Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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 represents a new class of gastric acid inhibitors, which inhibits the H+, K(+)-ATPase in the secretory membrane of the parietal cell. Single oral doses inhibited pentagastrin stimulated acid secretion with an ED50 of 27 mg. Almost complete inhibition could be achieved with a single dose of 80 mg. Acid secretion then slowly returned and reached normal levels after 3-4 days. Omeprazole also inhibited basal, histamine peptone and vagally stimulated acid secretion with similar potency. For clinical use omeprazole has been formulated as enteric coated granules. During repeated once daily dosing with this formulation the degree of acid suppression increased over the first days after the start of treatment but stabilized within about 4 days. Dose-response studies in both DU-patients and healthy subjects have shown that daily doses of 20-40 mg result in 80-100% reduction of stimulated acid secretion when measured 6 h after dose. Due to the long duration of action the inhibition was still 50-80% when measured 24 h after dose. Studies of 24 h intragastric acidity in DU-patients have shown that once daily treatment with 20 mg omeprazole results in a reduction of intragastric acidity by 97% which in the same study was superior to the 57% reduction caused by treatment with ranitidine, 150 mg twice daily. During omeprazole treatment, plasma gastrin increased in relation to the degree of acid suppression. The level of increase of 24 h plasma gastrin during once daily treatment with 20 mg omeprazole was slightly higher than for ranitidine, 150 mg twice daily, but similar to that seen after highly selective vagotomy.
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PMID:Effect of omeprazole on gastric acid secretion and plasma gastrin. 249 58

Antibodies to a membrane-bound antigen, localized to the canalicular structures of the parietal cell, are found in most sera of patients with chronic atrophic gastritis and pernicious anemia. In the present study immunoglobulins containing parietal cell antibodies were found to inhibit the activity of H+,K+-adenosine triphosphatase (EC 3.6.1.36) in a tubulovesicular membrane preparation from porcine gastric mucosa. The degree of inhibition correlated to the titer of parietal cell antibodies as assessed by an enzyme-linked immunosorbent assay. The specificity of the enzymatic inhibition was confirmed by the lack of effect of parietal cell antibodies on membrane-bound esterase. A possible interaction of parietal cell antibodies with gastrin binding at the receptor level was investigated in a radioreceptor assay employing 125I-gastrin 1 and gastric mucosal cell suspension from the guinea pig. No blocking capacity was found with immunoglobulins from patients with pernicious anemia as compared with immunoglobulins from healthy controls. The results thus demonstrate a direct inhibitory effect of parietal cell antibodies on the acid producing H+,K+-adenosine triphosphatase of the parietal cell, but also a lack of interaction with the gastrin receptor, and indicate that in the development of hypo/achylia H+,K+-adenosine triphosphatase autoantibodies could have a major pathogenic role.
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PMID:Parietal cell antibodies in pernicious anemia inhibit H+, K+-adenosine triphosphatase, the proton pump of the stomach. 254 Oct 40

A case of Zollinger-Ellison syndromes in a fifty year-old male that was successfully treated with a H+-K+ ATPase inhibitor (Omeprazol) is reported. The patient underwent a partial gastrectomy in 1984, but had been suffering from multiple refractory stomal and jejunal ulcers after the operation. In 1987, hypergastrinemia (760 pg/ml) was detected, and the presence of gastrinomas in the pancreatic head accompanied by a multiple liver metastasis was subsequently confirmed by CT-angiography and by the gastrin level detected in percutaneous, transhepatic, portal venous samples. A secretin provocation test proved to be negative, and the ulcers resisted the H2-receptor antagonists, but the patient was successfully cured shortly after the administration of an H+-K+ ATPase inhibitor.
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PMID:[A case of Zollinger-Ellison syndrome successfully treated with an H+-K+ ATPase inhibitor]. 255 Jun 87

There are two means of reducing acid secretion. The best studied is inhibition of stimulation of the parietal cell. There are three major types of receptors that activate secretion by this cell and two classes of receptor antagonists, as well as at least two intracellular messenger pathways. The receptors are for histamine (H2 subtype), acetyl choline (M2 subtype) and gastrin. Antagonists of these receptors include the H2-antagonist class (Tagamet, Zantac and Pepcid), the M1 muscarinic antagonists (pirenzepine, telenzepine) and the gastrin antagonist, proglumide. The major pathway for stimulation appears to be the H2-receptor, since this is the only receptor that stimulates adenylate cyclase, and both acetyl choline and gastrin release histamine locally within the gastric mucosa. However, these agonists elevate intracellular calcium, which has a partially independent action on acid secretion. Accordingly, the most efficacious type of receptor antagonist will be of the H2 class, which is borne out by clinical experience. Prostaglandins of the E type prevent adenylate cyclase stimulation by histamine and are also effective antisecretory agents. It will be difficult to abolish acid secretion entirely by a single receptor antagonist, although longer-acting H2-antagonists should show clinical superiority to short-acting antagonists of this type. An alternative approach to acid suppression is to block the terminal step of acid secretion, the gastric proton pump (H+, K(+)-ATPase). This enzyme is virtually unique to the parietal cell and, when active, forms a very acidic space within the parietal cell called the secretory canaliculus. Activation of acid secretion involves several steps. The enzyme is present in cytosolic membranes when the cell is at rest and moves to the membrane of the secretory canaliculus when stimulated. Simultaneously, there is an increased permeability of potassium chloride (KCl), which allows presentation of K+ to the luminal surface of the pump and H+ for K+ exchange. The result is the secretion of HCl into the canaliculus, and hence into the gland lumen and then the stomach. There are two classes of pump inhibitors. One class is K+ competitive and relatively selective for the H+, K(+)-ATPase, as exemplified by SCH28080. This class has not yet been used in man. The other class is specific to the functioning H+, K(+)-ATPase in the stomach. It is exemplified by omeprazole (Losec). This compound is a weak base with a pKa of 4. In the unprotonated, uncharged form it will penetrate cell membranes and, at pH less than 4, it becomes protonated and therefore charged.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Biological basis of omeprazole therapy. 256 65

We studied whether enprostil, a synthetic prostaglandin E2 derivative, might inhibit gastrin release and the trophic effects on gastric oxyntic mucosa induced by prolonged treatment with an inhibitor of hydrogen-potassium-stimulated adenosine triphosphatase, the substituted benzimidazole BY 831-78. Rats were treated intragastrically with enprostil (1 or 15 micrograms/kg b.i.d.), BY 831-78 (15 mumol/kg once daily), the combination of enprostil and BY 831-78, ranitidine (300 mumol/kg b.i.d.), and placebo. Plasma gastrin and somatostatin levels and gastric acid secretion were measured during a 1-day treatment in animals fitted with chronic gastric fistulas and repeatedly during 9 wk of treatment in intact rats. Despite inhibiting acid secretion, enprostil did not increase plasma gastrin. When combined with BY 831-78, enprostil transiently reduced the BY 831-78-induced increase of integrated plasma gastrin (1375 +/- 206 vs. 2137 +/- 256 pmol/L.12 h, p less than 0.05) in fasted rats with fistulas, but failed to prevent the marked hypergastrinemia following 9 wk of treatment with BY 831-78 (717 +/- 80 vs. 731 +/- 56 pmol/L) in intact rats. However, enprostil reduced the BY 831-78-induced increase of oxyntic mucosal volume (458 +/- 31 vs. 567 +/- 33 mm3, p less than 0.01), whereas BY 831-78 prevented the enprostil-induced increase of antral mucosal volume (42 +/- 3 vs. 56 +/- 3 mm3, p less than 0.01). These results demonstrate that some of the trophic effects induced by a hydrogen-potassium-stimulated adenosine triphosphatase inhibitor are not exclusively governed by gastrin.
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PMID:Enprostil reduces the increase of gastric corpus mucosal mass induced by the hydrogen-potassium-stimulated adenosine triphosphatase inhibitor BY 831-78 in the rat. 257 Jul 29

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

Cellular mechanisms underlying the actions of antisecretory agents were studied with dispersed canine fundic cells; aminopyrine accumulation monitored parietal cell (PC) function. Canine PC have pharmacologically typical histamine (H) H2 and muscarinic (M) receptors. PC also have gastrin (G) receptors, which were selectively blocked by gastrin/CCK antagonists. Potentiating interactions occurred between secretagogues, one of the components of the interdependency between regulatory pathways. Prostaglandins (PG) E2 inhibited H-stimulated PC function. Treatment of PC with pertussis toxin (PT), which inactivates the inhibitory GTP-binding protein of adenylate cyclase (Gi), markedly reduced PG inhibition, indicating PG action via Gi. PC function can also be directly inhibited by H+/K+-ATPase inhibitors, such as omeprazole. When canine mucosal cells were studied, stimulatory G and inhibitory M receptors were present on fundic somatostatin (S) cells. Histamine was localized to canine fundic mast cells, which lacked G or M receptors, a conclusion that may not pertain to fundic histamine cells in other species. Nonparietal cell receptors may be important modulators of the regulation of acid secretion.
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PMID:Mechanisms of action of antisecretory drugs. Studies on isolated canine fundic mucosal cells. 288 44

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

Parietal cell secretory function may be inhibited by three mechanisms. (1) Receptors for gastrin, histamine and acetylcholine are present on the canine parietal cell, and parietal cell function may be directly inhibited by specific antagonists for each of these receptors. (2) Receptor activation of parietal cell function is mediated by cyclic AMP-dependent (histamine) and calcium-dependent (cholinergic agents and gastrin) mechanisms. The antisecretory action of prostaglandins reflect interference with histamine activation of adenylate cyclase. The current generations of calcium channel blockers have only weak antisecretory actions in vivo and are unlikely to be useful in clinical practice. (3) A third mechanism of inhibition is blockade of H+/K(+)-ATPase by substituted benzimidazoles, such as omeprazole. Each of these three mechanism provides modalities of potential clinical usefulness for treating acid-peptic disease. Gastrin and acetylcholine receptors are present on other fundic cells, in addition to the parietal cell. These other cells include the somatostatin cell in the dog fundic mucosa and the histamine-containing enterochromaffin-like (ECL) cell present in the fundic mucosa of several species. The relative impact of these receptors on different cell types on the regulation of acid secretion remains uncertain, and is probably variable among different species. One gastrin receptor of considerable importance is the gastrin receptor that exerts a trophic effect on the ECL cell in the fundic mucosa. Sustained hypergastrinaemia in response to profound hypochlorhydria is associated with hyperplasia of this cell type; the elucidation of the conditions that promote this hyperplasia and the clinical consequences of this association are pressing challenges.
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PMID:Review: antisecretory drugs: cellular mechanisms of action. 297 19


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