Histamine-stimulated Gastric Acid Secretion Research Articles

Discovery of novel benzimidazole derivatives as potent potassium-competitive acid blockers for the treatment of acid-related diseases

H+, K+-ATPase, as the most critical enzyme in gastric acid secretion, has long been an attractive target for the treatment of acid-related diseases. In this study, a series of benzimidazole derivatives were designed and synthesized through conformational restriction and skeleton hopping strategies by using vonoprazan as the lead compound. Among them, compounds A12 (IC50 = 9.32 μM) and A18 (IC50 = 5.83 μM) showed better inhibition at the enzyme level. In addition, gastric acid secretion inhibition was assessed in vivo, and the results showed that A12 and A18 significantly inhibited basal gastric acid secretion, 2-deoxy-d-glucose (2DG) stimulated gastric acid secretion and histamine-stimulated gastric acid secretion. In further in vitro metabolic experiments, A12 and A18 demonstrated excellent stability and low toxicity. Pharmacokinetic studies showed that the p.o. and i.v. half-lives of A18 were 3.21 h and 8.67 ± 1.15 h, respectively. In summary, A18 might be a novel and effective potassium-competitive acid blocker, and this study provides strong support for it use in the treatment of acid-related diseases.

JP-1366: A novel and potent potassium-competitive acid blocker that is effective in the treatment of acid-related diseases.

The global prevalence of GERD is substantially increasing each year, and GERD is a chronic disease that reduces the quality of life of patients. The efficacy of conventional drugs is diverse, and most require long-term or lifetime administration; thus, the development of more effective therapeutic agents is needed. Herein, a more effective treatment for GERD was tested. We investigated whether JP-1366 affected gastric H+/K+-ATPase activity and used the Na+/K+-ATPase assay to confirm the selectivity of H+/K+-ATPase inhibition. To clarify the mechanism of enzyme inhibition, JP-1366 and TAK-438 were analyzed by Lineweaver-Burk. Also, we investigated the effects of JP-1366 in various models involving reflux esophagitis. We found that JP-1366 mediates strong, selective, and dose-dependent inhibition of H+/K+-ATPase. We found that JP-1366 significantly suppressed gastric acid secretion in histamine-treated pylorus-ligated rats in a dose-dependent manner. Additionally, we confirmed that JP-1366 inhibited histamine-stimulated gastric acid secretion in the HPD model. JP-1366 exhibited a more than 2-fold higher inhibitory effect on esophageal injury than TAK-438 in GERD lesions and had a more potent inhibitory effect in indomethacin- or aspirin-induced gastric ulcer rat models than TAK-438. Additionally, JP-1366 inhibited gastric ulcers. These results support the possibility that JP-1366 is a good candidate drug for treating acid-related diseases.

Design, synthesis and biological evaluation of novel 5-methyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole derivatives as potent potassium-competitive acid blockers

With the aim to discover a novel potent potassium-competitive acid blocker (P-CAB) agent, a series of 5-methyl-2,4,5,6-tetrahydropyrrolo[3,4–c]pyrazole derivatives were synthesized, and their H+/K+-ATPase inhibitory activities and inhibitory action on histamine-stimulated gastric acid secretion in rats were evaluated. Among the compounds synthesized, compound 3′-((3-(2-fluorophenyl)-5-methyl-5,6-dihydropyrrolo[3,4–c]pyrazol-2(4H)-yl)methyl)-[1,1′-biphenyl]-3-carboxamide not only exhibited potent H+/K+-ATPase inhibitory activity but olso showed potent inhibitory action in vivo on histamine-stimulated gastric acid secretion. In addition, the lead compound displayed favourable oral pharmacokinetic properties in rats, which was worthy of further study as a novel P-CAB agent.

Discovery, synthesis, and structure-activity relations of 3,4-dihydro-1H-spiro(naphthalene-2,2′-piperidin)-1-ones as potassium-competitive acid blockers

With the aim to discover a gastric antisecretory agent more potent than the existing proton pump inhibitors, novel 3,4-dihydro-1H-spiro(naphthalene-2,2′-piperidin)-1-one derivatives, which could occupy two important lipophilic pockets (described as LP-1 and LP-2) of H+,K+-ATPase and can strongly bind to the K+-binding site, were designed based on a docking model. Among the compounds synthesized, compound 4d showed a strong H+,K+-ATPase-inhibitory activity and a high stomach concentration in rats, resulting in potent inhibitory action on histamine-stimulated gastric acid secretion in rats. Furthermore, 4d exerted significant inhibitory action on histamine-stimulated gastric-acid secretion in rats with a rapid onset and moderate duration of action after the administration. These findings may lead to a new insight into the drug design of potassium-competitive acid blockers.

Healing and Antisecretory Effects of Aqueous Extract of Eremomastax speciosa (Acanthaceae) on Unhealed Gastric Ulcers.

Objective This work investigated the healing and antisecretory effects of the aqueous extract of Eremomastax speciosa on “unhealed gastric ulcers” associated with gastric acid hypersecretion. Materials and Methods “Unhealed gastric ulcers” were induced using indomethacin following the establishment of acetic-acid-induced chronic gastric ulcers. The extract (200 and 400 mg/kg, per os) was administered concomitantly with indomethacin (1 mg/kg, subcutaneously). The effects of the extract on both basal and histamine-stimulated gastric acid secretion were determined. Mucus secretion and oxidative stress parameters were measured, and histological assessment of ulcer healing was carried out. Results The extract significantly promoted the healing process in rats subjected to “unhealed gastric ulcers” (82.4–88.5% healing rates). Treatment with the extract significantly reduced the basal (25.95–49.51% reduction rates) and histamine-stimulated (24.25–47.41%) acid secretions. The healing effect of the extract was associated with a significant (p < 0.05) increase of mucus secretion and concentrations of antioxidant enzymes compared with the controls. The extract at the highest dose showed normalization of the mucosa, without glandular destruction and with the disappearance of fibrosis and lymphocyte infiltration. Conclusion The abilities of the extract to increase mucus secretion, to reinforce antioxidant status, and to inhibit acid secretion would be some of the mechanisms by which this extract would accelerate the healing process in “unhealed gastric ulcers.”

Docking-based Screening of Ficus religiosa Phytochemicals as Inhibitors of Human Histamine H2 Receptor.

Background:Ficus religiosa L. is generally known as Peepal and belongs to family Moraceae. The tree is a source of many compounds having high medicinal value. In gastrointestinal tract, histamine H2 receptors have key role in histamine-stimulated gastric acid secretion. Their over stimulation causes its excessive production which is responsible for gastric ulcer.Objective:This study aims to screen the range of phytochemicals present in F. religiosa for binding with human histamine H2 and identify therapeutics for a gastric ulcer from the plant.Materials and Methods:In this work, a 3D-structure of human histamine H2 receptor was modeled by using homology modeling and the predicted model was validated using PROCHECK. Docking studies were also performed to assess binding affinities between modeled receptor and 34 compounds. Molecular dynamics simulations were done to identify most stable receptor-ligand complexes. Absorption, distribution, metabolism, excretion, and screening was done to evaluate pharmacokinetic properties of compounds.Results:The results suggest that seven ligands, namely, germacrene, bergaptol, lanosterol, Ergost-5-en-3beta-ol, α-amyrin acetate, bergapten, and γ-cadinene showed better binding affinities.Conclusion:Among seven phytochemicals, lanosterol and α-amyrin acetate were found to have greater stability during simulation studies. These two compounds may be a suitable therapeutic agent against histamine H2 receptor.SUMMARY This study was performed to screen antiulcer compounds from F. religiosa. Molecular modeling, molecular docking and MD simulation studies were performed with selected phytochemicals from F. religiosa. The analysis suggests that Lanosterol and α-amyrin may be a suitable therapeutic agent against histamine H2 receptor. This study facilitates initiation of the herbal drug discovery process for the antiulcer activity. Abbreviations used: ADMET: Absorption, distribution, metabolism, excretion and toxicity, DOPE: Discrete Optimized Potential Energy, OPLS: Optimized potential for liquid simulations, RMSD: Root-mean-square deviation, HOA: Human oral absorption, MW: Molecular weight, SP: Standard-precision, XP: Extra-precision, GPCRs: G protein-coupled receptors, SASA: Solvent accessible surface area, Rg: Radius of gyration, NHB: Number of hydrogen bond

Potassium channel KCNJ15 is required for histamine-stimulated gastric acid secretion.

Gastric acid secretion is mediated by the K(+)-dependent proton pump (H(+),K(+)-ATPase), which requires a continuous supply of K(+) at the luminal side of the apical membrane. Several K(+) channels are implicated in gastric acid secretion. However, the identity of the K(+) channel(s) responsible for apical K(+) supply is still elusive. Our previous studies have shown the translocation of KCNJ15 from cytoplasmic vesicles to the apical membrane on stimulation, indicating its involvement in gastric acid secretion. In this study, the stimulation associated trafficking of KCNJ15 was observed in a more native context with a live cell imaging system. KCNJ15 molecules in resting live cells were scattered in cytoplasm but exhibited apical localization after stimulation. Furthermore, knocking down KCNJ15 expression with a short hairpin RNA adenoviral construct abolished histamine-stimulated acid secretion in rabbit primary parietal cells. Moreover, KCNJ15, like H(+),K(+)-ATPase, was detected in all of the parietal cells by immunofluorescence staining, whereas only about half of the parietal cells were positive for KCNQ1 under the same condition. Consistently, the endogenous protein levels of KCNJ15, analyzed by Western blotting, were higher than those of KCNQ1 in the gastric mucosa of human, mouse, and rabbit. These results provide evidence for a major role of KCNJ15 in apical K(+) supply during stimulated acid secretion.

Inhibition of Histamine-Stimulated Gastric Acid Secretion by Hydrogen Sulfide in Male Rats

Recently, hydrogen sulfide (H_2S) introduces as the third gaseous transmitter that has many physiologic and pharmacologic roles in the body. The aim of the present study was to investigate the effect of exogenously given H_2S on histamine-induced gastric acid secretion in rats. Thirtytwo male Wistar rats (150-200 g) were randomly assigned into 4 groups (8 per group). Animals were deprived of food but not water 24 h before the experiment and were randomly assigned into two control groups, distention-, and histamine-stimulated groups, and two NaHS-treated groups. To evaluate the effect of H_2S on histamine-induced gastric acid secretion, one group of animals were received an I.V. bolus of NaHS (a H_2S donor) at 80 μg/kg. To investigate the possible involved mechanism of the antisecretory effect of NaHS, mRNA expression of histidine decarboxylase (HDC) were evaluated by reverse-transcriptase PCR. The gastric acid output in response to histamine decreased by NaHS treatment (P＜0.01). Also the results showed that the level of gene expression of HDC was higher in NaHS-treated group than in control rats. The findings showed that the inhibitory effect of H_2S on gastric acid secretion was not related to a decrease in histamine release. It seems that up-regulation of HDC mRNA expression is secondary to inhibition of gastric acid secretion by NaHS.

Gastric acid anti-secretory effects of aqueous leaf extract of Nauclea latifolia (Rubiaceae) in rats

The aqueous leaf extract of Nauclea latifolia has been shown to have anti-ulcer effect. Objectives: The present study was undertaken to investigate the effects of aqueous leaf extract of N. latifolia on gastric acid secretion as the possible mechanism of its anti-ulcer actions in male albino rats. Materials and Methods: A total of sixty (60) male albino rats were divided into two experimental studies of thirty (30) rats each. Each of the experimental studies was further divided into groups according to study design. The extract was administered orally at the doses of 100, 200 and 400 mg/kg for the experimental groups while the control and reference groups received distilled water (2 ml/kg, p.o) and cimetidine (32 mg/kg, p.o) respectively, 60 minutes prior to oral administration of indomethacin (30 mg/kg) to induce gastric mucosal injury. In the second study, gastric acid output was measured by the continuous perfusion of rat’s stomach under anesthesia with normal saline at the rate of 1 ml/min. Results: Phytochemical analysis revealed the presence of saponins, tannins, flavonoids, alkaloids and cardiac glycosides. Acute toxicity studies showed there were no deaths within 24 h after the application of the extract up to 1600 mg/kg B.W (i.p). Rats pre-treated with N. latifolia exhibited significant (P&lt;0.05), and dose-dependent inhibition of indomethacin-induced gastric ulceration. A significant decrease in gastric acid secretion was produced by the extract at all doses studied. Conclusion: Findings of this study suggest that, aqueous extract of N. latifolia significantly reduced gastric acid secretion in indomethacin-induced gastric ulceration by inhibiting histamine-stimulated gastric acid secretion probably by occupying H2 - receptors in rats.

Acute high blood glucose level attenuates histamine-stimulated acid secretion in male Wistar rats

Studies have shown that the hyperglycemic state induced by intravenous glucagon or glucose infusion may lead to inhibition of gastric acid secretion through the inhibition of gastric vagus activity. Histamine is a well-known mammalian acid secretagogue and it stimulates acid secretion through H2 receptors. Therefore, the aim of this study was to determine what effect an acute hyperglycemic or hypoglycemic state would have on histamine-stimulated acid secretion. Male Wistar rats weighing between 200 and 250 g were divided into three groups that received an intravenous infusion of normal saline (control group), glucose (hyperglycemic group), or insulin (hypoglycemic group) followed by injection of histamine to stimulate acid secretion. The oesophageal and duodenal ends of the rats' stomach were cannulated with polythene tubing and the stomach was perfused at room temperature using a Langendoff perfusion apparatus. The effluent was collected in aliquots over 10 min per sample and its pH was measured. There was a significant (p<0.05) decrease in acid secretion following histamine injection in the hyperglycemic rats, while histamine injection led to an increase (p<0.05) in acid secretion in the hypoglycemic rats. These results show that hyperglycemic state would result in attenuated histamine-stimulated gastric acid secretion, while hypoglycemic state would lead to increased histamine-stimulated gastric acid secretion.

Sa2024 Involvement of Gastric Secretion and Primary Capsaicin-Sensitive Afferent Nerves in the Gastroprotection Induced by Hydrogen Sulfide in Rat Stomach

Hydrogen sulfide (H2S) modulates a number of physiological actions including vasodilatation, inhibition of oxidant stress and apoptosis. H2S which is formed in gastric epithelium by the activity of two enzymes cysthationine γ-lyase (CSE) and cystathionine β-synthetase (CBS) has been shown to protect the gastric mucosa from ethanol-induced gastric lesions but whether its efficacy against acid-dependent stress-induced damage has been little studied. It also remains unknown how the expression of CSE and CBS contribute to the mucosal damage induced by stress in the presence or absence of H2S. We studied the effect of NaHS, a H2S-donor and L-cysteine, a H2S precursor on 1) gastric acid secretion in rats equipped with chronic gastric fistulas (GF) and water immersion restraint stress (WRS)-induced gastric lesions with intact and capsaicin-denervated sensory nerves (large dose 125 mg/kg s.c for 3 days). Rats were pretreated 30 min before the WRS with A) NaHS (5 mg/kg i.g); B) Lcysteine (10 mg/kg i.g.) with or without the combination with inhibitors of CSE activity, beta-cyano-L-alanine (BCA, 50 mg/kg i.g.) and D,L-propargylglycine (PAG 15 80 mg/kg i.g.). The number of gastric lesions was measured by planimetry, the gastric blood flow (GBF) by H2-gas clearance technique and the mRNA expression of CSE, CBS, HIF-1 α and antioxidizing enzymes SOD and GPx was assessed by RT-PCR and Western Blot. NaHS (120 mg/kg) and cysteine (5-40 mg/kg) dose-dependently inhibited basal and histaminestimulated gastric acid secretion in GF rats. Exposure to WRS caused mucosal hemorrhagic lesions accompanied by the fall in GBF and upregulation of mRNA expression of CSE and CBS. Pretreatment with NaHS and L-cysteine significantly reduced WRS-induced gastric damage and significantly raised GBF and these effects were completely lost in animals with capsaicin denervation. BCA and PAG which dose-dependently augmented the number of WRS lesions, reversed the NaHS and L-cysteine-induced protection and hyperemia against WRS-induced gastric damage. Upregulation of mRNA expression for HIF-1 α mRNA, CSE and CBS in the gastric mucosa exposed to WRS was diminished by NaHS and L-cysteine and these effects were further enhanced in capsaicin-denervated rats treated with NaHS and L-cysteine. The increased expression of SOD and GPx mRNA was observed in NaHSand L-cysteine-pretreated rats but not in those with capsaicin-denervation. We conclude that: 1) an increase in the expression of CSE and CBS, key enzymes in H2S biosynthesis, could compensate for the stress-induced impairment of gastric mucosal defense; 2) antisecretory activity of H2S donors contributes to the attenuation of acid-dependent injury caused by WRS, and 3) sensory mediators and antioxidizing enzymes SOD and GPx play an important role in H2S-induced gastroprotection against WRS-induced ulcerogenesis.

Gastric Ulceration in Diabetes Mellitus: Protective Role of Vitamin C

The effect of vitamin C administration on gastric acid secretion and ulcer in diabetic rats was studied. Vitamin C (200 mg/kg b.w.) was administered to both streptozotocin-induced diabetic and control groups orally for 28 days. Gastric acid secretion was measured and ulcer was induced using ethanol. Histological changes were observed in the stomach. Basal and stimulated acid secretion in diabetic control rat was significantly (P < 0.01) decreased when compared to vitamin C-treated diabetic group and control. Administration of vitamin C significantly (P < 0.05) increased the histamine-stimulated gastric acid secretion in diabetics than control while reduction in gastric secretion by ranitidine was similar compared with control. Vitamin C treatment significantly (P < 0.05) reduced ulcer index in diabetic group and increased mucus weight when compared with diabetic group which was also confirmed with photomicrographs. The mean body weight of diabetic rats treated with vitamin C was comparable to the control. The blood glucose level was significantly (P < 0.01) reduced in diabetic group given vitamin C (8.9 ± 1.8 mMol/L) compared to the diabetic control (32.2 ± 2.1 g). It is concluded that vitamin C is beneficial in improving gastric acid secretion and protects against ulceration in streptozotocin-induced diabetes mellitus in rats due to its antioxidant potential.

Discovery, synthesis, and biological evaluation of novel pyrrole derivatives as highly selective potassium-competitive acid blockers

To discover a gastric antisecretory agent more potent than existing proton pump inhibitors, novel pyrrole derivatives were synthesized, and their H+,K+-ATPase inhibitory activities and inhibitory action on histamine-stimulated gastric acid secretion in rats were evaluated. Among the compounds synthesized, compound 17a exhibited selective and potent H+,K+-ATPase inhibitory activity through reversible and K+-competitive ionic binding; furthermore, compound 17c exhibited potent inhibitory action on histamine-stimulated gastric acid secretion in rats and Heidenhain pouch dogs.

The effect of SC-15396, atropine and mepyramine on gastrin-, bethanechol- and histamine-stimulated gastric acid secretion in rats and guinea-pigs.

Abstract The effect of SC-15396 (“antigastrin”; 2-phenyl-2-(2-pyridyl)thioacetamide), atropine and mepyramine on gastrin-, bethanechol- and histamine-stimulated gastric acid secretion was studied in rats and guinea-pigs. For all three stimulants parallel dose response curves were obtained except in guinea-pigs where bethanechol even in very high doses displays a poor activity in stimulating gastric acid secretion. The maximal secretory response was found to be 12·7 ± 5·0 μ-equiv HCl/10 min in rats and 53·2 ± 27£9 μ-equiv HCl/10 min in guinea-pigs. All stimulating effects on gastric acid secretion were reduced by SC-15396; atropine abolished the secretory responses to bethanechol. Mepyramine was ineffective. In accordance with these findings the mechanism of action of gastrin and a receptor model on the oxyntic cell are discussed.

A Study Comparing the Antisecretory Effect of TAK-438, a Novel Potassium-Competitive Acid Blocker, with Lansoprazole in Animals

Proton pump inhibitors (PPIs) are widely used for the treatment of acid-related diseases. However, several medical needs such as suppression of night-time acid secretion and rapid symptom relief remain unmet. In this study, we investigated the effects of 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine monofumarate (TAK-438), a novel potassium-competitive acid blocker, on acid secretion in rats and dogs under various conditions, in comparison with the PPI lansoprazole [2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl] methyl]sulfinyl]-1H-benzimidazole], to characterize the antisecretory action of TAK-438. TAK-438 showed a more potent and longer-lasting inhibitory effect than lansoprazole on the histamine-stimulated gastric acid secretion in rats and dogs. A pharmacokinetic study in rats showed that TAK-438 accumulated and was retained in the gastric tissue for more than 24 h, unlike that in the plasma. TAK-438 showed significant antisecretory activity with or without cimetidine pretreatment, in contrast to lansoprazole, which did not show antisecretory activity after cimetidine pretreatment in rats. TAK-438 increased the pH of the gastric perfusate to 5.7 in an unstimulated condition, and this effect was maintained in the presence of subsequent histamine stimulation. On the other hand, lansoprazole also increased the pH in an unstimulated condition, but this effect diminished after histamine stimulation. These results indicated that TAK-438 exerted a more potent and longer-lasting antisecretory effect than lansoprazole through high accumulation and slow clearance from the gastric tissue. In addition, TAK-438 was unaffected by the gastric secretory state, unlike PPIs. Therefore, TAK-438 can provide a novel mechanism of action to improve the present PPI-based treatment of acid-related diseases.

A Role for the Ca 2+ Channel TRPML1 in Gastric Acid Secretion, Based on Analysis of Knockout Mice

Mutations in TRPML1, a lysosomal Ca(2+)-permeable TRP channel, lead to mucolipidosis type IV, a neurodegenerative lysosomal storage disease. An unusual feature of mucolipidosis type IV is constitutive achlorhydria. We produced Trpml1(-/-) (null) mice to investigate the requirement for this protein in gastric acid secretion. Trpml1-null mice were generated by gene targeting. The expression of Trpml1 and its role in acid secretion by gastric parietal cells were analyzed using biochemical, histologic, and ultrastructural approaches. Trpml1 is expressed by parietal cells and localizes predominantly to the lysosomes; it was dynamically palmitoylated and dephosphorylated in vivo following histamine stimulation of acid secretion. Trpml1-null mice had significant impairments in basal and histamine-stimulated gastric acid secretion and markedly reduced levels of the gastric proton pump. Histologic and ultrastructural analyses revealed that Trpml1(-/-) parietal cells were enlarged, had multivesicular and multi-lamellated lysosomes, and maintained an abnormal intracellular canalicular membrane. The intralysosomal Ca(2+) content and receptor-mediated Ca(2+) signaling were, however, unaffected in Trpml1(-/-) gastric glands, indicating that Trpml1 does not function in the regulation of lysosomal Ca(2+). Loss of Trpml1 causes reduced levels and mislocalization of the gastric proton pump and alters the secretory canaliculi, causing hypochlorhydria and hypergastrinemia. The lysosomal enlargement and defective intracellular canaliculi formation observed in Trpml1(-/-) parietal cells indicate that Trpml1 functions in the formation and trafficking of the tubulovesicles. This study provides direct evidence for the regulation of gastric acid secretion by a TRP channel; TRPML1 is an important protein in parietal cell apical membrane trafficking.

Commentary on “An analysis of the depressor responses to histamine in the cat and dog: involvement of both H1 and H2 receptors” by JW Black, DAA Owen and ME Parsons

The qualitative part of this story was described briefly in 1972 when we reported on burimamide as a prototype histamine H2-receptor antagonist. The purpose of the present paper was to produce a quantitative account of the phenomenon. The phenomenon, namely the difficulty in blocking the hypotensive effects of histamine by antihistamine drugs, was first described by Staub in 1939. Folkow, Haeger and Kahlson in 1948 confirmed the observation and suggested that other histamine receptors might be involved. When we were developing burimamide we showed that the drug was unable to block the hypotensive effects of histamine in intact animals. My recollection is that we did not look at interactions between H1- and H2-receptor antagonists at that stage. The surprise for me happened when we started human studies. John Wylie was one of the earliest volunteers. The interaction between burimamide and histamine-stimulated gastric acid secretion was carried out on him after an intramuscular dose of the H1-receptor antagonist, mepyramine. In spite of the H1-receptor blockade the subsequent i.v. infusion of histamine produced a bright red face, engorged conjunctivae and a headache. However, when the H2-receptor antagonist was now infused all the vascular reactions to histamine (including a marked spreading flare around the vein being injected with histamine) gradually disappeared. I still love showing my colour slide of Wylie's face before and after, such was the impact of the observation on me. This paper shows that H2-receptor blockade has no effect on histamine-induced hypotension, that H1-receptor blockade produces a small shift in the dose-response curves and that after this, H2-receptor blockade can now move the dose-response curves out in parallel. We then used Ariens' two receptor model (Ariens, van Rossum & Simonis, 1959) to explain that this is the expected result where either receptor arm can produce a maximum response but the H2 receptor arm is about ten fold less potent. Another valedictory paper, this one winding up my part in the H2-receptor antagonist story.

E3710, a New Proton Pump Inhibitor, with a Long-Lasting Inhibitory Effect on Gastric Acid Secretion

We have investigated the pharmacology of sodium (R)-2-[4-(2,2-dimethyl-1,3-dioxan-5-yl) methoxy-3,5-dimethylpyridin-2-yl]methylsulfinyl-1H-benzimidazol (E3710), a new proton pump inhibitor (PPI), and its effect on gastric acid secretion. E3710 irreversibly inhibited H(+),K(+)-ATPase activity in pig gastric vesicles with an acidic internal environment with an IC(50) of 0.28 microM. Administration of E3710 (0.1, 0.2, 0.4, and 0.8 mg/kg; n = 6) intraduodenally in a gastric fistula model in dogs inhibited histamine-stimulated gastric acid secretion at 0 to 2 and 24 to 26 h after administration with ED(50) values of 0.18 and 0.22 mg/kg, respectively. The inhibition by E3710 was 2.3 times more potent than that of another representative PPI, esomeprazole (0.2, 0.4, 0.8, and 1.6 mg/kg; n = 6) at 0 to 2 h after administration (ED(50) = 0.40 mg/kg) and 2.8 times more potent at 24 to 26 h (ED(50) = 0.71 mg/kg). In the gastric fistula dogs, the intragastric pH was >or=4 for 17% (n = 27) of a 24-h period with vehicle alone, but when E3710 was administered, at 0.2 (n = 4), 0.4 (n = 8), and 0.8 mg/kg (n = 5), the pH was >or=4 for 40, 79, and 88% of a day, respectively. The corresponding values for esomeprazole at 0.8 (n = 4) and 1.6 mg/kg (n = 8) were 55 and 59%, respectively. In a crossover study with vehicle, E3710 at 0.4 mg/kg and esomeprazole at 1.6 mg/kg (n = 6), E3710 increased the intragastric pH to >4 for 82% of a day compared with 61% of a day with esomeprazole. These results show that E3710 is a long-acting inhibitor of gastric acid secretion and a promising novel therapy for acid-related diseases, such as gastroesophageal reflux disease.

The long-lasting effect of TU-199, a novel H+, K(+)-ATPase inhibitor, on gastric acid secretion in dogs.

We have used Heidenhain-pouch dogs to investigate the effects of (+/-)-5-methoxy-2-{[(4-methoxy-3,5-dimethylpyrid-2-yl)methyl]sulph inyl}-1H-imidazo[4,5-b]pyridine (TU-199), an imidazopyridine derivative, on gastric acid secretion stimulated by histamine, carbachol and tetragastrin. We have also investigated the duration of the antisecretory effect of TU-199 using a measurement of intragastric pH for 24 h in gastric fistula dogs whose gastric acid secretion was stimulated by histamine. Single oral administration of TU-199 (0.1, 0.2 and 0.4mgkg(-1)) dose-dependently suppressed gastric acid secretion stimulated by histamine infusion. Oral treatment with TU-199 (0.2, 0.4 and 0.8 mg kg(-1)) also dose-dependently inhibited acid secretion induced by carbachol and tetragastrin. The inhibitory effect of TU-199 on stimulated gastric acid secretion was more potent than that of omeprazole, a well-known H+,K(+)-ATPase inhibitor in dogs. Repeated oral treatment with TU-199 at a dose of 0.2 mg kg(-1) once a day for seven days markedly suppressed histamine-stimulated gastric acid secretion in dogs. This inhibitory effect of TU-199 reached a maximum level after three or four doses and was more pronounced than that of omeprazole or lansoprazole. In gastric fistula dogs, the duration of intragastric pH-elevation by administration of TU-199 (0.3 mg kg(-1)) was much longer than that of omeprazole (0.6mgkg(-1)) or lansoprazole (0.9mgkg(-1)). The IC50 values (doses resulting in 50% inhibition) of TU-199, omeprazole and lansoprazole with regard to H+,K(+)-ATPase activity in dog gastric mucosal microsomes were 8.6, 8.8 and 9.9 microM, respectively. These results indicate that TU-199 inhibits gastric acid secretion via suppression of a H+,K(+)-ATPase activity. Our findings also suggest that TU-199 might have potent and long-lasting effects on gastric acid secretion.

Inhibition of gastric acid secretion by Ya-hom in isolated mouse whole stomach

Background: Ya-hom, the traditional Thai formula for abdominal discomfort treatment has, been reported to inhibit gastric acid secretion in gastric fistula rats. However, the mechanism underlying its action remains unclear. Objective: To investigate the gastric acid inhibitory action of Ya-hom and its mechanism of action by using an isolated mouse whole stomach model. Methods: The gastric acid secretion of isolated mouse whole stomach was stimulated by histamine (5.0 μM) or bethanechol (10 or 100 μM) after adding the inhibitors (atropine 1 μM, ranitidine 10 μM, indomethacin 0.1 μM or L-NAME 300 μM) and/or Ya-hom to the serosal solution. The effluent perfusate was collected continuously in 10-minute fractions for 120 minutes after stimulation. Results: Re-dissolved lyophilized Ya-hom extract at doses of 2.5, 5.0, 10.0, and 20.0 mg/mL inhibited histaminestimulated gastric acid secretion in a dose-dependent manner. Inhibition of Ya-hom (10 mg/mL) was also observed in the presence of atropine (1 μM), which was used to eliminate effects of endogenous acetylcholine. Ya-hom inhibited bethanechol-stimulated gastric acid secretion in the presence and absence of ranitidine. While the inhibitory action of Ya-hom on histamine-stimulated gastric secretion was not affected by indomethacin, it was attenuated by concomitant treatment with the nitric oxide synthase inhibitor (L-NAME). Conclusion: Ya-hom did not stimulate gastric acid secretion in the isolated mouse whole stomach. Ya-hom significantly inhibited gastric acid secretion after this was stimulated via histamine or bethanechol. Nitric oxide stimulation plays an important role in the inhibitory action of Ya-hom.