Large Intestinal Transit Research Articles

Effect of ceftriaxone on intestinal transit time.

Ceftriaxone reduces gallbladder and ileal contractility. Many studies have shown that ceftriaxone causes biliary sludge and pseudolithiasis. However, its effect on intestinal transit time has not been investigated. This study aimed to investigate the effect of ceftriaxone on intestinal transit time. Sixteen rats were examined in two groups: The study group (group A, n= 8) was administered with 100 mg/kg ceftriaxone intramuscularly for 7days. The control group (group B, n= 8) was administered with intramuscular distilled water for 7days. On the seventh day, a mixture of 2ml barium and saline was given orally to both groups. Barium transit was evaluated using serial digital X-ray images. The stomach was full and the transition into the small intestine loop was observed in all rats at 45 min in both groups. At the 2nd hour, colonic transition was observed in two rats in group A (2/8, 25%) and in seven rats in group B (7/8, 87.5%). At the 4th hour, five (62.5%) rats in group A had transverse colonic transition, and all rats in group B (8/8, 100%) had transverse and/or left colonic transition. At the 6th hour, no rat in group A had rectal transition, and all rats in group B (8/8, 100%) had complete passage of colonic contrast material. Ceftriaxone significantly prolongs the small intestine transit time, large intestine transit time, and total intestinal transit times.

Contribution of Serotonin 3A Receptor to Motor Function and Its Expression in the Gastrointestinal Tract

Introduction: The serotonin 3A receptor (5-HT_3AR) is involved in vomiting and gastrointestinal motility. However, it is not well understood the expression pattern of 5-HT_3AR in the gut immunohistochemically and how much contribution of 5-HT_3AR to upper or lower intestinal motility. Objectives: We investigated the contribution of 5-HT_3AR to gastrointestinal motor function by using 5-HT_3AR KO mice and sought to identify 5-HT_3AR-expressing cells via immunohistochemical staining using 5-HT_3AR-GFP reporter mice. Methods: The expression of 5-HT_3AR was measured in each section of the gut through real-time PCR. The motor function of the stomach and colon was assessed via the ¹³C-octanoic acid breath test and colonic bead expulsion test, respectively, using 5-HT_3AR KO mice. 5-HT_3AR-expressing cells in the muscle layer of the gut were identified by immunohistochemical staining using 5-HT_3AR-GFP reporter mice. Results: 5-HT_3AR was expressed throughout the digestive tract, and 5-HT_3AR expression in the stomach and lower digestive tract was higher than that in the other sections. Motor function in the stomach and colon was lower in 5-HT_3AR KO mice than in WT mice. As a result of immunohistochemical staining using GFP reporter mice, cholinergic neurons and PDGFRα⁺ cells were shown to express 5-HT_3AR. In contrast, 5-HT_3AR indicated by GFP fluorescence was rarely detected in ICC and smooth muscle cells. Conclusions: These results show that 5-HT_3AR is highly expressed in the stomach and large intestine and that the activation of 5-HT_3AR accelerates gastric emptying and large intestine transit. Additionally, 5-HT_3AR is highly expressed in cholinergic neurons and some interstitial cells, such as PDGFRα⁺ cells.

Effects of acupuncture at Pericardium-6 and Stomach-36 on nausea, sedation and gastrointestinal motility in healthy dogs administered intravenous lidocaine infusions.

The objectives of this study were to assess gastrointestinal transit times, sedation, and signs of nausea associated with intravenous lidocaine infusions in dogs following targeted acupuncture at Pericardium-6 (PC6) and Stomach-36 (ST36). In a randomized, blind crossover design, 6 healthy, adult Beagles were fed thirty 1.5 mm barium-impregnated polyethylene spheres (BIPS), then were subject to 30 minutes of: 1) no acupuncture, 2) bilateral targeted acupuncture at PC6 and ST36, or 3) bilateral non-target acupuncture at Lung-5 (LU5) and Bladder-55 (BL55). Lidocaine was immediately administered at 1 mg/kg intravenously followed by 50 μg/kg/min. BIPS were tracked radiographically; sedation and nausea were scored at baseline (Time 0) and for 11 hours during lidocaine infusions. Transit times and sedation and nausea scores were analyzed with a linear mixed-effects model; the number of BIPS at defined time points was analyzed with a piecewise linear mixed-effects model. All P values were two-sided and P < 0.05 was considered significant. Sedation and nausea scores did not differ between treatments at any time point (all P > 0.05). However, nausea scores in all groups were significantly greater at Times 5 through 7 and at Time 11 compared to Time 0 whereas sedation scores in all groups were significantly greater at Times 2 through 11 compared to Time 0 (all P < 0.05). The number of BIPs found out of the stomach, the number found in the large intestine, gastric emptying and gastrointestinal transit times did not differ between treatments (all P > 0.05). Acupuncture at PC6 and ST36 did not alleviate nausea and sedation associated with lidocaine infusions in clinically normal animals or affect gastric emptying and gastrointestinal transit.

Pharmacologic effects of naldemedine, a peripherally acting μ-opioid receptor antagonist, in in vitro and in vivo models of opioid-induced constipation.

BackgroundNaldemedine (S‐297995) is a peripherally acting μ‐opioid receptor antagonist developed as a once‐daily oral drug for opioid‐induced constipation (OIC) in adults with chronic noncancer or cancer pain. This study characterized the pharmacological effects of naldemedine in vitro and in vivo.MethodsThe binding affinity and antagonist activity of naldemedine against recombinant human μ‐, δ‐, and κ‐opioid receptors were assayed in vitro. Pharmacologic effects of naldemedine were investigated using animal models of morphine‐induced inhibition of small and large intestinal transit, castor oil‐induced diarrhea, antinociception, and morphine withdrawal.Key ResultsNaldemedine showed potent binding affinity and antagonist activities for recombinant human μ‐, δ‐, and κ‐opioid receptors. Naldemedine significantly reduced opioid‐induced inhibition of small intestinal transit (0.03‐10 mg kg−1; P < 0.05) and large intestinal transit (0.3‐1 μmol L−1; P < 0.05). Naldemedine (0.03‐1 mg kg−1) pretreatment significantly reversed the inhibition of castor oil‐induced diarrhea by subcutaneous morphine (P < 0.01). Naldemedine (1‐30 mg kg−1) pretreatment (1 or 2 hours) did not alter the analgesic effects of morphine in a model measuring the latency of a rat to flick its tail following thermal stimulation. However, a significant delayed reduction of the analgesic effect of morphine was seen with higher doses of naldemedine (10‐30 mg kg−1). Some centrally mediated and peripherally mediated withdrawal signs in morphine‐dependent rats were seen with naldemedine doses ≥3 and ≥0.3 mg kg−1, respectively.Conclusions & InferencesNaldemedine displayed potent binding affinity to, and antagonistic activity against, μ‐, δ‐, and κ‐opioid receptors. Naldemedine tempered OIC in vivo without compromising opioid analgesia.

Contrast Radiography in Zarudni’s Spur-Thighed Tortoises (Testudo graeca zarudnyi) by Gastrografin®

Objective- In this study, the general anatomical features of the digestive tube and the transit time of the digestive tube of the Zarudni’s spur-thighed tortoises were examined by contrast radiology.Design - Experimental study.Animals - 4 adult female Zarudni’s spur-thighed tortoises (Testudo graeca zarudnyi).Procedures- At a temperature of 25-27°c a set of dorsoventral radiograph was taken to locate the Gastrografin position.Results- The normal gastric, small intestine and large intestine anatomy were obtained and the mean gastric, small intestine and large intestine transit times were 0.2 hr, 2.1 hr, and 27 hr, respectively. Our results showed some differences in the gastrointestinal transit time with that of other species.Conclusion and Clinical Relevance- The noninvasive diagnostic imaging techniques provide detailed information concerning gastrointestinal tract. Since there have not been any anatomical and radiological studies on this species in Iran, results of this study can use as a reference in this species.

Gastric Emptying and Gastrointestinal Transit Compared among Native and Hydrolyzed Whey and Casein Milk Proteins in an Aged Rat Model.

Little is known about how milk proteins affect gastrointestinal (GI) transit, particularly for the elderly, in whom digestion has been observed to be slowed. We tested the hypothesis that GI transit is faster for whey than for casein and that this effect is accentuated with hydrolysates, similar to soy. Adult male rats (18 months old) were fed native whey or casein, hydrolyzed whey (WPH) or casein (CPH), hydrolyzed blend (HB; 60% whey:40% casein), or hydrolyzed soy for 14 days then treated with loperamide, prucalopride, or vehicle-control for 7 days. X-ray imaging tracked bead-transit for: gastric emptying (GE; 4 h), small intestine (SI) transit (9 h), and large intestine (LI) transit (12 h). GE for whey was 33 ± 12% faster than that for either casein or CPH. SI transit was decreased by 37 ± 9% for casein and 24 ± 6% for whey compared with hydrolyzed soy, and persisted for casein at 12 h. Although CPH and WPH did not alter transit compared with their respective intact counterparts, fecal output was increased by WPH. Slowed transit by casein was reversed by prucalopride (9-h), but not loperamide. However, rapid GE and slower SI transit for the HB compared with intact forms were inhibited by loperamide. The expected slower GI transit for casein relative to soy provided a comparative benchmark, and opioid receptor involvement was corroborated. Our findings provide new evidence that whey slowed SI transit compared with soy, independent of GE. Increased GI transit from stomach to colon for the HB compared with casein suggests that including hydrolyzed milk proteins in foods may benefit those with slowed intestinal transit.

Gastroparesis and lipid metabolism-associated dysbiosis in Wistar-Kyoto rats.

Altered gastric accommodation and intestinal morphology suggest impaired gastrointestinal (GI) transit may occur in the Wistar-Kyoto (WKY) rat strain, as common in stress-associated functional GI disorders. Because changes in GI transit can alter microbiota composition, we investigated whether these are altered in WKY rats compared with the resilient Sprague-Dawley (SD) rats under basal conditions and characterized plasma lipid and metabolite differences. Bead transit was tracked by X-ray imaging to monitor gastric emptying (4 h), small intestine (SI) transit (9 h), and large intestine transit (12 h). Plasma extracts were analyzed by lipid and hydrophilic interaction liquid chromatography (HILIC) and liquid chromatography-mass spectrometry (LC-MS). Cecal microbial composition was determined by Illumina MiSeq 16S rRNA amplicon sequencing and analysis using the QIIME pipeline. Stomach retention of beads was 77% for WKY compared with 35% for SD rats. GI transit was decreased by 34% (9 h) and 21% (12 h) in WKY compared with SD rats. Excluding stomach retention, transiting beads moved 29% further along the SI over 4-9 h for WKY compared with SD rats. Cecal Ruminococcus, Roseburia, and unclassified Lachnospiraceae genera were less abundant in WKY rats, whereas the minor taxa Dorea, Turicibacter, and Lactobacillus were higher. Diglycerides, triglycerides, phosphatidyl-ethanolamines, and phosphatidylserine were lower in WKY rats, whereas cholesterol esters and taurocholic acids were higher. The unexpected WKY rat phenotype of delayed gastric emptying, yet rapid SI transit, was associated with altered lipid and metabolite profiles. The delayed gastric emptying of the WKY phenotype suggests this rat strain may be useful as a model for gastroparesis.NEW & NOTEWORTHY This study reveals that the stress-prone Wistar-Kyoto rat strain has a baseline physiology of gastroparesis and rapid small intestine transit, together with metabolic changes consistent with lipid metabolism-associated dysbiosis, compared with nonstress-prone rats. This suggests that the Wistar-Kyoto rat strain may be an appropriate animal model for gastroparesis.

Su1522 - Effects of Naldemedine, a Peripherally Acting μ-Opioid Receptor Antagonist, on Inhibition of Large Intestinal Transit Induced by Morphine in Rodent Models

Su1522 - Effects of Naldemedine, a Peripherally Acting μ-Opioid Receptor Antagonist, on Inhibition of Large Intestinal Transit Induced by Morphine in Rodent Models

Differences in the morphine-induced inhibition of small and large intestinal transit: Involvement of central and peripheral μ-opioid receptors in mice

Constipation is the most common side effect of morphine. Morphine acts centrally and on peripheral sites within the enteric nervous system. There are a few comprehensive studies on morphine-induced constipation in the small and large intestine by the activation of central and peripheral μ-opioid receptors. We investigated the differences in the inhibition of the small and large intestinal transit in normal and morphine-tolerant mice. Morphine reduced the geometric center in the fluorescein isothiocyanate–dextran assay and prolonged the bead expulsion time in a dose-dependent manner. The inhibitory effects of morphine were blocked by μ-opioid antagonist β-funaltrexamine, but not by δ- and κ-opioid antagonists. The peripheral opioid receptor antagonist, naloxone methiodide, partially blocked morphine's effect in the small intestine and completely blocked its effect in the large intestine. The intracerebroventricular administration of naloxone significantly reversed the delay of small intestinal transit but did not affect morphine-induced inhibition of large intestinal transit. Naloxone methiodide completely reversed the inhibition of large intestinal transit in normal and morphine-tolerant mice. Naloxone methiodide partially reversed the morphine-induced inhibition of small intestinal transit in normal mice but completely reversed the effects of morphine in tolerant mice. Chronic treatment with morphine results in tolerance to its inhibitory effect on field-stimulated contraction in the isolated small intestine but not in the large intestine. These results suggest that peripheral and central opioid receptors are involved in morphine-induced constipation in the small and large intestine during the early stage of treatment, but the peripheral receptors mainly regulate constipation during long-term morphine treatment.

Assessment of the Effect of Intestinal Permeability Probes (Lactulose And Mannitol) and Other Liquids on Digesta Residence Times in Various Segments of the Gut Determined by Wireless Motility Capsule: A Randomised Controlled Trial.

BackgroundWhilst the use of the mannitol/lactulose test for intestinal permeability has been long established it is not known whether the doses of these sugars modify transit time Similarly it is not known whether substances such as aspirin that are known to increase intestinal permeability to lactulose and mannitol and those such as ascorbic acid which are stated to be beneficial to gastrointestinal health also influence intestinal transit time.MethodsGastric and intestinal transit times were determined with a SmartPill following consumption of either a lactulose mannitol solution, a solution containing 600 mg aspirin, a solution containing 500 mg of ascorbic acid or an extract of blackcurrant, and compared by doubly repeated measures ANOVA with those following consumption of the same volume of a control in a cross-over study in six healthy female volunteers. The dominant frequencies of cyclic variations in gastric pressure recorded by the Smartpill were determined by fast Fourier transforms.ResultsThe gastric transit times of lactulose mannitol solutions, of aspirin solutions and of blackcurrant juice did not differ from those of the control. The gastric transit times of the ascorbic acid solutions were significantly shorter than those of the other solutions. There were no significant differences between the various solutions either in the total small intestinal or colonic transit times. The intraluminal pHs during the initial quartiles of the small intestinal transit times were lower than those in the succeeding quartiles. This pattern did not vary with the solution that was consumed. The power of the frequencies of cyclic variation in intragastric pressure recorded by the Smartpill declined exponentially with increase in frequency and did not peak at the reported physiological frequencies of gastric contractile activity.ConclusionsWhilst the segmental residence times were broadly similar to those using other methods, the high degree of variation between subjects generally precluded the identification of all but gross variation between treatments. The lack of any differences between treatments in either total small or large intestinal transit times indicates that the solutions administered in the lactulose mannitol test of permeability had no consistent influence on the temporal pattern of absorption. The negatively exponential profile and lack of any peaks in the frequency spectra of cyclic variation in gastric intraluminal pressure that were consistent with reported physiological frequencies of contractile activity profile suggests that the principal source of this variation is stochastic likely resulting from the effects of external events occasioned by normal daily activities on intra-abdominal pressure.Trial RegistrationAustralian New Zealand Clinical Trials Registry ACTRN12615000596505

Microgravity Simulated by the 6° Head-Down Tilt Bed Rest Test Increases Intestinal Motility but Fails to Induce Gastrointestinal Symptoms of Space Motion Sickness.

Space motion sickness (SMS) is the most relevant medical problem during the first days in microgravity. Studies addressing pathophysiology in space face severe technical challenges and microgravity is frequently simulated using the 6° head-down tilt bed rest test (HDT). We were aiming to test whether SMS could be simulated by HDT, identify related changes in gastrointestinal physiology and test for beneficial effects of exercise interventions. HDT was performed in ten healthy individuals. Each individual was tested in three study campaigns varying by a 30-min daily exercise intervention of either standing, an upright exercise regimen, or no intervention. Gastrointestinal symptoms, stool characteristics, gastric emptying time, and small intestinal transit were assessed using standardized questionnaires, (13)C octanoate breath test, and H2 lactulose breath test, respectively, before and at day 2 and 5 of HDT. Individuals described no or minimal gastrointestinal symptoms during HDT. Gastric emptying remained unchanged relative to baseline data collection (BDC). At day 2 of HDT the H₂ peak of the lactulose test appeared earlier (mean ± standard error for BDC-1, HDT2, HDT5: 198 ± 7, 139 ± 18, 183 ± 10 min; p: 0.040), indicating accelerated small intestinal transit. Furthermore, during HDT, stool was softer and stool mass increased (BDC: 47 ± 6, HDT: 91 ± 12, recovery: 53 ± 8 g/day; p: 0.014), indicating accelerated colonic transit. Exercise interventions had no effect. HDT did not induce symptoms of SMS. During HDT, gastric emptying remained unchanged, but small and large intestinal transit was accelerated.

Changes in Contractile Activity of the Large Intestine in Rabbits during the Poststress Period before and after Blockade of Muscarinic and Nicotinic Receptors

The rabbits were exposed twice to stress, fixation to a frame in the supine position, for 60 min. Contractile activity of all portions of the large intestine was shown to increase significantly during the poststress period. These changes were not observed under conditions of blockade of muscarinic and nicotinic receptors. This state can be considered as dyskinesia impairing large intestinal transit of chyme.

In vivo characterization of intestinal effects of endomorphin-1 and endomorphin-2 in type 1 diabetic mice

Previously, we have demonstrated that type 1 diabetes significantly attenuated the effects of endomorphins on mouse colonic contractions in vitro. In the present study, to further assess whether diabetes affects the in vivo effects of endomorphins on the mouse intestinal motility, we investigated the effects of endomorphins on colonic propulsion and large intestinal transit in diabetic mice. Both colonic bead expulsion and large intestinal transit were significantly delayed in 4 and 8 weeks diabetic mice compared to non-diabetic mice. Moreover, intracerebroventricular (i.c.v.) administration of EM-1 and EM-2 (0.5, 1.5 and 5nmol/mouse) significantly increased bead expulsion latency in a dose-dependent manner both in non-diabetic and diabetic mice. Similar results were found in large intestinal transit. However, the inhibitory effects of colonic propulsion induced by endomorphins were significantly attenuated in diabetes compared to non-diabetes. It is noteworthy that the inhibition of distal colonic propulsion induced by EM-1 in 8-week diabetes was lower than that of in 4 weeks diabetes. Nevertheless, there was no significant influence on endomorphins-induced inhibition of large intestinal transit caused by diabetes. Co-administration of naloxone (10nmol/mouse, i.c.v.) significantly attenuated the inhibitory effects of endomorphins (5nmol/mouse, i.c.v.) on colonic bead expulsion and large intestinal transit in 4 weeks diabetes, indicating that opioid receptor involved in these effects. Our results indicated that type 1 diabetes attenuated the inhibition of distal colonic propulsion induced by endomorphins in mice, but not the large intestine. The central opioid mechanism was involved in the endomorphins-induced intestinal effects in diabetes.

May the Truth Be with You: Lubiprostone as EP Receptor Agonist/ClC-2 Internalizing “Inhibitor”

Chronic constipation is a common clinical problem. Lubiprostone, a bicyclic fatty acid derived from prostaglandin (PG) E1, has been clinically used for the treatment of chronic constipation in adults. Camilleri et al. [1] first reported that lubiprostone inhibited gastric emptying, but accelerated small and large intestinal transit, which is associated with postprandial fullness. Subsequently, on the basis of clinical trials, investigators have reported a beneficial effect of lubiprostone in subjects with chronic constipation and functional bowel disease [2, 3]. Lubiprostone was marketed as belonging to a new therapeutic class, working by a mechanism described as a ClC-2 chloride channel activator. Cuppoletti et al. [4] first reported that lubiprostone increased Cl secretion by activation of the intestinal epithelial cell ClC-2 channel, localized on the apical membrane of enterocytes. Since epithelial Cl secretion is mainly mediated by the cystic fibrosis transmembrane conductance regulator (CFTR) [5], mutations of which cause the disease cystic fibrosis (CF), enhancement of CFTR-independent Cl secretion has been explored as a rescue treatment for CF. Mice with the CFTR mutation DF508, the most common mutation observed in CF patients [6], and CFTR knockout (KO) exhibit an intestinal phenotype, i.e., intestinal obstruction due to loss of Cl secretion, enhancing their utility as models of CF [7]. Nevertheless, the cellular localization and functional roles of epithelial ClC-2 channel and the mechanism of lubiprostone effects on Cl secretion have been questioned. First described in 1992 [8], ClC-2 channels are expressed in the stomach, intestine, colon, brain, heart, and muscles. ClC-2 was first proposed to provide a pathway for epithelial Cl secretion, in addition to CFTR [9]. This hypothesis, however, is not supported by the observation that combined ClC-2 KO/CFTR mutant mice survived longer than CFTR mutant mice, associated with an attenuated intestinal phenotype [10]. Ussing chamber experiments using colonic epithelia suggest that ClC-2 function is localized to the basolateral membrane, facilitating Cl reabsorption rather than Cl secretion. Ussing chamber studies using ClC-2 KO mice also demonstrate that basolateral epithelial ClC-2 has a major function promoting NaCl and fluid absorption, not secretion, in distal colon [11]. Immunohistochemical studies have localized ClC-2 to the basolateral membranes of distal colonic surface enterocytes [12–15], but not to the apical membranes. Therefore, the proposed property of lubiprostone as a ClC2 activator, on the basis of available data, seems questionable [16]. The mechanism of lubiprostone-induced Cl secretion is also controversial. Lubiprostone was originally proposed to increase the open probability of ClC-2 directly, independently of CFTR function [4]. Lubiprostone, however, activated PG E type (EP) receptors, especially EP4 Y. Akiba J. D. Kaunitz Greater Los Angles Veterans Affairs Healthcare System, Los Angeles, CA, USA

Ileal and faecal protein digestibility measurement in humans and other non-ruminants – a comparative species view

A comparative non-ruminant species view of the contribution of the large intestinal metabolism to inaccuracies in nitrogen and amino acid absorption measurements is provided to assess potential implications for the determination of crude protein/amino acid digestibility in adult humans consuming lower digestible protein sources. Most of the amino acids in the hindgut are constituents of the microorganisms and significant microbial metabolism of dietary and endogenous amino acids occurs. Bacterial metabolism of nitrogen-containing compounds leads to a significant disappearance of nitrogen in the large intestine. Literature data show that some 79 % of the nitrogen entering the large intestine of the horse is absorbed. For dogs, sows, and growing pigs these estimates are 49, 34 and 16 %, respectively. The coefficient of gut differentiation of humans compares closely to that of dogs while the coefficient of fermentation in humans is the lowest of all non-ruminant species and closest to that of cats and dogs. Large intestinal digesta transit times of humans compare closest to adult dogs. Significant amino acid metabolism has been shown to occur in the large intestine of the adult dog. Use of the growing pig as an animal model is likely to underestimate the fermentation of amino acids in the human large intestine. Based on the significant degree of fermentation of nitrogen-containing components in the large intestine of several non-ruminant species, it can be expected that determination of amino acid digestibility at a faecal level in humans consuming low quality proteins would not provide accurate estimates of the amino acids absorbed by the intestine.

Pharmacological basis for the medicinal use of muskmelon base (Pedicellus Melo.) for abdominal distention and constipation

Ethnopharmacological relevanceMuskmelon base (Pedicellus Melo.) has a long history (Ming Dynasty) as a Chinese traditional medicine. According to traditional use, it was prepared as rectal suppositories for treating abdominal distention and constipation. The present study was carried out on the pharmacological basis for the medicinal use of muskmelon base. Aim of the studyThe objective of this study was to determine the pharmacological basis for the medicinal use of the ethanol extract from muskmelon base (EMB) for abdominal distention and constipation. Materials and methodsIn this study, we report the gastrointestinal prokinetic action of EMB following single rectal or large intestinal administration. Laxative activity, gastric emptying and small intestinal transit tests were examined in ICR mice. SD rats were used to determine changes in large intestinal transit and contractile effects of the proximal colon in vivo. Guinea pigs were used to evaluate the contractile effects of the proximal colon and the possible mechanism or mechanisms on proximal colon activity ex vivo. Moreover, the acute toxicity of EMB was evaluated. ResultsIn the in vivo experiments, the acute toxicity test showed that the maximum tolerated dose (MTD) of EMB was 400mg/kg. A laxative effect was observed in mice at different dosages (6.5, 13 and 26mg/kg). EMB showed a dose-dependent acceleration of gastric emptying (13 and 26mg/kg). It also promoted both small intestinal (6.5, 13 and 26mg/kg) and large intestinal (4, 8 and 16mg/kg) transit activity. In the SD rat model, single rectal administration of EMB (8 and 16mg/kg) showed a significant increase in both the frequency and amplitude of proximal colon smooth muscle contractility. These increases in amplitude and frequency peaked 30–60min after EMB administration and corresponded with the results of the laxative activity test. The ex vivo experiments showed that varying doses of EMB (11.5, 23 and 46mg/kg) had a direct prokinetic effect that was sensitive to atropine. ConclusionsOur results show that EMB is a low dosage, fast acting drug with a large therapeutic window (4–400mg/kg) and shows significant gastrointestinal prokinetic action after single rectal or large intestinal administration. This gastrointestinal prokinetic effect was stronger in the intestines than in the stomach. This effect was sensitive to atropine, suggesting that EMB acts mainly through cholinergic mechanisms.

Dual effect of orally administered sennosides on large intestine transit and fluid absorption in the rat.

Quantity and consistency of the faecal output, large intestine transit time, and colonic net fluid absorption were investigated in rats after oral administration of sennosides A + B (12.5-200 mg kg-1). The release of normal faecal pellets was accelerated 3-4 h after drug administration; excretion of soft faeces was evident within 4-5 h and reached its maximum 5-7 h after administration. Large intestine transit time was dose- and time-dependently influenced by sennoside treatment. A highly significant reduction in transit time from more than 6 h in controls to 90 min for a 2 h pretreatment and a nearly maximal reduction to 30 min for a 4 h pretreatment was induced by a dose of 50 mg kg-1. Inhibition of net fluid absorption in the colon was maximal with the same dose, but clearly more pronounced after a 6 h pretreatment period than after a 4 h period. Since the increase in fluid volume due to net fluid secretion is delayed compared with the acceleration of large intestine transit, the early motility effect seems to be largely independent of the changes in absorption mechanisms. Therefore, the laxative effect of the sennosides consists of changes in colon motility as well as in colonic fluid absorption, but motility may be an earlier and more sensitive parameter than net absorption.

Acceleration of large intestine transit time in rats by sennosides and related compounds.

Sennosides A + B and their natural metabolites, sennidins A + B, rheinanthrone and rhein, as well as the synthetic laxative danthron, were investigated for their influence on small and large intestine transit time in rats. Carmine red, as a marker, was administered through a gastric tube for small intestine transit or intracaecally by a chronically implanted catheter for colon transit. High doses of sennosides (250-500 mg kg-1) given orally from 20 min or up to 6 h before marker administration had no effect on small intestine transit time. The metabolites and danthron (10-100 mg kg-1 p.o.) also did not accelerate upper gastrointestinal passage. Intracaecal administration at the same time as carmine red, however, reduced the time for the appearance of the first coloured faeces from more than 8 h in the controls to 46 +/- 9 min after sennosides, 34 +/- 11 min after sennidins, 53 +/- 83 min after rhein and 16 +/- 4 min after rheinanthrone (50 mg kg-1 of each). Danthron was ineffective. Thus, sennosides and their natural metabolites specifically influence large intestinal motility. Acceleration of colonic transport seems to be a major component of the laxative action whereas for danthron motility changes are not responsible for its laxative action. Indomethacin partly inhibited the acceleration of large intestine transit induced by sennosides. An involvement of endogenous prostaglandins may therefore be possible, although a local bolus administration of PGF2 alpha or PGE2 into the caecal lumen neither influenced transit time nor induced diarrhoea.

Inhibition of intestinal motility and secretion by flavonoids in mice and rats: structure-activity relationships.

Intraperitoneal administration of some flavonoids (apigenin, flavone, kaempferol, morin, myricetin, naringin and rutin; 12.5-50 mg kg-1) significantly (P < 0.05-0.01) reduced small (28-69%) and large (83-134%) intestinal transit in mice. Other flavonoids (naringenin, silibinin, silymarin and taxifolin, 100-200 mg kg-1) reduced (23-41%; P < 0.05-0.01) intestinal transit at doses of 100-200 mg kg-1 while hesperitin, catechin and phloridzin (up to 200 mg kg-1) had no effect. This effect was antagonized by yohimbine (87-96%) and phentolamine (87-91%) but not by prazosin, propranolol, atropine, hexamethonium, mepyramine, cyproheptadine and naloxone. Yohimbine (92-96%) also antagonized the inhibitory effect of flavonols (12.5-50 mg kg-1) (P < 0.05-0.01) on intraluminal accumulation of fluid and diarrhoea induced by castor oil. By contrast, verapamil potentiated the flavonol effect. It is suggested that these effects, influenced by the structure of the molecules, are mediated by alpha 2-adrenergic receptors and calcium.

Suppression of the Purgative Action of Rhein Anthrone, the Active Metabolite of Sennosides A and B, by Indomethacin in Rats

Rhein anthrone (12.48 mg kg-1) produces watery and mucoid diarrhoea approximately 20 min after intracaecal administration to rats. Pretreatment with the prostaglandin (PG) biosynthesis inhibitor indomethacin (10 mg kg-1, i.p.) only delayed and did not completely block the onset of the induced diarrhoea. Rhein anthrone stimulated PGE2 release into the rat colonic lumen and the increased release was depressed by indomethacin. Rhein anthrone also accelerated large intestinal transit and this acceleration could be partly inhibited by indomethacin, which was probably responsible for the delay in the onset of diarrhoea. Indomethacin prevented the enhanced water, K+ and mucus secretion and the reduced Na+ absorption in the colon which were induced by rhein anthrone. The net water secretion could not be reversed to net absorption and the mucus secretion was only slightly depressed by indomethacin. Thus, our findings suggest that other mechanisms, together with the PG-dependent mechanism, are involved in the purgative action of rhein anthrone in rats.