Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01350 (gastrin)
 9,683 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The prevalence and development of antibodies to H+,K+-ATPase were investigated with a sensitive enzyme-linked immunosorbent assay in 86 patients with autoimmune atrophic gastritis (type A). Sixty-nine of the patients had pernicious anemia, and 17 had simple atrophic gastritis. Elevated titers were found in 93% of pernicious anemia probands. Women had higher levels than men: 3.24 versus 1.58 U/l (p = 0.002) (upper reference limit, 0.55 U/l). The antibody levels did not change over 1-4 years, but a gradual decrease in titers over decades was observed. All patients with pernicious anemia had low levels of pepsinogen A, a product of the gastric chief and mucous neck cells (median, 8.5 micrograms/l; reference range, 10-90 percentile, 64.4-195.5 micrograms/l), and elevated serum gastrin values (greater than 55 pmol/l) were found in 87%. Serum pepsinogen A, but not serum gastrin, correlated with H+,K(+)-ATPase antibody titers (r = 0.35, p = 0.01). In the 17 cases with simple atrophic gastritis, H+,K(+)-ATPase antibodies correlated inversely with fundic mucosal gland destruction. The data indicate that H+,K(+)-ATPase antibody titers reflect the immune responsiveness of a given patient as well as the antigenic amount, dependent on the degree of mucosal destruction and the duration of the disease.
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PMID:H+,K-ATPase antibodies in autoimmune gastritis: observations on the development of pernicious anemia. 184 12

Prolonged achlorhydria leads to hypergastrinemia which must be matched by increased gastrin production. The extent to which the balance between synthesis and storage or secretion is shifted in achlorhydria remains uncertain. In the present study, rats were treated for 14 days with the hydrogen-potassium-stimulated ATPase inhibitor omeprazole, and the effects on plasma and tissue gastrin concentrations and on the abundance of gastrin messenger RNA were examined. To calculate the fractional release rates of gastrin, the metabolic clearance rate of synthetic unsulfated rat heptadeca peptide gastrin in anesthetized rats was also measured. Treatment with omeprazole for 14 days led to a profound hypergastrinemia, a twofold increase in antral gastrin stores, and a tenfold increase in messenger RNA. Calculations based on the metabolic clearance rate for rat heptadecapeptide gastrin suggested that in control rats, about 0.08% of stored gastrin was released per minute compared with about 0.4% in omeprazole-treated rats. No evidence was observed to suggest that changes in the efficiency of conversion of Gly-extended gastrins to amidated peptides were of any significance in accounting for the increased production of amidated gastrin. The increased gastrin synthesis in achlorhydria is therefore attributable to increased messenger RNA levels; most of the increase in gastrin production is directly secreted as changes in the stores of gastrin appear to be of lesser importance.
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PMID:The secretory kinetics of the G cell in omeprazole-treated rats. 201 68

Omeprazole is a specific inhibitor of H+,K(+)-ATPase or 'proton pump' in parietal cells. This enzyme is responsible for the final step in the process of acid secretion; omeprazole blocks acid secretion in response to all stimuli. Single doses produce dose-dependent inhibition with increasing effect over the first few days, reaching a maximum after about 5 days. Doses of omeprazole 20mg daily or greater are able to virtually abolish intragastric acidity in most individuals, although lower doses have a much more variable effect. Omeprazole causes a dose-dependent increase in gastrin levels. Omeprazole must be protected from intragastric acid when given orally, and is therefore administered as encapsulated enteric-coated granules. Absorption can be erratic but is generally rapid, and initially the drug is widely distributed. It is highly protein-bound and extensively metabolised. Its elimination half-life is about 1h but its pharmacological effect lasts much longer, since it is preferentially concentrated in parietal cells where it forms a covalent linkage with H+,K(+)-ATPase, which it irreversibly inhibits. Omeprazole binds to hepatic cytochrome P450 and inhibits oxidative metabolism of some drugs, the most important being phenytoin. Omeprazole has produced short term healing rates superior to the histamine H2-receptor antagonists in duodenal ulcer, gastric ulcer and reflux oesophagitis. It has also been shown to be highly effective in healing ulcers which have failed to respond to H2-receptor antagonists, and has been extremely valuable in treating patients with Zollinger-Ellison syndrome.
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PMID:Clinical pharmacology of omeprazole. 202 1

The H2-antagonist loxtidine and the H+/K(+)-ATPase inhibitor omeprazole inhibit gastric acid secretion and both have been associated with the appearance of gastric tumours in rat cancer studies. Loxtidine is not genotoxic in a range of in vitro and in vivo assays. As false negative results can occur if the organotropic nature of the drug is not considered, both drugs were evaluated using an assay which estimates the uptake of tritiated thymidine by cells of the gastric mucosa (the target tissue) in comparison with the positive control, N-methyl-N-nitro-nitrosoguanidine (MNNG), which others have shown to induce genetic damage in the stomach mucosa of rats. Such uptake may be, in part, indicative of unscheduled DNA synthesis (UDS) resultant from genotoxic damage. Serum gastrin levels were also determined at various times after either loxtidine or omeprazole treatment. Increased uptake of tritiated thymidine was only obtained after omeprazole or MNNG treatment, when this was estimated scintillometrically. The nature of the formulation of omeprazole was critical. The uptake of tritiated thymidine was greatest when omeprazole was administered in vehicle which had been buffered to pH 9. These effects were unlikely to be due to the trophic effects of gastrin since serum gastrin levels were similar after either loxtidine or omeprazole treatment. Autoradiographic analysis of stomach sections was also carried out and revealed a 2- to 3-fold increase in the number of labelled cells within the fundic mucosa as compared to the control values after treatment with MNNG or Losec (enteric coated granules of omeprazole).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Uptake of tritiated thymidine by cells of the rat gastric mucosa after exposure to loxtidine or omeprazole. 203 67

The rabbit gastric gland model was used to study the nature of the muscarinic cholinergic and gastrin responses of parietal cells. Carbachol (100 microM) stimulation of acid secretion, as measured by the accumulation of aminopyrine, was inhibited by the M1 antagonist pirenzepine with an IC50 of 13 microM; by the M2 antagonist 11,2-(diethylamino)methyl-1-piperidinyl acetyl-5,11-dihydro-6H-pyrido 2,3-b 1,4-benzodiazepin-6-one (AF-DX 116) with an IC50 of 110 microM; and by the M3 antagonist diphenylacetoxy-4-methylpiperidinemethiodide (4-DAMP) with an IC50 of 35nM. The three antagonists displayed similar IC50 values for the inhibition of carbachol-stimulated production of 14CO2 from radiolabeled glucose, which is a measure of the turnover of the H(+)-H(+)-ATPase. Intracellular calcium levels wer measured in gastric glands loaded with FURA2. Carbachol was shown both to release calcium from an intracellular pool and to promote calcium entry across the plasma membrane. The calcium entry was inhibitable by 20 microM La3+. The relative potency of the three muscarinic antagonists for inhibition of calcium entry was essentially the same as for inhibition of acid secretion or metabolism. However, the rise in cell calcium due to release of calcium from intracellular stores was inhibited by 4-DAMP with an IC50 of 1.7 nM. Image analysis confirmed that the effect of carbachol and of the antagonists on intracellular calcium was occurring in the partial cell. In particular, the high-affinity inhibition of calcium release by 4-DAMP occurs in the parietal cell. Accordingly, it appears that the secretory receptor of the parietal cell is of the M3 type, and acid secretion depends on the entry of calcium rather than on calcium release from intracellular stores. In parallel experiments gastrin (G-17-sulfated) produced a dose-dependent increase in intracellular calcium (EC50, 0.14 +/- 0.013 microM). No stimulation of acid secretion was observed, but pepsinogen secretion was stimulated dose-dependently (EC50 = 1.17 +/- 0.21 microM).
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PMID:Second messengers in the gastric gland: a focus on calcium. 204 37

We have investigated the effects of melatonin (Mel) and N-acetylserotonin (NAc-5HT) on the mitotic activity of gastric and colonic mucosa in adult male rats under basal conditions and after an administration of omeprazole (OM) (H+,K(+)-ATPase inhibitor). The metaphase-arrest technique was applied in the study. Additionally, serum gastrin levels were measured by RIA method in the OM-treated group and in respective polyethyleneglycol (PEG)-administered controls. We have found that: 1) OM-treatment increased serum gastrin levels in rats; 2) OM enhanced the mitotic activity of the colonic mucosa cells, although, unexpectedly, it did not exert such an effect on the gastric mucosa cells; 3) Mel suppressed the OM-induced increase of the colonic epithelium cell proliferation, while NAc-5HT failed to reveal that action: 4) NAc-5HT decreased the proliferation of gastric mucosa epithelial cells. The value of the mean mitotic activity rate (MMAR) of gastric mucosa after Mel-treatment also decreased, but that change was not statistically significant. The obtained data are in compliance with previous results from our laboratory concerning the inhibitory effect of pineal indoleamines on the jejunal epithelium mitotic activity. The stimulatory effect of OM on the proliferation of colonic epithelium is probably mediated by OM-induced hypergastrinaemia. The possibility of Mel interaction with intestinal gastrin receptors (a structural similarity occurs between Mel and benzotript, a specific gastrin receptor antagonist), as well as of the opposite effects of Mel and gastrin on intracellular cAMP content in the gut, are considered in the discussion of results.
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PMID:Influence of pineal indoleamines on the mitotic activity of gastric and colonic mucosa epithelial cells in the rat: interaction with omeprazole. 205 33

As clinical experience with patients with ZES has grown, increasing recognition has been made of the broad spectrum of symptoms associated with gastrinomas. Diarrhea and acid-induced esophageal injury have taken their place alongside chronic peptic ulcer disease as indications for screening for gastrinoma. Diagnostic testing should begin with fasting serum gastrin levels and should include intravenous secretin infusion if fasting serum levels of gastrin are nondiagnostic and the patient is not found to be hypochlorhydric. Tumor localization is critical to aid in the identification of patients with potentially curable localized disease. Preoperative evaluation utilizing CT scanning with intravenous contrast should be done early and should be supplemented by other imaging modalities as necessary. Exploratory laparotomy, including a thorough examination of the duodenum and perhaps intraoperative ultrasound, should be performed in all patients with sporadic gastrinoma who lack evidence of extensive metastatic disease on preoperative evaluation. By utilizing this approach, it is likely that at least 20% of patients with ZES can be cured. With the availability of the highly effective H(+)-K(+)-ATPase inhibitor omeprazole, excellent control of symptoms related to gastric acid hypersecretion can be expected. Patients with unresectable gastrinoma may thus avoid potentially morbid antisecretory surgery and be managed with a fairly simple medical regimen. Further developments in the chemotherapeutic management of these patients with unresectable disease should be forthcoming in the future.
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PMID:Zollinger-Ellison syndrome. 207 95

The objective of the study was to investigate the pharmacodynamics and pharmacokinetics of the gastric H+, K(+)-ATPase inhibitor pantoprazole in man following repeated i.v. dosing. 8 healthy male volunteers aged from 25 to 31 years (median: 29 years), body weight between 72 and 95 kg (median: 82 kg) entered this single-blind two-period cross-over study. Each subject underwent two treatment periods of 5 days each with daily infusion of 15 mg or 30 mg pantoprazole, respectively. A placebo day preceeded the trial. On the placebo day as well as on days 1, 4 and 5 of each treatment period, gastric secretion was stimulated submaximally by a pentagastrin infusion of 0.6 micrograms/h/kg over a period of 4 h, starting one hour before administration of drug or placebo. Repeated once-daily infusion (15 min) of pantoprazole resulted in a rapidly increasing pharmacodynamic effect: as compared to placebo the mean percent inhibition of acid output measured from 1 to 3 h after start of infusion was 22%, 63% and 78% for the 15 mg dose, and 56%, 97% and 99% for the 30 mg dose on days 1, 4 and 5, respectively. The pH also increased in relation to the dose and the duration of treatment. Mean fasting gastrin serum concentrations increased by about 50%, yet remained within the normal range. Only in one subject, one of the individual values was above the upper limit of the normal range.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Pentagastrin-stimulated gastric acid secretion and pharmacokinetics following single and repeated intravenous administration of the gastric H+, K(+)-ATPase-inhibitor pantoprazole (BY1023/SK&F96022) in healthy volunteers. 217 96

An acute challenge with gastrin-17 enhanced the uptake of 45Ca into sternum and several long bones in rats by about 10-30%; gastrectomy prevented this effect. Long-term treatment with (Leu15)-gastrin-17 (continuous infusion via osmotic minipumps for 4 weeks) enhanced the uptake of 45Ca into bone (examplified by radius and sternum) by 18-26% (tested on the last day of the infusion). Surgical removal of the acid-producing part of the stomach (fundectomy) or treatment with the anti-ulcer drugs, ranitidine (a histamine H2-receptor antagonist administered by continuous infusion) or omeprazole (an H+/K(+)-ATPase inhibitor administered daily by gastric tube for 4 weeks), induced sustained hypergastrinemia (through loss of acid feedback inhibition of gastrin release). The ranitidine- and omeprazole-evoked hypergastrinemia was associated with 32-62% enhancement of bone 45Ca uptake but the hypergastrinemia of fundectomized rats was not. Gastrectomy abolished the effect of omeprazole. We suggest that exogenous and endogenous gastrin influences calcium uptake into bone indirectly by releasing a calciotropic hormone (gastrocalcin) from the acid-producing part of the stomach. The bone ash weight was reduced by gastrectomy or fundectomy (4 weeks), but neither ranitidine nor omeprazole-evoked hypergastrinemia (4 weeks) raised the bone ash weight. The stimulated calcium uptake into bone of hypergastrinemic rats treated with ranitidine or omeprazole was associated with a 22-32% increase in the density of osteoclasts in the tibia. This finding is in line with the hypothesis that long-lasting hypergastrocalcinemia produces accelerated turn-over of bone rather than increased bone calcium content.
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PMID:Evidence that gastrin enhances 45Ca uptake into bone through release of a gastric hormone. 232 3

Basal, pentagastrin- and histamine-stimulated acid secretion were measured in gastric fistula rats treated with the H+/K(+)-ATPase inhibitor, omeprazole, and the H2-receptor antagonist, ranitidine. All doses of omeprazole (20, 30, 40, 80, 400 mumol/kg) and ranitidine (125, 187.5, 250, 375 mumol/kg) essentially abolished the basal acid output for various periods of time. Omeprazole, 80 mumol/kg, administered twice daily, reduced the 24-h basal acid secretion more effectively than did 400 mumol/kg given once daily. Four daily administrations of ranitidine reduced the 24-h basal acid output to a similar extent as omeprazole administered twice. Omeprazole (20, 80 mumol/kg) was more effective than ranitidine (125, 375 mumol/kg) in inhibiting acid secretion evoked by maximal doses of pentagastrin (650 nmol/kg per h) and histamine dihydrochloride (136 mumol/kg), whereas this difference was less pronounced for the inhibition of acid responses induced by a threshold dose (1.1 mumol/kg) of histamine. The inhibition evoked by omeprazole (80 mumol/kg x 2) and ranitidine (375 mumol/kg x 4) of basal and histamine (1.1 and 136 mumol/kg)-induced acid secretion was similar after 1 and 4 weeks of treatment. After the end of drug administration, the acid secretion induced by threshold doses of histamine was significantly elevated in the omeprazole-treated rats, whereas no significant hypersecretion of acid was seen during the recovery period in rats treated with ranitidine. Plasma gastrin concentrations were significantly elevated after 4 weeks of treatment with omeprazole but returned to pretreatment levels after 4 weeks of recovery.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Time course of inhibition of gastric acid secretion by omeprazole and ranitidine in gastric fistula rats. 236 99


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