Actions of the 5-hydroxytryptamine 1 receptor agonist sumatriptan on interdigestive gastrointestinal motility in man

Background—Pharmacological studies of the entericnervous system have shown the presence of several subtypes of5-hydroxytryptamine (5HT) receptor, which might be involved incontrol of the migrating motor complex.
Aims—To study the effect of sumatriptan, anagonist of enteric neuronal 5HT_1P receptors, oninterdigestive motility in man.
Subjects and methods—In 12 healthy subjects,interdigestive motility was recorded manometrically in the uppergastrointestinal tract. In seven subjects blood samples were drawnevery 15 minutes for radioimmunoassay of motilin and somatostatin.After two phase 3s of the migrating motor complex, 6 mg of sumatriptanwas administered subcutaneously. Recording continued until two morephase 3s had occurred.
Results—Sumatriptan induced a premature phase 3 in the jejunum after a median of 10 (8) minutes. The duration of themigrating motor complex cycle was shortened at the expense of phase 2. After sumatriptan, plasma somatostatin concentrations were reduced and gastric phase 3s were suppressed, although median motilinconcentrations and the occurrence of plasma motilin peaks were notaffected. Phase 3s of the migrating motor complex preceding sumatriptan were associated with motilin peaks, while phase 3s after sumatriptan were not. Furthermore, pretreatment with sumatriptan prevented theinduction of a gastric phase 3 by the motilin agonist erythromycin.
Conclusions—Administration of the5HT_1P receptor agonist sumatriptan induces a prematureintestinal phase 3, suppresses gastric phase 3s, prevents induct-ion of a gastric phase 3 by erythromycin, and reduces plasmasomatostatin concentrations.

Keywords:migrating motor complex; motilin; somatostatin; erythromycin; enteric nervous system

     

Association of 5-hydroxytryptamine (serotonin) receptor 4 (5-HTR4) gene polymorphisms with asthma

Background and objective: The neurotransmitter, 5‐hydroxytryptamine, acts as an immunomodulator by stimulating the release of inflammatory cytokines and regulating the function of dendritic cells and monocytes. The 5‐hydroxytryptamine receptor 4 (HTR4) gene is located in a region previously linked to an increased risk of asthma and atopy. The aim of this study was to investigate the association between HTR4 and asthma. Methods: Thirty‐two single nucleotide polymorphisms (SNP) in HTR4 were investigated by direct sequencing of 24 DNA samples from unrelated Korean subjects. Results: The 32 genetic variants comprised 22 intronic SNP, two SNP in the 3′‐untranslated region (exon 7) and eight SNP in the 3′‐downstream region. Logistic regression analysis showed that two intronic polymorphisms were significantly associated with the risk of asthma. Two minor HTR4 alleles, +142828G > A and +122769G > A, occurred at significantly higher frequencies in the asthmatic group than in the healthy control group (49.59% vs 42.29%, P = 0.003, and 47.99% vs 40.35%, P = 0.008, respectively), and these differences remained significant after correction for multiple testing (P = 0.05, dominant mode of inheritance; and P = 0.03, dominant mode, respectively). Haplotype analysis revealed three haplotype blocks. The frequency of haplotype 1 in block 2 was significantly higher in asthmatics (P = 0.003, dominant mode), whereas the frequency of haplotype 4 in block 3 was significantly lower in asthmatics (P = 0.0009, dominant mode). Conclusions: SNP and haplotypes of the HTR4 gene were associated with the asthma phenotype and genetic variation of HTR4 may affect susceptibility to the development of asthma.     

Effects of ethanol on adenosine 5'-triphosphate-gated purinergic and 5-hydroxytryptamine receptors

This report of the proceedings of a symposium presented at the 2005 annual meeting of the Research Society on Alcoholism highlights the actions of ethanol on purinergic (P2XRs) and 5-hydroxytryptamine3 (5-HT3Rs) receptors. Both P2XRs and 5-HT3Rs, are modulated by pharmacologically relevant concentrations of ethanol, with inhibition or stimulation of P2XR subtypes and stimulation of 5-HT3Rs, respectively. With regard to ethanol-modulatory actions, these 2 distinctly different receptor classes have been studied to a much lesser extent than other LGICs. The organizers and chairs were Daryl L. Davies and Tina K. Machu. John J. Woodward discusses the molecular pharmacology and physiology of P2XRs and 5-HT3Rs and sets the stage for a detailed investigation into the ethanol sensitivity of these channels by the invited speakers. Daryl L. Davies discusses the results from recent electrophysiological studies conducted in his and Dr. Woodward's laboratories, highlighting the actions of ethanol on P2XR subtypes. Jiang-Hong Ye discusses results from recent studies using loose-patch and whole-cell recordings on purinergic receptors expressed on neurons from the ventral tegmental area (VTA) in rats. Tina K. Machu discusses electrophysiological studies conducted in her and Dr. David Lovinger's laboratories on nonpore lining residues of the second transmembrane domain (TM2) of the 5-HT3A receptor. Li Zhang presents data demonstrating that F-actin cytoskeletons play a critical role in 5-HT3 receptor clustering in hippocampal neurons. Collectively, the presentations provided strong evidence that P2X and 5-HT3 receptors are important targets for ethanol action.     

Effects of 5-HT2B, 5-HT3 and 5-HT4 receptor antagonists on gastrointestinal motor activity in dogs

AIM:To study the effects of 5-hydroxytryptamine(5-HT)receptor antagonists on normal colonic motor activity in conscious dogs.METHODS:Colonic motor activity was recorded using a strain gauge force transducer in 5 dogs before and after 5-HT2B,5-HT3 and 5-HT4 receptor antagonist administration.The force transducers were implanted on the serosal surfaces of the gastric antrum,terminal ileum,ileocecal sphincter and colon.Test materials or vehicle alone was administered as an intravenous bolus injection during a quiescent period of the whole colon in the interdigestive state.The effects of these receptor antagonists on normal gastrointestinal motor activity were analyzed.RESULTS:5-HT2B,5-HT3 and 5-HT4 receptor antagonists had no contractile effect on the fasting canine terminal ileum.The 5-HT3 and 5-HT4 receptor antagonists inhibited phaseⅢof the interdigestive motor complex of the antrum and significantly inhibited colonic motor activity.In the proximal colon,the inhibitory effect was dose dependent.Dose dependency,however,was not observed in the distal colon.The 5-HT2B receptor antagonist had no contractile effect on normal colonic motor activity.CONCLUSION:The 5-HT3 and 5-HT4 receptor antagonists inhibited normal colonic motor activity.The5-HT2B receptor antagonist had no contractile effect on normal colonic motor activity.     

Role of cannabinoid receptors in the control of gastrointestinal motility and perception

The identification of endocannabinoids and cannabinoid CB1 receptors in key areas of the intestinal wall, such as cholinergic neurons, supports a role for cannabinoids in the control of gastrointestinal motility. Activation of CB1 receptors inhibits the peristaltic reflex and slows down gastrointestinal and colonic transit. Endocannabinoids play an important inhibitory role in the control of the occurrence of transient lower esophageal sphincter relaxations. Cannabinoid receptor agonists inhibit gastric emptying and intestinal motility in humans. There is strong anatomical support for a role of CB1 receptors in the control of gastrointestinal perception, since these receptors have been identified in key sites of the neuronal circuitry involved in the transmission of visceral pain. Experimental data indicate a visceral antinociceptive action of cannabinoid receptor agonists, which remains to be confirmed in humans.     

Effect of buspirone, a 5-HT1A receptor agonist, on esophageal motility in healthy volunteers

There are limited data concerning the effects of 5-HT(1A) receptor activation on esophageal motility. Sumatriptan, a 5-HT(1A) receptor agonist, was recently reported to enhance esophageal peristalsis after intravenous administration. Buspirone, an orally available 5-HT(1A) receptor agonist, was shown to modulate gastroduodenal motor function. Our aim was to evaluate the effect of buspirone on esophageal motility of healthy volunteers. On two separate visits, 20 healthy volunteers aged 21-29 years (nine women) underwent esophageal manometry before and 10, 30, and 60 minutes after the administration of buspirone 20-mg or placebo capsule, according to a double-blind crossover design. At each time point, we compared buspirone and placebo effects on: resting pressure of the lower esophageal sphincter (LES); residual pressure and duration of LES relaxation; amplitude, duration, and onset velocity of esophageal body contractions, during 10 swallows of 5 mL of water. Significant analysis of variance differences (P < 0.05) are presented as mean ± standard deviation. Buspirone significantly increased mean distal esophageal wave amplitude (151 vs. 87 mmHg, P < 0.05) and duration (6.1 vs. 4.2 seconds, P < 0.05). Similarly, buspirone significantly increased mean LES resting pressure (26 vs. 21 mmHg, P < 0.05) and mean residual LES pressure (7.9 vs. 2 mmHg, P < 0.05), whereas reduced mean LES relaxation duration (7.2 vs. 8.0 seconds, P < 0.05) and mean distal onset velocity (7.6 vs. 14.7 cm/second, P < 0.05). Buspirone enhances esophageal peristalsis and LES function in healthy volunteers. Further study is warranted on the effects of buspirone on esophageal function and symptoms in patients with ineffective esophageal motility.     

Tegaserod,a 5-hydroxytryptamine type 4 receptor partial agonist,is devoid of electrocardiographic effects

OBJECTIVES: Certain GI prokinetic agents have been shown to affect cardiac repolarization, which may be associated with life-threatening arrhythmias. The selective 5-hydroxytryptamine type 4 receptor partial agonist tegaserod is a novel promotile agent developed for the treatment of functional motility disorders such as irritable bowel syndrome (IBS). The aim of the study was to investigate the cardiac safety profile of tegaserod through analysis of electrocardiographic data from clinical studies conducted in patients with IBS and a study conducted in healthy male subjects. METHODS: In three randomized, double blind, placebo-controlled, parallel group clinical studies, 2516 IBS patients with symptoms of abdominal pain and constipation received tegaserod 2 or 6 mg b.i.d. (n = 1679) or placebo (n = 837) for 12 wk. In an additional study, 36 healthy male subjects received iv. single doses of tegaserod (0.8 mg to 20 mg) or placebo. Standard 12-lead electrocardiograms were recorded at baseline and during treatment. Baseline values were compared with data collected during the treatment period. RESULTS: The proportion of patients with prolongation of the QTc interval was the same for placebo and tegaserod, as was the frequency of overall electrocardiographic abnormalities. No ventricular or supraventricular tachycardia was observed. Comparable electrocardiographic results were obtained during placebo and tegaserod treatment. In healthy volunteers, tegaserod at i.v. doses resulting in plasma concentrations up to 100 times those measured after therapeutic doses (6 mg b.i.d.) did not influence electrocardiographic parameters. CONCLUSIONS: Tegaserod is devoid of electrocardiographic effects and is not expected to adversely influence cardiac function. These data confirm preclinical findings.     

Developmental profile of chromogranin, hormonal peptides, and 5-hydroxytryptamine in gastrointestinal endocrine cells

In this immunocytochemical study, we have analyzed the developmental profile and phenotypic expression of the endocrine cell antigens chromogranin, 5-hydroxytryptamine, gastrin/cholecystokinin, cholecystokinin (9-20), somatostatin, somatostatin 28 (1-14), somatostatin cryptic peptide, glucagon, glucagonlike peptides 1 and 2, glicentin, peptide YY, glucose-dependent insulinotropic peptide, secretin, neurotensin, and substance P in human fetal stomach and intestine. All currently identifiable endocrine cell types were detected by 10 wk of gestation. Immunostaining for the endocrine cell marker chromogranin revealed abundant endocrine cells in the earliest specimens (8 wk of gestation) with a relatively higher frequency in both proximal duodenum and distal colon/rectum compared with other areas. Quantification of endocrine cells showed an increase with age that was roughly parallel to the growth of the gut as a whole. These studies show that the diversity of the endocrine component of the gut appears to be established by 10 wk of gestation and that gut activity is preceded by the development of a fully differentiated endocrine component, which may subserve or even initiate the onset of functional maturity.     

5-羟色胺2A受体基因多态性与糖尿病血管舒张功能的关联

用PCR-RFLP方法检测79例T2DM患者与84例健康正常人的5-HT2AR基因1438A/G多态性,用彩色多谱勒超声测定肱动脉反应性充血后以及含服硝酸甘油后血管内径的变化。T2DM组GG型者血清5-HT水平显著升高（P〈0.01）,NO水平显著降低（P〈0.05）,内皮依赖性血管舒张功能减弱（P〈0.05）。结果说明5-HT2AR基因1438位碱基纯合突变可能与T2DM血管舒张功能减弱有关。     

胆碱能受体和肾上腺素受体在肺部的分布、功能与相互作用

肺主要由交感和副交感双重神经支配，交感和副交感神经则分别依赖于其肾上腺素能和M受体的活性。肾上腺素能受体和M受体都是G蛋白耦联受体，具有相似的信号转导分子。这些受体在肺内广泛表达，不同物种表达不一。在正常气道功能的调节中受体表达的定位和亚型很重要。副交感纤维释放的乙酰胆碱激活气道平滑肌上的M3受体，引起支气管收缩。与此相反，位于副交感神经上的M2受体则抑制乙酰胆碱释放。β2肾上腺素受体表达于气道平滑肌，其激活可引起支气管扩张。自主神经中也存在肾上腺素受体，调节神经递质的释放。这些G蛋白耦联受体的交互作用及其下游信息传递能确保正常的气道功能。突触前后的M受体和肾上腺素能受体能调控气道张力，其任何失衡或受体的选择性阻断都会引起这种调控减弱，导致气道高反应性的发生。在设计、研发和使用治疗气道疾病药物时，必须考虑到肾上腺素受体和M受体的定位、功能及交互作用。     

Estradiol induces expression of 5-hydroxytryptamine (5-HT) 4, 5-HT5, and 5-HT6 receptor messenger ribonucleic acid in rat anterior pituitary cell aggregates and allows prolactin release via the 5-HT4 receptor

Serotonin [5-hydroxytryptamine (5-HT)] is known to control prolactin (PRL) release at a hypothalamic level, but a pituitary site of action remains poorly studied. The present study explores the acute effect of 5-HT on PRL release in rat anterior pituitary aggregate cell cultures, the influence of steroid and thyroid hormones, and the 5-HT receptor (5-HTR) subtype(s) involved. 5-HT elicited a prompt increase in basal PRL release, an effect strongly potentiated by estradiol (E(2)) in the culture medium (dose response 1-100 nm). In E(2) condition, the PRL response was not affected by the nonselective 5-HTR antagonists methysergide and methiothepin nor by 5-HTR1, 5-HTR2, 5-HTR3, 5-HTR6, and 5-HTR7/5 antagonists, but was fully blocked by the 5-HTR4 antagonist GR 113808. Among various agonist analogs, only the 5-HTR4 agonist cisapride and the 5-HTR2 agonist alpha-methyl-5-HT evoked PRL release. The effect of alpha-methyl-5-HT also required E(2) during culture and was abolished by GR 113808 but not by combined 5-HTR2A, B, and C blockade. In E(2)-treated aggregates, 5-HT caused a 5-fold increase in cAMP levels. The intact anterior pituitary expressed mRNA of all known members of the 5-HTR family. In aggregates, 5-HTR4, 5-HTR5, and 5-HTR6 mRNA expression required E(2) during culture. The effect of 5-HT on PRL release was not affected by blocking the serotonin transporter or the vesicular monoamine transporter. The present data suggest a widespread expression of 5-HTRs in the rat anterior pituitary, several of which are up-regulated by estrogen, and that, in the presence of estrogen, one of these, the 5-HTR4, mediates acute PRL release.     

Changes in muscarinic acetylcholine receptors in guinea-pig lung: Effects of aging,inhalation of an allergen,administration of drugs,and vagotomy

This study was undertaken to investigate the effects of aging; inhalation of Konjak-Maiko, a typical Japanese allergen; administration of various drugs; and unilateral cervical vagotomy on muscarinic acetylcholine receptors (MAchR) in guinea-pig lung. We assessed the characteristics of MAchR by determining the affinity and the density of MAchR using [³H]quinuclidinyl benzilate, a potent muscarinic antagonist. A significant decrease in the density of MAchR was observed at 6 months of age and this decrease became more prominent until 2 years of age. No significant change in the affinity of MAchR was noted through the experimental period. Inhalation of Konjak-Maiko (60 min/day, for 10 days) did not affect either the affinity or the density of the receptors. Administration of ipratropium bromide (0.1 mg/kg/day, for 10 days) or prednisolone acetate (2 mg/kg/day, for 7 days) did not affect the characteristics of the receptors. In contrast to these drugs, diisopropyl fluorophosphate, an irreversible acetylcholinesterase inhibitor, produced a 26% reduction in the density without affecting the affinity of the receptors. The right cervical vagotomy increased the density of MAchR in the right lung by 17% without affecting the affinity of MAchR. These results suggest that the density of MAchR in lung may be controlled by changes in the activity of the receptors.     

Molecular characterization and distribution of motilin family receptors in the human gastrointestinal tract

Background Motilin and ghrelin have been recognized as important endogenous regulators of gastrointestinal motor function in mammals, mediated respectively by the motilin receptor and by the closely related ghrelin receptor. The aims of this study were to explore the distribution of motilin and ghrelin receptors along the human gastrointestinal tract and to establish the molecular nature of the human motilin receptor. Methods Post mortem and surgical human tissue specimens with no hemorrhage, necrosis, or tumor were obtained from various parts of the gastrointestinal tract. We analyzed levels of expression of mRNA for motilin and ghrelin receptors and examined their molecular identities. Portions of some specimens were also studied by immunohistochemistry for expression of the motilin and ghrelin receptor. Results The long form of the motilin receptor, but not the short form, was expressed in all parts of the gastrointestinal tract, and expressed at higher levels in muscle than in mucosa. Motilin receptor immunoreactivity was present in muscle cells and the myenteric plexus, but not in mucosal or submucosal cells. In contrast, ghrelin receptor mRNA was expressed equally in all parts of the gastrointestinal tract, with similar levels of expression in mucosal and muscle layers. Conclusions Both the motilin and ghrelin receptors are expressed along the human gastrointestinal tract, but they have clearly distinct distributions in regard to both level and layer. The diffuse muscle expression of the motilin receptor, at both the levels of the gene and the protein product, along the entire gastrointestinal tract makes it a useful potential target for motilide drugs for dysmotility.     

贲门组织中多巴胺受体基因的分布与表达

目的探讨人贲门组织中多巴胺受体（DR）基因（D4mRNA,D5mRNA）的表达,揭示D4mRNA,D5mRNA在贲门组织中的抗溃疡机制。方法应用RT-PCR方法检测贲门组织中D4mRNA,D5mRNA的分布与表达。结果在食管环行肌、胃底环行肌、钩状纤维、套索纤维中D4mRNA分别为0．112±0．053、0．124±0．047、0．122±0．03、60．125±0．027,D5mRNA分别为0．116±0．023、0．118±0．035、0．121±0．026、0．116±0．078,两者均呈低表达（P〉0．05）。在贲门的食管黏膜和胃黏膜中,D4mRNA分别为0．416±0．082和0．423±0．094,D5mRNA分别为0．248±0．068和0．252±0．070,均呈高表达（P〉0．05）。两种黏膜与4条肌束中D4mRNA和D5mRNA的表达均存在显著性差异（P〈0．01）。结论在贲门肌肉组织和黏膜中D4mRNA和D5mRNA的表达不同,推测在贲门、胃黏膜中的D4mRNA、D5mRNA受体有着重要的抗溃疡作用。     

Role of Toll-like receptors in health and diseases of gastrointestinal tract

The human gastrointestinal (GI) tract is colonized by non-pathogenic commensal microflora and frequently exposed to many pathogenic organisms. For the maintenance of GI homeostasis, the host must discriminate between pathogenic and non-pathogenic organisms and initiate effective and appropriate immune and inflammatory responses. Mammalian toll-like receptors (TLRs) are members of the pattern-recognition receptor (PRR) family that plays a central role in the initiation of innate cellular immune responses and the subsequent adaptive immune responses to microbial pathogens. Recent studies have shown that gastrointestinal epithelial cells express almost all TLR subtypes characterized to date and that the expression and activation of TLRs in the GI tract are tightly and coordinately regulated. This review summarizes the current understanding of the crucial dual roles of TLRs in the development of host innate and adaptive immune responses to GI infections and the maintenance of the immune tolerance to commensal bacteria through down-regulation of surface expression of TLRs in intestinal epithelial cells.