Gastrin Receptor Research Articles

The regulation of gastric acid secretion – clinical perspectives

The purpose of this review, based upon 40years of research, is to clear old controversies. The gastric juice is a strong acid with active enzymes (pepsin and lipase); ideal for killing swallowed microorganisms. Totally isolated rat stomach and histamine determination. Human gastric carcinomas were examined for ECL cell differentiation because tumours found in rodents after dosing with inhibitors of acid secretion were reclassified to be of ECL cell origin. The gastrin receptor is localized to the ECL cell only, where gastrin stimulates the function and growth. Drug-induced hypo-acidity induces hypergastrinaemia and ECL cell hyperplasia responsible for rebound acid hypersecretion. Every condition with long-term hypergastrinaemia disposes to ECL cell neoplasia. In man, both atrophic gastritis and gastrinoma lead to ECL cell carcinoids. Proton pump inhibitors induce hypergastrinaemia with ECL cell hyperplasia and ECL cell carcinoids that disappear when stopping treatment. The gastrin antagonist netazepide induces regression of ECL cell carcinoids due to atrophic gastritis. Human gastric carcinomas of diffuse type, particularly the signet-ring subtype, show ECL cell differentiation, suggesting involvement of gastrin in the carcinogenesis. Helicobacter pylori (Hp) causes gastritis and peptic ulcer, and when infecting the antrum only gives a slight hypergastrinaemia with acid hypersecretion predisposing to duodenal ulcer, but protecting from gastric cancer. When Hp infection spreads to oxyntic mucosa, it induces atrophy, reduced acid secretion and marked hypergastrinaemia and cancer.It is remarkable that the interaction between Hp and gastrin may explain the pathogenesis of most diseases in the upper gastrointestinal tract.

The gastrin/cholecystokinin-B receptor on prostate cells – A novel target for bifunctional prostate cancer imaging

The means of identifying prostate carcinoma and its metastases are limited.The contrast agents used in magnetic resonance imaging clinical diagnostics are not taken up into the tumor cells, but only accumulate in the interstitial space of the highly vasculated tumor.We examined the gastrin/cholecystokinin-B receptor as a possible target for prostate-specific detection using the C-terminal seven amino acid sequence of the gastrin peptide hormone. The correct sequence and a scrambled control sequence were coupled to the fluorescent dye rhodamine and the magnetic resonance imaging contrast agent gadolinium (Gd)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA).Expression analysis of the gastrin receptor mRNA was performed by reverse transcriptase polymerase chain reaction on PC3 prostate carcinoma cells, U373 glioma, U2OS osteosarcoma and Colo205 colon carcinoma cells. After having confirmed elevated expression of gastrin receptor in PC3 cells and very low expression of the receptor in Colo205 cells, these two cell lines were used to create tumor xenografts on nude mice for in vivo experiments.Confocal lasers scanning microscopy and magnetic resonance imaging showed a high specificity of the correct conjugate for the PC3 xenografts. Staining of the PC3 xenografts was much weaker with the scrambled conjugate while the Colo205 xenografts showed no marked staining with any of the conjugates.In vitro experiments comparing the correct and scrambled conjugates on PC3 cells by magnetic resonance relaxometry and fluorescence-activated cell sorting confirmed markedly higher specificity of the correct conjugate.The investigations show that the gastrin receptor is a promising tumor cell surface target for future prostate-cancer-specific imaging applications.

Correction: Netazepide, a Gastrin Receptor Antagonist, Normalises Tumour Biomarkers and Causes Regression of Type 1 Gastric Neuroendocrine Tumours in a Nonrandomised Trial of Patients with Chronic Atrophic Gastritis

Correction: Netazepide, a Gastrin Receptor Antagonist, Normalises Tumour Biomarkers and Causes Regression of Type 1 Gastric Neuroendocrine Tumours in a Nonrandomised Trial of Patients with Chronic Atrophic Gastritis

Effect of repeated doses of netazepide, a gastrin receptor antagonist, omeprazole and placebo on 24 h gastric acidity and gastrin in healthy subjects

To administer repeated oral doses of netazepide to healthy subjects for the first time, to assess safety, tolerability, pharmacokinetics and effect on 24 h gastric pH and plasma gastrin. We did two randomized, double-blind, parallel group studies. The first compared netazepide 25 and 100 mg 12 hourly, omeprazole 20 mg once daily and placebo for 7 days. On day 7 only, we measured pH and assayed plasma gastrin. The second study compared netazepide 5, 10 and 25 mg and placebo once daily for 14 days. We measured pH on days 1, 7 and 14 and assayed plasma gastrin on days 1 and 14. We compared treatments by time gastric pH ≥ 4 during 0-4, 4-9, 9-13 and 13-24 h after the morning dose, and by plasma gastrin. P < 0.05 was significant. Netazepide was well tolerated. On day 7 of the first study, netazepide increased pH significantly only during 9-13 h after the 100 mg dose, whereas omeprazole raised pH significantly during all periods. Both netazepide and omeprazole increased plasma gastrin significantly. Netazepide had linear pharmacokinetics. In the second study, netazepide caused dose-dependent, sustained increases in pH on day 1, but as in the first study, netazepide had little effect on pH on days 7 and 14. Again, netazepide increased plasma gastrin significantly. Although repeated doses of netazepide led to tolerance to its effect on pH, the accompanying increase in plasma gastrin is consistent with continued inhibition of acid secretion, via gastrin receptor antagonism and gene up-regulation.

Effects and mechanisms of ceramide signaling pathway in gastrin-inhibited cell apoptosis of large intestinal cancer

Objective To investigate the effects and mechanisms of ceramide signaling pathway in gastrin-inhibited cell apoptosis of large intestinal cancer.Methods Gastrin group and proglumide group were divided into five different densities with concentration gradient of gastrin and proglumide being 6.25,12.50,25.00,50.00,100.00 mg/L and 8.00,16.00,32.00,64.00,128.00 mg/L,respectively.The changes of proliferation of the HT-29 cells were detected by methyl thiazol tetrazolium (MTT) assay,and the optimal concentrations of gastrin and proglumide were determined.The changes of apoptosis rate of HT-29 cells were detected by using flow cytometry.The mRNA expression levels of gastrin receptor/cholecystokinin-B receptor (CCK-BR),ceramide,p38,B lymphocytes/leukemia-2 (bcl-2) and bcl-2 associated X protein (bax) were detected by using reverse transcriptase-polymerase chain reaction (RT-PCR).The protein expression levels of bcl-2,bax and ceramide,and p38 phosphorylation levels were detected by using Western blotting.Results Gastrin could promote the proliferation of HT-29 cells,and the optimal concentration was 25 mg/L (F =31.36,P ＜ 0.05).Proglumide could significantly inhibit the proliferation of HT-29 cells stimulated by gastrin,and the optimal concentration was 32 mg/L (F =24.31,P ＜ 0.05).The apoptosis rate of the gastrin group was significantly lower than in the control group and the gastrin + proglumid group (q =4.23,4.06,P ＜0.05).The mRNA and protein expression of bax and the levels of phosphorylated ceramide protein and phosphorylated p38 protein in the gastrin group were significantly lower than in the control group,the proglumid group,and the gastrin + proglumid group (q =5.50,6.00,7.50; 6.50,7.00,8.50; 8.00,8.50,10.00; 4.60,4.90,6.53,P＜0.05).On the contrary,the mRNA and protein expression of bcl-2 in the gastrin group was significantly higher than in the control group,the proglumid group,and the gastrin + proglumid group (q =4.95,4.24,7.07; 7.07,6.36,7.78,P ＜ 0.05).Conclusion Gastrin could inhibit the apoptosis of HT-29 cells by down-regulate the phosphorylation levels of ceramide and p38 protein,thus up-regulate bcl-2 and down-regulate bax through the ceramide signaling transduction pathway,while the effect can be restrained by gastrin receptor antagonist proglumide. Key words: Colorectal cancer; Gastrin ; Ceramide ; p38 ; B lymphocytes/leukemia-2 ; Bcl-2 associated X protein

Cholecystokinin receptors in Atlantic salmon: molecular cloning, gene expression, and structural basis

The peptide hormone cholecystokinin (CCK) exerts a wide range of digestive and CNS-related physiological signaling via CCK receptors in brain and gut. There is very limited information available on these receptors in Atlantic salmon. The aim of this study was to characterize CCK receptors in gut and brain of salmon. We have identified and cloned one CCK-1 receptor and duplicates of CCK-2 receptor in salmon. The phylogenetic analysis indicates the existence of one common ancestor gene for all CCK receptors. CCK-1R mRNA is highly expressed in pancreas followed by midgut, hindgut, gallbladder, and stomach indicating an involvement in pancreatic regulation and gallbladder contractions. CCK-2R1/gastrin mRNA is expressed at high levels in midgut and at relatively low levels in stomach, gallbladder, and pancreas. We postulate CCK-2R1/gastrin receptor to have gastrin-related functions because of its distribution and abundance in gastro-intestinal (GI) tissues. CCK-2R2 is relatively abundant in brain but has low expression levels in gut tissues supporting the hypothesis for involvement in the gut-brain signaling. Major functional motifs and ligand interaction sites in salmon are conserved with that of mammals. This information will be instrumental for comparative studies and further targeting receptor activation and selectivity of biological responses of CCK in salmon.

Netazepide, a Gastrin Receptor Antagonist, Normalises Tumour Biomarkers and Causes Regression of Type 1 Gastric Neuroendocrine Tumours in a Nonrandomised Trial of Patients with Chronic Atrophic Gastritis

IntroductionAutoimmune chronic atrophic gastritis (CAG) causes hypochlorhydria and hypergastrinaemia, which can lead to enterochromaffin-like (ECL) cell hyperplasia and gastric neuroendocrine tumours (type 1 gastric NETs). Most behave indolently, but some larger tumours metastasise. Antrectomy, which removes the source of the hypergastrinaemia, usually causes tumour regression. Non-clinical and healthy-subject studies have shown that netazepide (YF476) is a potent, highly selective and orally-active gastrin/CCK-2 receptor antagonist. Also, it is effective in animal models of ECL-cell tumours induced by hypergastrinaemia.AimTo assess the effect of netazepide on tumour biomarkers, number and size in patients with type I gastric NETs.MethodsWe studied 8 patients with multiple tumours and raised circulating gastrin and chromogranin A (CgA) concentrations in an open trial of oral netazepide for 12 weeks, with follow-up 12 weeks later. At 0, 6, 12 and 24 weeks, we carried out gastroscopy, counted and measured tumours, and took biopsies to assess abundances of several ECL-cell constituents. At 0, 3, 6, 9, 12 and 24 weeks, we measured circulating gastrin and CgA and assessed safety and tolerability.ResultsNetazepide was safe and well tolerated. Abundances of CgA (p<0.05), histidine decarboxylase (p<0.05) and matrix metalloproteinase-7(p<0.10) were reduced at 6 and 12 weeks, but were raised again at follow-up. Likewise, plasma CgA was reduced at 3 weeks (p<0.01), remained so until 12 weeks, but was raised again at follow-up. Tumours were fewer and the size of the largest one was smaller (p<0.05) at 12 weeks, and remained so at follow-up. Serum gastrin was unaffected.ConclusionThe reduction in abundances, plasma CgA, and tumour number and size by netazepide show that type 1 NETs are gastrin-dependent tumours. Failure of netazepide to increase serum gastrin further is consistent with achlorhydria. Netazepide is a potential new treatment for type 1 NETs. Longer, controlled trials are justified.Trial RegistrationEuropean Union EudraCT database 2007-002916-24 https://www.clinicaltrialsregister.eu/ctr-search/search?query=2007-002916-24 ClinicalTrials.gov NCT01339169 http://clinicaltrials.gov/ct2/show/NCT01339169?term=yf476&rank=5

Gastrin and D 1 Dopamine Receptor Interact to Induce Natriuresis and Diuresis

Oral NaCl produces a greater natriuresis and diuresis than the intravenous infusion of the same amount of NaCl. Gastrin is the major gastrointestinal hormone taken up by renal proximal tubule (RPT) cells. We hypothesized that renal gastrin and dopamine receptors interact to synergistically increase sodium excretion, an impaired interaction of which may be involved in the pathogenesis of hypertension. In Wistar-Kyoto rats, infusion of gastrin induced natriuresis and diuresis, which was abrogated in the presence of a gastrin (cholecystokinin B receptor [CCKBR]; CI-988) or a D1-like receptor antagonist (SCH23390). Similarly, the natriuretic and diuretic effects of fenoldopam, a D1-like receptor agonist, were blocked by SCH23390, as well as by CI-988. However, the natriuretic effects of gastrin and fenoldopam were not observed in spontaneously hypertensive rats. The gastrin/D1-like receptor interaction was also confirmed in RPT cells. In RPT cells from Wistar-Kyoto but not spontaneously hypertensive rats, stimulation of either D1-like receptor or gastrin receptor inhibited Na(+)-K(+)-ATPase activity, an effect that was blocked in the presence of SCH23390 or CI-988. In RPT cells from Wistar-Kyoto and spontaneously hypertensive rats, CCKBR and D1 receptor coimmunoprecipitated, which was increased after stimulation of either D1 receptor or CCKBR in RPT cells from Wistar-Kyoto rats; stimulation of one receptor increased the RPT cell membrane expression of the other receptor, effects that were not observed in spontaneously hypertensive rats. These data suggest that there is a synergism between CCKBR and D1-like receptors to increase sodium excretion. An aberrant interaction between the renal CCK BR and D1-like receptors (eg, D1 receptor) may play a role in the pathogenesis of hypertension.

Ectopic Duodenal Insulinoma: A Very Rare and Challenging Tumor Type. Description of a Case and Review of the Literature

Although most insulinomas are located in the pancreas, very rare ectopic cases have been described in the spleen, perisplenic tissue, duodenohepatic ligament, and adjacent to the ligament of Treitz. Moreover, three cases located in the duodenum have also been reported in the English literature. Ectopic insulinomas represent challenging neoplasms with clinical implications mainly due to the difficulties in their pre-operatory diagnosis and localization. In the present paper, we describe the fourth ectopic duodenal insulinoma so far reported. A 75-year-old woman presented at clinical observation due to neuroglycopenic symptoms that disappeared after glucose intake. Tumor was localized in the second portion of the duodenum in front of the papilla of Vater and was surgically enucleated. Microscopically, it was composed of monomorphic cells with eosinophilic cytoplasm arranged in trabecular and lobular patterns and diffusely positive for insulin, proinsulin, amylin, and PDX1. About 30% of tumor cells also showed immunoreactivity for somatostatin, while no positivity for glucagon, pancreatic polypeptide, gastrin, serotonin, and somatostatin receptor subtype 2A was found. The Ki67 proliferative index was 1%. We have also reviewed the literature on this topic to give the reader a comprehensive overview of this very rare tumor type.

Abstract 554: Gastrin and D 1 Dopamine Receptor Interact to Induce Natriuresis and Diuresis

Oral NaCl produces a greater natriuresis and diuresis as compared with an intravenous infusion of the same amount of NaCl, indicating the existence of a gastro-renal axis. Gastrin is the major gastrointestinal hormone, which could be taken up by the renal proximal tubule (RPT) cells. We hypothesized that gastrin and dopamine receptors in the kidney interact to synergistically increase sodium excretion, an impaired interaction may be involved in the pathogenesis of hypertension. In Wistar-Kyoto (WKY) rats, infusion of gastrin induced a natriuresis and diuresis, which was abrogated in the presence of CI-988, a gastrin receptor (CCK B R) antagonist, as well as SCH 23390, a D 1 -like receptor antagonist. Similarly, the natriuretic and diuretic effect of fenoldopam, a D 1 -like receptor agonist, was blocked by SCH23390 , as well as CI-988. However, the natriuretic effects of gastrin and fenoldopam were not observed in spontaneously hypertensive rats (SHRs). The gastrin/D 1 -like receptor interaction was also confirmed in RPT cells. In RPT cells from WKY but not SHRs, stimulation of either D 1 -like receptor or gastrin receptor inhibited Na + -K + -ATPase activity, an effect that was blocked by the presence of SCH23390 or CI-988. In RPT cells from WKY and SHRs, CCK B R and D 1 R co-immunoprecipitated, which were increased after stimulation of either D 1 R or CCK B R receptor in WKY cells, but not in SHR cells. Stimulation of one receptor increased RPT cell membrane expression of another receptor. The data suggest that there is a synergism between CCK B R and D 1 -like receptor to increase sodium excretion. Aberrant interaction between the renal CCK B R and D 1 -like receptors (e.g., D 1 R) may play a role in the pathogenesis of hypertension.

The Gastrin Receptor Antagonist Netazepide (YF476) Prevents Oxyntic Mucosal Inflammation Induced byHelicobacter PyloriInfection in Mongolian Gerbils

Long-term Helicobacter pylori infection causes gastritis leading to hypergastrinemia and predisposes to gastric cancer. Our aim was to assess the role of gastrin in oxyntic mucosal inflammation in H.pylori-infected Mongolian gerbils by means of the gastrin receptor antagonist netazepide (YF476). We studied 60 gerbils for 18months and left five animals uninfected (control group), inoculated 55 with H.pylori, and treated 28 of the infected animals with netazepide (Hp+YF476 group). Twenty-seven infected animals were given no treatment (Hp group). We measured plasma gastrin and intraluminal pH. H.pylori detection and histologic evaluations of the stomach were carried out. All 55 inoculated animals were H.pylori positive at termination. Eighteen animals in the Hp group had gastritis. There was a threefold increase in mucosal thickness in the Hp group compared to the Hp+YF476 group, and a threefold increase in oxyntic neuroendocrine cells in the Hp group compared to the Hp+YF476 group (p<.05). All animals in the Hp+YF476 group had macro- and microscopically normal findings in the stomach. Plasma gastrin was higher in the Hp group than in the control group (172±16pmol/L vs 124±5pmol/L, p<.05) and highest in the Hp+YF476 group (530±36pmol/L). Intraluminal pH was higher in the Hp group than in the Hp+YF476 group (2.51 vs 2.30, p<.05). The gastrin antagonist netazepide prevents H.pylori-induced gastritis in Mongolian gerbils. Thus, gastrin has a key role in the inflammatory reaction of the gastric mucosa to H.pylori infection in this species.

Gastrin Induces Sodium-Hydrogen Exchanger 3 Phosphorylation and mTOR Activation via a Phosphoinositide 3-Kinase-/Protein Kinase C-Dependent but AKT-Independent Pathway in Renal Proximal Tubule Cells Derived From a Normotensive Male Human

Gastrin is natriuretic, but its renal molecular targets and signal transduction pathways are not fully known. In this study, we confirmed the existence of CCKBR (a gastrin receptor) in male human renal proximal tubule cells and discovered that gastrin induced S6 phosphorylation, a downstream component of the phosphatidylinositol 3 kinase (PI3 kinase)-mammalian target of rapamycin pathway. Gastrin also increased the phosphorylation of sodium-hydrogen exchanger 3 (NHE3) at serine 552, caused its internalization, and decreased its expression at the cell surface and NHE activity. The phosphorylation of NHE3 and S6 was dependent on PI3 kinases because it was blocked by 2 different PI3-kinase inhibitors, wortmannin and LY294,002. The phosphorylation of NHE3 and S6 was not affected by the protein kinase A inhibitor H-89 but was blocked by a pan-PKC (chelerythrine) and a conventional PKC (cPKC) inhibitor (Gö6976) (10 μM) and an intracellular calcium chelator, 1,2-bis-(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid, tetra(acetoxymethyl)-ester, suggesting the importance of cPKC and intracellular calcium in the gastrin signaling pathway. The cPKC involved was probably PKCα because it was phosphorylated by gastrin. The gastrin-mediated phosphorylation of NHE3, S6, and PKCα was via phospholipase C because it was blocked by a phospholipase C inhibitor, U73122 (10 μM). The phosphorylation (activation) of AKT, which is usually upstream of mammalian target of rapamycin in the classic PI3 kinase-AKT-p70S6K signaling pathway, was not affected, suggesting that the gastrin-induced phosphorylation of NHE3 and S6 is dependent on both PI3 kinase and PKCα but not AKT.

Treatment of gastric carcinoids type 1 with the gastrin receptor antagonist netazepide (YF476) results in regression of tumours and normalisation of serum chromogranin A

Patients with chronic atrophic gastritis have long-term gastric hypoacidity, and secondary hypergastrinaemia. Some also develop gastric ECL cells carcinoids (type 1 GC). Most type 1 GC remain indolent, but some metastasise. Patients undergo surveillance, and some are treated with somatostatin analogues, endoscopic resection or surgery. Netazepide (YF476) is a highly selective, potent and orally active gastrin receptor antagonist, which has anti-tumour activity in various rodent models of gastric neoplasia driven by hypergastrinaemia. Netazepide has been studied in healthy volunteers. To assess the effect of netazepide on type 1 GC. Eight patients with multiple type 1 GC received oral netazepide once daily for 12 weeks, with follow-up at 12 weeks in an open-label, pilot trial. Upper endoscopy was performed at 0, 6, 12 and 24 weeks, and carcinoids were counted and measured. Fasting serum gastrin and chromogranin A (CgA) and safety and tolerability were assessed at 0, 3, 6, 9, 12 and 24 weeks. Netazepide was well tolerated. All patients had a reduction in the number and size of their largest carcinoid. CgA was reduced to normal levels at 3 weeks and remained so until 12 weeks, but had returned to pre-treatment levels at 24 weeks. Gastrin remained unchanged throughout treatment. The gastrin receptor antagonist netazepide is a promising new medical treatment for type 1 gastric carcinoids, which appear to be gastrin-dependent. Controlled studies and long-term treatment are justified to find out whether netazepide treatment can eradicate type 1 gastric carcinoids.

High Expression of Gastrin Receptor Protein in Injured Mucosa of Helicobacter pylori-Positive Gastritis

Gastrin is a growth factor for the gastric epithelial cells. However, it is unknown how gastric receptor (GR) expression is regulated in the gastric mucosa. We studied GR expression using a newly raised antibody and investigated the relationship between GR expression and gastritis. Gastric receptor expression in 63 human gastric mucosa was studied. Helicobacter pylori infection and histological gastritis status were evaluated in gastric biopsy samples. In gastric ulcer cases, additional biopsy specimens were taken from injured mucosa. Fasting sera were collected and serum gastrin level evaluated. MKN-28 cells were cultured at various pH conditions, and the change in GR expression was determined. Gastric receptor expression was detected in the foveolar epithelium of the gastric mucosa, and its expression was stronger in patients infected with H. pylori. In particular, higher expression was detected in regenerating injured mucosa. There was no association between gastritis score/serum gastrin level and GR expression in H. pylori-positive cases. In MKN-28 cells, GR protein expression was lower in neutral conditions than in acidic or alkaline conditions. Gastric mucosal injury with H. pylori infection destroys the pH barrier on the foveolar epithelium and may induce GR expression through pH changes.

Management of Gastric Carcinoids (Neuroendocrine Neoplasms)

Gastric neuroendocrine neoplasms of the stomach can be divided into the usually well-differentiated, hypergastrinemia-dependent type I and II lesions and the more aggressively behaving gastrin-independent type III lesions. Mainly due to better diagnostics and awareness of this tumor, the observed incidence has increased more than tenfold over the last 30years. Small (<15-20mm) localized type I and II lesions that are slowly proliferating (Ki67<2%) can usually be managed conservatively with endoscopic surveillance. Reducing hypergastrinemia by surgical removal of an underlying gastrinoma is important in inhibiting growth and induce reduction of type II lesions, while the specific gastrin receptor antagonist YF476 or gastrin antibodies may become useful for both type I and II lesions. Infiltrating and metastasized tumors and type III lesions require a more aggressive approach with surgical resection and consideration of modalities such as somatostatin analogs, cytotoxics, and peptide receptor targeted treatment.

Abstract 341: Synergistic Effects of Renal Dopamine and Gastrin Receptors in Hypertension

Oral NaCl produces stronger natriuresis and diuresis as compared with venous infusion of same amount of NaCl, indicating the existence of renal-gastric axis. Although numerous hormones are secreted in gastrointestinal tract, gastrin is evident one due to its natriuretic effects and taken-up by the renal proximal tubule (RPT) cells. We hypothesize that there is an interaction between gastrin and dopamine receptor in kidney, which synergistically increases sodium excretion, the impaired interaction would be involved in the pathogenesis of hypertension. In WKY rats, infusion of gastrin, via renal artery, induced natriuresis and diuresis, which was blocked in the presence of CI988, a gastrin receptor blocker. Similarly, the natriuretic and diuretic effect of fenoldopam, a D1-like receptor agonist, was blocked by the D1-like receptor antagonist, SCH23390 , indicating that gastrin and fenoldopam, via individual receptor, play natriuretic and diuretic effects. Our further study found that lower dosages of gastrin or fenoldopam could not induce natriuresis and diuresis alone, while putting together induced natriuretic and diuretic effects. The above-mentioned effects were lost in SHRs. We also found, in the presence of SCH23390 , gastrin-mediated natriuresis and diuresis was partially blocked. Similarly, in the presence of CI988, the natriuretic and diuretic effects of fenoldopam were partially blocked, indicating the interaction between gastrin and D1-like receptor. The gastrin/D1-like receptor interaction was also confirmed in the RPT cells. Stimulation of one receptor increased the expression of the other. Stimulation of either D1-like receptor or gastrin receptor inhibited the Na + -K + -ATPase activity in RPT cells, while in the presence of SCH23390 , the inhibitory effect of gastrin on Na + -K + -ATPase activity was partially blocked. In the presence of CI988, D1-like receptor-mediated inhibitory effect of Na + -K + -ATPase activity in RPT cells was partially inhibited. It indicated the synergistic effect between gastrin and D1-like receptor would increase the sodium excretion in WKY rats; the impaired interaction might be involved in the pathogenesis of hypertension.

764 SYNERGISTIC EFFECTS OF RENAL DOPAMINE AND GASTRIN RECEPTORS IN HYPERTENSION

764 SYNERGISTIC EFFECTS OF RENAL DOPAMINE AND GASTRIN RECEPTORS IN HYPERTENSION

Commentary: netazepide for gastric acid suppression – another kid on the block?

Just when it seemed all over, the manuscript by Boyce et al.1 examining the pharmacokinetics and pharmacodynamics of single dose administration of netazepide, a peripheral CCK-B (gastrin) receptor antagonist, in normal volunteers will most certainly reinvigorate interest in gastric acid secretion and its pharmacological inhibition. Netazepide appears to be a potent inhibitor of gastric acid secretion with rapid onset and a prolonged duration of action.1 If it can be shown to be both safe and effective as maintenance therapy, it may well give proton pump inhibitors (PPIs) a real run for their money. The PPIs, which irreversibly block the final common path of gastric acid production,2 have been the dominant class of antisecretory drugs for over two decades and their continuing supremacy was all but assured with the demise of the potassium competitive acid blockers (PCABs) (although there may be a comeback for this class of agents too3). In addition, concerns have surfaced recently about potential adverse effects from prolonged PPI use4 which has opened the door to other novel compounds such as netazepide. Of course, much work remains to be done with this agent and there are, as yet, many unanswered questions (some of which the authors may well address in two upcoming manuscripts concerning repetitive dosing of netazepide). For example, will tachyphylaxis develop after repeated administration of this competitive receptor antagonist, a phenomenon that has been well described with histamine H2 receptor antagonists, which act one step further along the gastric acid secretory pathway?5 In addition, the endocrine, neurocrine and paracrine networks that control gastric acid secretion and its feedback are redundant.6 It remains to be seen whether upregulation of other pathways could occur leading to additional loss of efficacy (tolerance) with time. Alternatively, will the drug, which appears to have a long secondary half-life, accumulate after repeated dosing leading to unexpected side effects? Moreover, little is known about the metabolism of this agent which has only been administered to a small cadre of normal volunteers. Will the effect of this agent be predictable in patients or will alterations in metabolism lead to ‘slow’ and ‘fast’ metabolisers and unpredictable antisecretory effects? Finally, will potent ECL-cell inhibition by netazepide lead to G-cell hyperplasia and hypergastrinaemia, with the potential for rebound ECL-cell histamine release and excessive gastric acid production4 on withdrawal of the drug? This possibility is of some interest given current concerns regarding rebound gastric acid hypersecretion in double-blind randomised trials of PPI use vs. placebo in normal volunteers.7, 8 On the other hand, judicious use of netazepide in concert with PPIs may lead to more precise titration of individual antisecretory effects, thereby mitigating ECL-cell hyperplasia and parietal cell hypertrophy. This is an exciting and provocative first-in-human study of a novel compound with significant potential. I fully agree with the authors' conclusions that ‘studies of repeated doses of netazepide are justified’.1 Declaration of personal interests: David Metz has served as a consultant and advisory board member for Novartis, as a consultant for AstraZeneca and Takeda, and has received research funding from Fercica. Declaration of funding interests: None

The gastrin receptor antagonist YF476 prevents oxyntic mucosal inflammation due to Helicobacter pylori infection in Mongolian gerbils

The gastrin receptor antagonist YF476 prevents oxyntic mucosal inflammation due to Helicobacter pylori infection in Mongolian gerbils

Single oral doses of netazepide (YF476), a gastrin receptor antagonist, cause dose‐dependent, sustained increases in gastric pH compared with placebo and ranitidine in healthy subjects

Nonclinical studies have shown netazepide (YF476) to be a potent, selective, competitive and orally active gastrin receptor antagonist. To administer to humans for the first time single oral doses of netazepide, to assess their tolerability, safety, pharmacokinetics and effect on 24-h gastric pH. We did two randomised double-blind single-dose studies in healthy subjects. The first (n = 12) was a six-way incomplete crossover pilot study of rising doses of netazepide (range 0.5-100 mg) and placebo. The second (n = 20) was a five-way complete crossover study of netazepide 5, 25 and 100 mg, ranitidine 150 mg and placebo. In both trials we collected frequent blood samples, measured plasma netazepide and calculated pharmacokinetic parameters. In the comparative trial we measured gastric pH continuously for 24 h and compared treatments by percentage time gastric pH ≥4. Netazepide was well tolerated. Median t (max) and t (½) for the 100 mg dose were about 1 and 7 h, respectively, and the pharmacokinetics were dose-proportional. Netazepide and ranitidine each increased gastric pH. Onset of activity was similarly rapid for both. All netazepide doses were more effective than placebo (P ≤ 0.023). Compared with ranitidine, netazepide 5 mg was as effective, and netazepide 25 and 100 mg were much more effective (P ≤ 0.010), over the 24 h after dosing. Activity of ranitidine lasted about 12 h, whereas that of netazepide exceeded 24 h. In human: netazepide is an orally active gastrin antagonist, and gastrin has a major role in controlling gastric acidity. Repeated-dose studies are justified. NCT01538784 and NCT01538797.