Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P61278 (somatostatin)
 22,083 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The regulation of acid secretion was clarified by the development of H2-receptor antagonists in the 1970s. It appears that gastrin and acetylcholine exert their effects on acid secretion mainly by stimulation of histamine release from the enterochromaffin-like (ECL) cell of the fundic gastric mucosa. The isolated ECL cell of rat gastric mucosa responds to gastrin/cholecystokinin (CCK), acetylcholine, and epinephrine with histamine release and to somatostatin and R-alpha-methyl histamine by inhibition of histamine release. Histamine and acetylcholine stimulate the parietal cell by elevation of cAMP or [Ca]i by activation of H2 or M3 receptors, respectively. These independent pathways converge to activate the gastric acid pump, the H+,K+ ATPase. Activation is a function of the association of the ATPase with a potassium chloride transport pathway that occurs in the membrane of the secretory canaliculus of the parietal cell. Hence the secretory canaliculus is the site of acid secretion, the acid being pumped into the lumen of the canaliculus. The pump is composed of two subunits, a large catalytic and a smaller glycosylated protein. This final step of acid secretion has become the target of drugs also designed to inhibit acid secretion. The target domain of the benzimidazole class of acid pump inhibitors is the extracytoplasmic domain of the pump that is secreting acid, and the target amino acids are the cysteines present in this domain. The secondary structure of the pump can be analyzed by determining trypsin-sensitive bonds in intact, cytoplasmic-side-out vesicles of the ATPase, and it has been shown that the alpha subunit has at least eight membrane-spanning segments. Omeprazole, the first acid pump inhibitor, forms a disulfide bond with cysteines in the extracytoplasmic loop between the fifth and sixth membrane-spanning segment and to a cysteine in the extracytoplasmic loop between the seventh and eight segments, preventing phosphorylation of the pump by ATP. As a result of the effective and long-lasting inhibition of acid secretion by the acid pump inhibitor, superior clinical results have been found in all forms of acid-related disease.
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PMID:Acid secretion and the H,K ATPase of stomach. 134 Oct 65

The present report describes the long-term effects of antrectomy, antrum exclusion, portacaval shunt, omeprazole treatment, or the combination of omeprazole treatment and portacaval shunt on the number and density of somatostatin cells in the oxyntic mucosa of the rat. Antrectomy, which is associated with hypogastrinemia, raised the number and density of the somatostatin cells, whereas antrum exclusion and omeprazole treatment, which are associated with hypergastrinemia, reduced the number and density of the somatostatin cells. Portacaval shunt, which is associated with hypogastrinemia, increased both the number and the density. Omeprazole treatment of portacaval--shunted rats suppressed or even reversed the somatostatin cell hyperplasia after portacaval shunt alone. From these findings it is unlikely that gastrin stimulates the proliferation of somatostatin cells in the oxyntic mucosa. In fact, there seems to be an inverse relationship between the serum gastrin concentration and the somatostatin cell number.
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PMID:Somatostatin cells in the oxyntic mucosa of hypo- or hypergastrinemic rats. 135 9

Gastric acid secretion is regulated by an intricate interplay of neural (acetylcholine), hormonal (gastrin), and paracrine (histamine, somatostatin) mechanisms. Receptors for each of these agents and the signal transduction pathways to which these receptors are coupled have been identified on the parietal cell. The stimulatory effect of acetylcholine and gastrin is mediated by an increase in cytosolic calcium, whereas that of histamine is mediated by activation of adenylate cyclase and generation of cAMP. Strong potentiation between histamine and either gastrin or acetylcholine reflects postreceptor interaction between the distinct pathways as well as the ability of acetylcholine and gastrin to release histamine from mucosal ECL cells. The inhibitory effects of somatostatin on acid secretion are mediated by receptors coupled by guanine nucleotide-binding proteins to inhibition of adenylate cyclase activity. All the pathways converge on and modulate the activity of the luminal enzyme, H+K(+)-ATPase, the proton pump of the parietal cell. Precise information on the mechanisms involved in gastric acid secretion has led to the development of potent drugs capable of inhibiting acid secretion. These include competitive antagonists that interact with stimulatory receptors (e.g., histamine H2-receptor antagonists) as well as noncompetitive inhibitors of H+K(+)-ATPase (e.g., omeprazole). The histamine H2-receptor antagonists (cimetidine, ranitidine, famotidine, and nizatidine) continue as first-line therapy for peptic ulcer disease and are effective in preventing relapse. Although they are generally well tolerated, histamine H2-receptor antagonists may cause untoward CNS, cardiac, and endocrine effects as well as interference with the absorption, metabolism, and elimination of various drugs. Omeprazole is a weak base that reaches the parietal cell through the bloodstream, diffuses through the cytoplasm, and becomes activated and trapped as a sulfenamide in the acidic canaliculus of the parietal cell. It covalently binds to H+K(+)-ATPase, thereby irreversibly blocking acid secretion in response to all modes of stimulation. The main drawback to its use is its extreme potency, which leads to virtual anacidity, gastrin and ECL cell hyperplasia, hypergastrinemia, and, in rats, to the development of carcinoid tumors.
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PMID:Control of gastric acid secretion. Histamine H2-receptor antagonists and H+K(+)-ATPase inhibitors. 135 65

This study compares the effects of lansoprazole and omeprazole on the activation and proliferation of enterochromaffin-like (ECL) cells in the rat stomach. Lansoprazole was given orally once daily for 10 weeks in two doses, 135 and 200 mumol/kg. Omeprazole was given by the same regimen in a dose of 400 mumol/kg, which is equipotent in terms of acid inhibition to the higher lansoprazole dose. Lansoprazole (both doses) as well as omeprazole raised the plasma gastrin levels about 11-fold 2 h after dosing and 8-to 10-fold 24 h after dosing, reflecting complete (2 h) and 70-80% (24 h) reductions of gastric acid secretion. Administration of either drug for 10 weeks increased the weight of the stomach and the oxyntic mucosa. The oxyntic mucosal histidine decarboxylase activity, histamine concentration and ECL cell density were increased to the same extent in the rats given either of the two lansoprazole doses or omeprazole. The numbers of antral gastrin cells were doubled and the numbers of antral somatostatin cells half that in the controls. These results show that long-standing lansoprazole-evoked hypergastrinemia affects the ECL cell similarly to omeprazole, ranitidine and other acid secretion inhibitors.
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PMID:Lansoprazole and omeprazole have similar effects on plasma gastrin levels, enterochromaffin-like cells, gastrin cells and somatostatin cells in the rat stomach. 135 46

Gastrin, somatostatin, H+/K(+)-ATPase and carbonic anhydrase are principal elements of acid secretion. We investigated in the conscious sheep the effect of 24 h omeprazole (an H+/K(+)-ATPase inhibitor) infusion on these elements at the level of synthesis, storage and secretion. Omeprazole inhibited acid secretion-pH increased from 3.0 to 7.1 at 24 h. Plasma amidated and glycine extended gastrin increased 3-fold while the ratio of amidated to glycine extended gastrins (4:1) remained unchanged. Despite the increase in circulating gastrin, antral gastrin concentration and mRNA did not change significantly. Gastrin-17 (amidated and glycine extended) was the predominant form in the circulation and antrum, although there were preferential increases in larger forms following omeprazole treatment. Omeprazole had no effect on somatostatin mRNA or peptide levels in the fundus. Similarly, plasma somatostatin remained unchanged. However, antral somatostatin increased significantly (63%) following omeprazole treatment accompanied by a 4-fold increase in its mRNA. Fundic H+/K(+)-ATPase mRNA was unchanged but a significant increase (87%) in carbonic anhydrase II mRNA was observed. Omeprazole induced hypergastrinaemia occurred without a measurable reduction in storage or increased synthesis of gastrin at 24 h. Increased antral somatostatin synthesis and storage may result from stimulation by plasma gastrin on antral D cells, independent of acid. The rise in carbonic anhydrase II mRNA in the absence of any change in H+/K(+)-ATPase mRNA may reflect the differential sensitivity of the genes encoding these two enzymes to the stimulatory action of gastrin.
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PMID:Achlorhydria induced changes in gastrin, somatostatin, H+/K(+)-ATPase and carbonic anhydrase in the sheep. 135 10

The H+/K(+)-ATPase is the dimeric enzyme responsible for H+ secretion by the gastric parietal cells. The present study examined the response of rat fundic mRNA levels of H+/K(+)-ATPase alpha-subunit and somatostatin to the inhibition of H+/K(+)-ATPase enzyme activity and gastric pH elevation by oral omeprazole administration. Omeprazole inhibits the alpha-subunit of H+/K(+)-ATPase covalently and stabilizes stimulated morphology of the parietal cell. After a single administration of omeprazole (100 mg/kg), H+/K(+)-ATPase alpha-subunit mRNA levels increased significantly by 57% at 3 h and remained elevated for 6 h, returning to the basal level by 24 h. After multiple administrations of omeprazole (100 mg/kg per day, every 24 h for 3 days), H+/K(+)-ATPase alpha-subunit mRNA levels were already elevated at the time of the last dose, reached maximum at 6 h (95% increase above control), and returned to the pre-treatment level after 36 h. Nuclear run-on assay indicated H+/K(+)-ATPase gene transcription was significantly increased by omeprazole pretreatment in vivo. In contrast, a significant decrease in fundic somatostatin mRNA occurred at 12 h after a single dose, and the inhibition was more pronounced and lasted longer after multiple doses of omeprazole. These data indicate that omeprazole, while effectively inhibiting H+/K(+)-ATPase activity, induces H+/K(+)-ATPase gene expression in the parietal cells. An inverse relationship exists between the regulation of somatostatin gene expression in fundic D-cells and H+/K(+)-ATPase gene expression. The increase in H+/K(+)-ATPase alpha-subunit mRNA could be due to alterations in extracellular gastrin/somatostatin ratios or could be induced by intracellular effects of omeprazole.
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PMID:Regulation of rat gastric H+/K(+)-ATPase alpha-subunit mRNA by omeprazole. 168 16

Antral gastrin and somatostatin mRNA concentrations were measured in rats during gastric neutralization produced either by resection of the acid-secreting portion of the stomach (fundectomy) or by omeprazole treatment. Fundectomy caused increases in gastrin mRNA concentrations to 570% of sham control after 4 days and to 650% after 28 days. Daily administration of omeprazole resulted in significant dose- and time-dependent increases in antral gastrin mRNA concentrations. Four-day treatment with omeprazole caused threefold increased gastrin mRNA. Antral somatostatin mRNA concentrations decreased significantly after fundectomy to 66% of sham control after 4 days and to 23% after 28 days. Omeprazole produced a more profound decrease in somatostatin mRNA to 22% of the vehicle control after 4 days. Antral beta-actin mRNA concentrations did not differ significantly between control and experimental animals. Transcription of gastrin mRNA in isolated antral mucosal nuclei, measured by a nuclear run on technique, was significantly increased after omeprazole treatment in vivo. Increases in plasma and antral gastrin concentrations in response to gastric neutralization were closely associated with increases in gastrin mRNA and were accompanied by reductions in somatostatin mRNA in the antrum. However, fundectomy produced relatively greater increases in gastrin mRNA and lesser reductions in somatostatin mRNA than observed after omeprazole pretreatment.
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PMID:Effects of inhibition of gastric secretion on antral gastrin and somatostatin gene expression in rats. 169 93

The critically ill patient is at increased risk for developing erosive injury of the stomach, duodenum, and esophagus. To date, the most effective way to prevent and treat this problem is by assuring excellent intensive care support and by reducing gastric acid secretion. The histamine H2-receptor antagonists (H2RAs) are effective in both prevention and treatment of such gastric mucosal injury. Newer agents are available that have potential for use in this setting, although none have been studied as extensively in critically ill patients as have the H2RAs. These new agents include proglumide, pirenzepine, misoprostol, omeprazole, and somatostatin. To date, only the latter has been extensively studied in critically ill patients. Omeprazole, which suppresses acid very effectively, may be problematic in the critically ill, limited by its oral dosage form, acid-labile properties, and potential drug interactions.
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PMID:Controlling gastric pH: the impact of newer agents on the critically ill patient. 198 Jan 81

The effect of acute suppression of acid secretion induced by administration of a single dose of omeprazole (2 mg/kg body wt) on postprandial gastrin release was studied in 10 conscious dogs. In omeprazole-treated dogs, a sustained gastrin release was observed during a 10-h period after feeding, although greater than 95% of the meal had left the stomach after 4 h. This sustained gastrin release could be inhibited by acidification of the gastric lumen, by somatostatin, and by atropine. Insulin and bombesin induced considerable gastrin release in omeprazole-treated dogs, but plasma gastrin concentrations returned almost to basal values after 3 h. Omeprazole administered alone had no significant effect on basal gastrin levels. These data indicate that, in dogs, when acid secretion is suppressed by omeprazole a meal induces a sustained gastrin release lasting for up to 10 h. This gastrin release is probably related to the fact that food has been in contact with the gastric lumen, as neither vagal nor bombesin stimulation induced such a sustained activity of the G cells.
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PMID:Effect of acute suppression of acid secretion by omeprazole on postprandial gastrin release in conscious dogs. 257 Jul 28

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.
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PMID:Reciprocal regulation of antral gastrin and somatostatin gene expression by omeprazole-induced achlorhydria. 290 31


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