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)

The H+, K(+)-ATPase inhibitor omeprazole has been made available on a compassionate basis for patients with Zollinger-Ellison syndrome considered resistant to, or with side-effects on, histamine H2-receptor antagonists. By December 1985, the first 80 patients, from 46 centres in 11 countries, had been treated for periods of 2 days to 4 years. Basal acid output was decreased to the desired level of less than 10 mmol.hour-1, and symptoms were rapidly relieved. Acid secretion and laboratory variables were checked regularly and endoscopic examinations made at intervals. Dosage was adjusted primarily on the basis of basal acid output, but also if symptoms recurred. The starting dose was generally 60 mg daily and the median dose ranged between 60 and 70 mg daily over the study period. There was no evidence of tachyphylaxis. More than 90% of the patients were successfully controlled on total daily doses of 120 mg or less; one-third of patients required divided doses. Tolerance was good: there were no obvious drug-related effects on laboratory variables, including fasting serum gastrin, and there were very few adverse events. Thirteen patients died (11 of the primary disease and two of other causes), four underwent successful tumour resection, six underwent total gastrectomy (though acid secretion was controlled in five), four patients' treatment was changed to other medical therapy, and one was lost to follow-up. Omeprazole thus appears to be both safe and very effective in controlling acid hypersecretion in this group of patients, and to provide a suitable alternative to total gastrectomy.
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PMID:Omeprazole in the treatment of Zollinger-Ellison syndrome: a 4-year international study. 297 29

It is strongly believed that cAMP mediates histamine H2 receptor activity, but does not mediate gastrin and acetylcholine stimulation of gastric acid secretion. Therefore, cAMP production could be a marker of H2 receptor activity. Whether endogenous histamine mediates gastrin and/or acetylcholine stimulation, at least partially, remains to be elucidated. If cAMP in the gastric juice reflects H2 receptor activity, we can investigate whether endogenous histamine mediates gastrin and/or acetylcholine stimulation in vivo. In this study, we investigated whether cAMP in the gastric juice reflected histamine H2 receptor activity in the Heidenhain pouch dog in vivo using different kinds of inhibitors of gastric secretion. Our hypothesis was as follows: Upon betazole stimulation, cimetidine, an H2 receptor antagonist, should decrease cAMP output into the gastric juice, but omeprazole, an H+, K+-ATPase blocker, should not, because it blocks at a site more peripheral than the H2 receptor and the production of cAMP. Sixty minutes after betazole administration, 4.0 mumol/kg of cimetidine and 0.18 mumol/kg omeprazole were administered intravenously and they inhibited gastric juice volume to a similar degree, that is, 49.6% and 52.1%, respectively. However, omeprazole caused a greater decrease in cAMP output than cimetidine. Inhibition with 4 mumol/kg/h of cimetidine or 0.2 mumol/kg of omeprazole from the beginning of betazole stimulation also caused similar decreases in gastric juice volume, 66.6% and 60.6%, respectively. Both inhibitors decreased cAMP output into the gastric juice in a similar fashion in the first two 30 minute periods. These results do not agree with our hypothesis.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cyclic AMP in gastric juice does not reflect histamine H2 receptor activity in Heidenhain pouch dog. 302 63

The parietal cells possess the unique capacity to produce large quantities of acid at a high concentration, and this is reflected in unique properties at the cellular level. The cells are comparatively large, and they are equipped with secretory canaliculi, a multitude of mitochondria, and cytoplasmic tubulovesicles. During secretion many of the tubulovesicles merge with the secretory canaliculi, which then expand. In the process H+, K+-ATPase is transferred from the tubulovesicular membrane to the secretory membrane. This enzyme catalyses the final step in the production of HCl. Parietal cell activity is regulated through receptors on the basolateral cell surfaces. In the isolated gland and in the isolated parietal-cell fractions, stimulation of receptors for histamine evokes higher secretion than receptor stimulation with cholinergic compounds or with gastrin. In these experimental models, specific inhibitors are required to block acid secretion; for example histamine H2-receptor antagonists will block histamine-induced secretion but will be inactive when secretion is evoked by gastrin or by cholinergic stimulation. These stimuli cause a more or less marked increase in the intracellular levels of Ca2+, which acts as a second messenger, leading to the activation of phosphokinases and, ultimately, to morphological transformation of the parietal cells and acid secretion. Another such intracellular messenger is cAMP, which is formed in response to histamine stimulation only; prostaglandins may prevent this process and block acid secretion. The final step in the production of acid requires K+ and Cl- channels in the secretory membrane and the H+, K+-ATPase-catalysed exchange of K+ for H+ across this membrane. This reaction consumes large amounts of energy and depends on the aerobic production of ATP by the parietal cells. Substituted benzimidazoles, such as omeprazole, accumulate in the acid compartments of the parietal cells and inhibit the H+, K+-ATPase, thereby blocking acid production.
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PMID:Physiology and pharmacology of the parietal cell. 304 49

The pharmacology, pharmacokinetics, clinical efficacy, adverse effects, and dosage and administration of omeprazole are reviewed. Omeprazole, a substituted benzimidazole, has a unique site and mechanism of action because it inhibits the proton pump--i.e., hydrogen, potassium adenosine triphosphatase (H+,K+-ATPase)--and consequently blocks the final common step in the gastric acid secretory pathway. Omeprazole inhibits basal and histamine-, gastrin- and pentagastrin-stimulated gastric hydrochloric acid secretion. It produces a dose-dependent reduction in gastric acidity, gastric acid output, and gastric juice volume and has variable effects on pepsin secretion. Omeprazole has no documented effect on esophageal motility or lower esophageal sphincter pressure. Omeprazole is variably absorbed from the gastrointestinal tract, and food appears to decrease the rate, but not the extent, of drug absorption. The drug is approximately 95% bound to plasma proteins and is metabolized to inactive components that are enterohepatically or renally eliminated. Omeprazole is more effective (in most studies) than H2-receptor antagonists in treating duodenal ulcer, at least as effective in treating benign gastric ulcer, and more effective in treating reflux esophagitis. Omeprazole has been used successfully in patients with Zollinger-Ellison syndrome refractory to treatment with H2-receptor antagonists. Gastrointestinal complaints (nausea and diarrhea) are the most commonly reported adverse effects associated with omeprazole therapy. The most frequently reported laboratory abnormality occurring with omeprazole use is elevation of serum aspartate aminotransferase and alanine aminotransferase concentrations. Omeprazole will serve a valuable role in the management of gastrointestinal tract ulcers and hypersecretory conditions.
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PMID:Therapeutic evaluation of omeprazole. 306 85

1. Gastric acid secretory responses to pentagastrin were characterized in the rat isolated gastric mucosa. In particular, the mechanisms underlying fade, declining response upon continued stimulation, and tachyphylaxis, progressively reduced responses upon repeated stimulation, were investigated. 2. Pentagastrin, 10(-9)-10(-7) M, resulted in concentration-related increases in acid secretion, with a mean maximum of 2.65 mumol cm-2 h-1 in response to pentagastrin, 10(-7) M. Higher concentrations of pentagastrin produced sub-maximal secretory rates; we define this as auto-inhibition. The responses to all concentrations of pentagastrin demonstrated fade. The rate of fade was correlated with the maximum acid secretory rate, declining at about 36% of the peak over the first 16 min. 3. The PO2, PCO2, [HCO3-], pH, [glucose], [lactate], [Na+] and [K+] did not decline during the fade of the acid secretory response to pentagastrin, 10(-7) M. Addition of a second aliquot of pentagastrin was not able to reverse fade, but these tissues were responsive to histamine. Replacement of the serosal solution, before addition of a second aliquot of pentagastrin, increased the acid response from 3% to 24% of the first response. 4. Serosal solution from donor tissues, allowed to respond to pentagastrin and then the acid secretion to fade, was able to stimulate secretion in fresh recipient tissues, although at lower rates. 5. Acid secretory responses to a second dose of pentagastrin were not significantly different, whether the tissues were previously unstimulated, or stimulated with pentagastrin washed out after attaining its peak secretory response (after 10-20 min). The second response was significantly reduced if the first response was allowed to fade with the pentagastrin in contact for 100 min; i.e. fade significantly influenced the extent of tachyphylaxis. 6. Proglumide, 10(-2) M, a gastrin receptor antagonist, and omeprazole, 10(-5) M, an inhibitor of the gastric (H+ + K+)-ATPase, both inhibited pentagastrin-stimulated acid secretion to similar extents. The second response to pentagastrin after pentagastrin alone, or pentagastrin plus omeprazole were both reduced compared to responses after no stimulation or omeprazole alone, respectively. After pentagastrin plus proglumide, the second response to pentagastrin was not lower than after proglumide alone. Proglumide, but not omeprazole, therefore, prevented pentagastrin tachyphylaxis. 7. It is concluded that gastrin fade and tachyphylaxis are related phenomena. Part of the fade may be due to release of an inhibitor(s). The major proportion of tachyphylaxis is a result of specific interaction of gastrin with its receptors.
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PMID:Fade and tachyphylaxis of gastric acid secretory response to pentagastrin in rat isolated gastric mucosa. 321 80

Mastomys is a rodent which has been reported to develop spontaneous antral endocrine tumors with acid hypersecretion and duodenal ulceration. This study documents the establishment of a breeding colony and the characterization of the tumors and their possible secretagogues. Parietal cell secretory characteristics were studied using isolated gastric glands (IGG) of both normal (n = 5) and tumor-bearing animals. Tumors (n = 6) and control gastric tissue samples were examined by light transmission microscopy and immunohistochemistry. Gastrin was measured by radioimmunoassay in both plasma and tissue. IGG were prepared by collagenase dispersion and acid sequestration assessed by [14C]AP accumulation. Secretory mechanisms of this species were identified by establishment of a histamine dose-response curve and use of 8-bromo-cAMP. Receptor and proton pump inhibitions were assessed using cimetidine (10(-5)M) and the H/K ATPase inhibitor omeprazole (10(-5]. Both reduced [14C]AP accumulation significantly (P less than 0.05). 8-Bromo-cAMP and histamine significantly stimulated [14C]AP accumulation (P less than 0.05). Although parietal cells were substantially increased in tumor animals as compared to controls, the physiological parameters of acid secretion appeared normal in both and were comparable to other species which have been studied. Tumors were Grimelius positive and contained diffuse electron-dense granules. Immunohistochemistry was negative for gastrin, bombesin, serotonin, neuron-specific enolase, calcitonin, and pancreatic polypeptide. Tumor histamine-like immunoreactivity was, however, positive. Normal stomach contained 1001 +/- 185 compared to less than 0.5 pmole/g gastrin in tumors. Plasma gastrin was normal in both groups (29 +/- 5) as compared to 26 +/- 8 pmole/liter. This study characterizes a spontaneous gastric endocrine tumor which is associated with apparent parietal cell hyperplasia and reports of increased acid secretion and duodenal ulceration. The observations are consistent with the elaboration by the tumor of a nongastrin acid-trophic secretagogue.
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PMID:Characteristics of the spontaneous gastric endocrine tumor of mastomys. 334 20

Omeprazole, a substituted benzimidazole inhibitor of the gastric H+/K+-ATPase, is a potent and long-acting antisecretory drug. Because of its high potency and because of the possible risk of long-term hypergastrinaemia intermittent therapy with this drug may be preferable to continuous treatment in patients requiring long-term treatment. We have therefore studied the effect of weekly 3-day courses of 20 mg/day omeprazole followed by a 4-day period without medication (weekend therapy) for 4 weeks on basal and bombesin- (150 ng/kg.h) and pentagastrin- (1.5 micrograms/kg.h) stimulated gastric acid secretion in 10 normal subjects. Gastric acid was measured in week 1, before (day 1) and immediately after the 3-day omeprazole course (day 4), and further on day 6 and day 8, immediately before the next course, and at similar intervals in week 4 (days 22, 25, 27, and 29). When compared with pretreatment values, basal and bombesin- and pentagastrin-stimulated gastric acid were significantly (p less than 0.01-p less than 0.05) inhibited on the days immediately after the courses (days 4 and 25) but were, except for a significant (p less than 0.05) reduction of pentagastrin-stimulated gastric acid on day 8, not significantly affected on all other days. Basal and integrated bombesin-stimulated serum gastrin values were not significantly changed, whereas bombesin-stimulated peak serum gastrin was significantly (p less than 0.05) increased on days 22 and 29. Since this schedule of omeprazole induces pronounced, but transient, inhibition of gastric acid secretion without provoking marked hypergastrinaemia, intermittent weekend therapy may be suitable for long-term maintenance treatment with this drug.
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PMID:Effect of intermittent weekend therapy with omeprazole on basal and bombesin- and pentagastrin-stimulated gastric acid and serum gastrin. 338 Oct 63

Dogs provided with a gastric fistula were treated orally for 1 week either with the H+, K+-ATPase inhibitor omeprazole, 80 mumol/kg once daily, or with the histamine H2 receptor antagonist ranitidine, 85-175 mumol/kg every 8 h. Acid secretion, serum gastrin levels and [3H]-thymidine incorporation in the corpus mucosa were determined before, during and after the treatment period. In order to examine differences between species, plasma gastrin levels and [3H]-thymidine incorporation in the oxyntic mucosa were also determined in female rats treated up to 1 week with omeprazole, 400 mumol/kg orally once daily. Histamine-stimulated gastric acid secretion in dogs treated with omeprazole or ranitidine was almost completely inhibited during the whole treatment period. As a consequence of that, the meal-stimulated gastrin levels were increased (7-fold) during treatment by both compounds. [3H]-thymidine incorporation in the dog corpus mucosa was increased approximately 4 times on day 5 both with omeprazole and ranitidine. After the treatment was stopped, gastric acid secretion, serum levels of gastrin and the rate of [3H]-thymidine incorporation were back to control level in both groups within 11 days. In the rats, the plasma gastrin levels increased 10-fold and the rate of [3H]-thymidine incorporation in the corpus mucosa increased 3-fold during treatment with omeprazole. In conclusion, a pronounced suppression of gastric acid secretion over the day with antisecretagogues results in hypergastrinemia in both dogs and rats. As a consequence of the trophic effect of gastrin, the incorporation of [3H]-thymidine in the oxyntic mucosa is increased.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of omeprazole and ranitidine on gastric acid secretion, blood gastrin levels and [3H]-thymidine incorporation in the oxyntic mucosa from dogs and rats. 341 Jan 71

Gastrin levels, in the peripheral venous blood of conscious dogs treated with apomorphine (0.05 mg/kg IV), were analysed with a radioimmunoassay. Pretreatment (30 min) with the gastric acid inhibitors cimetidine, ranitidine (H2 receptor antagonists, 4 mg/kg and 1 mg/kg respectively) or omeprazole (H+-K+ ATPase inhibitor, 1.6 mg/kg) prolonged the elevation of gastrin levels occurring in response to an administration of apomorphine. Haloperidol (0.1 mg/kg), but not the peripheral dopamine receptor antagonist domperidone (0.2 mg/kg), abolished the enhanced gastrin response to apomorphine occurring after pretreatment with cimetidine. Cimetidine did not increase the gastrin response to apomorphine in vagotomized dogs. The results are interpreted in terms of an additive gastrin response to apomorphine (different from the short lasting initial peak previously described) which is vagally mediated and inhibited by the gastric acid.
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PMID:A long lasting gastrin response to apomorphine revealed by inhibitors of gastric acid secretion. 362 88

It has been hypothesized that prolonged achlorhydria causes compensatory elevation of serum gastrin, and that there is an association in rats between sustained hypergastrinemia, hyperplasia of gastric enterochromaffin-like cells, and subsequent formation of gastric carcinoids in 2-year carcinogenicity studies. The present study examined whether daily administration of gastric antisecretory drugs in rats for 4 days could cause hypergastrinemia associated with inhibition of acid output. Rats were dosed orally for 4 days with the histamine H2-receptor antagonist ranitidine or the H+,K+-sensitive ATPase inhibitor omeprazole, and examined on day 5 for effects on gastric acid secretion and serum gastrin. Omeprazole (138 mg/kg/day significantly inhibited gastric acid secretion and increased serum gastrin levels. Large, single daily doses of ranitidine (1000-2000 mg/kg/day) had no effect on 24-hr acid or gastrin secretion; however, ranitidine did inhibit next-day acid secretion with associated increases in serum gastrin when administered in three divided doses. These results with ranitidine support the hypothesis that a sustained gastric antisecretory action will cause a compensatory hypergastrinemia, regardless of the antisecretory agent used. The ability to detect increased serum gastrin levels associated with inhibition of acid secretion, after administration of antisecretory agents for only 4 days, suggest that this short 5-day test may be useful for determining the potential of antisecretory agents to cause hypergastrinemia due to 24-hr inhibition of acid secretion and may be predictive of long-term hyperplastic changes.
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PMID:Use of a five-day test to predict the long-term effects of gastric antisecretory agents on serum gastrin in rats. 369 37


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