共查询到20条相似文献,搜索用时 31 毫秒
1.
Leming S Broad J Cozens SJ Otterson M Winchester W Lee K Dukes GE Sanger GJ 《Neurogastroenterology and motility》2011,23(10):958-e410
Background GSK962040, a small molecule motilin receptor agonist, was identified to address the need for a safe, efficacious gastric prokinetic agent. However, as laboratory rodents lack a functional motilin system, studies in vivo have been limited to a single dose, which increased defecation in rabbits. Motilin agonists do not usually increase human colonic motility, so gastric prokinetic activity needs to be demonstrated. Methods The effect of intravenous GSK962040 on gastro‐duodenal motility was assessed in fasted dogs implanted with strain gauges. Activity was correlated with blood plasma concentrations of GSK962040 (measured by HPLC‐MS/MS) and potency of GSK962040 at the dog recombinant receptor [using a Fluorometric Imaging Plate Reader (Molecular Devices, Wokingham, UK) after expression in HEK293 cells]. Key Results GSK962040 activated the dog motilin receptor (pEC50 5.79; intrinsic activity 0.72, compared with [Nle13]‐motilin). In vivo, GSK962040 induced phasic contractions, the duration of which was dose‐related (48 and 173 min for 3 and 6 mg kg?1), driven by mean plasma concentrations >1.14 μmol L?1. After the effects of GSK962040 faded, migrating motor complex (MMC) activity returned. Migrating motor complex restoration was unaffected by 3 mg kg?1 GSK962040 but at 6 mg kg?1, MMCs returned 253 min after dosing, compared with 101 min after saline (n = 5 each). Conclusions & Inferences The results are consistent with lower potency for agonists at the dog motilin receptor, compared with humans. They also define the doses of GSK962040 which stimulate gastric motility. Correlation of in vivo and in vitro data in the same species, together with plasma concentrations, guides further studies and translation to other species. 相似文献
2.
H. Liu D. Qiu X. Zhou W. Niu X. Qin Y. Cai J. Wang Y. Chen 《Neurogastroenterology and motility》2010,22(11):1232-1239
Background Motilin has been known to stimulate the motility of digestive organs peripherally via activation of motilin receptors located at gastrointestinal (GI) cholinergic nerve endings and/or smooth muscle cells. Recent studies have indicated that motilin may also promote GI motility via actions in the central nervous system; however the sites of action and the mechanisms are not clear yet. The present study aimed to test the hypothesis that motilin receptor agonist erythromycin alters the synaptic inputs of preganglionic gastric vagal motoneurons (GVMs) located in the dorsal motor nucleus of the vagus (DMV). Methods Gastric vagal motoneurons were retrogradely labeled by fluorescent tracer from the stomach wall of newborn rats. Fluorescently labeled GVMs in DMV were recorded using whole‐cell patch‐clamp in brainstem slices and the effects of motilin receptor agonist erythromycin on the synaptic inputs were examined. Key Results Erythromycin (100 nmol L?1, 1 μmol L?1, 10 μmol L?1) significantly inhibited the frequency of glycinergic spontaneous inhibitory postsynaptic currents (sIPSCs) of GVMs and significantly inhibited the amplitude at the concentration of 10 μmol L?1. These responses were prevented by GM‐109, a selective motilin receptor antagonist. In the pre‐existence of tetradotoxin (TTX, 1 μmol L?1), erythromycin (10 μmol L?1) caused significant decreases of the glycinergic miniature inhibitory postsynaptic currents (mIPSCs), in both the frequency and the amplitude. However, erythromycin (10 μmol L?1) didn’t cause significant changes of the GABAergic sIPSCs. Conclusions & Inferences Erythromycin selectively inhibits the glycinergic inputs of GVMs. 相似文献
3.
s. cellek r. thangiah † e. m. jarvie s. vivekanandan † o. lalude † & g. j. sanger 《Neurogastroenterology and motility》2008,20(5):539-545
Abstract 5‐Hydroxytryptamine (5‐HT4) receptor agonists increase gastrointestinal (GI) motility by enhancing enteric acetylcholine release which is then metabolized by acetylcholinesterase (AChE) to inactive metabolites. As both AChE inhibitors and, more usually, 5‐HT4 receptor agonists are used to increase GI motility, an understanding of how these two different types of drugs might interact becomes of great importance. Our aim was to investigate the hypothesis that the effect of AChE inhibition will synergise with the ability of 5‐HT4 receptor agonism to increase cholinergic activity, leading to an effect greater than that evoked by each action alone. We tested the activity of the 5‐HT4 receptor agonist, prucalopride (10 nmol L?1–30 μmol L?1) and an AChE inhibitor, neostigmine (1 nmol L?1–10 μmol L?1) on cholinergically mediated contractions elicited by electrical field stimulation of human isolated colon circular muscle and rat isolated forestomach longitudinal strips. The experiments with human colon were performed in the presence of an inhibitor of nitric oxide synthase (Nω‐nitro‐l ‐arginine methyl ester, 300 μmol L?1). Prucalopride and neostigmine both enhanced cholinergic contractions in both tissues. The effect of prucalopride was inhibited in both tissues by SB‐204070, a 5‐HT4 receptor antagonist. In the presence of a minimum effective concentration of neostigmine (30 nmol L?1) and a submaximum concentration of prucalopride (3 μmol L?1) the enhancement of contractions was greater than either compound alone in both tissues. These data demonstrate that the combination of prucalopride and neostigmine potentiate cholinergic contractions more than their arithmetic sum of their individual values. The results suggest that a synergy between 5‐HT4 receptor agonism and AChE inhibition could be established pharmacologically which could be utilized as a novel prokinetic approach to functional GI disorders. 相似文献
4.
G. Cipriani P. Santicioli S. Evangelista C. A. Maggi S. Riccadonna M. N. Ringressi P. Bechi M. S. Faussone‐Pellegrini M. G. Vannucchi 《Neurogastroenterology and motility》2011,23(1):96-e10
Background The present aim was to study the modulation of NK2 receptor internalization by two compounds, the spasmolytic otilonium bromide (OB) endowed with NK2 receptor antagonistic properties and the selective NK2 receptor antagonist ibodutant. Methods Full‐thickness human colonic segments were incubated in the presence of OB (0.1–10 μmol L?1) or ibodutant (0.001–0.1 μmol L?1), with or without the NK2 receptor selective agonist [βAla8]NKA(4–10) and then fixed in 4% paraformaldehyde. Cryosections were processed for NK2 receptor immunohistochemical revelation. Quantitative analysis evaluated the number of the smooth muscle cells that had internalized the NK2 receptor. Key Results Immuno‐histochemistry revealed that in basal condition, the NK2 receptor was internalized in about 23% of total smooth muscle cells. The exposure to the selective NK2 receptor agonist induced internalization of the receptor in more than 77% of the cells. Previous exposure to both OB or ibodutant, either alone or in the presence of the agonist, concentration‐dependently reduced the number of the cells with the internalized receptor. Conclusions & Inferences Both OB and ibodutant antagonize the internalization of the NK2 receptor in the human colon. As NK2 receptors are the predominant receptor mediating spasmogenic activity of tachykinins on enteric smooth muscle, we hypothesize that the antagonistic activity found for both OB and ibodutant should play a specific therapeutic role in gut diseases characterized by hypermotility. 相似文献
5.
n. a. mitchell † e. pepperell ‡ § s. ociepka j. d. brown ‡ j. witherington b. tuladhar † g. j. sanger k. lee & s. cellek 《Neurogastroenterology and motility》2009,21(7):760-e48
Abstract Although the putative 5‐HT1P receptor has been implicated to have a role in peristalsis, experiments which suggest this function are preliminary or have measured only components of the reflex. We have, therefore, further characterized a reported agonist at this receptor (5‐hydroxyindalpine; 5‐OHIP) and investigated the effects of 5‐OHIP and 5‐hydroxytrytophan‐dipeptide (5‐HTP‐DP), a reported 5‐HT1P receptor antagonist, on distension‐induced peristalsis in mouse colon. The effects of 5‐OHIP on intracellular calcium, cyclic adenosine monophosphate concentrations or GTPγS binding were measured in cell lines expressing human recombinant 5‐HT1A, 1B, 1D, 2A, 2B, 2C, 3, 4, 6, 7 and α1A, α1B, D1, D2, D3, H1, H3 receptors. The effects of 5‐OHIP and 5‐HTP‐DP on peristalsis were assessed by measuring changes in frequency and times to reach threshold of peristaltic contractions, as well as the threshold and maximum pressures of each peristaltic stroke. 5‐hydroxyindalpine (1 nmol L?1–10 μmol L?1) had no significant activity at any of the receptors studied. However, 5‐OHIP (0.1 nmol L?1–1 μmol L?1) concentration‐dependently increased the frequency of peristalsis (EC50 = 4.4 nmol L?1) and reduced the time taken to reach threshold and threshold pressure, without altering maximum pressures. The maximum effect of 5‐OHIP was at 1 μmol L?1 (68.0 ± 14.5% increase in frequency); 10 μmol L?1 decreased peristalsis. 5‐hydroxytrytophan‐dipeptide (1–300 nmol L?1) also increased the frequency of peristalsis and prevented the actions of 5‐OHIP. The higher concentration (1 μmol L?1) transiently inhibited peristalsis and after recovery, prevented the actions of 5‐OHIP but not the excitatory activity of the cholinesterase inhibitor neostigmine. In summary, the present data demonstrate an interaction of ‘5‐HT1P‐ligands’ with the peristaltic reflex. However, the absence of an effect of 5‐OHIP on a range of different monoamine receptors continues to highlight the need to investigate the identity of the putative 5‐HT1P receptor. 相似文献
6.
Mondal A Kawamoto Y Yanaka T Tsutsui C Sakata I Oda SI Tanaka T Sakai T 《Neurogastroenterology and motility》2011,23(12):1123-1131
Background It has been shown in human and canine studies that motilin, a gastroprokinetic hormone, induces gastric phase III contractions via the enteric nervous; however, the center of motilin action in the stomach has not been clearly revealed. In the present study, we investigated the neural pathway of motilin‐induced gastric contraction by using Suncus murinus, a new animal model for motilin study. Methods An isolated suncus stomach was used in vitro to determine the mechanism of motilin action through the myenteric plexus. Synthetic suncus motilin (10?11–10?7 mol L?1) was added to an organ bath, and the spontaneous contraction response was expressed as a percent of ACh (10?5 mol L?1) responses. Motilin‐induced contractions were also studied by a pharmacological method using several receptor antagonists and enzyme inhibitor. Key Results Suncus motilin induced a concentration‐dependent gastric contraction at concentrations from 10?9 to 10?7 mol L?1. The responses to suncus motilin in the stomach were completely abolished by atropine and tetrodotoxin treatment and significantly suppressed by administration of hexamethonium, verapamil, phentolamine, yohimbine, ondansetron, and naloxone, whereas ritanserin, prazosin, timolol, and FK888 did not affect the action of motilin. Additionally, N‐nitro l ‐arginine methylester slightly potentiated the contractions induced by motilin. Conclusions & Inferences The results indicate that motilin directly stimulates and modulates suncus gastric contraction through cholinergic, adrenergic, serotonergic, opioidergic, and NO neurons in the myenteric plexus. 相似文献
7.
D. Gallego P. Clavé J. Donovan R. Rahmati D. Grundy M. Jiménez M. J. Beyak 《Neurogastroenterology and motility》2008,20(12):1306-1316
Abstract Hydrogen sulphide (H2S) has been recently proposed as a transmitter in the brain and peripheral tissues. Its role in the gastrointestinal tract is still unknown despite some data which suggest an involvement mediating smooth muscle relaxation. The aim of this study was to investigate the effect of this gas on intestinal segments from mouse jejunum and colon, and muscular strips from the human and rat colon. In isolated segments of mouse colon and jejunum, bath applied sodium hydrogen sulphide (NaHS) (a H2S donor) caused a concentration‐dependent inhibition of spontaneous motor complexes (MCs) (IC50 121 μmol L?1 in the colon and 150 μmol L?1 in the jejunum). This inhibitory effect of NaHS on MCs was (i) unaffected by tetrodotoxin (TTX), capsaicin, pyridoxal‐phosphate‐6‐azophenyl‐2′,4′‐disulfonate and N‐nitro‐l ‐arginine suggesting a non‐neural effect and (ii) significantly reduced by apamin 3 μmol L?1. NaHS concentration‐dependently inhibited the spontaneous motility in strips from human colon (IC50 261 μmol L?1) and rat colon (IC50 31 μmol L?1). The inhibitory effect of NaHS on colonic strips was (i) unaffected by the neural blocker TTX (1 μmol L?1) with IC50 183 μmol L?1 for the human colon and of 26 μmol L?1 for the rat colon and (ii) significantly reduced by glybenclamide (10 μmol L?1), apamin (3 μmol L?1) and TEA (10 mmol L?1) with IC50 values of 2464, 1307 and 2421 μmol L?1 for human strips, and 80, 167 and 674 μmol L?1 for rat strips respectively. We conclude that H2S strongly inhibits in vitro intestinal and colonic motor patterns. This effect appears to be critically dependent on K channels particularly apamin‐sensitive SK channels and glybenclamide‐sensitive K (ATP) channels. 相似文献
8.
H. Matsuyoshi H. Kuniyasu M. Okumura H. Misawa R. Katsui G.‐x. Zhang K. Obata M. Takaki 《Neurogastroenterology and motility》2010,22(7):806-e226
Background It was recently reported that some 5‐HT4‐receptor agonists increased neuronal numbers and length of neurites in enteric neurons developing in vitro from immunoselected neural crest‐derived precursors. We aimed to explore a novel approach in vivo to reconstruct the enteric neural circuitry that mediates a fundamental distal gut reflex. Methods The neural circuit insult was performed in guinea pigs by rectal transection and subsequent end‐to‐end one layer anastomosis. A 5‐HT4‐receptor agonist, mosapride citrate (10–100 μmol L?1) (applied for a patent) was applied locally at the anastomotic site. Key Results Mosapride promoted the regeneration of the neural circuit in the impaired myenteric plexus and the recovery of the defecation reflex in the distal gut. Furthermore, mosapride generated neurofilament (NF)‐, 5‐HT4‐receptor‐ and 5‐bromo‐2′‐deoxyuridine (BrdU)‐positive cells and surprisingly formed neural network in the newly formed granulation tissue at the anastomotic site 2 weeks after enteric nerve circuit insult. Possible neural stem cell markers, anti‐distal less homeobox 2 (DLX2)‐ and p75‐positive and NF‐positive cells increased during the same time period. All actions by mosapride were inhibited by the specific 5‐HT4‐receptor antagonist, GR113808 (10 μmol L?1). Conclusions & Inferences These results indicate that activation of enteric neural 5‐HT4‐receptors promotes reconstruction of an enteric neural circuit leading to the recovery of the defecation reflex in the distal gut, and that this reconstruction involves possibly neural stem cells. These findings indicate that treatment with 5‐HT4 agonists could be a novel therapy for generating new enteric neurons to rescue aganglionic gut disorders. 相似文献
9.
Background The origin and modulation mechanisms controlling timing and amplitude of esophageal body peristalsis are not fully understood. We aimed to characterize the neurotransmitters involved in the origin and modulation of circular smooth muscle esophageal body (EB) contractions. Methods Responses of porcine EB strips to electrical stimulation of motor neurons (MNs) were assessed in organ baths and with microelectrodes. The effect of antagonists of inhibitory (L‐NAME 1 mmol L?1, MRS2179 10 μmol L?1) and excitatory neurotransmitters (atropine 1 μmol L?1; SR140333 1 μmol L?1‐NK1ra‐, GR94800 1 μmol L?1‐NK2ra‐) and of ganglionic neurotransmitters (hexamethonium 100 μmol L?1, ondansetron 1 μmol L?1, NF279 10 μmol L?1) were characterized. Key Results Electrical field stimulation (EFS) induced a frequency‐dependent off‐contraction (16.8 ± 0.8 g) following a latency period. Latency was significantly reduced by L‐NAME (?66.1 ± 4.1%) and MRS2179 (?25.9 ± 5.6%), and strongly increased by atropine (+36.8 ± 5.8%). Amplitude was reduced by L‐NAME (?69.9 ± 10.4%), MRS2179 (?34.1 ± 6.0%), atropine (?42.3 ± 4.7%), hexamethonium (?18.9 ± 3.3%), NF279 (?20.7 ± 3.5%), ondansetron (?16.3 ± 3.2%), GR94800 (?28.0 ± 4.8%) SR140333 (?20.9 ± 7.1%), and α‐chymotrypsin (?31.3 ± 7.0%). The EFS induced a monophasic nitrergic inhibitory junction potential. Conclusions & Inferences Our results suggest that timing (latency) and amplitude of esophageal contractions are determined by a balance of complex interactions between excitatory and inhibitory MNs. Latency depends on the activation of inhibitory MNs releasing NO and a minor purinergic contribution through P2Y1 receptors, and excitatory MNs releasing ACh. Amplitude depends on a major contribution of excitatory MNs releasing ACh and tachykinins, and also on inhibitory MNs releasing NO, ATP or related purines, and peptidergic neurotransmitters acting as strong modulators of the excitatory neuroeffector transmission. 相似文献
10.
J. W. Rychter L. Van nassauw J.‐P. Timmermans L. M. A. Akkermans R. H. S. Westerink A. B. A. Kroese 《Neurogastroenterology and motility》2011,23(2):e57-e68
Background The parasitized or inflamed gastrointestinal mucosa shows an increase in the number of mucosal mast cells (MMC) and the density of extrinsic primary afferent nerve fibers containing the neuropeptide, calcitonin gene‐related peptide (CGRP). Currently, the mode of action of CGRP on MMC is unknown. Methods The effects of CGRP on mouse bone marrow‐derived mucosal mast cells (BMMC) were investigated by measurements of intracellular Ca2+ [Ca2+]i and release of mMCP‐1. Key Results Bone marrow‐derived mucosal mast cells responded to the application of CGRP with a single transient rise in [Ca2+]i. The proportion of responding cells increased concentration‐dependently to a maximum of 19 ± 4% at 10?5 mol L?1 (mean ±SEM; C48/80 100%; EC50 10?8 mol L?1). Preincubation with the CGRP receptor antagonist BIBN4096BS (10?5 mol L?1) completely inhibited BMMC activation by CGRP [range 10?5 to 10?11 mol L?1; analysis of variance (anova) P < 0.001], while preincubation with LaCl3 to block Ca2+ entry did not affect the response (P = 0.18). The presence of the CGRP1 receptor on BMMC was confirmed by simultaneous immunofluorescent detection of RAMP1 or CRLR, the two components of the CGRP1 receptor, and mMCP‐1. Application of CGRP for 1 h evoked a concentration‐dependent release of mMCP‐1 (at EC50 10% of content) but not of β‐hexosaminidase and alterations in granular density indicative of piecemeal release. Conclusions & Inferences We demonstrate that BMMC express functional CGRP1 receptors and that their activation causes mobilization of Ca2+ from intracellular stores and piecemeal release of mMCP‐1. These findings support the hypothesis that the CGRP signaling from afferent nerves to MMC in the gastrointestinal wall is receptor‐mediated. 相似文献
11.
12.
a. boudaka † j. wörl t. shiina † y. shimizu † t. takewaki † & w. l. neuhuber 《Neurogastroenterology and motility》2009,21(2):180-188
Abstract Nitrergic myenteric neurons co‐innervating motor endplates were previously shown to inhibit vagally induced contractions of striated muscle in the rodent oesophagus. Immunohistochemical demonstration of putative co‐transmitters, e.g. galanin, in enteric neurons prompted us to study a possible role of galanin in modulating vagally mediated contractions in an in vitro vagus nerve‐oesophagus preparation of the mouse. Galanin (1–16) (1–100 nmol L?1), in the presence of the peptidase inhibitor, phenanthroline monohydrate, inhibited vagally induced contractions in a concentration‐dependent manner (control: 100%; galanin 1 nmol L?1: 95.6 ± 1.6%; galanin 10 nmol L?1: 57.3 ± 6.5%; galanin 100 nmol L?1: 31.2 ± 8.1%, n = 5). The non‐selective galanin receptor antagonist, galantide (100 nmol L?1), blocked the inhibitory effect of galanin (10 nmol L?1) while the selective non‐galanin receptor 1 and galanin receptor 3 antagonists, M871 (1 μmol L?1) and SNAP37889 (100 nmol L?1), respectively, and the nitric oxide synthase inhibitor, NG‐nitro‐l ‐arginine methyl ester (l ‐NAME) (200 μmol L?1), failed to affect this galanin‐induced response. Simultaneous application of galantide (100 nmol L?1) and l ‐NAME (200 μmol L?1) significantly reduced the inhibitory effect of capsaicin (30 μmol L?1) on vagally induced contractions when compared with its effect in the presence of l ‐NAME alone or in combination with the selective galanin receptor 2 or 3 antagonists. An inhibitory effect of piperine on vagally induced contractions was reduced neither by galantide nor by l ‐NAME. Immunohistochemistry revealed galanin immunoreactive myenteric neurons and nerve fibres intermingling with cholinergic vagal terminals at motor endplates. These data suggest that galanin from co‐innervating enteric neurons co‐operates with nitric oxide in modulating vagally induced contractions in the mouse oesophagus. 相似文献
13.
Background Vasoactive intestinal peptide (VIP) submucosal neurons, the main regulators of gut secretion, display inhibitory postsynaptic potentials mediated by somatostatin (SOM) acting on SST1 and SST2 receptors (SSTR1, SSTR2) in the guinea‐pig small intestine. We investigated the implications of this for neurally‐evoked mucosal secretion. Methods Mucosal‐submucosal preparations from guinea‐pig jejunum were mounted in Ussing chambers to measure Cl‐ secretion, measured by short circuit current (Isc). All drugs were added serosally. Veratridine (1 μmol L?1) was used to stimulate neurons and provide a robust secretory response for pharmacological testing.5‐hydroxytrptamine (5‐HT, 300 nmol L?1) was used to specifically activate non‐cholinergic secretomotor neurons, while 1,1‐dimethyl‐4‐phenylpiperazinium (DMPP, 10 μmol L?1) was used to stimulate all secretomotor neurons. Key Results Somatostatin (50 nmol L?1) induced a tetrodotoxin (TTX, 1 μmol L?1)‐sensitive decrease in secretion. Somatostatin also reduced the veratridine‐induced increase in Isc. The effects of SOM were significantly reduced by blocking SSTR1 and SSTR2individually or together. Blocking SSTR1abolished the inhibition produced by SOM. Quantitative PCR demonstrated that SSTR1and SSTR2were much more highly expressed in the submucosa than the mucosa. Submucosal SSTR1expression was several fold higher than SSTR2. Responses to DMPP (biphasic) and 5‐HT (monophasic) were TTX‐sensitive. Somatostatin significantly reduced the 5‐HT‐induced increase in Isc, and the second, more sustained phase evoked by DMPP. Conclusions & Inferences These data suggest that SOM exerts its antisecretory effects by suppressing firing of VIP secretomotor neurons, rather than via a direct action on mucosal enterocytes. 相似文献
14.
x. bian j. e. burda m. carrasquillo & j. j. galligan 《Neurogastroenterology and motility》2009,21(9):969-977
Abstract Neuromuscular transmission is crucial for normal gut motility but little is known about its postnatal maturation. This study investigated excitatory/inhibitory neuromuscular transmission in vitro using ileal nerve‐muscle preparations made from neonatal (≤48 h postnatal) and adult (~4 months postnatal) guinea pigs. In tissues from neonates and adults, nicotine (0.3–30 μmol L?1) contracted longitudinal muscle preparations in a tetrodotoxin (TTX) (0.3 μmol L?1)‐sensitive manner. The muscarinic receptor antagonist, scopolamine (1 μmol L?1), reduced substantially nicotine‐induced contractions in neonatal tissues but not adult tissues. In the presence of Nω‐nitro‐l ‐arginine (NLA, 100 μmol L?1) to block nitric oxide (NO) mediated inhibitory neuromuscular transmission, scopolamine‐resistant nicotine‐induced contractions were revealed in neonatal tissues. NLA enhanced the nicotine‐induced contractions in neonatal but not in adult tissues. Electrical field stimulation (20 V; 0.3 ms; 5–25 Hz, scopolamine 1 μmol L?1 present) caused NLA and TTX‐sensitive longitudinal muscle relaxations. Frequency–response curves in neonatal tissues were left‐shifted compared with those obtained in adult tissues. Immunohistochemical studies revealed that NO synthase (NOS)‐immunoreactivity (ir) was present in nerve fibres supplying the longitudinal muscle in neonatal and adult tissues. However, quantitative studies demonstrated that fluorescence intensity of NOS‐ir nerve fibres was higher in neonatal than adult tissues. Nerve fibres containing substance P were abundant in longitudinal muscle in adult but not in neonatal tissues. Inhibitory neuromuscular transmission is relatively more effective in the neonatal guinea pig small intestine. Delayed maturation of excitatory motor pathways might contribute to paediatric motility disturbances. 相似文献
15.
H. Jing J. Qin M. Feng T. Wang J. Zhu C. Wang F. Wang K. Liu J. Li C. Liu 《Neurogastroenterology and motility》2011,23(3):e125-e135
Background Arginine vasopressin (AVP) is widely used in the treatment of critical diseases with hypotension, but the reports about its effect on gastrointestinal motility are controversial. The purpose of this study was to characterize the role of AVP in the regulation of colonic motility and the underlying mechanism. Methods The contraction of the circular muscle strips (CM) of colon in male rats was monitored by a polygraph. The expressions of cytoplasmic inducible nitric oxide synthase (iNOS), I‐κB, and the nuclear P65 in proximal colon were measured by Western blot. The V1 receptors (V1Rs) and iNOS were localized by immunohistochemistry. The content of nitric oxide (NO) in the colon was measured by Griess reagent at the absorbance of 560 nm. Key Results Arginine vasopressin (10?10–10?6 mol L?1) caused a concentration‐dependent inhibition on CM contraction. Pretreatment with one of the following chemicals, including V‐1880 (10?7 mol L?1), TTX (10?5 mol L?1), l ‐NAME (10?4 mol L?1), NPLA (10?7 mol L?1), SMT (10?3 mol L?1), and PDTC (10?3 mol L?1), attenuated the inhibitory effect of AVP on CM contraction. Arginine vasopressin increased the expression of iNOS and the content of NO in proximal colon. These effects were attenuated by pretreatment with PDTC (10?3 mol L?1). Following AVP administration, the amount of cytoplasmic I‐κB decreased, but that of nuclear P65 increased. Double immunofluorescence labeling revealed that V1Rs and iNOS were co‐localized on the cells of myenteric plexus in proximal colon. Conclusions & Inferences Arginine vasopressin inhibited the contraction of CM in proximal colon. This effect was mediated by NO produced from NF‐κB–iNOS pathway and neuronal NOS activation in myenteric plexus. 相似文献
16.
b. lecea † ‡ e. martínez † ‡ § m. aulí á. opazo † ‡ & p. clavé † ‡ 《Neurogastroenterology and motility》2009,21(12):1342-e130
Abstract The mechanisms of stimulation of inhibitory and excitatory motor neurons (MNs) in the lower oesophageal sphincter (LOS) are not fully understood. The aim of this study was to assess the effect of selective stimulation of inhibitory and excitatory MNs in porcine LOS through nicotinic acetylcholine receptors (nAChRs), 5‐HT3 and P2X receptors. Circular LOS strips from adult pigs were studied in organ baths. We compared the effects of stimulation of MNs by electrical field stimulation (26 V, 0.3–20 Hz); nicotine (1–300 μmol L?1); 5‐HT and 2‐Me‐5‐HT (1 nmol?1–30 μmol L?1); and α,β‐methylene ATP (α,β‐meATP 1–100 μmol L?1); in standard Krebs solution; a non‐adrenergic non‐nitrergic non‐purinergic (NANNNP) solution; and a non‐adrenergic non‐cholinergic (NANC) solution. Electrical stimulation of inhibitory MNs caused an intense LOS relaxation (?78.94 ± 4.50% of LOS tone); and of excitatory MNs, a strong contraction (17.89 ± 1.96 g). Nicotine 100 μmol L?1 relaxed LOS (?84.67 ± 3.98%) in standard Krebs solution, an effect reduced by Tetrodotoxin (TTX) 1 μmol L?1. Nicotine induced a weak TTX‐sensitive contraction (1.64 ± 0.4 g) in NANNNP solution. 5‐HT 10 μmol L?1 and 2‐Me‐5‐HT 30 μmol L?1 contracted LOS in standard, NANC and NANNNP conditions, maximal responses (7.30 ± 1.52 g, 3.50 ± 0.18 g respectively) being reduced by TTX. α,β‐meATP 100 μmol L?1 caused a LOS relaxation (?17.45 ± 6.62%) unaffected by TTX in NANC solution, and a contraction (6.7 ± 0.85 g) antagonized by TTX in NANNNP solution. Our results suggest selective mechanisms for stimulation of intrinsic excitatory and inhibitory motor pathways in porcine LOS. Inhibitory MNs are strongly stimulated by nAChRs and do not respond to stimulation of 5‐HT3 and P2X receptors. By contrast, excitatory MNs are stimulated through 5‐HT3 and P2X receptors, stimulation through nACRs being difficult and causing a weak response. 相似文献
17.
Abstract Asimadoline is a potent κ‐opioid receptor agonist with a diaryl acetamide structure. It has high affinity for the κ receptor, with IC50 of 5.6 nmol L?1 (guinea pig) and 1.2 nmol L?1 (human recombinant), and high selectively with κ : μ : δ binding ratios of 1 : 501 : 498 in human recombinant receptors. It acts as a complete agonist in in vitro assay. Asimadoline reduced sensation in response to colonic distension at subnoxious pressures in healthy volunteers and in irritable bowel syndrome (IBS) patients without alteration of colonic compliance. Asimadoline reduced satiation and enhanced the postprandial gastric volume (in female volunteers). However, there were no significant effects on gastrointestinal transit, colonic compliance, fasting or postprandial colonic tone. In a clinical trial in 40 patients with functional dyspepsia (Rome II), asimadoline did not significantly alter satiation or symptoms over 8 weeks. However, asimadoline, 0.5 mg, significantly decreased satiation in patients with higher postprandial fullness scores, and daily postprandial fullness severity (over 8 weeks); the asimadoline 1.0 mg group was borderline significant. In a clinical trial in patients with IBS, average pain 2 h post‐on‐demand treatment with asimadoline was not significantly reduced. Post hoc analyses suggest that asimadoline was effective in mixed IBS. In a 12‐week study in 596 patients, chronic treatment with 0.5 mg and 1.0 mg asimadoline was associated with adequate relief of pain and discomfort, improvement in pain score and number of pain‐free days in patients with IBS‐D. The 1.0 mg dose was also efficacious in IBS‐alternating. There were also weeks with significant reduction in bowel frequency and urgency. Asimadoline has been well tolerated in human trials to date. 相似文献
18.
Maselli MA Trisolini P Petitta C Lorusso D Cicenia A Scirocco A Pezzolla F Severi C 《Neurogastroenterology and motility》2012,24(9):867-e399
Background Differences in the actions of enteric neurotransmitters on colonic circular and longitudinal muscle layers have not been clearly determined, nor the possible existence of intrinsic myogenic phenotypes that might contribute to regional differences in human colon motor activity. The aim of this study was to analyze the direct pharmaco‐mechanical coupling of carbachol (CCh) and vasoactive intestinal polypeptide (VIP) on human colonic smooth muscle strips and cells. Methods Circular and longitudinal muscle strips and cells were obtained from 15 human specimens of ascending and sigmoid colon. Both isometric tension on muscle strips and contraction and relaxation on cells were measured in response to increasing CCh and VIP concentrations. Key Results Circular muscle strips of ascending colon were more sensitive to the effect of CCh than that of sigmoid colon, EC50 values being, respectively, 4.15 μmol L?1 and 8.47 μmol L?1 (P < 0.05), although there were no differences in maximal responses. No regional differences were observed in longitudinal muscle strips or in smooth muscle cells. Maximal responses to CCh were higher on circular than longitudinal muscle strips and cells throughout the colon. A greater sensitivity to VIP was observed in ascending colon compared with sigmoid colon, both in circular (EC50: 0.041 and 0.15 μmol L?1, respectively, P < 0.01) and longitudinal (EC50: 0.043 and 0.09 μmol L?1, respectively, P < 0.05) strips, and similar differences were observed in longitudinal smooth muscle cells (EC50: 44.85 and 75.24 nmol L?1, respectively, P < 0.05). Conclusions & Inferences Regional myogenic differences in pharmaco‐mechanical coupling between the enteric neurotransmitters and smooth muscle contribute to the complex regional motor patterns of human colon. 相似文献
19.
D. Gallego M. Aulí J. Aleu E. Martínez L. Rofes J. Martí‐ragué M. Jiménez P. Clavé 《Neurogastroenterology and motility》2010,22(6):e180-e191
Background The mechanism of action of the spasmolytic compound otilonium bromide (OB) on human colonic motility is not understood. The aim of our study was to characterize the pharmacological effects of OB on contractile patterns in the human sigmoid colon. Methods Circular sigmoid strips were studied in organ baths. Isolated smooth muscle cells from human sigmoid colon were examined using the calcium imaging technique. Key Results Otilonium bromide inhibited by 85% spontaneous non‐neural rhythmic phasic contractions (RPCs), (IC50 = 49.9 nmol L?1) and stretch‐induced tone (IC50 = 10.7 nmol L?1) with maximum effects at micromolar range. OB also inhibited by 50% both on‐ (IC50 = 38.0 nmol L?1) and off‐contractions induced by electrical stimulation of excitatory motor neurons. In contrast, the inhibitory latency period prior to off‐contractions was unaffected by OB. OB inhibited acetylcholine‐, substance P‐, and neurokinin A‐induced contractions. The L‐type Ca2+ channel agonist BayK8644 reversed the effects of OB on RPCs, on‐ and off‐contractions. Hexamethonium, atropine, the NK2 antagonist, or depletion of intracellular Ca2+ stores by thapsigargin did not prevent the inhibitory effect of OB on RPCs and electrical contractions. KCl‐induced calcium transients in isolated smooth muscle cells were also inhibited by OB (IC50 = 0.2 μmol L?1). Conclusions & Inferences Otilonium bromide strongly inhibited the main patterns of human sigmoid motility in vitro by blocking calcium influx through L‐type calcium channels on smooth muscle cells. This pharmacological profile may mediate the clinically observed effects of the drug in patients with irritable bowel syndrome. 相似文献
20.
Motilin and motilin receptor agonist erythromycin were administered to healthy subjects where colonic motility was recorded manometrically from the hepatic flexure to the rectum. Experiments were carried out during the fasting basal state or when colonic motility was stimulated by the ingestion of a 1000 kcal lunch. A supraphysiological dose of motilin (100 ng kg?1, i.v.) increased the motor activity of the fasting sigmoid colon, but the response was smaller than the meal induced activity. The administration of erythromycin (200 mg, i.v.) during the inter digestive period induced, on the sigmoid region, a motor response that was not significantly different in amplitude from the post-prandial contractile profile. However, on the more proximal segments of the colon, motilin and erythromycin were inactive. When both agents were administered during the digestive period, both failed to modify the contractile stimulation normally seen in all regions of the colon after a meal. Therefore the colonic motor response obtained with stimulation of motilin receptors in man appears limited;it is restricted to the sigmoid, it can be seen only during fasting and it is of weak amplitude. 相似文献