Acid Secretion In Conscious Rats Research Articles

Effects of orexin and glucose microinjected into the hypothalamic paraventricular nucleus on gastric acid secretion in conscious rats

Orexin-A is a novel peptide that appears to play a role in regulation of gastric acid secretion. However, little is known about sites of its action. In addition, evidences suggest that some of orexin-A neurons respond to glucose. In this study, we address the hypothesis which demonstrates that orexin-A and glucose act in the hypothalamic paraventricular nucleus (PVN) to increase gastric acid secretion and juice volume in pyloric-ligated conscious rats. Male Wistar rats were implanted with guide canula directed to the PVN. Orexin-A (3-10 μg), glucose (350-750 ng) SB334867 (6-20 μg) were microinjected. The effect of pretreatment with an orexin-1 receptor antagonist, SB334867, on orexin-A and D-glucose induced acid secretion was assessed. Gastric acid secretion was measured using the pylorus-ligation method, and the amount of gastric acid was determined by titration with 0.01 N NaOH to a pH of 7.0. Intraparaventricular injection of orexin-A or D-glucose stimulated gastric acid secretion in a dose-dependent manner. The PVN injections of orexin-A receptor antagonist, SB334867, were associated with gastric acid secretion decrease and inhibited effects of PVN-injected orexin-A. Orexin-stimulated gastric acid secretion was decreased (~40%) after PVN lesions. Glucose-stimulated gastric acid secretion was also suppressed by intraperitoneal (IP) injection of SB334867. In addition, it was observed that co-injection of orexin-A and glucose at ineffective doses increased gastric secretion significantly. We suggest that orexin-A and glucose effects on the PVN stimulate gastric acid secretion. This stimulatory effect is probably mediated by orexin-1 receptors.

Role of the Ventromedial Hypothalamic Orexin‐1 Receptors in Regulation of Gastric Acid Secretion in Conscious Rats

Orexins play an important role on the central nervous system to modulate gastric acid secretion. The orexin receptors are distributed within the hypothalamus, and expression of orexin-1 receptors (OX1R) is greatest in the anterior hypothalamus and ventromedial nucleus. Therefore, we hypothesised that ventromedial hypothalamic OX1R may be involved in the control of gastric acid secretion. To address this question, we examined the effects of orexin-A and a selective OX1R antagonist, SB-3345867, on gastric acid secretion in pyloric-ligated conscious rats. Intraventromedial injection of orexin-A (0.5-2 microg/microl) stimulated gastric acid secretion in a dose-dependent manner. This stimulatory effect of orexin-A persisted over 3 h. In some experiments, SB-3345867 (10 mg/kg i.p.) was administered 30 min before orexin-A or saline injections. We found that i.p. injection of SB-334867 suppressed stimulated gastric acid secretion induced by orexin-A (2 microg/microl). Atropine (5 mg/kg) also inhibited the stimulatory effect of central injection of orexin-A on acid secretion. In conclusion, the present study suggests that endogenous orexin-A acts on the ventromedial hypothalamus to stimulates acid secretion. This stimulatory effect is probably mediated through OX1R.

Phytohaemagglutinin inhibits gastric acid but not pepsin secretion in conscious rats

Phytohaemagglutinin (PHA), a kidney bean lectin, is known for its binding capability to the small intestinal surface. There has been no data available, however, on the biological activity of PHA in the stomach. Recent observations indicate that PHA is able to attach to gastric mucosal and parietal cells. Therefore, we examined whether PHA affects gastric acid and pepsin secretion in rats. Rats were surgically prepared with chronic stainless steel gastric cannula and with indwelling polyethylene jugular vein catheter. During experiments, animals were slightly restrained. Gastric acid secretion was collected in 30 min periods. Acid secretion was determined by titration of the collected gastric juice with 0.02 N NaOH to pH 7.0. Pepsin activity was estimated by measuring enzymatic activity. Saline, pentagastrin and histamine were infused intravenously. PHA or bovine serum albumin (BSA) were dissolved in saline and given intragastrically through the gastric cannula. PHA significantly inhibited basal acid secretion. Inhibition of acid output reached 72% during the first collection period following PHA administration when compared, then gradually disappeared. Pentagastrin-stimulated acid secretion was repressed dose-dependently by PHA as well. Maximal inhibition was observed during the first 30 min following application of PHA. Histamine-stimulated acid secretion was inhibited by PHA in a similar manner. Pepsin secretion was not affected by PHA under either basal or stimulated conditions. These results provide evidence that PHA is a potent inhibitor of gastric acid secretion in conscious rats, but it does not affect pepsin output from the stomach.

Intracerebroventricular injection of glucagon-like peptide-1 (GLP-1) inhibits gastric acid secretion in conscious rats

Intracerebroventricular injection of glucagon-like peptide-1 (GLP-1) inhibits gastric acid secretion in conscious rats

Sustained cholecystokinin-B/gastrin receptor blockade does not impair basal or histamine-stimulated acid secretion in chronic gastric fistula rats.

Gastrin is a physiologically important secretagogue. It is thought to stimulate parietal cells indirectly by mobilizing histamine from enterochromaffin-like (ECL) cells in the oxyntic mucosa. Gastrin stimulates the secretory activity and growth of the ECL cells via an action on cholecystokinin-B/gastrin receptors. Acute cholecystokinin-B/gastrin receptor blockade is known to inhibit gastrin-stimulated acid secretion but whether sustained cholecystokinin-B/gastrin receptor blockade will impair basal, gastrin- and histamine-stimulated acid secretion remains uncertain. The present study was designed to study the effect of long-term (4 weeks) cholecystokinin-B/gastrin receptor blockade on basal and stimulated acid secretion in conscious rats. The selective cholecystokinin-B/gastrin receptor antagonist YM022 (3 mumol.kg-1.hr-1) was given to gastric fistula rats by continuous subcutaneous infusion via osmotic minipumps for various times from 2 hr to 4 weeks. Basal, gastrin- and histamine-stimulated acid secretion were examined during and after cessation of treatment. Basal and histamine-stimulated acid secretion was not affected by YM022 during the 4 week period of administration, whereas gastrin-induced acid secretion was inhibited. YM022 induced hypergastrinaemia in freely fed rats but did not affect the serum gastrin level in fasted rats. The serum gastrin concentration and gastrin-induced acid secretion returned to control levels 3-7 days after termination of YM022 administration.

New potent somatostatin receptor 2 antagonist inhibits srif and srif-mediated effects on pentagastrin-stimulated gastric acid secretion in conscious rats

New potent somatostatin receptor 2 antagonist inhibits srif and srif-mediated effects on pentagastrin-stimulated gastric acid secretion in conscious rats

Adrenomedullin, calcitonin gene related peptide and amylin are powerful inhibitors of gastric acid secretion in conscious rats

Adrenomedullin, calcitonin gene related peptide and amylin are powerful inhibitors of gastric acid secretion in conscious rats

Hypoxia Inhibits Gastric Emptying and Gastric Acid Secretion in Conscious Rats

This study examines the effects of hypoxia on the gastric function in conscious rats which adapted to a meal-feeding schedule, that allowed free access to a high protein (HP) diet (550 g casein/kg diet, Exp. 1, 2 and 4), a normal protein (NP) diet (200 g casein/kg diet, Exp. 3) or a nonpurified rat (NPR) diet (Exp. 5 and 6) for 4 h every day for 2 wk. In Exp. 1, after 4 h of consuming the HP diet, rats were exposed to 7.6 or 10.5% O2 normobaric hypoxia. Hypoxia delayed the excretion of urinary urea for 12 h. In Exp. 2 and 3, when rats were exposed to 7.6% O2 after 4 h of consuming the HP diet and exposed to 10.5% O2 after 4 h of consuming the NP diet, respectively, a significant delay in gastric emptying was found in the hypoxic rats. In Exp. 4, when rats were exposed to 7.6 O2 hypoxia after 4 h of eating the HP diet, the plasma gastrin concentration in the 7.6% O2 hypoxic rats was 2.3-fold that of the normoxic rats after 6 h of hypoxia. Furthermore, when rats that did not consume any HP diet on the day of the experiment were exposed to 7.6 or 10.5% O2 hypoxia, the plasma gastrin concentration was higher in both hypoxic groups than in the normoxic group after 3 and 6 h of hypoxia. In Exp. 5, rats that were not fed the NPR diet on the day of study were exposed to 7.6 or 10.5% O2 hypoxia for 3 h after pylorus ligation. Hypoxia inhibited the secretion of gastric acid and elevated the plasma gastrin concentration. In Exp. 6, unfed rats that had been consuming the NPR diet were exposed to 7.6% O2 hypoxia for 3 h after pylorus ligation and were orally administered HCl. The rise of the gastrin concentration due to hypoxia was completely inhibited by oral HCl. These results demonstrate that hypoxia inhibits gastric emptying and gastric acid secretion and that the inhibitory effect of hypoxia on gastric acid secretion stimulates gastrin release through positive feedback regulation.

Intracerebroventricular injection of somatostatin sst 5 receptor agonist inhibits gastric acid secretion in rats

Somatostatin and its analogs act in the brain to influence gastric acid secretion. Five different somatostatin receptor subtypes have been characterized (sst 1 to sst 5). We studied the influence of somatostatin (0.18–0.6 nmol/rat) and selective sst 2, sst 3 and sst 5 receptor ligands on basal gastric acid secretion in conscious rats equipped with chronic gastric and intracerebroventricular (i.c.v.) cannulae. Somatostatin-14 (0.36 nmol/rat), the sst 2, sst 3 and sst 5 receptor agonist, Des-AA 1,2,4,5,12,13-[ d-Tryp 8, d-Cys 14]somatostatin (SMS 201–995) (0.18–0.36 nmol/rat) and the sst 5 receptor agonist, BIM-23052, (0.8–1.2 nmol/rat) injected i.c.v. inhibited gastric acid secretion. Maximal inhibition reaching 42%, 60% and 42% was induced by somatostatin-14 (0.36 nmol/rat), SMS 201–995 (0.18 nmol/rat) and BIM-23052 (0.8 nmol/rat) respectively. The sst 2 receptor agonist, DC 32–87 (0.2–0.8 nmol/rat) and sst 3 receptor agonist, BIM-23056 (0.2–1.2 nmol/rat), did not modify gastric acid secretion, except the sst 3 receptor agonist at 0.4 nmol/rat which increased acid output at 20 min post-injection. The sst 2 receptor agonists (0.4 nmol/rat) co-injected i.c.v with a subthreshold dose of sst 5 (0.4 nmol/rat) inhibited gastric acid secretion. These results show that i.c.v. injection of somatostatin-14 inhibits basal gastric acid secretion in conscious rats through an action on sst 5 receptor subtype which can be potentiated by sst 2 receptor subtype.

Comparative Evaluation of the Role of Endogenous Gastrin in Basal Acid Secretion in Conscious Rats Provided with Chronic Fistula and Pylorus Ligation

We determined the relative contributions of endogenous gastrin, histamine and cholinergic tone to basal acid secretion in chronic fistula rats. Results were compared with those for acid secretion in pylorus-ligated rats. In chronic fistula rats, YM022 {(R)-1-[2,3-dihydro-1-(2'-methylphenacyl)-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-3-(3-methylphenyl)urea} dose-dependently inhibited pentagastrin-stimulated acid secretion and abolished this secretion at 1 μmol/kg, s.c., but did not affect histamine- and carbachol-induced acid secretion even at 10 μmol/kg. In contrast, famotidine at 1 μmol/kg completely inhibited not only the acid secretion induced by histamine but also those by pentagastrin and carbachol. Furthermore, atropine abolished carbachol- and pentagastrin-stimulated acid secretion and significantly suppressed histamine-stimulated acid secretion at 0.1 μmol/kg. YM022 dose-dependently inhibited basal acid secretion. The YM022 dosage required to inhibit basal acid secretion is consistent with that required to suppress pentagastrin-induced acid secretion. Famotidine (1 μmol/kg) and atropine (0.1 μmol/kg) also abolished basal acid secretion. In pylorus-ligated rats, YM022 inhibited acid secretion in a dose-dependent manner; the inhibition at 1 μmol/kg, i.v. was 65%. No additional effect was observed when rats were dosed at 30 μmol/kg. Famotidine partially inhibited acid secretion in these rats, whereas atropine abolished this secretion. These results indicate that the major part of basal acid secretion in rats is attributable to endogenous gastrin via histamine- and cholinergic tone-dependent pathways. Moreover, pylorus ligation reduces the relative contribution of gastrin to acid secretion due to the activation of cholinergic tone.

The mechanism of inhibitory action of secretin on gastric acid secretion in conscious rats.

1. Secretin has been recognized as an important enterogastrone. In order to investigate the mechanism of secretin-induced inhibition of gastric acid secretion, the effects of both anti-somatostatin antibody and indomethacin on acid secretion were examined in conscious rats with gastric cannulas. 2. Secretin given intravenously at 5.6 pmol kg-1 h-1 inhibited profoundly the acid secretion stimulated by pentagastrin at 0.3 microgram kg-1 h-1. 3. When a rabbit antisomatostatin serum was given intravenously, it not only abolished the secretin-induced inhibition on the pentagastrin-stimulated acid secretion, but also augmented both basal and pentagastrin-stimulated acid secretion. 4. Indomethacin also significantly augmented basal acid secretion, starting 45 min after the drug delivery began. It reversed the secretin-induced inhibition but it did not augment the pentagastrin-stimulated acid secretion. 5. Neither antisomatostatin serum influenced prostaglandin E2-induced inhibition of the pentagastrin-stimulated acid secretion, nor did indomethacin affect the inhibition by somatostatin, suggesting strongly that the inhibition by somatostatin is not mediated by endogenous prostaglandins, nor is that by prostaglandins E2 mediated by endogenous somatostatin. 6. It is concluded that the inhibitory action of secretin on pentagastrin-stimulated gastric acid secretion is mediated by both somatostatin and prostaglandins in conscious rats. The two inhibitors do not seem to interact endogenously for the inhibition of acid secretion. While endogenous somatostatin exerts a tonic inhibitory effect on both basal and pentagastrin-simulated acid secretion, prostaglandins augment basal acid secretion only.

Caloric restriction causes secretagogue specific changes of gastric acid secretion in conscious rats: [formula omitted], K.U. Chu, J. Ishizuka, G. Gomez, C.M. Townsend, Jr., and J.C. Thompson. Dept. of Surgery, The University of Texas Medical Branch, Galveston, TX

Caloric restriction causes secretagogue specific changes of gastric acid secretion in conscious rats: [formula omitted], K.U. Chu, J. Ishizuka, G. Gomez, C.M. Townsend, Jr., and J.C. Thompson. Dept. of Surgery, The University of Texas Medical Branch, Galveston, TX

Influence of intracisternal injection of somatostatin analog receptor subtypes 2, 3 and 5 on gastric acid secretion in conscious rats

Somatostatin (SST) and its analogs injected into the CSF induce different gastric acid response patterns. Five SST receptors have been characterized (SSTR-1 to -5). We studied the influence of selective SSTR-2, -3 and -5 ligands on basal gastric acid secretion after intracisternal (i.c.) injection in conscious rats equipped with chronic gastric and i.c. cannulae. Compared with pre-injection level, the SSTR-3 agonist, BIM-23056 (1 μg) increased acid secretion by 274 ± 43% while the SSTR-2 agonist, DC 32–87 (1 μg) inhibited acid secretion by 50.7 ± 13.3%. SST-14 (1 μg), the SSTR-5 agonist, BIM-23052, (0.5–1 μg), SSTR-3 (0.5 μg) and −2 (0.5 μg) or vehicle injected i.c. did not modify basal acid secretion. These results show that the activation of brainstem SSTR-3 receptors stimulate and SSTR-2 inhibit basal gastric acid secretion in conscious rats with chronic gastric fistulae.

Effects of the selective I1 imidazoline receptor agonist, moxonidine, on gastric secretion and gastric mucosal injury in rats

1. Previous reports of the effects of alpha 2-adrenoceptor stimulation on gastric secretion are inconsistent because it was not clear whether the compounds were activating alpha 2-adrenoceptors and/or newly described imidazoline receptors. In the present experiments, the effects of moxonidine, an I1-imidazoline receptor agonist and antihypertensive agent, on gastric secretion and on experimental gastric mucosal injury were examined. 2. Moxonidine (0.01, 0.1 and 1.0 mg kg-1, i.p.) potently inhibited basal (non-stimulated) gastric acid secretion in conscious rats with an ED50 of 0.04 mg kg-1. Two hours following administration of the highest dose of moxonidine (1.0 mg kg-1), gastric acid output was completely suppressed. Moxonidine also significantly increased intragastric pH, at the two highest doses. 3. The alpha 2-adrenoceptor agonist, clonidine (0.01, 0.1 and 1.0 mg kg-1, i.p.) decreased basal acid secretion at the lowest dose (37%) and at the highest dose (46%), while the intermediate dose did not affect gastric acid output. 4. In an ethanol-induced model of gastric mucosal injury, moxonidine decreased the length of lesions at the lowest and highest doses (0.01 and 1.0 mg kg-1) as well as the number of the lesions, at the highest dose (1.0 mg kg-1). 5. In pylorus-ligated rats, moxonidine significantly decreased acid secretion (all doses), total secretory volume (1.0 mg kg-1) as well as pepsin output (1.0 mg kg-1). 6. In comparison to clonidine, moxonidine appears to be a more potent anti-secretory and gastric-protective compound. These data indicate a potential role for imidazoline receptor agonists in the management of gastroduodenal diseases associated with hypertension. The relative contribution of the central and peripheral effects of moxonidine to these gastrointestinal actions remains to be determined.

Somatostatin antibody does not influence bombesin-induced inhibition of gastric acid secretion in rats

The influence of peripheral somatostatin immunoneutralization on intravenous (i.v.) and intracerebroventricular (ICV) bombesin-induced inhibition of gastric acid secretion (GAS) was investigated with the somatostatin monoclonal antibody, CURE.S6, in rats. The somatostatin antibody, injected i.v. in conscious rats with a chronic gastric fistula and i.v. catheter, did not modify basal GAS, whereas in urethane-anesthetized rats the basal GAS was increased by 150%. In conscious rats, somatostatin (15 micrograms/kg/h, i.v.) inhibited basal GAS by 50% after injection of control antibody but not after pretreatment with the somatostatin antibody. With pretreatment with a control antibody, bombesin (10 micrograms/kg/h, i.v.) inhibited basal GAS by 60% in conscious rats and by 50% the acid response to pentagastrin infusion in urethane-anesthetized rats. Bombesin injected ICV (3 and 10 ng/10 microliters/rat) inhibited basal GAS by 50% and 70%, respectively, in conscious rats pretreated with a control antibody. The somatostatin antibody injected i.v. before i.v. or ICV injection of bombesin did not influence bombesin-induced inhibition of GAS in conscious or anesthetized rats. These results show that peripheral somatostatin does not play a major role in the inhibition of gastric acid secretion induced either by ICV or i.v. administration of bombesin or basal acid secretion in conscious rats.

CGRP antagonists enhance gastric acid secretion in 2-h pylorus-ligated rats

The influence of calcitonin gene-related peptide (CGRP) antagonists on gastric acid secretion was investigated in rats. Intravenous injection of the CGRP receptor antagonist, CGRP(8-37) (128 nmol/kg) or the CGRP antibody #4901 (4.8 mg/kg, IV) completely prevented alpha-CGRP (3.9 nmol/kg/h)-induced inhibition of acid response to pentagastrin in urethane-anesthetized rats with gastric fistula. CGRP antibody (4.8 mg/kg, IV) increased by 93% gastric acid secretion in conscious rats with pylorus ligation for 2 h. (CGRP(8-73) (128 nmol/kg, IV) also enhanced the acid response measured 2 h after pylorus ligation in conscious rats and in urethane-anesthetized rats infused with pentagastrin by 91% and 56%, respectively. These results suggest that endogenous CGRP attenuates the gastric acid response measured 2 h after pylorus ligation.

A dopamine D 3 receptor agonist, 7-hydroxy-N,N-di-N-propyl-2-aminotetralin, reduces gastric acid and pepsin secretion and experimental gastric mucosal injury in rats

Dopamine D 1 DA 1 agonists are associated with significant gastroprotective and antisecretory effects. The new dopamine DA 3 agonist, 7-hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OHDPAT), possesses neural and behavioral properties that are similar to those of DA 1 agonists. In the present experiments, the effects of 7-OHDPAT on gastric acid secretion in conscious and anaesthetized rats, on restraint stress-induced gastric mucosal injury and on gastric adherent mucus levels were examined. 7-OHDPAT (2.5, 5.0 and 10.0 mg/kg) reduced significantly basal gastric acid secretion in conscious rats (66%, 92% and 78% inhibition, respectively). 7-OHDPAT also reduced signiicantly gastric acid and pepsin secretion in pylorus-ligated rats. 7-OHDPAT reduced stress-induced gastric mucosal injury at doses of 1.0, 5.0 and 10.0 mg/kg. Gastric adherent mucus was preserved only at the 5.0 mg/kg dose. Neither pretreatment with the DA 1 antagonist, SCH23390, nor with the DA 2 antagonist, eticlopride, affected 7-OHDPAT-induced reductions in gastric secretion or gastric mucosal injury. Although dopamine DA 3 receptors exhibit greater amino acid sequence homology with DA 2 receptors than with DA 1 receptors, the possibility nevertheless exists that some of the gastrointestinal actions of dopamine and its agonists - both anti-secretory and gastroprotective - may be exerted through activation of DA 3 receptors.

Central antisecretory and peripheral gastroprotective effects of GBR 12909, a selective dopamine uptake inhibitor

A variety of dopaminergic compounds influence gastric secretion and response to injury. In particular, agonists of the D 1 receptor are gastroprotective when given either centrally of peripherally. In the present studies, we show that an indirect dopamine (DA) promoter, GBR 12909, a selective DA uptake inhibitor given ip but not icv, protects against restraint-cold stress-induced gastric mucosal injury. This protection likely occurred through preservation of gastric adherent mucus, since all doses of GBR 12909 resulted in gastric mucus levels at or near control (non-stressed) values. When given, ip, GBR 12909 did not influence basal gastric acid secretion in conscious rats, however, when given icv, GBR 12909 inhibited gastric acid secretion with an ED 50 of about 0.5 ug (1.13 umoles). We conclude that both central and peripheral DA contributes to gastrointestinal integrity through reduction of aggressive elements in the gut as well as by enhancing gastric mucosal defence.

Somatostatin inhibits gastrin-induced histamine secretion and synthesis in the rat

Somatostatin is a potent inhibitor of gastric acid secretion. However, the effect of somatostatin on gastric histamine secretion and synthesis has not been well understood, despite the fact that histamine plays a key role in the regulation of gastric acid secretion. This study was designed to determine the effect of somatostatin on gastric histamine mobilization and acid secretion in conscious rats. In conscious rats with a gastric fistula, a 4 h intravenous infusion of gastrin-17 I (1 nmol/kg/h) evoked a marked increase in fundic histidine decarboxylase activity (the sole histamine-forming enzyme) and reduced fundic histamine content with a concomitant increase in gastric acid secretion. Somatostatin-14 (10 nmol/kg/h) significantly inhibited gastrin-induced gastric acid secretion and fundic histidine decarboxylase activity and prevented a gastrin-induced decrease in fundic histamine content. In conscious rats with a vesical fistula, somatostatin-14 (10 nmol/kg/h) significantly inhibited the urinary histamine excretion induced by a gastrin-17 I (1 nmol/kg/h) infusion. These findings suggest that the inhibitory action of somatostatin on gastrin-induced acid secretion is mediated by the inhibition of histamine mobilization.

Effect of gastrin and CCK receptor antagonists on peptone-stimulated gastric acid secretion in conscious rats

Effect of gastrin and CCK receptor antagonists on peptone-stimulated gastric acid secretion in conscious rats