Pituitary adenylate cyclase activating polypeptide-27 (PACAP-27) inhibits pentagastrin-stimulated gastric acid secretion in conscious rats.

Pituitary adenylate cyclase activating polypeptide (PACAP) is a novel neuropeptide and has two amidated forms, PACAP-27 and PACAP-38. Its chemical structure is similar to that of vasoactive intestinal peptide (VIP). In our previous studies, we found that PACAP has a stimulatory effect on rat exocrine pancreas secretion and an inhibitory effect on rat gastrointestinal motility. These effects of PACAP-27 were greater than those of PACAP-38 and VIP. In the present study, we examined the effect of PACAP-27 on basal and pentagastrin (PG)-stimulated gastric acid secretion in conscious rats and compared its effect with that of VIP. Rats were equipped with a chronic gastric fistula and a permanent IV line and separately housed in metabolic cages. The effects of PACAP-27 and VIP at doses of 1.25, 2.5, 5 and 10 nmol/kg/h on basal and PG (24 micrograms/kg/h)-stimulated gastric acid secretion were tested. Our results showed that: (1) VIP had no significant effect on basal and PG-stimulated gastric acid secretion at the tested doses. (2) PACAP-27 had no effect on basal acid secretion but had a dose-dependent inhibitory effect on PG-stimulated gastric acid secretion. The highest inhibition by PACAP-27, 68.2 + 8.1%, was achieved at 5 nmol/kg/h. We suggest that PACAP may have a regulatory role in gastric acid secretion.     

Regulation of gastrointestinal function by multiple opioid receptors

Agonist and antagonist drugs possessing selectivity for individual types of opioid receptors have been employed in vitro and in vivo to determine the mechanisms by which opioids regulate gastrointestinal functions. Selective mu opioid agonists given by intracerebroventricular (i.c.v.) injection, by intrathecal (i.t.) injection, or by peripheral (s.c. or i.v.) injection in rats or mice decreased gastrointestinal transit and motility, inhibited gastric secretion, and suppressed experimentally-induced diarrhea. Selective delta agonists, by contrast, inhibited gastrointestinal transit after i.t., but not after i.c.v. or s.c. administration. Delta agonists also did not alter gastric secretion after i.c.v. or s.c. injection. However, delta agonists exhibited antidiarrheal effects after i.c.v., i.t., or s.c. administration. Kappa agonists given i.c.v. had no effect on gastrointestinal transit in rats or mice or on gastric secretion in rats, but exhibited antidiarrheal effects in mice. The kappa agonist U-50, 488H given peripherally increased gastric acid secretion. Different types of opioid receptors in different anatomical sites influence differently gastrointestinal motility and propulsion, gastric secretion, and mucosal transport. Brain, spinal cord, enteric neural and smooth muscle opioid receptors represent chemosensitive sites for regulation of gastrointestinal function.     

Effects of juice from Morinda citrifolia (Noni) on gastric emptying in male rats

The effects of juice from Morinda citrifolia (noni) on gastric emptying, gastrointestinal transit, and plasma level of cholecystokinin (CCK) in rats were studied. Male rats were given noni by gavage at levels of 0.25, 1, or 4 ml/kg once per day for one or 7 days. The rats in the control group were given water, while the rats in the experimental group were fasted overnight before measurement of gastrointestinal motility. Gastrointestinal motility was assessed in rats 15 min after intragastric instillation of a test meal containing charcoal (10%) and Na251CrO4 (0.5 microCi/ml). Gastric emptying was determined by measuring the amount of radiolabeled chromium contained in the small intestine as a percentage of the initial amount received. Then, gastrointestinal transit was evaluated by calculating the geometric center of distribution of the radiolabeled marker. Finally, blood samples were collected for measurement of CCK by radioimmunoassay. The administration of noni at 0.25 ml/kg, but not at 1 ml/kg and 4 ml/kg, for 1 day significantly inhibited gastric emptying. In contrast, gastric emptying was significantly inhibited by oral noni (0.25, 1, or 4 ml/kg) for 7 days. Intraperitoneal injection of lorglumide (5 or 10 mg/kg), a selective CCK1 receptor antagonist, effectively attenuated the noni-induced inhibition of gastric emptying. The intestinal transit and body weight, food intake, water intake, urine volume as well as feces weight were not altered by the administration of noni either acutely or chronically, but the administration of oral noni (1 ml/kg) for 7 days increased the level of plasma CCK in male rats. These results suggest that oral noni inhibits gastric emptying in male rats via a mechanism involving stimulation of CCK secretion and CCK1 receptor activation.     

Gastric effects of thyrotropin-releasing hormone microinjected into the dorsal vagal nucleus in cats

We investigated the gastric acid secretory and motility responses to microinjection of thyrotropin-releasing hormone (TRH) into the dorsal motor nucleus of the vagus (DMV) in anesthetized cats. Gastric acid output was collected every 15 min through a gastric cannula after saline flush and titrated to pH 7.0. Antral and corpus contractions were continuously recorded by extraluminal force transducers. TRH dissolved in 200 nl of saline and microinjected unilaterally into the DMV induced a dose-dependent (50-200 ng) increase in gastric acid secretion. The acid secretory response began in the first 15 min collection and lasted 45 min. TRH frequently increased the force of contractions of the antrum and corpus within one minute of microinjection. The minimal effective dose for eliciting increased motility was lower than for inducing acid secretion. These results demonstrate that TRH acts in the DMV of cats to stimulate gastric acid secretion and contractions.     

Potentiation of the gastro-protective effect of sulglicotide in the presence of cimetidine in the rat

The effects of sulglicotide, alone or combined with cimetidine, have been investigated on mucosal lesions induced in rats by pylorus ligation. In the same animals, the measurement of acid and pepsin output and of soluble and barrier mucus has been performed. Dose-dependent sulglicotide prevented the development of mucosal lesions and its protective effect was achieved without significant modifications in gastric acid secretion. The secretion of pepsin and of mucus was markedly inhibited at every dosage of the compound. Neither the damage to gastric mucosa nor the secretion of acid, pepsin and mucus were affected by cimetidine. The combination of the highest doses of both compounds resulted in a synergistic gastro-protective effect, not dependent on a synergistic effect on the reduction in acid secretion.     

Nesfatin-1及MCH对大鼠胃酸分泌和胃运动的影响

目的:本实验主要探究nesfatin-1对胃运动和胃酸分泌的影响,以及弓状核(ARC)-下丘脑外侧区(LHA)nesfatin-1神经通路在该过程中的作用。方法:采用逆行追踪和免疫组织化学染色实验观察ARC-LHA nesfatin-1神经通路的构成;在体胃运动实验观察nesfatin-1对胃运动的影响以电刺激ARC对胃运动的影响;采用幽门结扎法测量胃液和胃酸分泌量。结果:LHA微量注射nesfatin-1抑制胃运动和胃酸分泌,但是预先注射黑色素浓集激素(MCH)受体拮抗剂PMC-3881-PI减弱nesfatin-1对胃运动和胃酸分泌的抑制作用。电刺激ARC后,胃收缩幅度和频率显著增强,胃酸分泌明显增多。nesfatin-1抗体或PMC-3881-PI对电刺激ARC诱导的胃运动没有显著影响,但是能够改变电刺激ARC诱导的胃酸分泌。结论:ARC-LHA间nesfafin-1通路可调控大鼠胃运动和胃酸分泌,并且黑色素浓集激素也参与调节该过程。     

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.     

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.     

Orexin-A对大鼠胃功能的影响

目的:探讨Orexin-A对大鼠胃功能的影响。方法:通过大鼠迷走神经复合体微量注射Orexin-A后,观察大鼠胃运动、胃液和胃酸分泌的变化。结果:DVC微量注射Orexin-A后,大鼠胃收缩幅度以及收缩频率明显升高,且呈明显剂量依赖关系(P0.05),SB334867可显著阻断Orexin-A对促胃运动效应(P0.05)。DVC微量注射orexin-A后,大鼠胃液及胃酸分泌且呈剂量依赖性增加(P0.05)。结论:迷走神经复合体微量注射Orexin-A能影响胃的运动以及胃内体液的分泌。     

下丘脑室旁核orexin-A对大鼠摄食和胃动力影响及调控机制

目的:探讨下丘脑室旁核orexin-A对大鼠摄食和胃动力影响及调控机制。方法:采用免疫组化观察下丘脑室旁核(paraventricular nucleus,PVN)orexin受体表达情况;PVN注射orexin-A观察大鼠摄食、胃运动、胃酸分泌和胃排空的改变。结果:免疫组化实验显示大鼠PVN中存在orexin受体免疫阳性细胞。PVN注射orexin-A后,大鼠前三小时摄食增加,6 h和24 h摄食无显著改变。PVN微量注射orexin-A后,大鼠胃运动幅度和频率增加、胃排空增快并且胃酸分泌增多。[D-Lys-3]-GHRP-6可部分阻断orexin-A对摄食、胃运动、胃排空和胃酸分泌的促进作用,SB334867可完全阻断orexin-A对胃运动、胃排空和胃酸分泌的促进作用。结论:下丘脑室旁核orexin-A可能通过生长激素促泌素GHSR受体信号通路调控大鼠摄食及胃功能。     

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.     

The effects of [Arg14, Lys15] nociceptin/orphanin FQ, a highly potent agonist of the NOP receptor, on in vitro and in vivo gastrointestinal functions

Nociceptin/orphanin FQ (N/OFQ) administered into the lateral left cerebral ventricle of rats has been reported to inhibit in vivo gut motor and secretory functions. Recently, a novel N/OFQ analog, [Arg14, Lys15] N/OFQ, was synthesized and demonstrated to behave as a highly potent agonist at the human recombinant N/OFQ peptide (NOP) receptors and to produce long-lasting effects in vivo in mice compared with the natural ligand N/OFQ. In the present study, the pharmacological profile of [Arg14, Lys15] N/OFQ was further evaluated and compared with that of N/OFQ in vitro on guinea pig exocrine pancreas and in vivo on gastric emptying, colonic propulsion and gastric acid secretion in rats. [Arg14, Lys15] N/OFQ and N/OFQ significantly decreased the KCl-evoked amylase secretion from isolated pancreatic lobules of the guinea pig. In in vivo experiments, [Arg14, Lys15] N/OFQ mimicked the effects of N/OFQ, inducing, after intracerebroventricular injection, a delay (up to 70%) in the gastric emptying of a phenol red meal, an increase (about 40 times) of the mean bead colonic expulsion time and a decrease (up to 90%) of gastric acid secretion in water loaded rats after 90 min pylorus ligature. In all these assays, [Arg14, Lys15] N/OFQ was more effective than N/OFQ, and its effective doses were at least 10-fold lower than N/OFQ effective doses. The highly selective NOP receptor antagonist, UFP-101, decreased the efficacy of [Arg14, Lys15] N/OFQ in in vitro and in vivo assays above reported. These findings: (a) show that pancreatic NOP receptors mediate an in vitro inhibitory effect on stimulated guinea pig amylase secretion; (b) confirm that the stimulation of central NOP receptors exerts an inhibitory control on gastric emptying, colonic motility and gastric secretion in rats and (c) put in evidence that [Arg14, Lys15] N/OFQ, being more potent and effective than the natural ligand N/OFQ, represents a new pharmacological tool for the study of the physiological and pharmacological roles mediated by the N/OFQ-NOP receptor system.     

Calcium rather than calcitonin is dominant to mediate gastric emptying in thyroidectomized rats

Both calcium and calcitonin are important in mediating gastrointestinal motility. Present study tried to study what was the dominant role of calcitonin or calcium replacement on the gastric emptying in thyroidectomized animals. Adult Sprague-Dawley male rats received thyroidectomy or sham operation and then housed for two weeks until motility study, which was conducted using radiochromium to measure gastric emptying. Before motility study these rats were i.p. injected with saline or human calcitonin in the doses of 0.1, 1 and 10 microgM/kg, respectively. Another group of thyroidectomized rats received i.v. infusion of saline or CaCl2 for 30 min before motility study. Among thyroidectomized rats, neither saline nor various doses of calcitonin treatment disturbed gastric emptying compared to this of sham operated rats. Thyroidectomy diminished plasma calcium level, however, additional calcitonin treatment did not restore the suppressed calcium level (P<0.01). Of rats following saline or CaCl2 infusion, thyroidectomy did not change gastric emptying, whereas CaCl2 infusion enhanced gastric emptying (P<0.05). In conclusion, exogenous calcium treatment further enhances gastric emptying in thyroidectomized rats, whereas calcitonin replacement has no effect on gastric emptying. We suggest that calcium rather than calcitonin is dominant to mediate gastric emptying.     

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 D₁ 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 ED₅₀ 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.     

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。     

Regulation of feeding behavior,gastrointestinal function and fluid homeostasis by apelin

Apelin was first identified and characterized from bovine stomach extracts as an endogenous ligand for the APJ receptor. Apelin/APJ system is abundantly present in peripheral tissues and central nervous system. Apelin plays a broad role in regulating physiological and pathological functions. Recently, many reports have showed the effects of apelin on feeding behavior, however the results are inconsistent, due to different administration routes, animal species, forms of apelin, etc. Apelin has been involved in stimulating gastric cell proliferation, cholecystokinin (CCK) secretion, histamine release, gastric acid and bicarbonate secretion, and regulation of gastrointestinal motility. In addition, apelin produced regulatory effects on drinking behavior, diuresis, arginine vasopressin (AVP) release and glucocorticoids secretion. This article reviews the role of apelin on feeding behavior, gastrointestinal function and fluid homeostasis.     

High potency of bombesin for stimulation of human gastrin release and gastric acid secretion

Dose-response studies were performed in 6 human volunteer subjects to determine the threshold and optimal doses of intravenous bombesin for stimulation of gastric acid secretion and gastrin release. A significant stimulation of both acid and gastrin was obtained with a very low dose, 3 pmol · kg^?1 · h^?1. Peak stimulation of acid secretion (67% of pentagastrin PAO) was obtained at 12.5 pmol · kg^?1 · h^?1. Serum gastrin response to this dose of bombesinn was similar to that obtained after a high protein meal. Higher doses of bombesin caused further increases in serum gastrin but not in acid secretion. Since very low doses of bombesin, too small to produce detectable increases in immunoreactive serum bombesim, caused parallel increases in gastrin and acid secretion, it is possible that the bombesin-like peptides present in human gastrointestinal tissues contribute to regulation of human gastric secretion.     

Nesfatin-1对大鼠摄食、胃酸分泌、胃运动及胃排空的影响

目的:观察Nesfatin-1对大鼠摄食、胃酸分泌、胃运动及胃排空的影响并探究其可能机制。方法:将大鼠随机分为摄食实验组、胃酸实验组、胃运动实验组以及胃排空实验组。大鼠经腹内侧核置管后给予nasfatin-1,检测大鼠摄食量,使用Na OH滴定法测定大鼠胃酸分泌,记录清醒大鼠胃运动,以比色法测定大鼠胃排空。结果:低剂量和高剂量nesfatin-1均减少2小时累积食物摄入量;高剂量组4小时累积食物摄入量仍显著低于NS对照组。Nesfatin-1能够抑制2-DG对胃酸分泌的促进作用。SHU9119能够部分阻断nesfatin-1对2-DG的抑制作用。Nesfatin-1能够抑制胃运动及胃排空,SHU9119可部分阻断nesfatin-1对胃运动及胃排空的抑制作用。结论:Nesfatin-1能够调控大鼠摄食、胃酸分泌、胃运动及胃排空,黑皮质素信号通路可能也参与该调控过程。     

Effects of centrally injected GLP-1 in various experimental models of gastric mucosal damage

Glucagon-like peptide-1 (GLP-1) is accepted to be a peptide involved in the central regulation of gastrointestinal function, but its potential gastroprotective effect is not clear. The aim of this study was to investigate whether intracerebroventricularly injected GLP-1 has protective effects on gastric mucosal lesions induced by several models, and if yes, whether these effects are due to the gastric antisecretory effect of the peptide. GLP-1 which was injected in three different doses (1, 10, 100 ng/10 microl; i.c.v.) to conscious rats prevented the mucosal lesions induced by reserpine and ethanol, but did not prevent the gastric mucosal lesions induced by pyloric ligation. In addition, 1 ng/10 microl dose of centrally injected GLP-1 inhibited gastric acid secretion in pylorus-ligated rats. As a result, we conclude that intracerebroventricularly injected GLP-1 may play a role in the prevention of gastric mucosal lesions induced by certain experimental models and this gastroprotective effect may be independent from its antisecretory effect.     

Body temperature dependency in baclofen-induced gastric acid secretion in rats relation to capsaicin-sensitive afferent neurons

Body temperature dependency in gastric functional responses to baclofen, a GABA(B) agonist, such as acid secretion, mucosal blood flow (GMBF) and motor activity, was examined in urethane-anesthetized rats under normal (37+/-1 degrees C) and hypothermic (31+/-1 degrees C) conditions. A rat stomach was mounted in an ex-vivo chamber, perfused with saline, and the acid secretion was measured using a pH-stat method, simultaneously with GMBF by a laser Doppler flowmeter. Gastric motility was measured using a miniature balloon as intraluminal pressure recordings. Intravenous administration of baclofen significantly increased acid secretion at the doses > 0.3 mg/kg under hypothermic conditions, yet it caused a significant stimulation only at doses > 10 mg/kg under normothermic conditions. The increases in gastric motility and GMBF were similarly induced by baclofen, irrespective of whether the animals were subjected to normothermic or hypothermic conditions. These functional responses to baclofen under hypothermic conditions were totally attenuated by either bilateral vagotomy or atropine (3 mg/kg, s.c.). Baclofen at a lower dose (1 mg/kg i.v.) significantly increased the acid secretion even under normothermic conditions when the animals were subjected to chemical deafferenation of capsaicin-sensitive neurons or pretreatment with intracisternal injection of CGRP8-37 (30 ng/rat). These results suggest that 1) gastric effects of baclofen are dependent on body temperature in stimulating acid secretion but not GMBF or motor activity, 2) the acid stimulatory action of baclofen is enhanced under hypothermic conditions, and 3) the suppression of baclofen-induced acid response under normothermic conditions may be related to capsaicin-sensitive afferent neuronal activity, probably mediated by central release