5-羟色胺在胃机械感觉过敏中的作用

目的探讨5羟色胺(5HT)在胃感觉过敏中的作用。方法运用RT PCR半定量方法分别测定23例功能性消化不良(FD)患者(感觉正常组8例,感觉过敏组15例)和15名正常人近端胃黏膜组织中的5羟色胺酸脱羧酶(5HTPDC)、5HT转运体及5HT1A受体mRNA的表达情况。结果感觉过敏FD患者近端胃黏膜中5HTPDC和5HT1A受体mRNA的表达明显高于感觉正常组和对照组(1.275±0.136比0.730±0.106比0.710±0.142,P<0.05;1.402±0.140比0.834±0.094比0.816±0.047,P<0.01),感觉正常FD患者和对照组之间差异无统计学意义(P>0.05)。5HT转运体mRNA表达在三组间差异无统计学意义(0.895±0.160比0.833±0.184比0.886±0.257,P>0.05)。结论胃感觉过敏可能与近端胃黏膜中5HT合成增加及5HT1A受体表达增高有关。     

Functions of peripheral 5-hydroxytryptamine receptors, especially 5-hydroxytryptamine4 receptor, in gastrointestinal motility

The multiple 5-hydroxytryptamine (5-HT, serotonin) receptor subtypes are distinguished. In this article, we described mainly the 5-HT₄ receptor of four subtypes of functional 5-HT receptors, 5-HT₁, 5-HT₂, 5-HT₃, and 5-HT₄, recognized in the gastrointestinal tract. In-vivo microdialysis experiments determined that activation of the 5-HT₄ receptor stimulated intestinal motor activity associated with a local increase in acetylcholine (ACh) release from the intestinal cholinergic neurons in the whole body of dogs. The 5-HT₄ receptor-mediated response of ACh release in the antral, corporal, and fundic strips isolated from guinea pig stomach corresponds to the presence of 5-HT₄ receptor in the myenteric plexus. In-vitro receptor autoradiograms of the stomach and colon indicate that the distribution of 5-HT₄ receptors in human tissues is similar to that in the guinea pig, although density of 5-HT₄ receptors in the myenteric plexus of human tissues is lower than that in guinea pig tissues. The 5-HT₄ receptors located in the myenteric plexus may participate in gastrointestinal motility, and thus the 5-HT₄ agonists and antagonists may be available for treatment of dysfunction of gastrointestinal motility. Received: November 22, 1999 / Accepted: March 24, 2000     

Role of 5-hydroxytryptamine in endotoxin-induced respiratory failure of pigs

The porcine pulmonary vascular and airway responses to exogenous 5-hydroxytryptamine (5-HT), norepinephrine, prostaglandin F2 alpha (PGF2 alpha), and angiotensin II were evaluated before and after ketanserin, a 5-HT2 receptor antagonist. Ketanserin blocked the 5-HT-induced increases in airway and pulmonary artery pressures, whereas the increases in airway and pulmonary artery pressures caused by norepinephrine, PGF2 alpha, or angiotensin II were not significantly modified by ketanserin, indicating a relatively high degree of specificity for 5-HT2 receptors. The role of endogenous 5-HT in mediating endotoxin-induced respiratory failure was evaluated by treating pigs with ketanserin. Escherichia coli endotoxin (055-B5) was infused intravenously into anesthetized 10- to 14-wk-old pigs at 5 micrograms/kg the first h, followed by 2 micrograms/kg/h for 3.5 h. Ketanserin was infused at 300 micrograms/kg before endotoxin plus 67 micrograms/kg/h during endotoxemia. During Phase 1 (i.e., 0 to 2 h), the endotoxin-induced increases in pulmonary vascular resistance and room air alveolar-arterial oxygen difference and the decreased cardiac index and lung dynamic compliance were not significantly modified by ketanserin. However, during Phase 2 (i.e., 2 to 4.5 h) endotoxemia, ketanserin attenuated the endotoxin-induced pulmonary hypertension and the increases in pulmonary vascular resistance, alveolar dead space ventilation, and alveolar-arterial oxygen difference. Ketanserin also attenuated the Phase 2 bronchoconstriction and the decreased cardiac index, but did not modify the endotoxin-induced increase in alveolar-capillary permeability. These results indicate that 5-HT plays little or no role in mediating the early (i.e., less than 2 h) response to endotoxin.(ABSTRACT TRUNCATED AT 250 WORDS)     

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

     

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.     

大鼠孤束核在五羟色胺介导的胰腺外分泌中的作用

目的:探讨在五羟色胺(5-HT)介导的胰腺外分泌中,大鼠孤束核所起的作用,并进一步阐明与这些作用相关的神经物质. 方法:在十二指肠内恒流灌注0.86 mol/L NaCl、10-4mol/L 5-HT,然后对各处理组中不同的孤束核切面(孤束核嘴侧平面、中间平面、尾侧平面)进行c-Fos免疫组化、c-Fos- NK1-R双重免疫组化染色方法(免疫荧光-免疫酶学),同时计数其中c-Fos阳性细胞数,并行定量分析;另外每15min 收集胆胰混合液一次,测定胰液蛋白含量. 结果:在孤束核各平面,5-HT组、0.86 mol/L NaCl组内c-Fos阳性神经元数量均高于假手术组(P<0.01),且在孤束核尾侧平面5-HT组(22.00±1.80)明显高于0.86 mol/L NaCl组(18.5±1.7)(P<0.01),另外两组在孤束核内的c- Fos阳性表达密集区域内均有NK1-R表达,而假手术组则未见c-Fos与NK1-R很好的重叠.胰蛋白测定方面:与假手术组胰液蛋白相比,5-HT组以及0.86 mol/L NaCl组在实验进行60 min(灌注后15 min)至135 min均有明显升高, 有统计学意义(P<0.01);且5-HT组(29.6±1.4 mg/15 min) 与0.86 mol/L NaCl组(18.1±2.4 mg/15 min)相比较,胰蛋白含量增加更为明显(P<0.01). 结论:在5-HT介导的胰液蛋白分泌中,大鼠孤束核起着感知及整理信息的作用,且这种作用的发挥与P物质受体有关.     

Role of 5-hydroxytryptamine in intestinal water and electrolyte movement during gut anaphylaxis.

Exposure of sensitised intestine to specific allergen is known to produce appreciable reduction in water and electrolyte absorption. The mediators participating in this process have not been fully characterised. The effects of the 5-hydroxytryptamine2 (5-HT2) and 5-HT3 receptor antagonists, ketanserin and granisetron, respectively, on water movement during intestinal anaphylaxis were studied. Hooded Lister rats (120-150 g) were sensitised to ovalbumen and 14 days later, intestinal water and electrolyte movement was assessed at 10 minute intervals by in situ jejunal perfusion with a plasma electrolyte solution (PES) or PES containing 20 mg/l ovalbumen. Within 20 minutes of exposure to PES+ovalbumen, net water secretion that could be completely prevented by the mast cell stabilising agent doxantrazole occurred compared with absorption with PES alone (median -20 microliters/min/g (interquartile range -43 to -5), n = 11), v (107 (86 to 113), n = 10; p < 0.01). Pre-treatment with subcutaneous ketanserin 200 micrograms/kg (n = 7) or granisetron 300 micrograms/kg (n = 8) partially inhibited the secretory response to PES+ovalbumen (18 (11 to 48) and 13 (6 to 32) respectively; both p < 0.01 compared with PES+ovalbumen control). After 40 minutes perfusion with PES+ovalbumen, the changes in water movement were less pronounced 24 (-3 to 43) and neither ketanserin or granisetron had any effect (ketanserin: 48 (28 to 87), granisetron: 41 (32 to 83); NS). In all experiments, sodium and chloride movement paralleled that of water. Thus, the profound water secretion that occurs in the early stages of intestinal anaphylaxis is partly 5-HT dependent because it can be reversed by 5-HT2 and 5-HT3 receptor antagonists. Other mediators must also be involved, especially in the late phase of anaphylaxis.     

Polymorphism of thymidylate synthase gene and chemosensitivity of 5‐fluorouracil regimen in metastatic gastrointestinal cancer

OBJECTIVE: To explore the polymorphism of thymidylate synthase (TS) gene and chemosensitivity of a 5‐fluorouracil (5‐FU)‐containing regimen in metastatic colorectal and gastric cancer. METHODS: Sixty‐eight patients with metastatic gastric or colorectal cancer were included in this study. Doublets or triplets of 28 base pairs (bp) in the 5‐untranslated region (UTR) of TS gene promoter were detected by polymerase chain reaction (PCR) analysis. Fragments of polymorphic products, 2R/2R, 2R/3R and 3R/3R were detected by the Agilent BioAnalyzer chip‐lab system. All patients were followed up until the censoring date. A χ2 test was used to analyze the polymorphism. A Kaplan–Meier curve and a log‐rank test were used to determine disease progression and overall survival. RESULTS: Among 68 patients, polymorphism expressions were 4.4% in 2R/2R, 29.4% in 2R/3R and 66.2% in 3R/3R, and clinical responses were 33.3%, 73.3% and 47.6%, respectively (2R/3R versus 3R/3R, P= 0.058). In the 64 evaluable cases, the median time to progression (TTP) was 4 months and the TTP were 3 months in 2R/2R, 6 months in 2R/3R and 4 months in 3R/3R, separately (log‐rank test, P= 0.0316). Response rates to the 5‐FU regimen were also better in the 2R/3R group than in the 3R/3R group both in metastatic colorectal cancer and advanced gastric cancer. CONCLUSION: Our study suggested that polymorphism of 3R/3R was more common in Chinese gastrointestinal cancer patients. Patients with a TS polymorphism expressed as 2R/3R might be more sensitive to 5‐FU regimen than those with a polymorphism expressed as 3R/3R.     

Circulating 5-hydroxytryptamine concentrations in preterm newborns

Alterations in circulating 5-hydroxytryptamine (5-HT) concentrations play a role in the pathophysiology of respiratory failure in adults. We undertook a study to develop a micromethod and measure circulating free 5-HT concentrations in preterm newborns with and without respiratory distress. Forty-six samples of platelet-poor plasma were obtained from 29 preterm newborns with varying degrees of respiratory distress. Samples were taken on days 2-3 and 6-7 of life. For measuring 5-HT concentrations we used a precolumn sample enhancement technique followed by ion exchange HPLC with electrochemical detection. The assay allowed detection of extremely small (50 pg) amounts of 5-HT from small (0.2 ml) amounts of blood. The mean 5-HT concentration on days 2-3 was 1.77 +/-0.74 ng/ml (mean +/- 95% confidence limits) and on days 6-7 was 0.69 +/- 0.23 ng/ml. This represented a significant fall in 5-HT concentrations (P = 0.01). All of 16 paired serial samples fell with time (P = 0.006). We conclude that platelet-poor plasma 5-HT concentrations in premature newborns are low, that there is a significant decline in these values over the first week of life, and that, in contrast with adults, the presence of respiratory failure is not associated with increased free 5-HT concentrations. The low 5-HT concentrations seen in newborns may reflect the ability to increase pulmonary uptake.     

P-glycoprotein expression and chemosensitivity in highly purified fresh human gastrointestinal cancer cells

BACKGROUND/AIMS: Colorectal cancer is one of the tumors most refractory to treatment by chemotherapy. One of the major problems associated with cancer chemotherapy is drug-resistance of tumor cells, and resistance to doxorubicin (DOX) is mainly due to the effect of P-glycoprotein. We have tried to prove the correlation between P-glycoprotein expression and DOX-sensitivity in highly purified fresh human colorectal cancer and, moreover, to prove the differentiation of P-glycoprotein expression between the different kinds of cancers, including gastric cancer. METHODOLOGY: The present study was designed to quantify P-glycoprotein expression by flow cytometry, and DOX-sensitivity by MTT assay in highly purified fresh human tumor cells obtained from 29 cancer patients including 13 colorectal cancers and 16 gastric cancers. RESULTS: DOX-sensitivity decreased in proportion to P-glycoprotein expression in colorectal cancer. P-glycoprotein expression in colorectal cancer was higher than that in gastric cancer. Particularly, P-glycoprotein expression in colorectal cancer in the DOX low-sensitivity group was higher than in the DOX high-sensitivity group. CONCLUSIONS: The chemotherapeutic management of patients with colorectal cancer might be more effective if we can circumvent the effect of P-glycoprotein.     

Role of vitamins in gastrointestinal diseases

A tremendous amount of data from research was published over the past decades concerning the roles of different vitamins in various gastrointestinal diseases.For instance,most vitamins showed an inverse relationship with the risk of colorectal carcinoma as well as other malignancies like gastric and esophageal cancer in observational trials,however interventional trials failed to prove a clear beneficial preventive role.On the other hand,more solid evidence was obtained from high quality studies for a role of certain vitamins in specific entities.Examples for this include the therapeutic role of vitamin E in patients with nonalcoholic steatohepatitis,the additive role of vitamins B12 and D to the standard therapy of chronic hepatitis C virus,the role of vitamin C in reducing the risk of gallstones,the positive outcome with vitamin B12 in patients with aphthous stomatitis,and the beneficial effect of vitamin D and B1 in patients with inflammatory bowel disease.Other potential uses are yet to be elaborated,like those on celiac disease,pancreatic cancer,pancreatitis,cholestasis and other potential fields.Data from several ongoing interventional trials are expected to add to the current knowledge over the coming few years.Given that vitamin supplementation is psychologically accepted by patients as a natural compound with relative safety and low cost,their use should be encouraged in the fields where positive data are available.     

Aggregation of duck thrombocytes by 5-hydroxytryptamine

The nucleated thrombocytes of Aylesbury ducks are aggregated by relatively low concentrations of 5-hydroxytryptamine (5-HT, serotonin) and by a saline suspension of duck tendons. Aggregation by 5-HT is dose dependent and reversible at low 5-HT concentrations, but irreversible at high concentrations. Methysergide, a 5-HT antagonist, inhibits the action of 5-HT and tendon suspension. Aggregation by 5-HT is also inhibited by adenosine, 2-chloroadenosine, prostaglandin E₁, compound RA233 and EGTA.     

5-羟色胺信号系统与肠易激综合征

5-羟色胺(5-HT)是参与调节胃肠道运动和分泌功能的重要神经递质,5-HT信号系统异常可导致胃肠动力及分泌功能异常、内脏高敏感性,与IBS的病理生理改变相关。此文旨在探讨5-HT信号系统在IBS肠道运动和感觉的调节、脑肠轴异常、精神症状、神经保护等方面的作用。