Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P01350 (gastrin)
 9,683 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.
 ...
PMID:Effect of omeprazole on gastric acid secretion and plasma gastrin. 249 58

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.
 ...
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)
 ...
PMID:Biological basis of omeprazole therapy. 256 65

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.
 ...
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.
 ...
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.
 ...
PMID:Review: antisecretory drugs: cellular mechanisms of action. 297 19

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.
 ...
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)
 ...
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.
 ...
PMID:Physiology and pharmacology of the parietal cell. 304 49

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.
 ...
PMID:Fade and tachyphylaxis of gastric acid secretory response to pentagastrin in rat isolated gastric mucosa. 321 80


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>