Ghrelin/GHS-R激动剂和MTL/MTL-R激动剂与胃肠动力关系的研究进展

Ghrelin和胃动素(MTL)主要由消化道分泌,有促进胃肠道运动的作用。胃肠动力疾病(DGIM)是主要由神经支配调节障碍导致的胃肠动力或感觉性疾病,以恶心、呕吐、腹痛、腹胀为主要症状。越来越多研究表明,ghrelin、MTL及其受体激动剂与DGIM发生关系密切。本文就ghrelin/GHS-R激动剂和MTL/MTL-R激动剂与DGIM关系的研究进展作一综述。     

模拟失重对大鼠血浆ghrelin、VIP和胃肠动力的影响

目的探讨模拟失重状态下胃肠激素ghrelin和VIP的改变以及对胃肠动力的影响。方法 32只Wistar大鼠,随机分为4组,每组8只,按模拟失重的时程分为14 d组和21 d组,并分别设立非悬吊14 d对照组和非悬吊21 d对照组。先后进行胃浆膜肌电的描记、葡聚糖蓝2000标记法测定胃残留率和小肠推进率,血浆ghrelin和VIP浓度分别用酶免法(ELISA)和放免法(RI)测定。结果悬吊14 d组与21 d组与相应对照组比较,ghrelin浓度下降VIP浓度升高,同时表现为胃肌电延缓,胃残留率增加;小肠推进率下降,差异均具有统计学意义(P<0.05)。结论模拟失重状态下血浆ghrelin下降和VIP升高可能是导致胃肠动力下降的重要因素之一。     

功能性消化不良患者血浆ghrelin变化及其与胃排空的关系

背景：ghrelin已被证实具有促进胃肠动力的作用,而胃肠动力障碍是功能性消化不良（FD）的重要发病机制,目前关于ghrelin与FD关系的临床研究较少。目的：探讨FD患者血浆ghrelin变化及其与临床症状和胃排空的关系。方法：纳人40例FD患者．其中餐后不适综合征（PDS）25例,上腹痛综合征（EPS）15例,并以20名健康者作为对照。评估临床症状评分,以实时B超检测胃半排空时间（GET1/2）,ELISA法检测血浆酰基化ghrelin水平,并分析血浆酰基化ghrelin水平与临床症状评分和GET1的关系。结果：与对照组相比,PDS组GET1/2和血浆酰基化ghrelin水平明显升高（P〈0．05）,而EPS组无明显差异（P〉0．05）。FD患者餐后饱胀与早饱症状评分之和与GET1/2呈正相关（r=0．33,P=0．04）,但与血浆酰基化ghrelin水平无关。PDS组和EPS组患者血浆酰基化ghrelin水平与临床症状评分均无关。PDS组患者血浆酰基化ghrelin水平与GET1/2呈正相关（r=0．43,P=0．033）,而EPS组中两者无关。结论：PDS患者血浆酰基化ghrelin水平明显升高,并与胃排空功能相关,提示ghrelin在FD的发生过程中发挥一定的作用。     

Ghrelin与胎儿及新生儿生长发育和能量代谢的关系

Ghrelin是生长激素释放激素受体的内源性配体,在胎儿及新生儿生长发育和能量代谢过程中发挥重要作用.胎儿期血循环中ghrelin来源于自身分泌(主要是胰腺,胃分泌较少)和胎盘,既有辛酰基化又有去酰基化ghrelin存在,可直接刺激细胞增殖、骨生长,诱导神经管发生.脐血ghrelin水平明显高于母血,并与胎盘重量、胰岛素样生长因子-1、出生体重及身长呈负相关.新生儿期ghrelin主要由胃黏膜细胞分泌,新生儿肠内营养物质的摄入促进胃肠ghrelin分泌细胞的成熟和分泌.新生儿血清总ghrelin水平高于脐血,并与出生体重、身长呈负相关,小于胎龄儿血ghrelin水平高于正常胎龄儿和大于胎龄儿.     

Ghrelin对心血管系统作用的研究进展

本文主要就ghrelin的生物学效应,特别是在心血管方面的作用作一综述。Ghrelin是新发现的一种胃肠多肽,作用于下丘脑和垂体,可刺激生长激素(GH)释放,增强食欲,促进脂肪堆积。Ghrelin依赖于第3位丝氨酸残基辛酰基化的特征性结构,与一种G蛋白偶联受体结合,发挥内分泌调节作用。值得注意的是,ghrelin具有独立于生长激素之外的心脏保护作用。     

Ghrelin对胰腺功能的影响

Ghrelin是生长激素促泌剂受体的内源性配体。作为中枢神经一消化器官轴系统中的多肽,ghrelin及其受体广泛分布于中枢神经系统(下丘脑、垂体)和消化系统(胃、肠、胰腺)中。Ghrelin具有增加胃酸分泌、提高胃肠蠕动、促进生长激素分泌、促进食欲、调节能量代谢等多种作用。研究证明,ghrelin不仅影响胰腺的内分泌功能,而且也影响胰腺的外分泌功能。这为今后胰腺内、外分泌功能的研究提供了新的方向。     

游泳对大鼠胃肠动力及血浆胃动素的影响

运动锻炼可引起机体的多种反应,其对肌肉系统、心血管和呼吸系统的影响研究较多。但运动锻炼对胃肠道的作用很少引起注意。胃肠运动是消化道的重要功能,其研究日益受到重视。胃肠运动障碍为临床常见疾病,主要表现为胃肠收缩减弱、胃排空延迟。血浆胃动素在胃肠运动中起重要作用,许多胃肠动力障碍疾病如胃-食管反流、功能性消化不良、消化性溃疡、肠易激综合征等都伴有胃动素的改变。在运动锻炼状态下胃肠动力和血浆胃动素如何变化尚不清楚。本文就此在动物实验中探讨游泳运动对二者的作用。     

ghrelin与功能性消化不良

功能性消化不良（FD）患者尽管未发现胃肠道器质性病变,但是研究提示FD可能存在胃动力、胃排空、胃十二指肠神经调节或内脏敏感性等胃肠道功能的改变。ghrelin作为主要由胃X／A样细胞产生的一种多肽,影响胃的动力、排空和分泌功能。最近的研究表明血清中的ghrelin水平与FD有一定的关系,提示其可能在FD的发病机制中起一定的作用,值得深入的研究。     

Ghrelin与生长激素关系的研究进展

Ghrelin是最近发现的一种脑—肠肽,具有强烈的促生长激素(GH)释放的作用,此外还能调节能量代谢、食欲、睡眠等。目前认为,ghrelin可同时作用于人体腺垂体和下丘脑,与促生长激素释放激素协同促进GH分泌。Ghrelin的分泌具有性别差异,可被生长抑素抑制,但外周GH水平对ghrelin的分泌无明显影响。另外,胰岛素样生长因子1可通过下调ghrelin受体的表达而影响其作用。     

Ghrelin与生长激素关系的研究进展

Ghrelin是最近发现的一种脑-肠肽,具有强烈的促生长激素（GH）释放的作用,此外还能调节能量代谢、食欲、睡眠等.目前认为,ghrelin可同时作用于人体腺垂体和下丘脑,与促生长激素释放激素协同促进GH分泌.Ghrelin的分泌具有性别差异,可被生长抑素抑制,但外周GH水平对ghrelin的分泌无明显影响.另外,胰岛素样生长因子1可通过下调ghrelin受体的表达而影响其作用.     

Ghrelin family of peptides and gut motility

Acyl ghrelin, des-acyl ghrelin, and obestatin are three peptides isolated from the gastrointestinal tract and encoded by the same preproghrelin gene. Three ghrelin gene products participate in modulating appetite, adipogenesis, glucose metabolism, cell proliferation, immune, sleep, memory, anxiety, cognition, and stress. We have investigated the effects of ghrelin family of peptides on fed and fasted motor activities in the stomach and duodenum of freely moving conscious rats by manometric method. Intracerebroventricular (ICV) and intravenous (IV) administration of acyl ghrelin induced fasted motor activity in the duodenum in fed rats. ICV and IV administration of des-acyl ghrelin disrupted fasted motor activity in the antrum. Changes in gastric motility induced by IV administration of des-acyl ghrelin were antagonized by ICV administration of a corticotropin-releasing factor (CRF) 2 receptor antagonist. IV administration of obestatin decreased the percentage motor index in the antrum and prolonged the time taken to return to fasted motility in the duodenum in fed rats. ICV administration of CRF 1 and 2 receptor antagonists prevented the effects of obestatin on gastroduodenal motility. Ghrelin gene products regulate feeding-associated gastroduodenal motility. Stomach may regulate various functions including gastrointestinal motility via acyl ghrelin, des-acyl ghrelin and obestatin as an endocrine organ. Increasing knowledge of the effects of ghrelin family of peptides on gastrointestinal motility could lead to innovative new therapies for functional gastrointestinal disorders.     

Ghrelin enhances gastric motility through direct stimulation of intrinsic neural pathways and capsaicin-sensitive afferent neurones in rats

BACKGROUND: Ghrelin may stimulate gastric motility via the vagal nerve pathway. However, the mechanism of ghrelin-induced changes in gastrointestinal motility has not yet been clearly defined. The present study was designed to investigate whether ghrelin accelerates gastric emptying via capsaicin-sensitive afferent neurones and directly affects the enteric neuromuscular function. METHODS: Gastric emptying of nutrient solids was assessed after intravenous administration of saline or ghrelin in conscious rats. The effects of ghrelin on gastric emptying were also examined in rats pretreated with capsaicin. Gastric emptying and intestinal transit of non-caloric liquids were evaluated using 51Cr solution. The effects of ghrelin on spontaneous contractile activities of isolated strips from stomach and jejunum were also investigated and the influence of ghrelin on motor responses to carbachol and electrical field stimulation was examined. RESULTS: Ghrelin significantly accelerated gastric emptying of both nutrient solids and non-caloric liquids in conscious rats. The intestinal transit of non-caloric liquids was also enhanced by ghrelin. Pretreatment with capsaicin prevented the ghrelin-induced acceleration of gastric emptying of nutrient solids. Ghrelin did not modulate spontaneous and carbachol-induced contractions of strips of gastric body, gastric antrum and jejunum. However, electrical field stimulation-induced contractions were significantly enhanced by ghrelin in the gastric body. CONCLUSIONS: The results suggest that the stimulatory effects of ghrelin on gastric motility are mediated by direct stimulation of the enteric neural pathway and capsaicin-sensitive afferent neurones.     

Effects of ghrelin on gastric distension sensitive neurons and gastric motility in the lateral septum and arcuate nucleus regulation

Background

Ghrelin is an endogenous ligand for the growth hormone secretagogue receptor (GHS-R) and a peptide hormone that promotes food intake and gastric motility. Our aims are to explore the effects of ghrelin on gastric distension (GD) sensitive neurons in the lateral septum, and the possible regulation of gastric motility by ghrelin through the hypothalamic arcuate nucleus (ARC).

Methods

Single-unit discharges were recorded, extracellularly, and the gastric motility was monitored by the administration of ghrelin in the lateral septum. The projection of nerve fiber and expression of ghrelin were observed by retrograde tracer and fluo-immunohistochemistry staining. The expression of GHS-R and ghrelin was determined by real-time polymerase chain reaction and western blotting analysis.

Results

There were GD neurons in the lateral septum. The administration of ghrelin could excite both GD-excitatory (GD-E) and GD-inhibitory (GD-I) neurons in the lateral septum. Gastric motility was significantly enhanced by the administration of ghrelin in the lateral septum in a dose-dependent manner. Pretreatment with [d-Lys-3]-GHRP-6, however, could completely abolish the ghrelin-induced effects. Electrical stimulation of the ARC could significantly excite the response of GD neurons to ghrelin, increase ghrelin protein expression in the lateral septum and promote gastric motility. Nevertheless, these effects could be mitigated by pretreatment of [d-Lys-3]-GHRP-6. Electrical lesion of the lateral septum resulted in decreased gastric motility. The GHS-R and Ghrelin/FG-double labeled neurons were observed in the lateral septum and ARC, respectively.

Conclusions

It is suggested that the lateral septum may receive afferent information from the gastrointestinal tract and promote gastric motility. Ghrelin plays an important role in promoting gastric motility in the lateral septum. The ARC may be involved in the regulation of the lateral septum’s influence on gastric motility.     

康尔胃2号药效学研究

目的:观察康尔胃2号对动物胃肠运动及胃粘膜损伤的影响.方法:将5种动物模型分为空白对照组、阳性药物对照组及康尔胃2号大、中、小剂量组进行干预,比较各组作用及疗效.结果:康尔胃2号能防治乙醇致大鼠胃粘膜损伤,促进正常小鼠胃排空和小肠推进,对大鼠体内胃自发活动有抑制作用,对体外兔肠自发活动及氯化钡负荷下肠自发活动有抑制作用.结论:康尔胃2号有调整动物胃肠运动,保护胃粘膜等药理作用.     

Ghrelin: a gut hormonal basis of motility regulation and functional dyspepsia

Functional dyspepsia (FD) is a functional gastrointestinal disorder (FGID). Several pathophysiological mechanisms have been indicated as possible etiological factors, such as delayed gastric emptying, impaired proximal gastric accommodation and visceral hypersensitivity. Ghrelin is an important gut hormone. It is a motilin-related peptide that was discovered in the stomach, and it acts as an endogenous ligand of growth hormone secretagogue receptor. Ghrelin plays an important role in the stimulation of food intake and gut motility. Acyl ghrelin stimulates the percentage motor index (%MI) in the antrum and induces fasted motor activity in the duodenum. Des-acyl ghrelin decreases food intake and decrease gastric emptying. Although some studies have demonstrated that plasma acyl ghrelin levels tend to be lower in FD patients than in controls, the association between plasma ghrelin levels and FD remains controversial. Previous reports have demonstrated that hunger sensation was elevated through the administration of ghrelin to patients with FD. However, there have been few clinical reports relating to the administration of ghrelin. Altered gut-brain interactions may underlie the symptoms of FD. Ghrelin may be associated with FD through its effect on the regulation of gut motility. Further studies are needed to examine the effects of ghrelin in FD.     

Ghrelin-producing endocrine tumors of the stomach and intestine

Ghrelin is a novel gastrointestinal hormone produced by about 20% of the rat and human gastric neuroendocrine cell population, which possesses strong GH-releasing activity, but also plays other central and peripheral roles, including influence on food intake, gastric motility, and acid secretion. The aim of the present study was to determine whether gastrointestinal endocrine hyperplastic and neoplastic lesions produce ghrelin, at both protein (immunohistochemistry) and mRNA (in situ hybridization and/or RT-PCR) levels, and express the GH secretagogue receptor mRNA by RT-PCR. Sixteen gastric and 20 intestinal carcinoids as well as normal gastrointestinal mucosa and atrophic gastritis-associated neuroendocrine cell hyperplasia were studied. The majority (12 of 16, 75%) of gastric carcinoids and only 5 of 18 (27%) of intestinal endocrine tumors were immunoreactive for ghrelin. In situ hybridization confirmed the immunohistochemical data, but also showed ghrelin mRNA in 1 gastric and 8 intestinal additional tumors. RT-PCR showed ghrelin mRNA in 14 of 14 cases, indicating a low level of ghrelin gene expression in all gastrointestinal endocrine tumors tested. Gastric neuroendocrine hyperplastic cells were also strongly positive for ghrelin. GH secretagogue receptor mRNA was absent in 3 gastric, but present in 7 of 11 intestinal carcinoids studied by RT-PCR. These findings demonstrate that most gastric carcinoids (and related neuroendocrine cell hyperplasias) and some intestinal carcinoids produce ghrelin. These hyperplastic/neoplastic conditions could represent the clinical model to clarify the existence and impact of ghrelin hypersecretion on endocrine and nonendocrine functions.     

Des-acyl ghrelin acts by CRF type 2 receptors to disrupt fasted stomach motility in conscious rats

BACKGROUND & AIMS: Although it has been shown that des-acyl ghrelin decreases food intake and gastric emptying, no previous studies have examined the effects of des-acyl ghrelin on physiologic fed and fasted motor activity in the gastrointestinal tract. METHODS: We examined the effects of intraperitoneal (IP) administration of des-acyl ghrelin on food intake and the effects of intracerebroventricular (ICV) or intravenous (IV) administration of des-acyl ghrelin on gastroduodenal motility using freely moving conscious rat models. The brain nuclei responding to these effects were examined by c- fos immunohistochemistry of the brain sections. RESULTS: IP injection of des-acyl ghrelin decreased food intake, and this effect was not altered by capsaicin treatment. IP injection of des-acyl ghrelin enhanced c- fos expression in the arcuate and paraventricular nucleus but not in the nucleus of the solitary tract. Both ICV and IV injection of des-acyl ghrelin disrupted fasted motor activity in the antrum but not in the duodenum. Changes in gastric motility induced by IV injection of des-acyl ghrelin were completely antagonized by ICV injection of a selective corticotropin-releasing factor (CRF) 2 receptor antagonist; however, the CRF 1 receptor antagonist had no effects. CONCLUSIONS: The results suggest that des-acyl ghrelin decreases food intake and disrupts the fasted motor activity of the antrum in freely moving conscious rats. Peripheral des-acyl ghrelin may induce this function by direct activation of brain receptor by crossing the blood-brain barrier but not by the activation of vagal afferent pathways. In the brain, CRF 2 receptor, but not CRF 1 receptor, is involved in this action.     

干细胞与胃肠动力研究进展

干细胞能够无限地自我更新和分化成机体内几乎所有类型的细胞,具有巨大的治疗应用潜能。其在胃肠动力的基础和临床研究中发挥了一定作用。此文简述了干细胞与Cajal间质细胞(ICC)的关系,并对干细胞移植对胃排空和胃肌电活动的影响和其治疗某些胃肠动力障碍性疾病的尝试作一综述。