Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.6.1.3 (ATPase)
 65,361 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Omeprazole, believed to inhibit H+, K+-ATPase, was used to study acid secretion dynamics in isolated gastric mucosa. Tissue was mounted in a chamber and continuously supplied with both fresh nutrient and secretory solution (flow-through). Acid secretion was monitored on and recorded by a pH-stat microprocessor set-up. In spontaneously secreting mucosa the continuous presence of omeprazole causes a monotonic decline in secretion rate to a new lower steady state. The relationship between the inhibited steady-state acid secretion rate and omeprazole concentration is expressed by the sum of two hyperbolic functions with K1s differing by a factor of more than 100. When omeprazole is removed, the secretion rate always recovers. The amount of acid suppressed depends uniquely on omeprazole exposure: it is proportional to the exposure at low exposure and disproportionate (logarithmic) at high exposure. The index of conservation declines with omeprazole exposure, i.e. the inhibition by omeprazole ranges from conservative (no net loss of acid) to non-conservative (net loss of acid). Dithiothreitol causes the inhibition by omeprazole to be conservative (index of conservation = 0) at even higher omeprazole exposure. The index of conservation was introduced to allow for numerical evaluation of both inhibitory and stimulatory effects regardless of the magnitude of the effect. It is concluded that omeprazole acts at two different sites, possibly with inhibition by sulphoxide derivatives on the formation step and sulphide derivatives on the translocation step.
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PMID:Omeprazole: inhibitor of both acid formation and translocation in gastric mucosa. 261 61

Omeprazole is the first H+-K+-adenosine triphosphatase antagonist available for clinical use. It has a very strong, long-lasting inhibitory effect on gastric acid secretion. The effect is very selective: pepsin and intrinsic factor secretion are unaffected. Once-daily doses of 30-40 mg cause a more than 95% reduction of intragastric acidity. Lower doses have less predictable results. During treatment with omeprazole serum gastrin levels increase. After cessation of treatment gastric acid secretion and serum gastrin levels rapidly return to pretreatment levels. No rebound phenomena are observed after treatment.
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PMID:Effects of omeprazole on gastric secretory functions. 269 7

Due to its potent and long-lasting antisecretory properties is omeprazole, the first clinically used H+/K+-adenosine triphosphatase inhibitor, highly effective in healing of duodenal and gastric ulcers and reflux oesophagitis. Omeprazole is superior to all other presently available antiulcer drugs in the treatment of Zollinger-Ellison syndrome and refractory ulcers. Short-term administration of the drug is safe. However, serum gastrin and gastric enterochromaffin-like cells should be carefully monitored during long-term treatment with the drug.
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PMID:H+/K+-adenosine triphosphatase inhibitors. A new approach to the treatment of acid-peptic diseases. 269 16

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.
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PMID:Studies on the mechanism of action of the omeprazole-derived cyclic sulphenamide. 283 Aug 83

The difference in functional SH groups between two isozymes (alpha(+) and alpha forms) of (Na+ + K+)-ATPase was examined using omeprazole, a hydrophobic drug which was reported to modify SH groups of gastric (H+ + K+)-ATPase. Omeprazole inhibited rat brain and kidney (Na+ + K+)-ATPase activities in a time- and dose-dependent manner, and it inhibited incorporation of [3H]NEM into the catalytic subunit of the enzymes. The inhibition was greater in the brain enzyme than in the kidney enzyme. The inhibition of the brain enzyme showed a lag time, whereas the kidney enzyme was inhibited according to pseudo-first order kinetics. The inhibition by omeprazole of Na+-dependent phosphorylation and K+-stimulated phosphatase activity in the brain enzyme preparation was parallel with that of the overall (Na+ + K+)-ATPase reaction, while the partial reactions of the kidney enzyme showed different sensitivities to inhibition by omeprazole. Furthermore, the inhibition by omeprazole of [3H]NEM reactivity in the brain alpha(+) form was greater in the presence of SDS than in the absence, whereas the inhibition in the brain and kidney alpha forms was less in the presence of SDS than in the absence. These findings suggest that the isozymes of (Na+ + K+)-ATPase differ in hydrophobicity of SH groups of their catalytic subunits.
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PMID:Difference between two isozymes of (Na+ + K+)-ATPase in the interaction with omeprazole. 283 35

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.
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PMID:Omeprazole, SCH 28080 and doxepin differ in their characteristics to inhibit H+/K+-ATPase driven proton accumulation by parietal cell membrane vesicles. 284 47

Effects of omeprazole, an anti-ulcer drug, on (H+-K+) ATPase activity and gastric acid secretion in a gastric mucosal gland preparation from rabbits were investigated. The mode of action of the substance was compared with famotidine, and H2 antagonist, by examining the effects of both drugs on the (H+-K+) ATPase of the rabbit gastric mucosa and on gastric acid secretion from the isolated rabbit gastric glands. Optimal assay conditions for (H+-K+) ATPase activity differed slightly from that reported for pig gastric mucosa, and they were pH 7.0, 2 mM of MgCl2 and 50 mM of KCl. Omeprazole dose-dependently inhibited the enzyme activity with an IC50 of 4.2 microM, whereas famotidine was not inhibitory even at the highest concentration of 100 microM. Acid secretion in the glands was determined by measuring accumulation of 14C-aminopyrine. Omeprazole and famotidine showed almost the same inhibitory effect against histamine-stimulated gastric secretion, and their IC50 values were 0.35 microM. Omeprazole inhibited dibutyryl cyclic AMP-stimulated gastric acid secretion, but famotidine was not inhibitory even at the highest concentration of 100 microM. The reason for this difference was that (H+-K+) ATPase activity is linked to the final step of acid secretion. From these results, omeprazole can be expected to be useful for the treatment of peptic ulcer disease.
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PMID:[Effects of omeprazole and famotidine on (H+-K+) ATPase and acid secretion in rabbit gastric glands]. 285 55

The results reported in this paper indicate that representative H2-receptor antagonists are capable of maximally inhibiting gastric acid secretion in animals under the two general circumstances in which it occurs physiologically. Interdigestive or basal secretion was examined in chronic gastric fistula rats and food-stimulated secretion in vagally innervated, lesser curvature pouch dogs. The H2 antagonists studied and omeprazole, an inhibitor of the proton pump H+, K+-adenosine triphosphatase, also decreased pepsin secretion in rats, although not to the same maximal degree as acid secretion. Gastric emptying was increased by each H2 antagonist but only at high acid inhibitory doses. Omeprazole, in contrast, did not alter gastric emptying at a similar antisecretory dosage level. In dogs, a representative H2-receptor antagonist markedly inhibited food-stimulated acid secretion. These data suggest that the predominant effect of omeprazole and H2-receptor antagonists upon gastric function is to inhibit acid secretion and that H2-receptor antagonists may be capable of maximally inhibiting endogenous acid secretion in humans, as does omeprazole, if given under proper conditions.
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PMID:Effects of H2-receptor antagonists upon physiological acid secretory states in animals. 285 83

The substituted benzimidazole, omeprazole, is a potent inhibitor of the ATP-dependent proton pump of the parietal cell. Since there is accumulating evidence that hepatic lysosomes also possess an ATP-dependent proton pump system to maintain internal acidification, and since antibodies to the putative lysosomal proton pump protein are immunologically similar to the parietal cell (H+ + K+) ATPase, we studied the effects in rats of six days of omeprazole treatment on hepatic lysosomal function. Omeprazole, 5 mg kg-1, a dose five times the ED50 for gastric acid secretion inhibition in rats, did not alter the activity of three representative lysosomal enzymes in liver (acid phosphatase, beta-galactosidase and N-acetyl-beta-glucosaminidase) nor did it alter lysosomal enzyme latency, a measure of the integrity of the lysosomal membrane. Furthermore, bile flow and the secretion of lysosomal enzymes into bile were also unaffected by omeprazole. These data indicate that in rats short-term treatment with omeprazole, in doses that markedly inhibit gastric acid secretion, has no major biological effect on liver lysosomal integrity and lysosomal enzyme activity.
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PMID:Lack of effect of omeprazole, a potent inhibitor of gastric (H+ + K+) ATPase, on hepatic lysosomal integrity and enzyme activity. 287 Jan 66

Gastric acid exerts a feedback inhibition on the secretion of gastrin from antral G cells. This study examines whether gastrin gene expression is also regulated by changes in gastric pH. Achlorhydria was induced in rats by the gastric H+/K+ ATPase inhibitor, omeprazole (100 mumol/kg). This resulted in fourfold increases in both serum gastrin (within 2 h) and gastrin mRNA levels (after 24 h). Antral somatostatin D cells probably act as chemoreceptors for gastric acid to mediate a paracrine inhibition on gastrin secretion from adjacent G cells. Omeprazole-induced achlorhydria reduced D-cell activity as shown by a threefold decrease in antral somatostatin mRNA levels that began after 24 h. Exogenous administration of the somatostatin analogue SMS 201-995 (10 micrograms/kg) prevented both the hypergastrinemia and the increase in gastrin mRNA levels caused by omeprazole-induced achlorhydria. Exogenous somatostatin, however, did not influence the decrease in antral somatostatin mRNA levels seen with achlorhydria. These data, therefore, support the hypothesis that antral D cells act as chemoreceptors for changes in gastric pH, and modulates somatostatin secretion and synthesis to mediate a paracrine inhibition on gastrin gene expression in adjacent G cells.
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PMID:Reciprocal regulation of antral gastrin and somatostatin gene expression by omeprazole-induced achlorhydria. 290 31


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