Peptide YY (PYY) stimulates intrinsic enteric motor neurones in the rat small intestine

Summary The effects of peptide YY (PYY) on motor activity of the rat small intestine, were studied using isolated organ bath preparations arranged for recording muscle activity in the longitudinal axis. PYY induced TTX sensitive concentration-dependent contractions and/or relaxations of the longitudinal muscle in different regions of the small intestine. In the duodenum PYY evoked only cholinergic contractions (3 × 10^–8–3 × 10^–7 M). In the jejunum, PYY-evoked concentrations were non-cholinergic, and contractions were never seen in the ileum. In the jejunum and ileum, PYY-evoked relaxations (3 × 10^–3 × 10^–7 M) were unaffected by adrenoceptor or cholinergic receptor blockade, thus indicating that these relaxations were mediated by non-adrenergic, non-cholinergic (NANC) inhibitory nerves. Another action of PYY was to cause inhibition of field stimulation-evoked cholinergic concentrations. This inhibitory action was primarily due to antagonism of post-junctional, cholinergic receptor mediated events. In addition, PYY inhibited histamine evoked contractions of the longitudinal muscle. All regions of the small intestine could be desensitized to PYY. Such PYY-densensitization did not affect the ability of the longitudinal muscle to relax in response to applied ATP or papaverine. These results suggest PYY has potent concentration-dependent stimulatory actions at intrinsic inhibitory and excitatory motor nerves. In addition, PYY interferes with contractions but not relaxations of the longitudinal muscle.This study was funded by a development grant from the Medical Research Council of Canada Send offprint requests to A. Krantis at the above address     

T2毒素在原位灌流大鼠小肠中的吸收和代谢动力学

应用原位肠灌流标本研究了T2毒素在大鼠小肠中的吸收和代谢功力学,T2毒素对小肠标本进行血管灌流时消除半衰期为46.9 min.主要代谢产物HT2毒素的生成半衰期为12.9 min.当T2毒素由十二指肠注射后再进行灌流时,可同时发生吸收前和吸收后的小肠代谢转化,并主要以HT2,3’-OHHT2等代谢产物的形式吸收,此时毒素在小肠中的吸收和消除半衰期分别为33.0和25.6 min,实验结果表明肠道也是代谢消除T2毒素的主要器官,尤其在消化道中毒时,毒素将经历显著的肠道首过代谢.     

Kinetics of zinc transport in vitro in rat small intestine and colon: interaction with copper

The present study was planned to investigate the kinetic transport of zinc, in the intact intestine of the rat, in order to establish if more than one transporter is involved as well as the existence of a preferent sector in the cation uptake. Using an in vitro technique, the influx of zinc across the brush border membrane in three sectors of the small intestine (proximal, mid and distal) and in the colon of the rat was measured at six different concentrations (from 0.0007 to 11 mM). The kinetic study showed that intestinal transport of zinc occurs by a saturable process in the small intestine. The K_m value obtained in the proximal segment (10.78±4.40 mM) is clearly higher than those obtained in the mid and distal segments (1.94±0.39 and 3.04±0.44 mM, respectively). The same occurs with the J_max values. These results seem to indicate that more than one transporter may be implicated in zinc transport. In colon the most probable mechanism is non-saturable diffusion, the diffusive permeability, P, being 2.95·10⁻⁷±0.43·10⁻⁷ cm/h. The statistical comparison of the fluxes indicated that, on the whole, there is not a well defined preferent sector in zinc transport. Additionally, the influence of copper on zinc transport, in three sectors of the small intestine, has been evaluated quantifying the influx of zinc at 0.037 mM in the absence and presence of three different concentrations of copper. The results showed that copper significantly reduced the influx of zinc, in the three sectors studied, in a concentration-dependent manner.     

Formation of chlorpromazine sulphoxide and monodesmethylchlorpromazine by microsomes of small intestine

Summary The metabolism of chlorpromazine by microsomal preparations of the small intestine from guinea pig and rat was studied. ³⁵S-chlorpromazine was incubated with these preparations in Krebs-Ringer bicarbonate buffer at 37°C. Control values were obtained by performing the assay at 0°C. The metabolites were extracted with dichloroethane and separated by TLC. In incubations with intestinal microsomes from guinea pigs chlorpromazine sulphoxide and monodesmethyl chlorpromazine were identified as main metabolites. The apparent Michaelis constant for sulphoxidation of chlorpromazine is approximately 20–30 M and for N-demethylation in the range of 30–100 M.Using microsomal preparations from rat intestine, however, noteworthy formation of chlorpromazine metabolites could not be found. This observation can be explained by the fact that the cytochrome P₄₅₀ content of rat intestinal microsomes was extremely low compared with that determined in guinea pig microsomes.Preliminary reports of this study were presented at the 17th Spring Meeting of the Deutsche Pharmakologische Gesellschaft, Mainz, March 23, 1976 (Knoll et al., 1976) and at the 5th International Symposium on Medicinal Chemistry, Paris, July 19, 1976     

替硝唑大鼠小肠吸收的研究

目的 :研究替硝唑在大鼠小肠中的吸收情况。方法 :以pH8的磷酸盐缓冲液为溶剂 ,采用倍率系数法在 2 90 ,318nm处测定替硝唑 ;以 0 .1mol·L-1氢氧化钠为溶剂 ,以双波长法在 5 5 8,5 70nm处测定酚红。结果 :药物吸收符合一级动力学方程 ,平均吸收半衰期为 (2 .34± 0 .4)h ,最终吸收程度为 5 7.5 7%。结论 :本方法操作简便 ,结果准确可靠。     

Characterization of WR-1065 absorption in the rat small intestine

A circulating in situ rat small intestine absorption model was used to study the lumenal metabolism and absorption of [14C]WR-1065. WR-1065 was found to be more tissue reactive and toxic than its phosphorylated form, ethiofos, at equimolar perfusate concentrations. The disappearance profiles of the radiolabeled drug and free WR-1065 indicate that WR-1065 is extensively metabolized in the intestinal lumen prior to absorption. Coadministration of disodium ethylenediaminetetraacetic acid enhances the absorption of the free thiol although not to the same extent as seen with ethiofos. Perfusion of WR-1065 in citrate buffer decreased lumenal degradation of the drug but resulted in decreased absorption. The total material converted to WR-1065 portal blood profiles following ethiofos and WR-1065 perfusion were altered possibly due to distribution and metabolism differences. This study coupled with earlier work completed on ethiofos have increased our understanding of the significant barriers to absorption observed following oral administration of these compounds.     

Effects of pharmaceutical excipients on membrane permeability in rat small intestine

Pharmaceutical excipients should not disturb the effects of drug therapy. In recent years, however, it has been reported that excipients induce some changes to the tight junction (TJ) and P-glycoprotein (P-gp), which can affect drug disposition. In this study, we examined the effects of 20 common pharmaceutical excipients from different classes on mucosal membrane and the differences of such effects among regions of the small intestine. We used the in vitro sac method in rat jejunum and ileum to study the effects of excipients on the membrane permeation of 5(6)-carboxyfluorescein (5-CF). 5-CF was used as a model of water-soluble compounds. In some dosage conditions of methyl-β-cyclodextrin, the membrane permeability of 5-CF was significantly increased in the jejunum, but such change was not observed in the ileum. Similarly, in the cases of sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose and croscarmellose sodium, the membrane permeability of 5-CF was significantly increased in the jejunum, but no change was observed in the ileum. On the other hand, in both the jejunum and the ileum, the membrane permeation of 5-CF was decreased with 0.02% (w/v) hydroxypropyl cellulose, but significantly increased with it at 0.20% (w/v). It was shown that excipients affected the membrane permeability of water-soluble compounds via the paracellular route, and these effects on absorption differed among regions of the small intestine. Moreover, in the case of 20 excipients, not only an increase in membrane permeability but also a decrease was observed. Therefore, it was suggested that a more effective formulation could be designed by changing the combination of excipients.     

Protective effects of proton pump inhibitors against indomethacin-induced lesions in the rat small intestine

Proton pump inhibitors (PPIs) have been shown to be effective in preventing gastric and duodenal ulcers in high-risk patients taking nonsteroidal anti-inflammatory drugs (NSAIDs); by contrast, scarce information is available concerning the effects of PPIs on intestinal damage induced by NSAIDs in humans or in experimental animals. We examined the effects of lansoprazole and omeprazole on the intestinal injury induced by indomethacin in the conscious rat. PPIs were administered by the intragastric route at 30, 60 and 90 μmol/kg, 12 h and 30 min before and 6 h after indomethacin treatment. The effects of omeprazole and lansoprazole were evaluated on: (1) macroscopic and histologic damage; (2) mucosal polymorphonuclear cell infiltration; (3) oxidative tissue damage and (4) bacterial translocation from lumen into the intestinal mucosa. Lansoprazole and omeprazole (at 90 μmol/kg) significantly decreased (P<0.01) the macroscopic and histologic damage induced by indomethacin in the rat small intestine. Furthermore, both drugs greatly reduced (P<0.01) the associated increases in myeloperoxidase levels and lipid peroxidation induced by indomethacin, whereas they only moderately affected (P<0.05) the translocation of enterobacteria from lumen into the intestinal mucosa. These data demonstrate that omeprazole and lansoprazole can protect the small intestine from the damage induced by indomethacin in the conscious rat. The intestinal protection, possibly related to antioxidant and anti-inflammatory properties of these drugs, may suggest new therapeutic uses of PPIs in intestinal inflammatory diseases.     

原发性小肠淋巴瘤的诊断和外科治疗

目的探讨原发性小肠淋巴瘤（primary small intestine lymphoma,PSIL）的临床表现、CT特点,提出临床策略。方法回顾性分析2003年1月至2007年7月收治的15例PSIL的患者临床资料。结果15例患者中男9例,女6例,平均51.6岁。PSIL常见的临床表现为：腹痛、腹部肿物、肠梗阻、消化道出血及消瘦;血CEA、CA199均正常。术前15例均行CT检查,CT初诊检出肿瘤15例,定性诊断准确12例;15例中,11例行消化道钡餐检查,4例检出病变,仅1例提示淋巴瘤可能。15例患者均行手术治疗,无围手术期死亡,术后病理结果为PSIL,术后1年生存率为85.7%。结论PSIL无特异性临床症状,消化道钡餐诊断率低,CT扫描具有一定的特征,结合临床具有较高的诊断价值。早期诊断对改善PSIL的预后十分重要,积极手术切除和辅助化疗可以获得良好效果。     

Absorption and metabolism of acetaminophen by the in situ perfused rat small intestine preparation

The in situ perfused rat small intestine preparation was used to examine the extents of segmental absorption and metabolism of acetaminophen (A). Additionally, the preparation was employed to investigate any intestinal excretion of A and its conjugates from the circulation to the intestinal lumen. In this preparation, blood perfusate (300 ml) recirculated the intestinal preparation at 7.5 ml/min, entering via the superior mesenteric artery and returned to the reservoir via the portal vein. To demonstrate the extent of segmental absorption, metabolism, and excretion by different segments of the intestine, tracer doses of 3H-A (0.41 to 0.55 mumol in 0.3 ml of saline) were administered into the (a) entire intestine; (b) segments (first, second, and third) of one-third the length of the intestine, by instillation of the dose into the lumens of the segments; and (c) reservoir of perfusate. Exudates of luminal fluid from the injected segment and segments not exposed to drug were monitored for A and its conjugates during the experiment and at the end of 2 hr. Absorption of A was usually complete by 60 min; the extent of absorption of A at the end of 2 hr by the entire length of the intestine and by its three (first, second, and third) individual segments were 71.7 +/- 2.6, 50.5 +/- 4.0, 73.9 +/- 2.1, and 58.8 +/- 6.1% of dose (mean +/- SE), respectively. At the end of 2 hr, the total amount of acetaminophen glucuronide in perfusate and luminal fluid accounted for 3.1-5.5% and 0.14-0.1% of dose, respectively, among these preparations; acetaminophen sulfate was present only as a small percentage of dose in the lumen. Glucuronidation activity, when expressed as a percentage of the absorbed dose, was fairly constant for the entire intestine and first and second segments (8%) but decreased slightly for the third segment (7%). When A was present in blood perfusing the intestine, no metabolite was detected in perfusate or luminal fluid. Instead, unchanged A was excreted (5.6% dose) into the lumen. The effect of dose and vehicle on the extents of absorption and metabolism of A in the preparation was investigated by the instillation of different doses of A (0.16, 99.2, and 396.9 mumol in 0.3 ml of polyethene glycol 400) into the entire intestine at the duodenum.(ABSTRACT TRUNCATED AT 400 WORDS)     

Characterization of ethiofos absorption in the rat small intestine.

The absorption characteristics of ethiofos were studied using the rat in situ intestine circulating perfusion technique. Slow absorption kinetics were observed for ethiofos with varying rates of absorption and metabolism/degradation in situ as a function of buffer and absorption enhancers. In most cases less than 10 per cent of the radiolabeled compound is lost from the circulating perfusate in 90 min. In addition, over the same time period greater than 40 per cent of the intact parent compound was lost by degradation. Much of the difference can be accounted for in the formation of the free thiol metabolite. WR-1065, suggesting ester hydrolysis or metabolic activity. Good stability was observed in all perfusate systems ex vivo indicating that the degradation occurs in situ. The disodium salt of ethylenediaminetetraacetic acid (EDTA) was shown to be an effective absorption enhancer of ethiofos. The enhancement of intestinal absorption by EDTA was dose-dependent resulting in a 20-fold increase in blood levels of ethiofos in the portal blood. Follow-up studies in the rhesus monkey confirm this observation. Salicylate and dimethylsulfoxide (DMSO) also resulted in absorption enhancement although to a lesser degree than that seen after EDTA treatment. Addition of several alkaline phosphatase inhibitors did not significantly improve absorption of ethiofos in the rat small intestine. Proposed mechanism(s) for intestinal absorption and absorption enhancement of ethiofos are discussed.     

Calcium transport in rat small intestine in vitro and in vivo

Summary Intestinal calcium (Ca) transport was studied in the rat jejunum by the in vitro perfusion technique of Fisher and Parsons and in the tied loop in vivo. Mucosal uptake and absorption of Ca was examined under the following conditions: rising intraluminal Ca-concentrations (0.5–128 meq/l); inhibition of energy dependent metabolism (2,4-dinitrophenol, N₂, low temperature); net water flow, out of or into the intestinal lumen; addition of strontium (Sr); pretreatment with low Ca-diet and with 6-methyl-prednisolone.The concentration-dependent Ca absorption curve rose steeply at low Ca-concentrations but changed to a slowly rising straight line above 16 meq/l Ca⁺⁺. In contrast, Ca uptake into the intestinal wall was directly related to Ca concentration, was linear from the beginning and paralleled the straight part of the absorption curve.Ca absorption was decreased by inhibition of energy dependent metabolism, addition of Sr and pretreatment with prednisolone. Pretreatment with low Ca diet increased Ca absorption and direction of net water flow (solvent drag) had no effect on it.Mucosal uptake of Ca was similar to Ca absorption except that metabolic inhibition increased Ca uptake but decreased Ca absorption.These results are compatible with the concept of a passive mucosal uptake and of an active absorption of Ca at low intraluminal Ca concentrations with additional passive component at high Ca concentrations.Supported by the Deutsche Forschungsgemeinschaft.     

木香超临界水提液对豚鼠离体肠和小鼠肠推动的作用研究

目的观察木香超临界后水提液对小鼠小肠推进运动和豚鼠离体回肠平滑肌收缩的影响。方法以正常、新斯的明负荷和肾上腺素负荷为研究模型,采用碳末推动法和离体肠实验方法。结果木香Ⅰ组、木香Ⅱ组和木香Ⅲ组碳末推进率均高于正常对照组,差异有统计学意义（P〈0.05和P〈0.01）。肾上腺素组碳末推进率明显低于正常对照组,差异有统计学意义（P〈0.01）;木香Ⅰ组、木香Ⅱ组和木香Ⅲ组碳末推进率明显高于肾上腺素组,差异有统计学意义（P〈0.01）。新斯的明组碳末推进率明显高于正常对照组,差异有统计学意义（P〈0.01）;木香Ⅰ组、木香Ⅱ组和木香Ⅲ组碳末推进率均低于新斯的明组,差异有统计学意义（P〈0.05和P〈0.01）。给药后豚鼠自发收缩活动频率和振幅均高于给药前,差异有统计学意义（P〈0.05和P〈0·01）,且振幅随着木香超临界水提液剂量的增加而增大。结论木香超临界水提液有促进小鼠小肠运动的作用,对肾上腺素所致小鼠小肠推进抑制有显著的促进作用,对新斯的明所致的小鼠小肠推进亢进有拮抗作用,对豚鼠离体回肠自发活动有兴奋作用。     

大鼠在体肠回流法研究环孢素纳米脂质体的吸收行为

目的 :研究环孢素纳米脂质体在大鼠小肠的吸收行为。方法 :利用旋转薄膜 超声法制备环孢素纳米脂质体。采用大鼠在体回流法研究脂质体在大鼠小肠的吸收行为。结果 :当脂质体中药物浓度从 1g·L- 1逐渐增至 2 .4 g·L- 1时 ,累积吸收量从(0 .0 2 5±s 0 .0 2 4 )mg·cm- 2 增至 (0 .0 6 7± 0 .0 0 7)mg·cm- 2 ,但当浓度继续增至 7.5 g·L- 1时 ,累积吸收量缓慢增至 (0 .0 85± 0 .0 11)mg·cm- 2 ,呈现饱和现象。使用载体竞争剂和降低Na+浓度 ,对累积吸收量没有显著影响 (P >0 .0 5 ) ;应用能量抑制剂 (二硝基苯酚 )和P 糖蛋白抑制剂 (维拉帕米 )均使累积吸收量从 (0 .0 90± 0 .0 2 0 )mg·cm- 2 增至 (0 .15± 0 .0 3)mg·cm- 2 ,有显著促进作用 (P <0 .0 1)。结论 :环孢素纳米脂质体在大鼠小肠的吸收可能通过淋巴系统吞噬作用进行     

运用单向灌流模型研究抗糖尿病创新药物西格列松大鼠在体肠的吸收

目的研究西格列松大鼠在体各肠段的吸收情况。方法运用单向灌流模型、采用高效液相色谱法对药物的质量浓度进行检测来研究药物在不同质量浓度、不同pH值下的吸收。结果西格列松在各肠段的表观吸收系数有显著性差异(P<0.05);不同质量浓度药物的表观吸收系数无显著性差异(P>0.05);不同pH值条件下药物的表观吸收系数有显著性差异(P<0.05)。结论西格列松的吸收不受药物质量浓度的影响,药物在较大质量浓度下(100 mg.L-1)也无饱和现象,在肠黏膜的转运为被动扩散过程;药物吸收有pH值依赖性,pH值越低吸收越好。     

原发性小肠恶性肿瘤误诊原因分析

目的探讨原发性小肠恶性肿瘤的临床特点及误诊原因。方法回顾性分析1998年以来我院外科诊治的26例原发性小肠恶性肿瘤患者的临床特点及诊断、治疗。结果肿瘤位于十二指肠3例（11．5％），空肠9例（34．6％），回肠14例（53．9％）；病类型腺癌3例，印戎细胞癌2例，平滑肌肉瘤18例，恶性淋巴瘤3例。常见症状为：腹痛、腹部肿块、不明原因肠梗阻和消化道出血。术前误诊或不能明确诊断18例（69．2％）。26例均手术治疗，术后死亡3例。结论原发性小肠恶性肿瘤少见，缺乏特异性症状和体征，误诊率高，对诊断不明确的患者应综合各项检查，必要时尽早行剖腹探查术。治疗应以手术切除为主。     

腹部闭合性损伤合并单纯小肠破裂130例诊治体会

目的：提高单纯性小肠破裂的诊断水平。方法：总结作者诊治过的腹部闭合性损伤合并单纯性小肠破裂130例临床经验。结果：术前确诊为单纯性小肠破裂者30例，其余100例均在手术探查中确诊。破裂口大小为0.5-3cm，治愈率为92.3％，死亡率为7.7％。结论：掌握单纯性小肠破裂的特点，早期诊断，掌握好探查指征，早期手术，可提高治愈率，减少死亡率。     

Release of cholecystokinin-immunoreactivity into the vascular bed of the guinea-pig small intestine during peristalsis

Summary The release of cholecystokinin-immunoreactivity (CCK-IR) into the venous effluate of the isolated and vascularly perfused guinea-pig small intestine was measured. Raising the intraluminal pressure by 5 mbar for 8 min initiated peristalsis and was associated with an increased release of CCK-IR. The ganglion stimulant dimethylphenylpiperazinium failed to alter the release of CCK-IR. The results are discussed in the light of a possible involvement of CCK-containing neurones in intestinal peristalsis.     

Protective effects of nitroglycerin-induced preconditioning mediated by calcitonin gene-related peptide in rat small intestine

Previous studies of myocardium have shown that ischemic preconditioning could be mimicked by nitroglycerin through stimulating the release of calcitonin gene-related peptide (CGRP). The present study examined whether nitroglycerin could also provide a preconditioning stimulus in the peripheral vascular bed (the anse intestinalis of rat), and whether endogenous CGRP is involved in this process. The model of in situ perfusion was prepared with rat small intestine. One hour of ischemia and 15 min of reperfusion caused a significant impairment of intestinal morphology and an increase in the release of both lactate dehydrogenase and malondialdehyde. Pretreatment with nitroglycerin, 10⁻⁷, 3×10⁻⁷, 10⁻⁶ M for 5 min produced a significant improvement of intestinal tissue morphology and a decrease in the release of both lactate dehydrogenase and malondialdehyde. However, the protection afforded by nitroglycerin was abolished by CGRP-(8-37), a selective CGRP acceptor antagonist. Pretreatment with capsaicin, which specifically depletes the transmitter content of sensory nerves, also abolished the protection by nitroglycerin. In addition, the content of CGRP-like immunoreactivity in the effluent was increased during nitroglycerin perfusion. On the other hand, the results from the in vivo experiment showed that nitroglycerin (i.v. 0.13 mg/kg) injected 5 min before prolonged ischemia could provide significant protection against the injury caused by 30-min ischemia and 1-h reperfusion in the rat small intestine, but would also cause a significant increase in the levels of CGRP in the plasma. All these findings suggest that nitroglycerin-induced preconditioning is related to stimulation of CGRP release in the rat small intestine.     

大鼠在体吸收连翘苷的机理研究

目的研究连翘苷在大鼠消化道内的吸收机理。方法采用HPLC测定大鼠在体实验中连翘苷的含量,分别进行大鼠原位胃吸收、结肠、小肠全肠段、分肠段(十二指肠、空肠、回肠)合用吸收促进剂(SDS、牛胆盐、冰片、卡波姆)的连翘苷吸收机理研究。结果连翘苷各时间点含量几乎不变。结论口服连翘苷在大鼠消化道内并无吸收。