzyme activity was ten fold greater in this fraction than in a crude parietal cell homogenate. The substituted benzimidazoles, omeprazole and picoprazole, inhibited K+-ATPase (IC50 1.8 +/- 0.5 mumol l-1 and 3.1 +/- 0.4 mumol l-1, respectively). Detailed kinetic analysis indicated that these compounds were non-competitive and reversible inhibitors of the enzyme. In contrast cimetidine and verapamil were without effect on the enzyme. The relevance of the inhibition of K+-ATPase to the antisecretory activity of the benzimidazoles, in experimental animals and man, is discussed.

2-Pyridinylmethylsulfinylbenzimidazoles↗