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 purpose of the present series of experiments was to measure and compare the effects of an anticholinergic drug (isopropamide) and an antagonist of the histamine H2 receptor (metiamide) on food-stimulated acid secretion. Patients with duodenal ulcers were stimulated by a steak meal, and acid secretion was measured by in vivo intragastric titration. The largest dose of isopropamide that can be taken clinically without producing intolerable side effects (maximum tolerated dose) suppressed food-stimulated acid secretion by 35%. By contrast, metiamide in a 400-mg dose produced no side effects and almost completely abolished food-stimulated acid secretion. A dose-response curve revealed that a 50-mg dose of metiamide was required to suppress food-stimulated acid secretion by 50%. Further studies showed that metiamide and isopropamide are additive in suppressing food-stimulated acid secretion, and that metiamide has no effect on serum gastrin concentration or on gastric emptying.
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PMID:The effect of an H2-receptor antagonist on food-stimulated acid secretion, serum gastrin, and gastric emptying in patients with duodenal ulcers. Comparison with an anticholinergic drug. 23 81

In a series of 24 hour studies, intragastric acidity and plasma gastrin concentration were measured simultaneously in 46 healthy subjects before, during, and 24 to 48 hours after abrupt withdrawal of a histamine H2 receptor antagonist regimen. For 34 days subjects were given either cimetidine 800 mg at night (n = 8), ranitidine 150 mg twice daily (n = 10), ranitidine 300 mg at night (n = 12), nizatidine 300 mg at night (n = 8), or famotidine 40 mg at night (n = 8). All subjects responded to H2 blockade by a decrease in 24 hour intragastric acidity. Withdrawal of H2 blockade resulted in a significant rise in median nocturnal integrated intragastric acidity in 42 of 46 subjects (+36%; 95% CI +19, +55%) compared with prestudy values, but this rise was not associated with a significant change in the median integrated plasma gastrin concentration (+1%; 95% CI -12, +13%). A statistically significant rise in nocturnal acidity was observed after all regimens, except after dosing with famotidine. After stopping, median daytime integrated acidity and plasma gastrin concentrations in the whole group were raised, but not significantly: values were +15% (95% CI +4, +34%) and +5% (95% CI -2, +12%), respectively. A statistically significant increase in daytime acidity was observed only after dosing with ranitidine. In conclusion, intragastric hyperacidity occurs in most subjects after abrupt withdrawal of a histamine H2 receptor blocker, but this phenomenon is not associated with hypergastrinaemia.
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PMID:Rebound intragastric hyperacidity after abrupt withdrawal of histamine H2 receptor blockade. 168 65

Certain substances when given orally to rats have effects on the neuroendocrine cells of the fundic stomach. Such compounds also have effects on acid or its secretion, which is to a greater or lesser extent suppressed, with a consequent rise in serum gastrin, followed by an increase in the number of histamine-secreting ECL cells. These changes are seen with the histamine H2 receptor antagonists loxtidine, SKF 93479, ICI 162,846 and ranitidine; with the hypolipidaemic agents clofibrate, ciprofibrate and benzofibrate; with sodium bicarbonate and pentagastrin; and with omeprazole, a potent inhibitor of the parietal cell proton pump mechanism. Changes in the pH of the rat stomach stimulate the neuroendocrine G cells of the pylorus to secrete gastrin, which acts on the ECL cells of the fundus causing the production of histamine, which in turn stimulates the parietal cell. This sequence leads to an excess of circulating gastrin, which is detectable within 5 days. Subsequently increases in the number of ECL cells occur, the hyperplasia being related to hypergastrinaemia and the degree of acid suppression. The hyperplastic response is rapid, being so obvious with loxtidine at 39 days that there is good reason to suppose it could well be detected earlier. Using omeprazole, hyperplasia was found at 28 days after oral doses of 140 mg/kg/day. In order to get an equivalent degree of acid suppression with ranitidine it was necessary to deliver 420 mg/kg/day by subcutaneous infusion using an osmotic minipump, when hyperplasia occurred. Interestingly, only omeprazole produced a hyperplastic response of G cells. Such results reflect the covalent binding of omeprazole to the proton pump as opposed to the competitive binding of ranitidine to the histamine H2 receptor site. In addition to ECL cell hyperplasia there is ample evidence from lifetime studies in rats and mice that neoplasia may result. Neuroendocrine carcinomas (carcinoids) of the rat fundic stomach have been observed with loxtidine, omeprazole, SKF 93479 and ICI 162,846. They are seen late in the 2-year rat studies and are most unlikely to have arisen purely as an extension of the hyperplastic response. It is possible that the prolonged disturbance of gastric homoestasis resulting from achlorhydria result in the production of a carcinogen or carcinogens, in which event it is not too surprising, in view of the neuroendocrine hyperplasia, that the tumours seen are neuroendocrine carcinomas.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Neuroendocrine cell hyperplasia and neuroendocrine carcinoma of the rodent fundic stomach. 204 87

Patients with hypergastrinaemic duodenal ulcer disease were studied to determine whether chronic moderate hypergastrinaemia produces hyperplasia of gastric enterochromaffin-like cells in man. Eight patients had peak postprandial plasma gastrin concentrations greater than 200 pmol/l, which is the 92nd percentile for patients with duodenal ulcer disease in this laboratory. The control group was eight patients with duodenal ulcers whose peak postprandial gastrin concentrations were less than 200 pmol/l. Basal and peak postprandial plasma gastrin concentrations were 107 (37) and 306 (66) pmol/l (mean (SEM] respectively in the hypergastrinaemic patients compared with 26 (4) and 137 (14) pmol/l respectively in the controls. There was no significant difference in the density of gastrin enterochromaffin-like cells between the two groups. The number of enterochromaffin-like cells per high power field was 53 (8) in the hypergastrinaemic patients compared with 50 (8) in the controls. We conclude that chronic moderate hypergastrinaemia does not produce hyperplasia of enterochromaffin-like cells in man. Our hypergastrinaemic group had plasma gastrin concentrations similar to, or greater than those reported during treatment with drugs such as omeprazole and histamine H2 receptor blockers.
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PMID:Gastric enterochromaffin-like (ECL) cells in hypergastrinaemic duodenal ulcer disease. 231 72

1. In the isolated vascularly-perfused stomach of the rat, gastrin 1-17 (520 pmol 1(-1)) increased acid output from basal values of 13.7 +/- 2.7 to 92.5 +/- 11.4 mumol h-1 and venous histamine output from 10.1 +/- 2.3 to 54.7 +/- 7.9 nmol h-1 (mean +/- s.e.mean). 2. The H1 receptor agonist 2-methylhistamine (10 mumol 1(-1)) increased acid output to 21.6 +/- 2.9 mumol h-1 (P less than 0.05) and reduced basal histamine output to 4.0 +/- 0.8 nmol h-1 (P less than 0.05). Gastrin-stimulated acid secretion and vascular histamine output was not significantly affected by 2-methylhistamine (10 mumol 1(-1)). 3. The H2 receptor agonist, impromidine, dose-dependently increased basal acid secretion, reaching a maximal value of 145.5 +/- 11.7 mumol h-1 with impromidine (10 mumol 1(-1)), and maximal gastrin-stimulated acid secretion to 167.4 +/- 15.1 mumol h-1 with impromidine (10 mumol 1(-1)). Impromidine dose-dependently inhibited basal and gastrin-stimulated vascular histamine output. 4. The H3 receptor agonist R-a-methylhistamine, (1 and 10 mumol 1(-1)) minimally increased basal acid secretion. R-a-methylhistamine (10 mumol 1(-1)) did not significantly affect maximal gastrin-stimulated acid secretion. Basal and gastrin-stimulated vascular histamine outputs decreased to 4.0 +/- 0.8 (P less than 0.05) and 24.7 +/- 4.7 nmol h-1 (P = 0.05) with R-a-methylhistamine (10 mumol 1(-1)). 5. The H2 receptor antagonist ranitidine (2 mumol 1(-1)) did not inhibit basal acid secretion, but acid outputs with gastrin and all histamine agonists were reduced. Ranitidine did not affect histamine release in the basal state, with gastrin or with any histamine agonist tested. 6 We conclude that gastric histamine release in the rat is regulated via a histamine H2 receptor sensitive to the histamine agonists tested, but not to ranitidine. It is unlikely that the inhibition of histamine release is secondary to increased gastric acidity.
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PMID:Histamine release in the isolated vascularly perfused stomach of the rat: regulation by autoreceptors. 247 Apr 53

The control of gastric secretion may be obtained by means of several pharmacological compounds: histamine H2 receptor antagonists and anticholinergics are so far the most widely employed drugs in pharmacological experiments and in clinical practice. The H2 blockers are able to inhibit the secretory response to histamine, acetylcholine and gastrin; they are effective and safe and at present they have been employed in several million patients suffering from diseases characterized by acid hyperproduction. The compounds available on the market are cimetidine, ranitidine, famotidine and nizatidine; however, approximately 11,000 compounds of the family have been synthesized and about 20 of these are under clinical evaluation. The blockade of H2 receptors is the primary action of these drugs; however, they possess also secondary actions which may represent untoward effects but in some cases may be actually useful (increase in prostaglandin synthesis, inhibition of LTB4 synthesis, etc.) The 'classic' anticholinergics appear to be decidedly less important mainly from a therapeutic point of view. However, the new compounds like pirenzepine and telenzepine, which block specifically the so-called M1 receptors located in the ganglia of the myenteric plexus, may represent an alternative to the H2 blockers since they are virtually devoid of the untoward reactions typical for the old atropine-like compounds (dry mouth, mydriasis, tachycardia, etc.) Both H2 blockers and the new antimuscarinic compounds may have effects not only on the parietal cells but also on other sites (G-cells, histaminocytes, D-cells) which control the function of the parietal cells themselves.
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PMID:Control of gastric acid secretion by histamine H2 receptor antagonists and anticholinergics. 257 Apr 17

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

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

Biological active 125I-synthetic human gastrin (125I- SHG ) appeared to bind specifically on human gastric mucosal membrane preparations. Gastrin binding was reversible, saturable and of high affinity (Kd = 3.44 +/- 3.44 X 10(-10)M) with the binding site (3.66 +/- 0.34 fmol/mg protein) at 37 degrees C for 30 min (pH 7.4). Specific gastrin binding was present in the fundic mucosa and absent from the antral, duodenal, jejunal, and colonic mucosa. Gastrin analogues (tetragastrin, pentagastrin, caerulein, and synthetic human gastrin) inhibited 125I- SHG specific binding. However, the specific gastrin binding was not inhibited by glucagon, insulin, acetylcholine, atropine, histamine, or cimetidine. It was suggested that gastrin and histamine H2 receptor or gastrin and muscarinic cholinergic receptor did not share the same locus.
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PMID:A specific gastrin receptor in human gastric mucosa. 632 54

A series of aminoalkyl-substituted pyridylureas has been prepared and evaluated as inhibitors of gastric acid secretion. N,N-Dimethyl-N'-[2-(diisopropylamino)ethyl]-N'-(4,6-dimethyl-2-pyridyl)urea (8g) was the most potent example of the class. Comparison of this compound with cimetidine showed it to be equipotent in dogs stimulated with gastrin tetrapeptide but approximately half as potent in dogs stimulated with histamine. Inhibition of secretion does not appear to result from antagonism of the histamine H2 receptor, since the compounds show only weak inhibition of the H2 receptor in vitro.
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PMID:Inhibitors of gastric acid secretion: antisecretory 2-pyridylurea derivatives. 683 86


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