Histamine-induced Gastric Acid Secretion Research Articles

Light at Night Exposure Effects on Differentiation and Cell Cycle in the Rat Liver With Autonomic Nervous System Denervation.

Introduction: N Exposure to artificial light at night (LAN) affects human health and causes several functional modifications in the body. Obesity, diabetes, and hormonal changes are reported after exposure to LAN in humans. This study aims to highlight the critical features of biological terms that are affected in the liver of rats which received autonomic nervous system denervation. Methods: The liver gene expression profiles of 8 male Wistar rats that received sympathetic plus parasympathetic hepatic denervation and were exposed to LAN from Gene Expression Omnibus (GEO) for 1 hour were compared with 5 controls. The significant differentially-expressed genes (DEGs) were screened by the protein-protein interaction (PPI) network analysis STRING database (an application of Cytoscape software). Also, CuleGO and CleuDedia, the 2 applications of Cytoscape software, were used for more analysis. Results: Among 250 DEGs, 173 characterized genes with fold change more than 2 plus 100 added relevant genes were included in the PPI network. The analysis of the main connected component (MCC) led to introducing 15 hubs and 15 bottlenecks. CCT2, COPS7A, KAT2A, and ERCC1 were determined as hub-bottlenecks. Among hubs and bottlenecks, DHX15, KAT2A, CCT2, HSP90AB1, CCNE1, DHX16, LSM2, WEE1, CWC27, BAZ1B, RAB22A, DNM2, and DHX30 were linked to each other by various kinds of actions. CCT2 and KAT2A, the 2 hub-bottlenecks, were included in the interacted genes in the action map. Four classes of biological terms including negative regulation of non-motile cilium assembly, negative regulation of transforming growth factor beta activation, alpha-tubulin acetylation, and histamine-induced gastric acid secretion were identified as the critical biochemical pathways and biological processes. Conclusion: Several essential functions such as differentiation, cell cycle, ribosome assembly, and splicing are affected by LAN in rat livers with autonomic nervous system denervation.

The natural flavonoid myricetin inhibits gastric H+, K+-ATPase

Myricetin (3,3’,4’,5,5’,7-hexahydroxyflavone), a major flavonoid in berries and red wine, has been recently used as a health food supplement based on its antioxidant and antitumor properties. We report here that myricetin preferentially exerts inhibitory effects on gastric H+, K+-ATPase. Myricetin inhibited H+, K+-ATPase with a sub-micromolar IC50 value in an enzyme assay using freeze-dried tubulovesicles prepared from hog stomach. Na+, K+-ATPase and Ca2+-ATPase were also inhibited by myricetin in a dose-dependent manner, but the IC50 values for these enzymes were approximately an order of magnitude higher compared to the H+, K+-ATPase. In structure-inhibitory functional analysis of sixteen myricetin derivatives, several phenolic hydroxy groups attached to the flavonoid backbone were highlighted as essential modifications for the inhibition of P2-type ATPases. Furthermore, oral administration of myricetin significantly attenuated histamine-induced gastric acid secretion in an in vivo mouse assessment. Therefore, myricetin derivatives seem to be useful seed compounds for developing new drugs and supplements to alleviate gastric acid secretion.

Tegoprazan, a Novel Potassium-Competitive Acid Blocker to Control Gastric Acid Secretion and Motility.

Tegoprazan [(S)-4-((5,7-difluorochroman-4-yl)oxy)-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide], a potassium-competitive acid blocker (P-CAB), is a novel potent and highly selective inhibitor of gastric H+/K+-ATPase. Tegoprazan inhibited porcine, canine, and human H+/K+-ATPases in vitro with IC50 values ranging from 0.29 to 0.52 μM, while that for canine kidney Na+/K+-ATPase was more than 100 μM. A kinetic analysis revealed that tegoprazan inhibited H+/K+-ATPase in a potassium-competitive manner and the binding was reversible. Oral single administrations of tegoprazan ranging from 0.3 to 30 mg/kg in dogs were well absorbed into the blood stream and distributed in gastric tissue/fluid higher than in plasma. Tegoprazan potently inhibited histamine-induced gastric acid secretion in dogs, and a complete inhibition was observed at 1.0 mg/kg starting from 1 hour after administration. Moreover, an oral administration of tegoprazan at 1 and 3 mg/kg reversed the pentagastrin-induced acidified gastric pH to the neutral range. Interestingly, 3 mg/kg tegoprazan immediately evoked a gastric phase III contraction of the migrating motor complex in pentagastrin-treated dogs and similar effects was observed with the other P-CAB, vonoprazan. Tegoprazan is the novel P-CAB that may provide a new option for the therapy of gastric acid-related and motility-impaired diseases.

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.

Antisecretory Action of the Extract of the Aerial Parts ofEremomastax speciosa (Acanthaceae)Occurs through Antihistaminic and Anticholinergic Pathways

Objective. The objective of this study was to find out the possible antiulcer mechanism of action of Eremomastax speciosa. Method. Carbachol- and histamine-induced hypersecretion, associated with the pylorus ligation technique, were used in rats. Gastric mucosal ulceration, mucus production, pH, gastric volume, and acidity were measured. Results. Histamine and carbachol raised gastric acidity to 86.50 and 84.80 mEq/L, respectively, in the control rats, and the extracts (200 mg/kg) reduced gastric acidity to 34.60 and 39.00 mEq/L, respectively. Intraduodenal aqueous extract (400 mg/kg) in histamine- and carbachol-treated rats produced significant (P < 0.001) decreases in acid secretion to 28.50 and 28.80 mEq/L, respectively, and 100 percent inhibition of gastric ulceration. Augmented histamine-induced gastric acid secretion (90.20 mEq/L) was significantly reduced to 52.60 and 27.50 mEq/L by the 200 and 400 mg/kg doses of the aqueous extract, respectively. The extract significantly reduced (P < 0.001) the volume of gastric secretion and significantly increased mucus production. The ulcer inhibition potential of the extract significantly dropped to 25–44% (oral extract) and to 29–37% (duodenal extract) in carbachol/indomethacin-treated rats. Conclusion. The aqueous extract of E. speciosa has both cytoprotective and antisecretory effects. The antisecretory effect may involve a mechanism common to both cholinergic and histaminergic pathways.

Antiulcerogenic effects and possible mechanism of action of Quassia amara (L. Simaroubaceae) extract and its bioactive principles in rats.

The effects of Quassia amara extract (Q. amara) and its bioactive principles-quassin and 2-methoxycanthin-6-one on gastric ulceration were studied in albino rats. Q. amara (200-800 mg/kg p.o.; 5-20 mg/kg i.p) and 2-methoxycanthin-6-one (12.5, 25.0 and 50.0 mg/kg p.o; 1, 2 and 4 mg/kg i.p) but not quassin (12.5, 25.0 and 50 mg/kg p.o; 1, 2 and 4 mg/kg i.p) significantly inhibited gastric ulceration induced by indomethacin (40mg/kg). Administration of Q. amara (800 mg/kg p.o and 20 mg/kg i.p) and 2-methoxycanthin-6-one (12.5 mg/kg p.o; 4 mg/kg i.p) caused between 77%-85% cytoprotection against indomethacin (40 mg/kg, i.p) - induced gastric ulceration. Quassin did not cause any significant change in indomethacin-induced gastric ulceration. The inhibition of gastric ulceration produced by Q. amara and 2-methoxycanthin-6 one was accompanied by significant dose-dependent decreases (P< 0.01) in total gastric acidity. To investigate the probable mechanism of action, the individual effects of the extract and its principles alone and in combination with histamine (1 mg/kg) or cimetidine (0.12 mg/kg) on gastric acid secretion in situ were studied. Q. amara (20 mg/kg) and 2-methoxycanthin-6-one (4 mg/kg) but not quassin significantly (P< 0.01) inhibited the basal and histamine-induced gastric acid secretion. Inhibition of gastric acid secretion by Q. amara and 2-methoxycanthin-6-one was accentuated by cimetidine. The results suggest that Q. amara and its bioactive principle, 2-methoxycanthin-6-one possess antiulcer activity probably acting via histamine H2 receptor. This could be a potential source of potent and effective antiulcer agents.

Adenosine and its Related Nucleotides may Modulate Gastric Acid Secretion by Inhibiting Calcium Permeability

Studies on lumen-perfused rat isolated stomachs showed that adenosine, adenosine monophosphate (AMP) and reduced nicotinamide adenine dinucleotide (NADH) inhibited histamine-induced gastric acid secretion. The inhibitions and the calcium levels of the serosal solution exhibited inverse relationship. Adenosine and AMP were shown to antagonise calcium-induced swelling of mitochondria. It was thus thought, by extension, that inhibition of calcium entry might be one of the mechanisms by which the purines regulate gastric functi Keywords:Purines: Gastric hypoacidity; anti-mitochondrial swellingBio-Research Vol. 6 (1) 2008: pp. 348-350

Inhibitory effects of ascaris suum extract On gastric acid secretion in rats

The effects of Ascars Suum (A. Suum) extract on gastric acid secretion were investigated in urethane-anaesthetised rats. Three determinations were done viz (1) the acid content when no drug was administered (2) the acid content when histamine was injected and (3) the acid content when the A. Suum extract was given alone or after histamine was administered. The extract (5.5 or 14mg/kg) reduced histamine-induced gastric acid secretion to the control value. At 14mg/kg the extract also reduced basal gastric acid secretion. At the peak of histamine-induced gastric acid secretion, the administration of the extract promptly reduced the gastric acid secretion to basal values. These results indicate that extracts of Ascaris Suum inhibit gastric acid secretion.

The anti-secretory and anti-ulcer activities of esomeprazole in comparison with omeprazole in the stomach of rats and rabbits

Proton pump inhibitors (PPIs) are widely used to treat hyperacid secretion and stomach ulcers. The study investigated the anti-secretory and anti-ulcer effects of esomeprazole, the S-isomer of omeprazole on dimaprit, histamine and dibutyryl adenosine 3, 5 cyclic monophosphate (dbcAMP)-evoked gastric acid secretion, acidified ethanol (AE) and indomethacin (INDO)-induced haemorrhagic lesions and on prostaglandin E2 (PGE2) level in the rat in vivo and rabbit in vitro preparations. The effect of omeprazole was also investigated for comparison. Dimaprit-induced acid secretion was significantly (P < 0.05) inhibited by both PPIs in a dose-dependent manner. In the isolated rabbit gastric glands, both PPIs elicited marked reductions in histamine- and dbcAMP-evoked acid secretion with similar potency. The lesions induced by either AE or INDO were significantly (P < 0.05) reduced in the presence of either esomeprazole or omeprazole compared to control values. Increasing doses of esomeprazole before AE treatment resulted in a marked degree of cytoprotection and an elevation in the concentration of bound PGE2 in the stomach tissue homogenate. The results show that esomeprazole and omeprazole were equally effective against gastric haemorrhagic lesions induced by either AE or INDO and in inhibiting dimaprit-, dbcAMP- and histamine-induced gastric acid secretion in the rat and rabbit stomach both in vivo and in vitro. The gastro-protective effect of esomeprazole was found to be proportional to the bound PGE2 levels in the glandular area of the stomach.

Effect of Nitric Oxide on Histamine-Induced Cytological Transformations in Parietal Cells in Isolated Human Gastric Glands

Previous studies have shown that nitric oxide (NO) inhibits histamine-induced gastric acid secretion in isolated human gastric glands. NO synthase has been found to be present in the human oxyntic mucosa and has been suggested to serve as a paracrine regulator of gastric acid secretion. Histamine stimulation of parietal cells induces cytoskeletal rearrangements, recruitment of H+/K+-ATPase-rich tubulovesicles to the apical membrane and expansion of intracellular canaliculi. The aim of the present study was thus to investigate (i) the effect of an NO donor on histamine-induced cytological transformations and (ii) the influence of increased [Ca2+]i on NO-induced morphological changes in human parietal cells. Human gastric glands were isolated and subjected to the NO donor SNAP prior to histamine administration. [Ca2+]i was increased by photolysis of the caged Ca2+ compound NP-EGTA. The distribution of F-actin, ezrin, and H+/K+-ATPase was assessed by confocal microscopy. Ultrastructural analysis was performed using transmission electron microscopy. SNAP did not influence the histamine-induced translocation of F-actin, ezrin, and H+/K+-ATPase but prevented an increase in the canalicular size. Elevation of [Ca2+]i in resting cells was found to mimic histamine-induced intraparietal cell transformations; however, NO-induced parietal cell morphology was unaffected by a rise in [Ca2+]i. These results indicate that NO inhibits secretion of fluid into the canalicular lumen without affecting membrane recruitment and that this effect is Ca2+-insensitive.

Gastroprotective effect of a traditional Chinese herbal drug “Baishouwu” on experimental gastric lesions in rats

“Baishouwu” is an appellative name of dried root tubers from three Asclepiadaceae plants: Cynanchum auriculatum Royle ex Wight, Cynanchum bungei Decne and Cynoctonum wilfordii Maxim. In order to establish the pharmacological basis for the ethnomedicinal use of Baishouwu in gastric disorders, this study examined the effects of ethanol extracts and fractions from root tubers of Cynanchum auriculatum, Cynanchum bungei and Cynoctonum wilfordii on ethanol-, indomethacin-induced gastric lesions and histamine-induced gastric acid secretion in rats. Plant materials were collected from various areas of China. Oral administration of ethanol extract and chloroform fraction of Cynoctonum wilfordii collected from Changbai Cordillera at doses of 150 and 68 mg/kg, respectively, significantly inhibited the development of ethanol- and indomethacin-induced gastric lesions and also caused significant decrease of gastric acid secretion after histamine-induced gastric lesion. Oral administrations of ethanol extract and chloroform fraction of Cynanchum auriculatum collected from Binhai at the doses of 300 and 69 mg/kg, respectively, significantly inhibited ethanol- and indomethacin-induced gastric lesions. This study demonstrates the gastroprotective property of Baishouwu for the first time.

Effects of Azadirachta indica extract on gastric ulceration and acid secretion in rats

The effect of Azadirachta indica extract on gastric ulceration was studied in albino rats. Azadirachta indica extract (100–800 mg/kg p.o., 100–250 mg/kg i.p.) significantly inhibited gastric ulceration induced by indomethacin (40 mg/kg). Administration of 800 mg/kg p.o. and 250 mg/kg i.p. caused 100% cytoprotection against indomethacin (40 mg/kg, i.p.)-induced gastric ulceration. This action was accompanied by a dose-dependent decrease in total gastric acidity. In order to investigate the probable mechanism of Azadirachta indica antiulcer activity, the effect of the extract alone and in combination with histamine (1 mg/kg) and cimetidine (0.12 mg/kg) on gastric acid secretion in situ was studied. Azadirachta indica (250 mg/kg) significantly inhibited the basal and histamine-induced gastric acid secretion. Cimetidine seemed to augment Azadirachta indica inhibition of gastric acid secretion. The results suggest that the stem bark extract of Azadirachta indica possesses antiulcer agents, which probably act via histamine H 2 receptor.

Minor diterpenoids from cascarilla (Croton eluteria Bennet) and evaluation of the cascarilla extract and cascarillin effects on gastric acid secretion.

Three new diterpenoids belonging to the clerodane (2-3) and halimane (4) structural types have been isolated from the bark of Croton eluteria Bennet, commonly known as cascarilla. Their structures have been fully characterized by spectroscopic means. Cascarilla extract and its major component, cascarillin, were found to significantly increase histamine-induced gastric acid secretion in the mouse stomach. These preliminary results provide the first rationale for the use of cascarilla in bitter preparations aimed at improving digestion.

Anti-ulcer compound from Voacanga africana with possible histamine H2 receptor blocking activity

Voacanga africana is used in Cameroonian ethnomedicine for the treatment of peptic ulcers. We have tested the cytoprotective, anti-secretory and ulcer healing actions of an alkaloid (TN) obtained from the fruit extract. Oral administration of TN (50-100 mg/kg) dose-dependently prevented ulcer formation by HCl/ethanol (36-75%), absolute ethanol (43-75%), HCl-ethanol/indomethacin (58-84%), Pylorus ligation (31-100%), cold restraint stress (68-100%) and histamine (49-100%). The inhibitory effect at 50 and 100 mg/kg against HCl/ethanol was not suppressed by pre-treatment with indomethacin (20 mg/kg, i.p.). TN reduced Shay-ligated gastric acid secretion from 77 mEq/l in the controls to 46 and 25 mEq/l for the 50 and 100 mg/kg doses. Augmented histamine-induced gastric acid secretion was reduced from 84 mEq/l in the controls to 45 and 21 mEq/l for the two doses of TN, with total inhibition of gastric and duodenal ulcers by the 50 mg/kg dose. Healing rate of chronic acetic acid-induced ulcers was 62 and 83%, respectively, for the dose of 50 and 100 mg/kg of TN compared with the controls. TN has gastric anti-secretory effects similar to histamine receptor blockers. Its cytoprotective and ulcer healing properties are related to its ability to strengthen gastric mucosal defenses through enhanced gastric mucus production.

ANTI-ULCER ACTIVITY OF SKP-450, A NOVEL POTASSIUM CHANNEL ACTIVATOR, IN RATS

The anti-ulcer effects of SKP-450, a new potassium channel activator, were evaluated on basal and histamine-induced gastric acid secretion, and against experimentally-induced ulcers such as ethanol-induced and NaOH-induced gastric ulcers. In the pylorus-ligated rat, SKP-450 (0.1–0.5 mg kg−1) significantly decreased volume and concentration of gastric juice, and total acid output (ED50: 0.12 mg kg−1). SKP-450 (0.3–3.0 mg kg−1) also inhibited histamine-induced gastric acid secretion, maximal effects being achieved at 1.0 mg kg−1(37.9% inhibition). In the 95% ethanol-treated rats, SKP-450 significantly reduced the mucosal lesions (46.9 and 31.4% inhibition at 0.1 and 0.2 mg kg−1, respectively). A significant reduction in the ulcer index by SKP-450 was also observed in 0.3 n NaOH-treated rats (31.5 and 64.3% inhibition at 0.5 and 1.0 mg kg−1, respectively). The effects of SKP-450 on histamine-induced acid secretion and on NaOH-induced ulcers were inhibited by glibenclamide (20 mg kg−1, i.v.), a selective blocker of ATP-sensitive potassium channel. These results indicate that SKP-450 possesses anti-ulcer effects and its effects may be mediated by activation of ATP-sensitive potassium channels.

Histamine-induced gastric acid secretion in horses

Abstract Objective To determine gastric secretory responses in horses treated with histamine and to determine the dose of histamine needed to elicit maximal gastric secretion. Animals 6 adult horses with an indwelling gastric cannula. Procedure Gastric contents were collected in 15-minute periods, and volume, pH, hydrogen ion concentration, hydrogen ion output, sodium concentration, and sodium output were determined. Values were determined without any treatment (baseline), after administration of pyrilamine maleate (1 mg/kg of body weight, IV, given during a 15-minute period), and during 1-hour infusions of histamine at 3 rates (7.5, 15, and 30 μg/kg/h, IV). Results Volume and hydrogen ion concentration of gastric contents and hydrogen ion output were significantly increased, compared with baseline values, during histamine infusion. Mean hydrogen ion concentration and hydrogen ion output were significantly greater during infusion of histamine at a rate of 15 or 30 μg/kg/h than at a rate of 7.5 μg/kg/h. Sodium concentration was significantly decreased, compared with baseline value, during histamine infusion, but sodium output was unchanged. Conclusions Histamine at doses of 15 and 30 μg/kg/h, IV stimulated maximal gastric secretion in horses. Histamine appeared to induce only parietal secretion. Clinical Relevance This study provides additional information related to equine gastric physiology, which may benefit further understanding of the pathogenesis of peptic ulcer disease. (Am J Vet Res 1998;59:1303–1306)

Inhibitory effect of Nω-nitro- l-arginine on gastric secretion induced by secretagogues and vagal stimulation in the isolated stomach

The involvement of endogenous nitric oxide (NO) in the control of gastric acid secretion induced by some secretagogues was studied in the mouse isolated whole stomach. The gastric acid secretion induced by McNeil A-343 {4-[[[(3-chlorophenyl)amino]carbonyl]oxy]- N, N, N,-trimethyl-2-butyn-1-aminium chloride}, a muscarinic M 1 receptor agonist, pentagastrin or electrical vagus nerve stimulation was markedly inhibited by pretreatment with the NO synthase inhibitor N ω -nitro- l-arginine (L-NNA). This inhibitory effect of L-NNA was reversed by l-arginine, but not by d-arginine. Histamine-induced gastric acid secretion was not influenced by treatment with L-NNA. Famotidine completely inhibited the gastric acid secretion induced by McNeil A-343, pentagastrin or electrical vagus nerve stimulation, showing that these stimulations induced gastric acid secretion mainly through histamine release from histamine-containing cells in the gastric mucosa. Moreover, the pentagastrin- and bethanechol-induced histamine release from gastric mucosal cells was significantly inhibited by L-NNA. The NO donor, sodium nitroprusside, at a concentration not affecting histamine-induced gastric acid secretion, increased the acid secretory response, and this response was inhibited by famotidine. These results suggest that endogenous NO is involved in the gastric acid secretion via histamine release from histamine-containing cells.

Synthesis and antiulcer activity of N-2-(2-hydroxy-2-phenyl)ethyl-N"-(methanesulfonyl)guanidine analogue of ranitidine. Development of a new antiulcer agent T-593

A series of the aryl-substituted N'-2-(2-hydroxy-2-phenyl)ethyl derivatives of N"-methanesulfonyl-N-2-((5-dimethylaminomethyl or 5-methylaminomethyl) furfurylthio)ethylguanidine have been synthesized as potential antisecretory and mucosal protective antiulcer agents. The synthetic routes involves, at the last stage, the reaction of 2-hydroxy-2-phenylethylamines with N-2-(furfurylthio)-ethyl-N'-methanesulfonyl-S-methylisothiourea or its O-phenylisourea counterpart. The primary screening test to assess the inhibitory activity of the synthetic compounds on histamine-induced gastric acid secretion was carried out in anesthetized rats by the lumen-perfusion technique of Ghosh and Schild and also by the pylorus-ligated preparation method. The best profile of histamine H2-antagonist activity was much better than that of the prototype ranitidine, and obtained with N'-(2-(2-hydroxy-2-(4-hydroxyphenyl)) ethyl-N"-methanesulfonyl-N-2-(5-(methylaminomethyl)furfurylthio)et hylguanidine (12f), which was also characterized by enhancing the gastric mucosal blood flow in rabbits as observed by the thermoelectric method. This compound 12f, designated as T-593, significantly inhibited the formation of the indomethacin-induced gastric lesions in rats; 3.5-fold more potent than ranitidine, but 4-fold less active than famotidine. On the other hand, T-593 and famotidine displayed comparable activities in healing the acetic acid-induced gastric ulcer with and without the dosing of indomethacin. Additional notable features of T-593, as determined in rats, are that its protective effect on the hemorrhagic shock-induced lesion under the prior dosing of histamine is ca. 10- and 2-fold greater than ranitidine and famotidine, respectively, and that a decrease in the gastric mucosal blood flow caused by a partial blood-withdrawal is more strongly recovered with T-593 than with famotidine. These experimental results suggest that the antiulcer efficacy of T-593 can be explained by its dual activities: antisecretion of gastric acid and, more importantly, protection of gastric mucous membrane.

Stress, the brain, and the gastric mucosa

Exposure of rats to 2 hours of cold water restraint is associated with both macroscopic and microscopic gastric mucosal injury. Administration of neurotensin into the lateral ventricle or into the nucleus accumbens, one of the mesolimbic dopamine system nuclei, is associated with protection when given before exposure to cold water restraint. Under conditions of cold water restraint, pretreatment with central neurotensin is associated with maintenance of gastric mucosal blood flow and an increase in endogenous gastric mucosal PGE 2 activity. In addition, pretreatment with 6-hydroxy dopamine into the mesolimbic nuclei, which depletes them of endogenous dopamine, prior to exposure to cold water restraint, ameliorates the protective effect of central neurotensin. Centrally administered neurotensin inhibits basal, pentagastrin-, carbachol-, and 2-deoxy-D-glucose-induced but not histamine-induced gastric acid secretion. This antisecretory effect is ameliorated by parenteral pretreatment with haloperidol and domperidone. Taken together, these observations support the hypothesis that centrally administered neurotensin, particularly into the nuclei of the mesolimbic dopamine system, confers protection against gastric mucosal injury produced by 2 hours of cold water restraint. This affect may be due, in part, to inhibition of acid secretion and maintenance of mucosal blood flow mediated by an increase in gastric mucosal PGE 2 activity.

Nicotinamide derivatives as a new class of gastric (H+/K+)-ATPase inhibitors. III. Synthesis and gastric antisecretory activity of 2-[(2- and 4-aminobenzyl, and alpha-methylbenzyl)sulfinyl]-N-(4-pyridinyl) -3-pyridinecarboxamides.

A new series of 2-[(2-aminobenzyl, 4-aminobenzyl, and alpha-methylbenzyl) sulfinyl]-N-(4-pyridinyl)-3-pyridinecarboxamides. was synthesized and evaluated for gastric antisecretory activities. Several of the compounds synthesized exhibited potent inhibitory activities against [14C]aminopyrine accumulation stimulated by dibutyryl cyclic AMP in isolated rabbit parietal cells and histamine-induced gastric acid secretion in pylorus-ligated rats by intraduodenal administration. In particular, the more polar diastereoisomer of 2-[(4-methoxy-alpha-methylbenzyl)sulfinyl] -N-(4-pyridinyl)-3-pyridinecarboxamide (13b) showed in vivo inhibitory activity equivalent or superior to that of omeprazole and was a more selective (H+/K+)-ATPase inhibitor than omeprazole.