Central noradrenergic-cholinergic interaction in regulation of gastric acid secretion in rats

Possible roles of noradrenaline (NA) and acetylcholine (ACh) within the lateral hypothalamic area (LHA) in regulation of gastric acid secretion were examined in urethane anesthetized rats. When NA 30 nmoles was given into the LHA, the gastric acid output decreased and this inhibitory effect of NA was potentiated in rats pretreated with reserpine (2 mg/kg, i.p., 20 hr). Even in a dose of 3 nmoles which was without effect in non-treated control animals, there was a remarkable decrease in acid output. In these reserpinized animals, ACh in a dose of 30 nmoles induced a remarkable increase in acid output, while in the controls this ACh-induced increase was observed only with a 10 times higher dose. In the rats not given reserpine, the cholinergic muscarinic agonist bethanechol (10 nmoles) increased the gastric acid output while nicotine (30 nmoles) was without effect. Therefore, in rats, the central noradrenergic inhibitory mechanisms related to regulation of gastric function may be present at the level of LHA as well as the ala cinerea (area of the dorsal motor nucleus of vagi and the nucleus tractus solitarius). In addition, in the LHA, a cholinergic muscarinic mechanism which elevates gastric acid secretion may be antagonized by a noradrenergic inhibitory mechanism.     

Central and peripheral regulation of gastric acid secretion by peptide YY

Peptide YY (PYY) released postprandially from the ileum and colon displays a potent inhibition of cephalic and gastric phases of gastric acid secretion through both central and peripheral mechanisms. To modulate vagal regulation of gastric functions, circulating PYY enters the brain through the area postrema and the nucleus of the solitary tract, where it exerts a stimulatory action through PYY-preferring Y1-like receptors, and an inhibitory action through Y2 receptors. In the gastric mucosa, PYY binds to Y1 receptors in the enterochromaffin-like cells to inhibit gastrin-stimulated histamine release and calcium signaling via a pertussis toxin-sensitive pathway.     

Central regulation of gastric acid secretion: The role of neuropeptides

A variety of stimuli can act through the central nervous system to alter gastric acid secretion. Lesioning and stimulation experiments have established roles for the lateral and ventromedial hypothalamus and the limbic system in the central regulation of gastric acid secretion. Recently a number of neuropeptides have been demonstrated to alter gastric acid secretion after central administration. Thyrotropin-releasing hormone (TRH) and gastrin both increase gastric acid secretion, whereas bombesin, calcitonin, the endogenous opioid peptides and neurotensin decrease gastric acid secretion. With the exception of bombesin, all the other neuropeptides appear to produce their effects through a vagally mediated mechanism. In addition, a number of these neuropeptides, when centrally administered, have been demonstrated to exert a potent cytoprotective effect against stress ulcer development. This review develops a peptidergic hypothesis of gastric acid secretion, suggesting that the final integration of the cephalic phase of gastric acid secretion is brought about by maintaining a delicate balance in the concentration of a number of interacting peptides and monoamines.     

胃酸分泌的外周调节

肠神经节后神经纤维支配了胃粘膜壁细胞、ＥＣＬ细胞、Ｇ细胞和Ｄ细胞,某些体液因子也可影响后三种内分泌细胞的分泌功能,它们相互作用最终调节组织胺的释放,从而组织胺、胃泌素、乙酰胆碱、生长抑素共同调节壁细胞的泌酸功能,以控制胃内适当的酸度。这些中调节机制涉及神经、体液、内分泌、旁分泌、自然分泌和神经一一内分泌等的过程。     

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.     

Central noradrenergic inhibition of gastric mucosal blood flow and acid secretion in rats

To investigate the role of central noradrenaline (NA) in gastric functions, changes in mucosal blood flow (MBF) and acid secretion following electrical stimulation of the lateral hypothalamic area (LHA) and the effects of NA on these parameters were examined in rats anesthetized with urethane. NA 10 μg/animal injected into the lateral ventricle decreased the basal value of both the gastric MBF and acid output, while the same dose of acetycholine or dopamine was without effect. Repetitive electrical stimulation of LHA at 10 cycles/sec, 0.5 mA, 2 msec for 10 min elicited a significant, reproducible increase in both gastric MBF and acid output. NA 10 μg/animal injected into the lateral ventricle completely blocked these increases induced by the electrical stimulation. These data suggest that a central noradrenergic inhibitory mechanism is involved in regulation of the gastric MBF and acid secretion.     

Modulation of gastric acid secretion by adenosine in conscious rats

Basal (nonstimulated) gastric acid output was determined in conscious rats fitted with indwelling gastric cannulae. The adenosine deaminase resistant analog of adenosine, R-phenylisopropyladenosine, elevated intraluminal pH beyond 7.0 and decreased gastric acid secretion when given at doses of 0.10 or 1.0 mg/kg, while S-phenylisopropyladenosine at similar doses did not affect either gastric acid output or pH. The potent adenosine receptor antagonist, 8-phenyltheophylline, given at doses of 0.1, 1.0, and 2.5 mg/kg augmented gastric acid output and, at doses of 0.01, 0.1, 1.0, and 2.5 mg/kg, blocked the acid-reducing effect of R-phenylisopropyladenosine (0.1 mg/kg). These data suggest that adenosine systems may be important regulators of gastric function.     

Role of ghrelin in the regulation of gastric acid secretion involving nitrergic mechanisms in rats

Ghrelin, an endogenous ligand for growth hormone secretagogue receptor (GHS-R), has been identified in the rat and human gastrointestinal tract. Ghrelin has been proposed to play a role in gastric acid secretion. Nitric oxide (NO) was shown as a mediator in the mechanism of ghrelin action on gastric acid secretory function. However, there is a little knowledge about this topic. We have investigated the role of ghrelin in gastric acid secretion and the role of NO as a mediator. Wistar albino rats were used in this study. The pyloric sphincter was ligated through a small midline incision. By the time, saline (0.5 ml, iv) was injected to the control group, ghrelin (20 microg/kg, iv) was injected to the first experimental group, ghrelin (20 microg/kg, iv) + L-NAME (70 mg/kg, sc) was injected to the second group and L-NAME (70 mg/kg, sc) was administered to the third group. The rats were killed 3 h after pylorus ligation; gastric acid secretion, mucus content and plasma nitrite levels were measured. Exogenous ghrelin administration increased gastric acid output, mucus content and total plasma nitrite levels, while these effects of ghrelin were inhibited by applying L-NAME. We can conclude that ghrelin participates in the regulation of gastric acid secretion through NO as a mediator.     

Mechanism and regulation of neutrophil priming by platelet-activating factor

Although a weak direct stimulus of superoxide anion (O₂^?) production, platelet-activating factor (PAF) markedly enhances responses to chemotactic peptides (such as n-formyl-met-leu-phe, FMLP) and phorbol esters (such as phorbol myristate acetate, PMA) in human neutrophils. The mechanism of priming was explored first through inhibition of steps in the signal transduction pathway at and following PAF receptor occupation. Priming was not altered by pertussis toxin or intracellular calcium chelation, but the PAF receptor antagonist WEB 2086 and the protein kinase C (PKC) inhibitors sphinganine and staurosporine significantly inhibited the primed response. In order to study the regulation of PAF priming, the effect of PAF alone was desensitized by exposure to escalating doses of PAF prior to exposure to the secondary stimuli. The priming effect of PAF was not desensitized under these conditions. The role of PKC in desensitization was also studied. Prior exposure to PAF also desensitized the increase in membrane PKC activity evoked by a single concentration of PAF. However, when the PAF response was desensitized, PKC priming of the response to FMLP or PMA still occurred, suggesting that PKC activity may play a role in the maintenance of the primed state despite PAF desensitization. These data suggest that: (1) PAF priming is receptor- and PKC-mediated but is independent of pertussis toxin-inhibitable G-proteins or intracellular calcium, (2) during migration in vivo, neutrophils may be desensitized to the direct effects of PAF but maintain the capacity for enhanced responses to other stimuli, (3) desensitization of PAF-induced particulate PKC activity also occurs, but PAF primes PKC activity despite PAF desensitization, and (4) distinct mechanisms govern the direct and priming effects of PAF on oxidative metabolism. © 1993 Wiley-Liss, Inc.     

Sauvagine: inhibition of gastric acid secretion in rats

Sauvagine (SV) powerfully inhibits gastric acid secretion by both the central and peripheral mechanisms. We examined whether adrenergic mechanisms or prostaglandin pathways might mediate the inhibitory action of SV on acid production in pylorus-ligated rats. Adrenalectomy altered the extent of the SV suppressive effect, suggesting that adrenal-derived substances participate in the action of the peptide. Blockade of adrenergic receptors by propranolol did not modify the antisecretory effect of SV, while the alpha-adrenergic antagonist, phentolamine, and the dopaminergic antagonist, haloperidol, potentiated the gastric response to the peptide. The action of SV appeared to be independent of prostaglandin pathways. We conclude that the antiacid effect of SV may be mediated by the adrenal but probably not by adrenergic or prostaglandin mechanisms.     

Zinc acexamate reduces gastric damage induced by platelet-activating factor

We have tested the ability of zinc acexamate (ZAC) to prevent platelet-activating-factor (Paf) induced gastric damage in rats. Lesions were characterized by a vascular congestion affecting the entire mucosa, oedema, haemorrhage and frequent necrosis of the more superficial areas. The gastric damage appearing after Paf was accompanied by degranulation of gastric mast cells. Leukocytes were often seen at the submucosal level. Oral pretreatment with ZAC reduced in a dose-dependent manner both gastric damage and mast cell degranulation observed after Paf. ZAC administered orally at a dose of 100 mg kg-1 statistically inhibited (p less than 0.01) gastric damage and mast cell degranulation. ZAC did not affect the hypotension induced by Paf confirming that gastric damage and hypotension appearing in rats after Paf administration are two independent phenomena. The present findings indicate that the inhibitory effect of ZAC upon gastric lesions induced by Paf may be related to the different protective actions exhibited by this zinc compound in a wide variety of experimental models of gastric ulcer.     

Coordinated regulation of gastric chloride secretion with both acid and alkali secretion

Gastric secretion of hydrochloric acid requires protons and chloride, yet the mechanisms and regulation of gastric chloride secretion remain unclear. We developed an in vivo technique to simultaneously measure acid/base and chloride secretion into the gastric lumen of anesthetized rats. The cannulated stomach lumen was perfused with weakly pH-buffered chloride-free solution containing a chloride-sensitive fluorophore [5 microM N-(ethoxycarbonylmethyl)-6-methoxyquinolinium bromide (MQAE)]. Gastric acid and chloride secretion was detected in gastric effluents by 1) flow-through pH electrode and 2) MQAE fluorescence. Gastric effluent was also collected at 1-min intervals for independent determination of chloride amount by chloridometer. In all conditions, both optical and chemical determinations of chloride report similar amounts of secreted chloride. During luminal perfusion with pH 5 solution, net acid and chloride secretion into the lumen was observed. Pentagastrin stimulated both secretions. In contrast, proton pump inhibition (omeprazole) caused alkalinization of the gastric effluent, but chloride secretion was not diminished. During luminal pH 3 perfusion, net alkali secretion was observed, and chloride secretion at luminal pH 3 was greater than pH 5. When tissue is pretreated with omeprazole at luminal pH 3, the addition of prostaglandin E2 synchronously stimulates both alkali and chloride secretion. Results suggest that both acid and alkali secretions are separately coupled with chloride secretion.     

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.     

Sauvagine: effects on gastric acid secretion in rats

Intracerebroventricular (ICV) and subcutaneous (SC) injections of sauvagine powerfully inhibited gastric acid secretion stimulated by gastric distension and by 2-deoxy-D-glucose, but not by histamine in pylorus-ligated rats. Naloxone failed to antagonize the antisecretory effects of SC and ICV sauvagine. Intravenous infusion of sauvagine completely suppressed bethanechol-stimulated gastric secretion, significantly decreased pentagastrin-stimulated gastric secretion and did not modify histamine-stimulated gastric secretion in gastric-perfused rats. The inhibitory effect of sauvagine on gastric secretory response is not mediated through opioid or histamine receptors. It appears to be dependent on a vagal mechanism as well as other mechanisms that await further elucidation.     

Histamine dependence of pentagastrin-stimulated gastric acid secretion in rats.

Does gastrin stimulate gastric acid secretion by direct action on oxyntic cells, by releasing histamine, or by being potentiated by histamine? Previous studies in the mouse pointed to gastrin-regulated histamine release. Guinea pig and rat are well known to vary in their sensitivity to histamine. Therefore, the effects of histamine and pentagastrin were compared quantitatively on isolated, lumen-perfused, stomach preparations from these species in the absence and presence of histamine H2-receptor blockade. The loss of potency of histamine in the rat was mirrored by a loss of potency of pentagastrin consistent with the idea that pentagastrin acts by releasing histamine. In the rat, a well-defined pentagastrin curve was obtained in the presence of histamine H2-receptor block as though pentagastrin acts both directly on the oxyntic cell and indirectly by releasing histamine. It was not necessary to invoke a potentiating interaction between histamine and pentagastrin at the oxyntic cell; the two effects appeared simply to add. Potentiation was observed, however, between other combinations of stimuli, for example, between vagal nerve and pentagastrin stimulation. The physiological consequences of these results are discussed.     

Central nervous system action of basic fibroblast growth factor: inhibition of gastric acid and pepsin secretion

To examine the effects of basic fibroblast growth factor (bFGF) on gastric secretion, the present study was carried out using pylorus-ligated rats. Intracisternally injected bFGF inhibited the secretion of both gastric acid and pepsin, and this gastric antisecretory action of bFGF was a dose-related response. On the other hand, the intraperitoneal injection of bFGF did not change gastric secretion. These results strongly suggested for the first time that bFGF, a growth factor that promotes the proliferation of various cell types, might also be a chemical messenger that is involved in the central regulation of gastric secretion. This biological action of bFGF may be considered as a novel nonmitogenic activity of this growth factor.     

Effect of atrial peptide on gastric acid secretion in rats

The effect of synthetic rat atriopeptin (AP) II was examined on basal, vagally and carbachol-induced gastric acid secretion in anesthetized rats. AP II infusion, at stepwise increasing doses of 2, 20 and 100 ng/kg/min, had no effect on basal acid secretion. At doses of 2 and 20 ng/kg/min, AP II augmented vagally induced acid secretion significantly. The secretory response to vagal stimulation + AP II 20 ng/kg/min was completely abolished by atropine. In contrast a higher dose of AP II (50 ng/kg/h) reduced vagally induced acid secretion significantly. This dose of AP II also reduced acid secretion during direct cholinergic stimulation by carbachol, while the lower dose of 20 ng/kg/min had no effect on carbachol-induced acid secretion. The present data demonstrate for the first time an effect of atrial peptide on gastric acid secretion. At lower doses AP II augments the vagal influence on parietal cell function perhaps by augmenting vagally induced acetylcholine release. At higher doses AP II exerts an inhibitory effect on parietal cell function during vagally and carbachol-induced acid secretion, suggesting different and as yet unknown mechanisms of action. These results raise the possibility that the heart can exert a hormonally mediated influence on the regulation of gastric acid secretion.     

Central nervous system inhibition of pentagastrin-stimulated acid secretion by insulin-like growth factor II

The ability of intracisternal insulin-like growth factor II (IGF II) to inhibit gastric acid secretion was studied in rats. Centrally-administered IGF II dose-dependently inhibited acid secretion stimulated by pentagastrin. The effect was abolished by vagotomy. IGF II did not inhibit acid secretion stimulated by histamine or PCP-GABA.     

Central action of somatostatin analog, SMS 201-995, to stimulate gastric acid secretion in rats

The effects of intracisternal and intravenous injections of the somatostatin analog, SMS 201-995, on gastric acid secretion were investigated in rats with pylorus ligation or gastric cannula. Intracisternal injection of SMS 201-995 induced a dose-related (0.1-0.3 microgram) and long-lasting stimulation of gastric acid output with a peak response at 3 h postinjection in conscious, pylorus-ligated rats. Intracisternal SMS 201-995 increased histamine levels in the portal blood, whereas plasma gastrin levels were not modified. Atropine, cimetidine and adrenalectomy abolished the stimulatory effect of intracisternal SMS 201-995 (0.3 microgram). SMS 201-995 (0.03 microgram), microinjected unilaterally into the dorsal vagal complex, increased gastric acid output in urethane anesthetized rats. SMS 201-995, injected intravenously at 0.5 microgram, did not alter gastric secretion, whereas higher doses (5-20 micrograms) resulted in a dose-related inhibition of gastric acid secretion in conscious pylorus-ligated rats. These data indicate that SMS 201-995, a selective ligand for somatostatin-1 receptor subtype, induces a centrally mediated stimulatory effect on gastric acid secretion in rats. The central action involves the parasympathetic system, muscarinic and H2 receptors as well as adrenal-dependent pathways.