Ghrelin accelerates gastric emptying via early manifestation of antro-pyloric coordination in conscious rats

doi:10.1016/j.regpep.2007.08.022

Regulatory Peptides

Volume 146, Issues 1–3, 7 February 2008, Pages 112-116

https://doi.org/10.1016/j.regpep.2007.08.022 Get rights and content

Abstract

Ghrelin is known to enhance gastric motility and accelerate gastric emptying of liquid and solid food in rats. As solid gastric emptying is regulated by the coordinated motor pattern between the antrum and pylorus (antro-pyloric coordination), we studied the correlation between solid gastric emptying and antro-pyloric coordination in response to ghrelin. Rats were given 1.5 g of solid food after a 24-h fasting. Immediately after the ingestion, ghrelin (0.4–8.0 μg/kg) or saline was administered by intraperitoneal (IP) injection. Ninety minutes after the feeding, rats were euthanized and gastric content was removed to calculate gastric emptying. To evaluate the antro-pyloric coordination, strain gauge transducers were sutured on the antrum and pylorus. The incidence of postprandial antro-pyloric coordination was compared between ghrelin-and saline-injected rats. In saline-injected rats, gastric emptying was 58.3 ± 3.7% (n = 6). Ghrelin (4.0–8.0 μg/kg), accelerated gastric emptying. Maximum effect was obtained by ghrelin (4.0 μg/kg), which significantly accelerated gastric emptying to 77.4 ± 3.7% (n = 6, p < 0.05). The number of antro-pyloric coordination 20–40 min after feeding was significantly increased in ghrelin-injected rats, compared to that of saline-injected rats (n = 4, p < 0.05). It is suggested that enhanced antro-pyloric coordination play an important role in accelerated solid gastric emptying induced by ghrelin.

Introduction

Ghrelin was discovered as an endogenous ligand for growth hormone secretagogue receptor (GHS-R) [1]. Ghrelin enhances food intake [2], [3] and stimulates gastrointestinal (GI) motility [4] and promotes solid gastric emptying in humans [5], rats [6] and mice [7]. Gastric emptying of non-nutrient liquid is also accelerated by ghrelin in rats [6], [8], [9] and mice [10], [11].

However, it is not well established how ghrelin mediates the acceleration of gastric emptying. Two major pathways are suggested; vagal pathway and intrinsic neural pathway.

Ghrelin receptors are synthesized in vagal afferent neurons and transported to the afferent terminals. Blockade of the gastric vagal afferent abolished ghrelin-induced feeding and GH secretion, indicating that the gastric vagal afferent is the major pathway conveying ghrelin's signals for starvation and GH secretion to the brain [12].

Others also showed the presence of GHS-R in the afferent nerve in the nodose ganglion which projects to the stomach [13]. The stimulatory effect of ghrelin on gastric motility is abolished by the pretreatment with atropine or bilateral vagotomy in rats [4]. These suggest that the stimulatory effect of ghrelin on gastric emptying is mediated via vagal pathways.

On the other hand, intravenous administration of ghrelin alters gastric contractions from fed pattern to fasted pattern even in vagotomized rats [14], suggesting that the effect of ghrelin on gastric motor activity is mediated via vagal-independent pathway in vagotomized rats.

In vitro muscle strip study showed that ghrelin enhances electrical field stimulation (EFS)-evoked contractions in rats [6], [15], [16] and mice [17], suggesting the direct action of ghrelin on the gastric myenteric plexus.

The mechanism of regulating gastric emptying is different between liquids and solids. The emptying of liquids from the stomach is thought to be primarily a function of the pressure gradient between the stomach and the duodenum [18]. On the other hand, the antral pump and pyloric opening are importance factor for the emptying of solid foods. Large solid particles are retained in the stomach by the pyloric closure and retropelled and triturated in the antral mill [18], [19].

The coordinated motor pattern between the antrum and pylorus is observed in emptying period in humans [19] and dogs [20]. This has also been demonstrated as antro-pyloric coordination in rats [21], [22], [23]. It is generally accepted that coordination between the antrum and pylorus is an important factor in the emptying of solid foods [18], [19], [22], [24], [25].

The antro-pyloric coordination is abolished by atropine or truncal vagotomy in rats [22]. Treatment by vagal blockade or hexamethonium significantly reduced postprandial antral contractions and pyloric relaxations in dogs [20]. These suggest that the antro-pyloric coordination is mediated via vagal nerve.

In the current study, we studied whether ghrelin affects postprandial antro-pyloric coordination in conscious rats.

Section snippets

Animals

Male Sprague-Dawley rats weighing 240–290 g were housed in-group cages under conditions of controlled temperature (22–24 °C) and illumination (12-h light cycle starting at 7:00 am) for at least seven days before experiments and maintained on laboratory chow and water. Before the experiment, rats were fasted for 24 h but given free access to water. Protocols describing the use of rats were approved by the Institutional Animal Care and Use Committee of Duke University Medical Center and in

Effect of ghrelin on solid gastric emptying

In saline-treated rats, solid gastric emptying was 58.3 ± 3.7% (n = 6). IP-administration of ghrelin (4.0–8.0 μg/kg) significantly accelerated gastric emptying. Maximum effect was observed at 4.0 μg/kg of ghrelin, which accelerated gastric emptying at 76.7 ± 3.7% (n = 6). Ghrelin (8.0 μg/kg) did not further accelerate solid gastric emptying (Fig. 1).

Effect of ghrelin on postprandial antro-pyloric coordination

In this study, all rats ate the 1.5 g of solid food within 8–10 min (8.4 ± 0.2 min, n = 8). In saline-injected rats, feeding of rat chow immediately caused

Discussion

It is well established that ghrelin causes phase III-like contractions in a fasting state in rats [14], [26]. Several reports demonstrated that ghrelin accelerates gastric emptying of liquid non-nutrients in rats [6], [8], [9] and mice [10], [11].

Non-nutrients study doesn't reflect the postprandial gastric motor function. The stimulatory effects of ghrelin on gastric emptying of liquid non-nutrients may be explained by its stimulatory action on the motor activity (phase III-like contractions)

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In order to test the universality of vagal afferent insensitivity to gut peptides following T3-SCI, rats were administered the pro-kinetic peptide, ghrelin. Ghrelin is secreted from oxyntic cells within the gastric mucosa (Date et al., 2000; Grönberg et al., 2008) and is known to exert stimulatory effects upon gastric motility and acid secretion (Ariga et al., 2007; Ariga et al., 2008; Kobashi et al., 2009; Masuda et al., 2000; Wang et al., 2008). Furthermore, ghrelin has been frequently proposed as an endogenous promotility agent (Greenwood-Van Meerveld et al., 2011).
The gastrointestinal tract of vertebrates is a heterogeneous organ system innervated to varying degrees by a local enteric neural network as well as extrinsic parasympathetic and sympathetic neural circuits located along the brainstem and spinal axis. This diverse organ system serves to regulate the secretory and propulsive reflexes integral to the digestion and absorption of nutrients. The quasi-segmental distribution of the neural circuits innervating the gastrointestinal (GI) tract produces varying degrees of dysfunction depending upon the level of spinal cord injury (SCI). At all levels of SCI, GI dysfunction frequently presents life-long challenges to individuals coping with injury. Growing attention to the profound changes that occur across the entire physiology of individuals with SCI reveals profound knowledge gaps in our understanding of the temporal dimensions and magnitude of organ-specific co-morbidities following SCI. It is essential to understand and identify these broad pathophysiological changes in order to develop appropriate evidence-based strategies for management by clinicians, caregivers and individuals living with SCI. This review summarizes the neurophysiology of the GI tract in the uninjured state and the pathophysiology associated with the systemic effects of SCI.
Electroacupuncture for functional dyspepsia and the influence on serum Ghrelin, CGRP and GLP-1 levels
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To observe the clinical efficacy of electroacupuncture for functional dyspepsia (FD), and explore the corresponding mechanism.
Sixty-four FD patients were randomly divided into electroacupuncture group and western medicine group, with 32 cases in each group. In electroacupuncture group, electroacupuncture at Zúsānlĭ (足三里ST 36), Sānyīnjiāo (三阴交SP 6), Gōngsūn (公孙SP 4) and Nèiguān (内关PC 6) was performed for once a day, and the needles were retained for 30 min. In western medicine group, oral administration of mosapride citrate dispersible tablets in a dosage of 5 mg/time was carried out for 3 times a day. Treatment was conducted for 30 consecutive days in both groups. The scores of Leeds dyspepsia questionnaire (LDQ) and functional digestive disorder quality of life (FDDQL) of patients in both groups were recorded before and after treatment. Serum Ghrelin, CGRP and GLP-1 levels of patients were tested before and after treatment respectively, and the clinical efficacy of patients in both groups was evaluated after treatment.
In western medicine group, LDQ score after treatment was lower than that before treatment (P < 0.05), FDDQL score after treatment was higher than that before treatment, while the differences were not statistically significant (P > 0.05). LDQ score in electroacupuncture group after treatment was lower than that before treatment (P < 0.05), and also lower than that in western medicine group at the same time point (P < 0.05). FDDQL score in electroacupuncture group after treatment was higher than that before treatment (P < 0.05), and also higher than that in western medicine group at the same time point (P < 0.05). In western medicine group, Ghrelin level after treatment was higher than that before treatment (P < 0.05), CGRP level reduced, and the differences were not statistically significant (P > 0.05). GLP-1 level after treatment was also higher than that before treatment (P < 0.05). In electroacupuncture group, Ghrelin level after treatment was higher than that before treatment, CGRP level reduced, and GLP-1 level after treatment was also higher than that before treatment (both P < 0.05). According to the comparison of values of each index between electroacupuncture group and western medicine group after treatment, the differences were all statistically significant (all P < 0.05). The total effective rate in electroacupuncture group was 90.63% (29/32) which was higher than that in western medicine group 68.75%(22/32), and the differences were statistically significant (P < 0.05).
Electroacupuncture at ST 36, SP 6, SP 4 and PC 6 can effectively improve the clinical symptoms of FD patients, and the mechanism might be related with the increase of serum Ghrelin and GLP-1 levels and the decrease of serum CGRP level.
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The pylorus is innervated by vagal mechanoreceptors that project to gastrointestinal smooth muscle, but the distributions and specializations of vagal endings in the sphincter have not been fully characterized. To evaluate their organization, the neural tracer dextran biotin was injected into the nodose ganglia of rats. Following tracer transport, animals were perfused, and their pylori and antra were prepared as whole mounts. Specimens were processed to permanently label the tracer, and subsets were counterstained with Cuprolinic blue or immunostained for c-Kit. Intramuscular arrays (IMAs) in the circular muscle comprised the principal vagal afferent innervation of the sphincter. These pyloric ring IMAs were densely distributed and evidenced a variety of structural specializations. Morphometric comparisons between the arbors innervating the pylorus and a corresponding sample of IMAs in the adjacent antral circular muscle highlighted that sphincter IMAs branched profusely, forming more than twice as many branches as did antral IMAs (means of 405 vs. 165, respectively), and condensed their numerous neurites into compact receptive fields (∼ 48% of the area of antral IMAs) deep in the circular muscle (∼ 6 μm above the submucosa). Separate arbors of IMAs in the sphincter interdigitated and overlapped to form a 360° band of mechanoreceptors encircling the pyloric canal. The annulus of vagal IMA arbors, putative stretch receptors tightly intercalated in the sphincter ring and situated near the lumen of the pyloric canal, creates an architecture with the potential to generate gut reflexes on the basis of pyloric sensory maps of high sensitivity and fine spatial resolution.
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Irritable bowel syndrome (IBS) is a common gastrointestinal disorder with a prevalence of 5–20% and an incidence of 200/100,000. It is not known to be associated with the development of serious disease or with increased mortality, but it does considerably reduce the quality of life for patients and is an economic burden to society. Diet plays an important role in triggering the symptoms of IBS, especially the intake of foods that are rich in fermentable oligo-, di-, and monosaccharides, and polyols (FODMAPs), by influencing the dominance of Clostridium spp. in the intestinal flora and inducing abnormalities in gut endocrine cells. Dietary guidance aimed at establishing healthy eating habits by avoiding foods rich in FODMAPs and insoluble fiber and adjusting food composition has been found to reduce symptoms and improve the quality of life in IBS patients. Endocrine cells that produce several anorexigenic hormones in the gut are depleted in IBS patients, but the impact of this on appetite and body mass index in IBS patients is not known. Further studies are urgently needed to clarify this issue.
Involvements of the lateral hypothalamic area in gastric motility and its regulation by the lateral septum
2013, General and Comparative Endocrinology
Ghrelin is an endogenous ligand for the growth hormone secretagogue receptor (GHS-R) pre-dominantly produced in the stomach. Recent studies have shown that it may promote food intake and gastric motility. We aim to explore effects of ghrelin on the gastric distension (GD) sensitive neurons and gastric motility in the lateral hypothalamic area (LHA), and the possible regulation by the lateral septum. Extracellular single unit discharges were recorded and the gastric motility was monitored by administration of ghrelin into LHA and electrical stimulation of lateral septum. Expression of GHS-R was determined by polymerase chain reaction (PCR), western blot and immunohistochemistry staining. Projection of nerve fiber and expression of ghrelin were observed by retrograde tracer and fluo-immunohistochemistry staining. Results revealed that there were GD neurons in the LHA, and administration of ghrelin could excite both GD-excitatory (GD-E) and GD-inhibited (GD-I) neurons in the LHA. The gastric motility was significantly promoted by administration of ghrelin into LHA with a dose dependent manner, which could be completely abolished by treatment with ghrelin receptor antagonist [D-Lys-3]-GHRP-6 or BIM-28163. c-Fos expression was significantly increased after ghrelin administration to the LHA. Electrical stimulation of the lateral septum could significantly excite GD neurons responsive to ghrelin in the LHA as well as promote gastric motility. However, those effects could be absorbed by pre-treatment of [D-Lys-3]-GHRP-6. GHSR-1a expression in the LHA had no change after ghrelin administration to the LHA or electrical stimulating lateral septum. Electrical lesion of the LHA resulted in the decrease of gastric motility. GHS-R and Ghrelin/FG-double labeled neurons were observed in the LHA and lateral septum, respectively. It is suggested that the LHA may involve in promoting gastric motility via ghrelin. The Lateral septum projects to the LHA and exerts some regulating function on the LHA.
Ghrelin receptor is activated by naringin and naringenin, constituents of a prokinetic agent Poncirus fructus
2013, Journal of Ethnopharmacology
Citation Excerpt :
The cyclical plasma levels of motilin are synchronized to strong peristaltic contractions initiated from the stomach and migrating to the small intestine, modulating interdigestive migrating contractions in the GI tract (Ohno et al., 2010). Similar to motilin, peripheral administration of ghrelin expedites gastric emptying in rodents, enhancing coordinated motor pattern between the antrum and pylorus (antro-pyloric coordination) (Ariga et al., 2008). Ghrelin, when administered intraperitoneally, alleviates symptoms of dyspepsia in relevant animal models (Liu et al., 2006).
Poncirus fructus (PF), also known as a dried immature fruit of Poncirus trifoliata (L.) Raf. (Rutaceae), has long been traditionally used for the various gastrointestinal disorders in Eastern Asia.
The aqueous extract of PF (PF-W) has the strong prokinetic effect, yet the underlying mechanism is still elusive. The present study investigated whether PF-W has any effect on motilin receptor or ghrelin receptor, since these receptors enhance intestinal motility when activated.
The effect of PF-W and its components on motilin or ghrelin receptor was determined by calcium imaging and whole-cell patch clamp methods.
PF-W activates the ghrelin receptor, but not the motilin receptor, resulting in a transient increase of intracellular calcium levels. Furthermore, among various constituents of PF, only naringin and naringenin evoked the intracellular calcium augmentation via the ghrelin receptor. Moreover, cortistatin-8 – a ghrelin receptor inhibitor – specifically blocked naringin- and naringenin-induced calcium increases. In addition, naringin and naringenin induced inward currents in ghrelin receptor-expressing cells under whole-cell patch clamp configuration.
PF-W activates the ghrelin receptor, and naringin and naringenin are key constituents responsible for the activation of ghrelin receptor. Therefore, the present study suggests that the ghrelin receptor is a molecular entity responsible for the strong prokinetic activity of PF-W.

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Ghrelin accelerates gastric emptying via early manifestation of antro-pyloric coordination in conscious rats

Abstract

Introduction

Section snippets

Animals

Effect of ghrelin on solid gastric emptying

Effect of ghrelin on postprandial antro-pyloric coordination

Discussion

Gastroenterology

Biochem Biophys Res Commun

Regul Pept

Regul Pept

Gastroenterology

Neurosci Lett

Neuroscience

Eur J Pharmacol

Gastroenterology

Gastroenterology

Auton Neurosci

Peptides

Regul Pept

Ghrelin is a growth-hormone-releasing acylated peptide from stomach

Nature