Effects of L-glutamic acid on acid secretion and mucosal blood flow in the rat stomach

The effect of intravenous administration of L-glutamic acid (L-Glu) on gastric acid secretion and gastric mucosal blood flow (GMBF) in anesthetized rats were investigated. Infusion with synthetic L-Glu alone had no effect on spontaneous acid secretion. However, L-Glu reduced histamine- (2 mg/kg/hr) or oxotremorine- (1 microg/kg/hr) stimulated acid secretion, whereas L-Glu had no effect on acid secretion induced by pentagastrin (8 microg/kg/hr). Furthermore, this inhibitory effect of L-Glu on histamine- or oxotremorine-stimulated acid secretion was blocked by 6,7-dinitroquinoxaline-2,3-dione (DNQX), a non-NMDA receptor antagonist. The effect of L-Glu on gastric mucosal microcirculation in the anesthetized rats was evaluated by using Laser Doppler Flowmetry (LDF). The results showed that L-Glu did not significantly reduce both mucosal and serosal blood flow in stomach. No significant modulatory effect on histamine- or oxotremorine-stimulated increase in GMBF was noted after infusion with L-Glu. It is concluded that L-glutamic acid is capable of the modulating of gastric acid secretion via ionotropic non-NMDA receptors, but do not affect on GMBF. However, L-glutamic acid showed no effect on acid secretion by itself.     

Roles of endogenous prostaglandins and nitric oxide in gastroduodenal ulcerogenic responses induced in rats by hypothermic stress.

We examined the roles of endogenous prostaglandins (PGs) and nitric oxide (NO) in the gastroduodenal ulcerogenic responses to hypothermic stress (28 approximately 30 degrees C) in anesthetized rats. Lowering body temperature provoked damage in the gastroduodenal mucosa, with an increase of gastric acid secretion and motility. These responses were completely abolished by bilateral vagotomy or atropine, while 16,16-dimethyl PGE2 decreased the mucosal ulcerogenic response with no effect on acid secretion. The non-selective COX inhibitors, indomethacin or aspirin, worsened these lesions with enhancement of gastric motility and no effect on acid secretion, while the selective COX-2 inhibitor NS-398 did not affect any of these responses. On the other hand, the non-selective NOS inhibitor L-NAME but not aminoguanidine (a relatively selective inhibitor of iNOS), significantly potentiated the acid secretory and mucosal ulcerogenic responses in the stomach but reduced the duodenal damage in response to hypothermia, the effects being antagonized by co-administration of L-arginine. Hypothermia itself decreased duodenal HCO3- secretion under both basal and mucosal acidification-stimulated conditions. Both indomethacin and aspirin further decreased the HCO3- response to the mucosal acidification, while L-NAME significantly increased the HCO3- secretion even under hypothermic conditions, similar to 16,16-dimethyl PGE2. These results suggest that 1) hypothermic stress caused an increase of acid secretion and motility as well as a decrease of duodenal HCO3-secretion, resulting in damage in both the stomach and duodenum, 2) the COX-1 but not COX-2 inhibition worsened these lesions by enhancing gastric motility and further decreasing duodenal HCO3- response, 3) the cNOS but not iNOS inhibition worsened gastric lesions by increasing acid secretion but decreased duodenal damage by increasing HCO3- secretion. Thus, it is assumed that the gastroduodenal ulcerogenic and functional responses to hypothermic stress are modified by cNOS/NO as well as COX-1/PGs.     

Effect of alpha and beta adrenoreceptor antagonists on glucagon-induced inhibition of gastric acid secretion in cats

The aim of the present study was to examine the effect of alpha and beta adrenoceptor blockade on gastric acid secretion, mucosal blood flow (GMBF) and catecholamine content of the gastric mucosa during glucagon-induced inhibition of gastric acid secretion. The secretory response to continuous infusion of pentagastrin (6 micrograms/kg/h) was reduced by regitine (0.5 mg/kg/h) and propranolol (25 micrograms/kg/h). Glucagon (25 ng/kg/h) further slightly decreased HCl secretion. GMBF was also significantly inhibited by regitine and propranolol. Administration of glucagon continued decreasing of the GMBF. By determining the change in the ratio of blood flow to secretory rate, this reduction in mucosal blood flow was found to be secondary to a fall in secretion. In these studies a concomitant increase in noradrenaline content of the gastric mucosa was observed: after regitine by 50%, after propranolol--by 32.5%, after these blockers given simultaneously--by 75%. The level of noradrenaline was higher after subsequent administration of glucagon. Our results indicate that more than one component is responsible for the inhibitory effect of glucagon on pentagastrin-stimulated gastric acid secretion.     

大鼠浸水应激性胃粘膜损伤机制的研究

本工作观察了室温下单纯束缚加生理盐水,浸水应激加生理盐水,浸水应激加阿托品(0.5mg/kg),浸水应激加酚苄明(10mg/kg),浸水应激加戊巴比妥钠(30mg/kg)5组大鼠的胃粘膜损伤程度,胃酸分泌,胃壁结合粘液分泌和胃运动的变化。结果表明:大鼠浸水应激后胃粘膜损伤严重,胃酸分泌增加,胃壁结合粘液分泌减少,胃运动亢进;预先应用阿托品再浸水应激可显著减轻胃粘膜损伤程度,抑制胃酸分泌和胃运动,但增加胃壁结合粘液的分泌;预先应用应巴比妥钠亦显著减轻胃粘膜损伤程度,抑制胃运动和增加胃壁结合粘液的分泌,但对胃酸分泌无影响;预先应用酚苄明对胃粘膜损伤程度、胃酸分泌、胃壁结合粘液分泌和胃运动均无明显影响。上述结果提示,胃运动亢进、胃壁结合粘液分泌减少及胃酸分泌增加均不同程度地参与了浸水应激性胃粘膜损伤的形成,但在胃运动受到抑制及胃壁结合粘液分泌增加的情况下,仅胃酸的存在不致引起胃粘膜严重损伤。     

Gastric acid and vagus nerve response to GABA agonist baclofen

Baclofen [beta-(p-chlorophenyl)-gamma-aminobutyric acid], a lipophilic derivative of GABA, was studied for its effect upon the efferent activity of the left cervical vagus in urethane-anesthetized rats. Baclofen (4 mg/kg, s.c.) produces neural discharges in the multifiber vagus preparation. The time course of vagal activation is well correlated with the profile of stimulation of gastric acid secretion recorded every 2 min. Atropine pretreatment (1 mg/kg) did not modify baclofen stimulation of vagal activity. These results demonstrated that a GABAB receptor agonist stimulates the parasympathetic outflow through mechanisms independent of interaction with muscarinic receptors leading to stimulation of gastric acid secretion.     

Adenosine: a novel ulcer modulator in stomachs.

Adenosine has been demonstrated for its actions on gastric secretion and stress-induced gastric ulceration in animals. We examined the pharmacological actions of adenosine on ethanol-evoked gastric lesions and gastric mucosal blood flow (GMBF) in rats, because both of them are closely related. Adenosine pretreatment, in dose of 7.5 mg/kg increased GMBF and protected against ethanol-evoked gastric lesion formation. However, this antiulcer action was followed by an aggravation of gastric lesions and reduction in GMBF. We further investigated whether these actions could act through the adenosine A1 or A2 receptors, therefore L-phenylisopropyladenosine (L-PIA) or N-ethylcarboxamidoadenosine (NECA), the adenosine A1 or A2 receptor agonists, respectively, were used. The drugs given in doses of 10 or 50 micrograms/kg for L-PIA and 1 or 5 micrograms/kg for NECA, dose-dependently inhibited GMBF and potentiated ethanol-induced gastric damage. When the two drugs were given together to animals, they did not further aggravate the severity of ulceration and reduction of GMBF. These findings indicate that the antiulcer action of adenosine is not mediated via the adenosine A1 and A2 receptors but if acts through different adenosine receptor subtypes. It was because the lesion worsening effects of adenosine at the second stage of the biphasic responses were similar to the actions of L-PIA and NECA, the ulcer potentiating effect is probably acting through adenosine A1 and A2 receptors in anaesthetised rats.     

The effect of neurotensin and secretin on gastric acid secretion and mucosal blood flow in man

Neurotensin stimulates pancreatic secretion directly and by potentiating the effect of secretin. Neurotensin also inhibits gastric secretion. Secretin inhibits gastric secretion as well, but whether it also interacts with neurotensin is not known. Secretin is known to inhibit gastric mucosal blood flow (GMBF). The effect of neurotensin on GMBF is not known. Acid secretion (triple lumen perfused orogastric tube) and GMBF ([14C]aminopyrine clearance) were therefore measured in 6 subjects during neurotensin, secretin and neurotensin plus secretin infusions. Neurotensin plus secretin reduced acid secretion by a median 130 (range 34-394) mumol/min which was significantly greater than either neurotensin at 36 (7-67) mumol/min or secretin 54 (20-347) mumol/min alone (P less than 0.05). This effect appeared independent of GMBF. Neurotensin plus secretin reduced GMBF by 14 (12-27) ml/min but not significantly more than neurotensin at 11 (3-20) ml/min or secretin 18 (2-27) ml/min alone. Further, there was no correlation between changes in acid output and GMBF during infusion of the peptides. We conclude that the inhibitory effects of neurotensin and secretin on gastric secretion are at least additive and together they may function as an 'enterogastrone'.     

Ghrelin stimulates gastric acid secretion and motility in rats

Ghrelin, a novel growth-hormone-releasing peptide, was discovered in rat and human stomach tissues. However, its physiological and pharmacological actions in the gastric function remain to be determined. Therefore, we studied the effects of rat ghrelin on gastric functions in urethane-anesthetized rats. Intravenous administrations of rat ghrelin at 0.8 to 20 microgram/kg dose-dependently increased not only gastric acid secretion measured by a lumen-perfused method, but also gastric motility measured by a miniature balloon method. The maximum response in gastric acid secretion was almost equipotent to that of histamine (3 mg/kg, i.v.). Moreover, these actions were abolished by pretreatment with either atropine (1 mg/kg, s.c.) or bilateral cervical vagotomy, but not by a histamine H(2)-receptor antagonist (famotidine, 1 mg/kg, s.c.). These results taken together suggest that ghrelin may play a physiological role in the vagal control of gastric function in rats.     

Stimulatory effects of endogenous and exogenous nitric oxide on gastric acid secretion in anesthetized rats

We previously reported the stimulatory effect of endogenous nitric oxide (NO) on gastric acid secretion in the isolated mouse whole stomach and histamine release from gastric histamine-containing cells. In the present study, we investigated the effects of endogenous and exogenous NO on gastric acid secretion in urethane-anesthetized rats. Acid secretion was studied in gastric-cannulated rats stimulated with several secretagogues under urethane anesthesia. The acid secretory response to the muscarinic receptor agonist bethanechol (2 mg/kg, s.c.), the cholecystokinin(2) receptor agonist pentagastrin (20 microg/kg, s.c.) or the centrally acting secretagogue 2-deoxy-D-glucose (200 mg/kg, i.v.) was dose-dependently inhibited by the NO synthase inhibitor N(omega)-nitro-L-arginine (L-NNA, 10 or 50 mg/kg, i.v.). This inhibitory effect of L-NNA was reversed by a substrate of NO synthase, L-arginine (200 mg/kg, i.v.), but not by D-arginine. The histamine H(2) receptor antagonist famotidine (1 mg/kg, i.v.) completely inhibited the acid secretory response to bethanechol, pentagastrin or 2-deoxy-D-glucose, showing that all of these secretagogues induced gastric acid secretion mainly through histamine release from gastric enterochromaffin-like cells (ECL cells). On the other hand, histamine (10 mg/kg, s.c.)-induced gastric acid secretion was not inhibited by pretreatment with L-NNA. The NO donor sodium nitroprusside (0.3-3 mg/kg, i.v.) also dose-dependently induced an increase in acid secretion. The sodium nitroprusside-induced gastric acid secretion was significantly inhibited by famotidine or by the soluble guanylate cyclase inhibitor methylene blue (50 mg/kg, i.v.). These results suggest that NO is involved in the gastric acid secretion mediated by histamine release from gastric ECL cells.     

Baclofen and NOS inhibitors interact to evoke synergistic hypothermia in rats

Our laboratory recently demonstrated that a drug combination of baclofen and L-NAME, a nonspecific nitric oxide synthase (NOS) inhibitor, evokes synergistic hypothermia in rats. These data are the first demonstration of synergy between a GABA agonist and NOS inhibitor. While the hypothermic synergy suggests a role for NOS in baclofen pharmacology, it is unclear whether the super-additive hypothermia is specific for baclofen and L-NAME or extends to drug combinations of baclofen and other NOS inhibitors. The site of action (central or peripheral) and isoforms of NOS that mediate the synergy are also unknown. Here, we confirm the hypothermic synergy with additional data and discuss potential mechanisms of the drug interaction. Baclofen (2.5, 3.5, 5 and 7.5 mg/kg, i.p.) was administered to rats by itself or with 7-nitroindazole (7-NI), a neuronal NOS inhibitor. 7-NI (10 mg/kg, i.p.) did not affect body temperature. For combined administration, 7-NI (10 mg/kg, i.p.) increased the relative potency of baclofen (F=18.9, P<0.05). The present data validate the hypothermic synergy caused by the drug combination of baclofen and L-NAME and implicate nNOS in the synergy. In a context broader than thermoregulation, NO production and transmission may play an important role in baclofen pharmacology.     

Motilin Stimulates Gastric Acid Secretion in Coordination with Ghrelin in Suncus murinus

Motilin and ghrelin constitute a peptide family, and these hormones are important for the regulation of gastrointestinal motility. In this study, we examined the effect of motilin and ghrelin on gastric acid secretion in anesthetized suncus (house musk shrew, Suncus murinus), a ghrelin- and motilin-producing mammal. We first established a gastric lumen-perfusion system in the suncus and confirmed that intravenous (i.v.) administration of histamine (1 mg/kg body weight) stimulated acid secretion. Motilin (0.1, 1.0, and 10 μg/kg BW) stimulated the acid output in a dose-dependent manner in suncus, whereas ghrelin (0.1, 1.0, and 10 μg/kg BW) alone did not induce acid output. Furthermore, in comparison with the vehicle administration, the co-administration of low-dose (1 μg/kg BW) motilin and ghrelin significantly stimulated gastric acid secretion, whereas either motilin (1 μg/kg BW) or ghrelin (1 μg/kg BW) alone did not significantly induce gastric acid secretion. This indicates an additive role of ghrelin in motilin-induced gastric acid secretion. We then investigated the pathways of motilin/motilin and ghrelin-stimulated acid secretion using receptor antagonists. Treatment with YM 022 (a CCK-B receptor antagonist) and atropine (a muscarinic acetylcholine receptor antagonist) had no effect on motilin or motilin-ghrelin co-administration-induced acid output. In contrast, famotidine (a histamine H₂ receptor antagonist) completely inhibited motilin-stimulated acid secretion and co-administration of motilin and ghrelin induced gastric acid output. This is the first report demonstrating that motilin stimulates gastric secretion in mammals. Our results also suggest that motilin and co-administration of motilin and ghrelin stimulate gastric acid secretion via the histamine-mediated pathway in suncus.     

Involvement of nitric oxide in the gastroprotective effects of an aqueous extract of Pfaffia glomerata (Spreng) Pedersen, Amaranthaceae, in rats

The plants belonging to Pfaffia genus are used in folk medicine to treat gastric disturbances. This study examined the effects of an aqueous extract of Pfaffia glomerata (Spreng) Pedersen (AEP) on the gastrointestinal tract. Wistar rats were pretreated orally (p.o.) with the AEP (125, 250, 500 and 1000 mg.kg(-1)) before induction of ulcers by hypothermic restraint stress (HRS, 3 h restraint stress at 4 degrees C), ethanol (ET, 70%; 0.5 ml/animal; p.o.) or indomethacin (IND, 20 mg.kg(-1); s.c.). Control animals received water (C) or ranitidine (60 mg.kg(-1)) p.o. The AEP protected rats against HRS and ET-induced ulcers, but was not able to protect the gastric mucosa against IND-induced ulcers. When injected into the duodenal lumen, the AEP reduced total acidity and both basal and histamine-stimulated acid secretion in pylorus-ligated rats. In addition, gastric secretion from AEP-treated animals exhibited increased concentrations of nitrite and nitrate. Treatment of animals with L-NAME (120 mg.kg(-1), p.o.) prevented both the reduction of total acidity and the increase in NOx levels promoted by AEP treatment. In conclusion, AEP effectively protected the gastric mucosa and inhibited gastric acid secretion in rats, probably by involving the histaminergic pathway and an enhanced production of nitric oxide in the stomach.     

Sensitivity of embryonic spontaneous motility to the GABA agonists baclofen and muscimol

The development of the sensitivity of spontaneous motor activity to the GABA agonists baclofen (10 mg/kg egg weight, systemic administration) and muscimol (0.8 mg/kg e.w., systemic administration) was tested in 11-day to 19-day-old chick embryos. 1) Baclofen already significantly depressed the frequency of spontaneous movements in 11-day embryos; its effect attained the maximum (85% depression of spontaneous motility) in 13-day embryos. After the 15th day of incubation, it reduced spontaneous motor activity by 50-60%. In spinal embryos, baclofen had the same, but a quantitatively more pronounced effect, demonstrated from its direct action on the spinal cord uninfluenced by supraspinal modulation, which began to be manifested after the 15th day of incubation. 2) Muscimol did not begin to inhibit spontaneous motility significantly until the 13th day of incubation. Subsequently, the latent period of its effect shortened, its duration lengthened and, lastly, its quantitative result also increased. 3) A comparison of the effect of GABA (Sedlácek 1978), muscimol and baclofen in 17-day chick embryos showed that the depressive effect increased in the sequence baclofen less than GABA less than muscimol, but that GABA took effect faster than the others. The results testify that the maturation of the individual elements of the GABA-ergic central inhibition system is a complex process.     

Effect of peripherally-injected glucagon-like peptide-1 on gastric mucosal blood flow

The aim of this study was to investigate the mechanisms involved in the effect of glucagon-like peptide-1 (GLP-1) on the decrease in gastric mucosal blood flow (GMBF) induced by intragastric ethanol.After preparation of the stomach for GMBF recording, a probe was placed to the gastric mucosa and basal GMBF recordings were obtained by a laser Doppler flowmeter after a 30-minute stabilization period. Following GLP-1 (1000 ng/kg; i.p.) injection, 1 ml of absolute ethanol was applied to the gastric chamber and GMBF was recorded continuously during a 30-minute period. GLP-1 (1000 ng/kg; i.p.) prevented the decrease in GMBF induced by ethanol. Nitric oxide (NO) synthase inhibitor L-NAME, (30 mg/kg; s.c.), calcitonine gene-related peptide (CGRP) receptor antagonist CGRP-(8–37) (10μg/kg; i.p.), and cyclooxygenase inhibitor indomethacin (5 mg/kg; i.p.) all inhibited the GMBF-improving effect of GLP-1.We concluded that, NO, CGRP and prostaglandins may be involved in the effect of peripherally-injected GLP-1 on GMBF reduction induced by intraluminal ethanol.     

Effect of chlorpromazine on ulcer formation by indomethacin in histamine- and insulin-stimulated rats.

The effect of chlorpromazine on ulcer formation by indomethacin and on total gastric secretion and gastric acid secretion was studied in rats. Secretion and ulceration were evaluated under basal conditions and after the administration of histamine or insulin, i.e. substances stimulating gastric acid secretion. The authors confirmed that chlorpromazine inhibits basal secretion and found that it also inhibits histamine- and insulin-stimulated gastric secretion, in correlation to the dose. It also strongly inhibits the formation of stomach lesions caused by indomethacin under basal conditions and after pretreatment with histamine (3 and 10 mg/kg) and insulin (0.3 IU/kg). Chlorpromazine did not inhibit lesions formed after combining indomethacin with insulin in a dose of 3 IU/kg. The results show that although chlorpromazine inhibits both basal and centrally or peripherally stimulated gastric secretion, its effect on stomach lesions caused by indomethacin is not uniform. Pretreatment with insulin in a dose of 3 IU/kg demonstrates that indomethacin-induced stomach lesions are markedly potentiated by this dose of insulin and are not dependent on gastric secretion only. The inability of chlorpromazine to inhibit these lesions gives the evidence that other--probably central--mechanisms play a role in their development.     

Mechanisms by which endogenous glucocorticoid protects against indomethacin-induced gastric injury in rats

We investigated the mechanisms underlying the protective action of glucocorticoids against indomethacin-induced gastric lesions. One-week adrenalectomized rats with or without corticosterone replacement (4 mg/kg sc) were administered indomethacin (25 mg/kg sc), and gastric secretion (acid, pepsin, and mucus), motility, microvascular permeability, and blood glucose levels were examined. Indomethacin caused gastric lesions in sham-operated rats, with an increase in gastric motility and microvascular permeability as well as a decrease in mucus secretion. Adrenalectomy significantly worsened the lesions and potentiated these functional disorders. Glucose levels were lowered by indomethacin in sham-operated rats, and this response was enhanced by adrenalectomy. The changes observed in adrenalectomized rats were prevented by supplementations of corticosterone at a dose mimicking the indomethacin-induced rise in corticosterone, whereas the protective effect of corticosterone was attenuated by RU-38486, a glucocorticoid receptor antagonist. We conclude that the gastroprotective action of endogenous glucocorticoids may be provided by their support of glucose homeostasis and inhibitory effects on enhanced gastric motility and microvascular permeability as well as maintaining the production of mucus.     

Modulation of gastric acid secretion by cannabinoids in rats

The current study aimed to evaluate the role of cannabinoid receptors in the regulation of gastric acid secretion and oxidative stress in gastric mucosa. To fulfill this aim, gastric acid secretion stimulated with histamine (5 mg/kg, subcutaneous [SC]), 2‐deoxy‐ d ‐glucose (D‐G) (200 mg/kg, intravenous) or ‐carbachol (4 μg/kg, SC) in the 4‐hour pylorus‐ligated rats. The CB1R agonist ( N‐arachidonoyl dopamine, 1 mg/kg, SC) inhibited gastric acid secretion stimulated by D‐G and carbachol but not in histamine, reduced pepsin content, and increased mucin secretion. Furthermore, it decreased malondialdehyde (MDA) and nitric oxide (NO) contents with an increase in glutathione (GSH) and paraoxonase 1 (PON‐1). Meanwhile, CB2R antagonist (AM630, 1 mg/kg, SC) inhibited gastric acid secretion stimulated by D‐G and reduced MDA and NO contents with an increase in GSH and PON‐1. Meanwhile, CB1R antagonist rimonabant or CB2R agonist GW 405833 had no effect on stimulated gastric acid secretion. Therefore, both CB1R agonist and CB2R antagonist may exert antisecretory and antioxidant potential in the stomach.     

Pharmacological study of Stachytarpheta cayennensis Vahl in rodents

Freeze-dried aqueous extracts (AEs, 0.1–1 g/kg body wt., p.o.) obtained from entire or selected parts of Stachytarpheta cayennensis were tested for their effects on gastric secretion, gastric motility, inflammation and pain in rodents, with the purpose of validating the plant's ethnomedical uses. The AE-Total, AE-Flowers and AE-Leaves but not AE-Stems inhibited the gastric acid secretion in pylorus-ligated rats with varying potency. Purification of AEs yielded the semipurifed fractions EtFs rich in iridoids. All the EtFs with exception of EtF-Stems inhibited gastric acid secretion of pylorus ligated mice. While AE-Total stimulated the intestinal transit of mice by 43%, AE-Leaves delayed it by 38%. These effects on intestinal transit were not observed when the EtFs were tested. Only AE-Leaves and AE-Flowers altered the gastric emptying of semisolids, increasing it by 45% and 69%, respectively. These results indicate that the compounds related to inhibition of gastric acid secretion and gastrointestinal motility are different. The AE-Total reduced abdominal writhing induced by acetic acid potently (ED₅₀ VALUE=700 mg/kg, p.o.) without altering the writhes induced by acetylcholine. Attempts to identify the mechanism of analgesia were unsuccessful since the AE-Total did not show analgesic effects when tested in different models of pain such as formalin and capsaicin or the tail-flick test. Pretreatment of animals with AE-Total did not show antiinflammatory activity in any of the acute (paw edema induced by carrageenin, dextran or histamine, pleurisy induced by carrageenin and capsaicin-induced mouse ear edema) or chronic (air pouch) models used. No toxic signs were observed after administration of the different extracts up to 2 g/kg body wt., p.o.

Collectively, the results confirmed folk information indicating presence of analgesic, mild laxative and potent inhibition of gastric secretion activities in the aqueous extracts of S. cayennensis. The results do not, however confirm the folk use of the plant as an antiinflammatory medicine.     

Nesfatin-1 inhibits gastric acid secretion via a central vagal mechanism in rats

Nesfatin-1, a novel hypothalamic peptide, inhibits nocturnal feeding behavior and gastrointestinal motility in rodents. The effects of nesfatin-1 on gastrointestinal secretory function, including gastric acid production, have not been evaluated. Nesfatin-1 was injected into the fourth intracerebral ventricle (4V) of chronically cannulated rats to identify a nesfatin dose sufficient to inhibit food intake. Nesfatin-1 (2 μg) inhibited dark-phase food intake, in a dose-dependent fashion, for >3 h. Gastric acid production was evaluated in urethane-anesthetized rats. Nesfatin-1 (2 μg) was introduced via the 4V following endocrine stimulation of gastric acid secretion by pentagastrin (2 μg·kg(-1)·h(-1) iv), vagal stimulation with 2-deoxy-d-glucose (200 mg/kg sc), or no stimulus. Gastric secretions were collected via gastric cannula and neutralized by titration to determine acid content. Nesfatin-1 did not affect basal and pentagastrin-stimulated gastric acid secretion, whereas 2-deoxy-d-glucose-stimulated gastric acid production was inhibited by nesfatin-1 in a dose-dependent manner. c-Fos immunofluorescence in brain sections was used to evaluate in vivo neuronal activation by nesfatin-1 administered via the 4V. Nesfatin-1 caused activation of efferent vagal neurons, as evidenced by a 16-fold increase in the mean number of c-Fos-positive neurons in the dorsal motor nucleus of the vagus (DMNV) in nesfatin-1-treated animals vs. controls (P < 0.01). Finally, nesfatin-induced Ca(2+) signaling was evaluated in primary cultured DMNV neurons from neonatal rats. Nesfatin-1 caused dose-dependent Ca(2+) increments in 95% of cultured DMNV neurons. These studies demonstrate that central administration of nesfatin-1, at doses sufficient to inhibit food intake, results in inhibition of vagally stimulated secretion of gastric acid. Nesfatin-1 activates DMNV efferent vagal neurons in vivo and triggers Ca(2+) signaling in cultured DMNV neurons.     

Enhancing effect of DQ-2511 on gastric emptying of spontaneously hypertensive rats

The present study was designed to clarify the potential of DQ-2511 (3-[[[2-(3,4-dimethoxyphenyl)ethyl]carbamoyl]methyl]amino-N-methylbenzamide: ecabapide) as a gastroprokinetic agent in spontaneously hypertensive rats (SHR). The gastric emptying of SHR was clearly retarded relative to that of weight-matched normotensive Wistar-Kyoto (WKY) rats when evaluated by the acetaminophen (APAP) method with the semi-solid test meal. There was, however, no significant difference between both strains in gastric mucosal blood flow (GMBF) determined by means of a laser doppler flowmetry. A 2-week treatment of SHR with DQ-2511 (1 mg/kg, oral) stimulated gastric emptying without affecting body weight gain or indirect systolic blood pressure (SBP), whereas cisapride (3 and 10 mg/kg, oral) had no effect under the same conditions. The pharmacological characteristics of DQ-2511 as a gastroprokinetic agent are discussed on the basis of these results.