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)

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

The mechanism of action of gastrin was investigated using cytochemical quantitation of hydroxyl ion production (HIP) in guinea pig gastric oxyntic mucosa. The reaction depends upon the trapping of OH ions produced during gastric stimulation and is blocked by the benzimidazole, Hassle 149/94, which inhibits the K+ + H+-ATPase and by acetazolamide, an inhibitor of carbonic anhydrase activity. It is thus a measure of hydroxyl ions produced during stimulation of the oxyntic cell and reflects upon hydrogen ion production. Gastrin (2.5 X 10(-16) -2.5 X 10(-12) M) caused a linear dose-dependent stimulation of HIP in the oxyntic cells. The response was biphasic, with an early peak at 90 s and a secondary rise at 240 s, which persisted for 10 min. Natural human gastrin (sulfated and nonsulfated) and the active COOH-terminal octapeptide fragment of gastrin stimulated HIP, whereas the biologically inert NH2-terminal (1-13) fragment of gastrin had no effect. The activation of oxyntic cell HIP by gastrin was neutralized by an antiserum directed towards the COOH-terminus of gastrin and not by nonimmune serum. Cimetidine (10(-5) M) blocked 25% and atropine (10(-5) M) had no effect on gastrin-stimulated HIP. EGTA (10(-3) M) and LaCl3 (10(-3) M) inhibited the action of gastrin by 67 and 52%, respectively. The calmodulin antagonists, trifluoperazine (10(-5) M), pimozide (10(-5) M), and the naphthalene sulfonamides, W-7 and W-13 (10(-5) M), inhibited gastrin-stimulated HIP by 45.6 38.5, 42.3, and 37.2%, respectively. Higher doses of W-7 and W-13 (10(-4) M) inhibited gastrin-stimulated HIP by 83 and 67%. The Ca2+ ionophore, A23187 (10(-4) M), stimulated HIP. Thus, it appears that gastrin stimulation of HIP is complex. 25% of its action is via a histamine-dependent pathway. 45% of its action is dependent upon extracellular Ca2+. Its action is also in part dependent upon a Ca2+/calmodulin mechanism.
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PMID:Action of gastrin in guinea pig oxyntic cells. Studies using quantitative cytochemistry. 633 Jan 72

We have studied the physiologic factors regulating oxyntic cell activity using cytochemical quantification of carbonic anhydrase (CA) activity. Gastrin (10 (-16) to 10(-12)M), histamine (10(-17) to 10(-13) M), and carbamylcholine (10(-13) to 10(-8) M) caused a dose-dependent increase in CA in the oxyntic cells in guinea pig gastric fundus, maximal at 90 sec. The stimulation of CA by all three secretagogues was inhibited by the CA inhibitor, acetazolamide. The agonist activities were selectively blocked by respective antagonists. The benzimidazole derivative compound Hassle 149/94 (10(-3)M) abolished the actions of all agonists. Thus, histamine, gastrin and carbamylcholine have independent actions on oxyntic cell CA. The inhibition of the activity of all three secretagogues by H149/94 suggests a close link between CA activity and the functioning of the proton pump H+ + K+-ATPase.
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PMID:Cytochemical quantification of physiologic regulation of oxyntic cell carbonic anhydrase. 643 Jan 97

Isolated guinea pig parietal cells, the function of which is similar to that of human parietal cells, were used in this study. The accumulation of 14C-aminopyrine (14C-AP) was measured to study the inhibitory mechanism of leminoprazole in cells. Stimulation by 10 microM histamine, 0.1 mM carbachol, 1 microM gastrin or 1 mM db-cAMP brought about satisfactory incorporation of 14C-AP, and leminoprazole concentration-dependently inhibited acid secretion induced by these stimulants. At 10(-5) M, almost 100% inhibition was observed. The IC50 values of leminoprazole obtained from its inhibitory action on histamine, carbachol, gastrin and db-cAMP-stimulated acid secretion were 4.0 x 10(-7) M, 3.5 x 10(-7) M, 2.5 x 10(-7) M and 5.6 x 10(-7) M, respectively. Thus the extent of inhibition was the same for the responses to all the secretagogues. These results indicate that the site of action of leminoprazole is intracellular and distal from cAMP (intracellular second messenger), but not at the receptor sites. The results also strongly suggest that the inhibitory action of leminoprazole on H+,K(+)-ATPase may contribute to the inhibitory effect of this drug on gastric acid secretion.
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PMID:Inhibitory effect of leminoprazole on acid secretion in parietal cells isolated from guinea pig gastric mucosa. 749 78

Peripheral regulation of gastric acid secretion is initiated by the release of gastrin from the G cell. Gastrin then stimulates the cholecystokinin-B receptor on the enterochromaffin-like cell beginning a calcium signaling cascade. An exocytotic release of histamine follows with concomitant activation of a C1- current. The released histamine begins the H2-receptor mediated sequence of events in the parietal cell, which results in activation of the gastric H+/K+ - ATPase. This enzyme is the final common pathway of acid secretion. The H+/K+ - ATPase is composed of two subunits: the larger alpha-subunit couples ion transport to hydrolysis of ATP, the smaller beta-subunit is required for appropriate assembly of the holoenzyme. Both the membrane and extracytoplasmic domain contain the ion transport pathway, and therefore, this region is the target for the antisecretory drugs of the post-H2 era. The 100 kDa alpha-subunit has probably 10 membrane spanning segments with, therefore, five extracytoplasmic loops. The 35 kDA beta-subunit has a single membrane spanning segment, and most of this protein is extracytoplasmic with the six or seven N glycosylation consensus sequences occupied. Omeprazole is an acid-accumulated, acid-activated, prodrug that binds covalently to two cysteine residues at positions 813 (or 822) and 892, accessible from the acidic face of the pump. Lansoprazole binds to cys321, 813 (or 822) and 892; pantoprazole binds to cys813 and 822. The common binding site for these drugs (cys813 or 822) is responsible for the inhibition of acid transport. Covalent inhibition of the acid pump improves control of acid secretion, but since the effective half life of the inhibition in man is about 48 hr, full inhibition of acid secretion, perhaps necessary for eradication of Helicobacter pylori in combination with a single antibiotic, will require prolongation of the effect of this class of drug.
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PMID:Gastric acid secretion: activation and inhibition. 750 35

Both receptor antagonists and acid pump inhibitors are clinically useful suppressants of acid secretion. The latter class of drugs, the substituted benzimidazoles, inhibit acid secretion more effectively and, therefore, provide superior symptom relief and healing in all acid-related diseases. The H2-receptor antagonists competitively block the action of histamine on the H2-receptors of parietal cells. This histamine is released from enterochromaffin-like cells (ECL cells) due to gastrin, acetylcholine or epinephrine stimulation. In addition, parietal cells have M3-receptors which can function independently of H2-receptors. Hence, there is no single common pathway for parietal cell stimulation. Stimulation of acid secretion by parietal cells requires activation of the acid pump, the gastric H+,K(+)-ATPase. The target site for the benzimidazoles is the activated gastric H+,K(+)-ATPase, and, in particular, the cysteines of the pump that are exposed to the acid space of the secretory canaliculus of the parietal cells. Pantoprazole in its protonated form selectively reacts with cysteines present in both the fifth and sixth membrane segments of the ATPase, explaining its mechanism of inhibiting proton transport by this enzyme.
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PMID:Continuing development of acid pump inhibitors: site of action of pantoprazole. 751 42


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