Generality in effects of transmucosal fluid movement and glucose on drug absorption from the rat small intestine.
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Animals↗
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[Physiological functions of protease-activated receptor-2].
Protease-activated receptors (PARs) are a family of G-protein-coupled-seven-trans-membrane-domain-receptors activated by specific proteases, consisting of four family members. PAR-2, a receptor activated by trypsin, tryptase or coagulation factors VIIa and Xa, is unevenly distributed throughout the mammalian body, modulating multiple physiological functions. In the gastrointestinal tract, PAR-2 is involved in gastric mucosal cytoprotection, smooth muscle motility modulation, salivary and pancreatic exocrine secretion, intestinal ionic transport, etc. In the circulatory system, endothelial PAR-2, upon activation, induces vascular relaxation by mechanisms dependent on nitric oxide or endothelium-derived hyperpolarizing factor (EDHF), resulting in hypotension in vivo. In the respiratory system, PAR-2 appears to play a dual role, being pro- and anti-inflammatory. In the nervous system, PAR-2 present in capsaicin-sensitive sensory neurons participates in processing of pain information. PAR-2 is thus involved in a variety of physiological and pathophysiological functions. PAR-2 is now considered one of the most important molecules as a target for drug development.
Animals↗
Cannabinoids for gastrointestinal diseases: potential therapeutic applications.
Delta(9)-Tetrahydrocannabinol (the active ingredient of marijuana), as well as endogenous and synthetic cannabinoids, exert many biological functions by activating two types of cannabinoid receptors, CB(1) and CB(2) receptors. CB(1) receptors have been detected on enteric nerves, and pharmacological effects of their activation include gastroprotection, reduction of gastric and intestinal motility and reduction of intestinal secretion. The digestive tract also contains endogenous cannabinoids (i.e., the endocannabinoids anandamide and 2-aracidonylglycerol) and mechanisms for endocannabinoid inactivation (i.e., endocannabinoids uptake and enzymatic degradation). Cannabinoid receptors, endocannabinoids and the proteins involved in endocannabinoids inactivation are collectively referred as the 'endogenous cannabinoid system'. A pharmacological modulation of the endogenous cannabinoid system could provide new therapeutics for the treatment of a number of gastrointestinal diseases, including nausea and vomiting, gastric ulcers, irritable bowel syndrome, Crohn's disease, secretory diarrhoea, paralytic ileus and gastroesophageal reflux disease. Some cannabinoids are already in use clinically, for example, nabilone and delta(9)-tetrahydrocannabinol are used as antiemetics.
Animals↗
Protease-activated receptors: potential therapeutic targets in irritable bowel syndrome?
Protease-activated receptors (PARs) are a family of four G-protein-coupled receptors (PAR-1 to PAR-4) activated by the proteolytic cleavage of their N-terminal extracellular domain. This activation first involves the recognition of the extracellular domain by proteases, such as thrombin, but also trypsin or tryptase which are particularly abundant in the gastrointestinal tract, both under physiological circumstances and in several digestive diseases. Activation of PARs, particularly of PAR-1 and -2, modulates intestinal functions, such as gastrointestinal motility, visceral nociception, mucosal inflammatory response, and epithelial functions (intestinal secretion and permeability). As these physiological properties have been shown to be altered in various extents and combinations in different clinical presentations of irritable bowel syndrome, PARs appear as putative targets for future therapeutic intervention in these patients.
Humans↗
Cellular distribution of the P2X4 ATP receptor mRNA in the brain and non-neuronal organs of rats.
RNA blot analysis has shown that an ionotropic ATP receptor P2X4 is widely distributed, as compared with other P2X subtypes. Cellular distribution of the P2X4 ATP receptor mRNA was investigated by in situ hybridization technique in the brain and non-neuronal organs. In the brain, transcripts of the P2X4 were widely distributed in various regions, with the highest signals in the cerebellar Purkinje cells and granule cells. In other organs, intense and selective expression was detected in seminiferous tubules of the testis and intestinal crypts of the colon, suggesting an involvement of ATP in spermatogenesis and intestinal secretion. A low but significant level of the P2X4 mRNA was detected in the adenohypophysis and the cortex of the adrenal gland. The tissue- or cell-specific expression of the P2X4 mRNA is of importance to understand the functional roles of the purinergic transmission system.
Adrenal Glands↗
Diagnosis of small bowel obstruction: the contribution of diagnostic ultrasound.
The hallmark of intestinal obstruction, whether due to a mechanical cause or to absence of peristalsis, is the intraluminal accumulation of fluid. The presence of air simply makes it easier to visualize dilated fluid-filled loops of plain radiographs. When gas is absent, secondary to vomiting or to cessation of air swallowing, the fluid-filled loops may be difficult to identify. In closed loop obstruction, air cannot enter the involved bowel, and in this situation sonography may provide important information concerning the status of the intestinal tract. In nonstrangulating obstruction, sonography offers confirmatory evidence of dilated fluid-filled loops of bowel. In some instances, ultrasonography may correctly identify the gastrointestinal tract origin of a problem thus enabling appropriate management of the patient. We describe three patients in whom ultrasound enabled prompt diagnosis of fluid-filled loops.
Adult↗
CT detection of duodenal perforation.
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Abscess↗
Intestinal cannulation of cattle and sheep with a T-shaped cannula designed for total digesta collection without externalizing digesta flow.
An intestinal cannula was prepared that was designed to have the advantages of a reentrant cannula without permanently exteriorizing digesta flow or adding significantly to the resistance of digesta flow. The cannula was fabricated in the shape of a T from a Teflon fluorocarbon polymer. Total passage of digesta through the lumen of the cannula was accomplished by suturing a support boot around the outside of the intestine at the cannulation site. The support boot prevented the intestine from stretching away from the cannula. Digesta leakage around the barrel of the cannula was eliminated by a special peritoneal ring attached to the cannula in a position that interrupted the continuity of the tubular scar tissue that formed from the intestine alongside the barrel to the skin. The cannula was supported by an outer ring held in place by a simple stainless steel retaining ring. The low external profile of the cannula minimized mechanical disturbance of the cannula and cannula site. Diet consumption and growth rates were normal, and no blockage was encountered in either the duodenal or the ileal cannula with a wide variety of diets, indicating that the cannula added no significant resistance to digesta flow. Total digesta collection or simultaneous collection and addition were easily accomplished with special collection gates. The cannula preparation has a long functional life; in one case, the cannula remained functional for more than 2 1/2 years.
Animals↗
Further studies on the effect of ASF factor on Cl- permeability across the Deiters' neurone plasma membrane.
Experiments have been performed in order to assess whether the antisecretory factor (ASF) can influence the permeation of Cl- ions across the Deiters' neurone plasma membrane in the outward direction. ASF is a naturally occurring, acidic protein with a molecular weight of about 60,000, which specifically inhibits enterotoxin-induced intestinal secretion. Both basal and "intracellular" GABA activated Cl- permeability was studied, and the result confirmed the existence of GABAA receptors on the Deiters' membrane cytoplasmic side. ASF completely abolished the effect of "intracellular" GABA on Cl- permeability in the outward direction. However, ASF did not influence the basal Cl- permeability in the outward direction.
Animals↗
Intestinal dipeptidases. Dipeptidase activities in human intestinal juice.
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Adult↗
Experimental studies on fluid pathophysiology in small intestinal obstruction in the rat. I. Effects of intraluminal hyperosmolality.
An experimental model is described which is intended to simulate and accentuate the movement of fluids across the intestinal mucosa resulting from simple small intestinal obstruction as well as to provide a means for measuring these fluid shifts. Working on the hypothesis that the increase in fluid in the obstructed small intestine is a consequence of increased osmolality resulting from enzymatic breakdown of the intestinal contents, a solution of high osmolality was introduced into an intestinal segment of known size and position. Under these conditions the intestinal mucosa functioned in the manner of a semipermeable membrane and permitted only fluids of low osmolality to enter the intestinal lumen, thus tending to normalize its hyperosmolal contents. The process of dilution followed a simple dilution curve. At the same time hemoconcentration and increased serum osmolality reflected the mobilization of fluids from the extravascular and vascular compartments. The transfer of fluids into the intestinal lumen continued throughout the test period, despite the fact that there was a linear increase in intraluminal pressure to a relatively high level, indicating increased smooth muscle tone probably due to the hyperosmolal provocation. The observed accumulation of fluid was well reproducible and associated with predictable effects on the vascular and extra-vascular compartments.
Animals↗
Diagnosis of bacterial overgrowth of the small intestine. Comparison of the 14C-D-xylose breath test and jejunal cultures in 60 patients.
Sixty consecutive patients suspected of having bacterial overgrowth of the small intestine (BOG) had aerobic and anaerobic bacterial cultures made of fasting upper jejunal fluid and also a 14C-D-xylose breath test (XBT). Culture-proven BOG was present in 23 patients. In another 15 patients the presence of BOG was ruled out (diagnoses: irritable bowel syndrome, 8; chronic diarrhoea, 6; and lactose malabsorption, 1). These patients were used as controls. The other 22 of the 60 patients could not be placed in either group owing to the presence of factors known to predispose for BOG; none of them had abnormal jejunal cultures, but several had strong clinical suspicion of BOG. An abnormal XBT, defined as values exceeding upper 90% confidence limits (upper range) of the 15 patient control values within a 4-h period, was observed with the following frequencies in the 23 patients with BOG: after 60 min, 35%; after 120 min, 44%; after 180 min, 61%; and after 240 min, 65%. An abnormal XBT was observed in 41% of the 22 patients with normal jejunal cultures but with predisposition for, and clinical suspicion of, BOG. It is concluded that, compared with a relevant control material, the XBT tends to be rather insensitive and that a negative outcome of jejunal cultures is inadequate to exclude the presence of BOG.
Adult↗
Luminal bacteria and small-intestinal permeability.
BACKGROUND: The influence of luminal bacteria on small-intestinal permeability has not been fully assessed. This study addressed this issue. METHODS: Thirty-four subjects (mean age 64 years; range 22-95 years) were investigated for possible small-intestinal bacterial overgrowth (SIBO) with culture of a small-intestinal aspirate. A lactulose/mannitol small-intestinal permeability test was performed, small-intestinal histology assessed and serum vitamin B12 concentrations measured in all subjects. Permeability was also assessed in a control group of 34 asymptomatic volunteers. RESULTS: Urinary lactulose/mannitol ratios were significantly increased in subjects with SIBO with colonic-type flora (P < 0.0005), even in the absence of villous atrophy. Urinary lactulose/mannitol ratios were increased in this group due to significantly increased urinary lactulose concentrations (P < 0.0005) rather than reduced urinary mannitol levels, after correcting for inter-subject variations in renal function. Counts of intraepithelial lymphocytes of CD8 phenotype were significantly increased in this group (P = 0.003). Although a significant correlation was found between intraepithelial lymphocyte counts and small-intestinal permeability overall (P < 0.002), these counts were not significantly different in subjects with SIBO with colonic-type flora whose permeability values were < or = > 0.028, the upper limit of normal in asymptomatic controls. Serum vitamin B12 concentrations did not differ significantly between groups (P > 0.5). Ageing did not independently influence small-intestinal permeability (P > 0.5). CONCLUSIONS: Small-intestinal permeability is increased in subjects with SIBO with colonic-type bacteria. This effect is independent of ageing and not mediated by vitamin B12 deficiency. Although counts of intraepithelial lymphocytes of CD8 phenotype are increased in this disorder, it is also unlikely that these cells play an important causative role in this process. Routine light microscopic assessment underestimates the prevalence of small-intestinal functional disturbance in this disorder.
Bacterial Infections↗
Metabolism of sertindole: identification of the metabolites in the rat and dog, and species comparison of liver microsomal metabolism.
1. The main exretion pathways of a novel antipsychotic drug, sertindole, in the rat and dog are faecal excretion via intestinal secretion and biliary excretion respectively. 2. Similar liver microsomal metabolic patterns were observed in the rat, monkey, and man, and Lu 30-131 (5-hydroxy-serindole) and Lu 30-148 (4-hydroxy-serindole) were the major metabolites, and Lu 25-073 (nor-sertindole) and Lu 28-092 (dehydro-sertindole) were minor ones. In the dog, however, Lu 31-096 (3'-fluoro-4'-hydroxy-sertindole) and Lu 30-148 (4-hydroxy-sertindole) were the major metabolites, and Lu 25-073 (nor-sertindole), Lu 28-092 (dehydro-sertindole), and Lu 30-131 (5-hydroxy-sertindole) were minor ones. These findings suggest that the metabolism of sertindole in man resembles those in the rat and monkey and is different from that in the dog. 3. Rat in vitro and in vivo liver metabolites, dog liver microsomal metabolites, and dog biliary metabolites were isolated and identified by liquid chromatography/mass spectrometry and/or 1H-nmr. 4. Two metabolites, Lu 31-096 (3'-fluoro-4'-hydroxy-sertindole) and Lu 31-154 (3'-fluoro-4'-hydroxy-dehydro-sertindole), were formed via the 'NIH shift' mechanism. 5. Sertindole is metabolized by hydroxylation at the 4- and 5-positions on the imidazolidinone ring, N-dealkylation, and an NIH shift at the fluorophenyl group. Further metabolism (dehydration, oxidation, hydroxylation, glucuronidation and sulphation) was also observed. 6. In the rat, oxidation at the imidazolidinone ring and N-dealkylation are the main metabolic reactions. On the other hand, in the dog, the NIH shift at the fluorophenyl group, followed by conjugation is the main metabolic pathway.
Animals↗
Selectivity, specificity and kinetics of the androgen regulation of the ocular secretory immune system.
The purpose of the present investigation was to determine the selectivity, specificity and kinetics of the androgen regulation of the ocular secretory immune system. To examine the mucosal selectivity of hormone action, tears, saliva, respiratory and intestinal secretions, urine and serum were collected from orchiectomized rats following four days of treatment with saline or testosterone. Androgen administration significantly increased the tear levels of IgA and free SC. In contrast, this combined hormone response was not duplicated in other mucosal secretions or serum. Consequently, it appears that the androgen control of the ocular secretory immune system is unique to the eye. To evaluate androgenic specificity, orchiectomized rats were treated for four days with saline, testosterone, 5 alpha-androstan-17 beta-o1 ('5 alpha'), 4-estren-7 alpha-methyl-17 beta-o1-3-one ('4-E') or the synthetic analogue, danazol. Results demonstrated that testosterone and '4-E', a potent androgen, both stimulated the accumulation of tear IgA and free SC, compared to amounts in tears of saline-treated controls. The weak androgen '5 alpha' induced a slight rise in tear free SC, but not IgA, levels, whereas danazol had no effect on the ocular secretory immune system. These findings indicate that androgen structure is of critical importance in modulation of mucosal immunity in the eye. Lastly, to assess the kinetics of hormone action on tear IgA and free SC, orchiectomized rats were acutely (0, 1.5, 4, 7, 12, or 24 hours) or chronically (0, 4, 7, 11, 14, or 17 days) exposed to testosterone. Acute androgen exposure for less than 12 hours did not elicit any change in the tear content of IgA or free SC. In comparison, chronic androgen treatment induced a progressive and dramatic rise in the levels of both tear proteins. By 17 days of hormone exposure, the IgA and free SC concentrations in tears had increased by 14- and 18-fold amounts, respectively, relative to amounts in placebo-treated controls. Of interest, the temporal pattern of accumulation of tear IgA and free SC were different. Overall, these results show prolonged, but not abbreviated, exposure to androgens has a profound impact on the IgA and free SC profile in tears.
Androgens↗
[Effects of a high-fructose diet on various characteristics of metabolism in rat small intestine].
During the fructose intestinal transfer in vitro, in the rats receiving a normal diet, no glucose is synthetized. In the high-fructose diet rats, glucose appears in the intestinal wall and in the serosal fluid. This synthesis is probably realized from fructose. When fructose is used as substrate, the intestinal tissue of these latter animals shows a greater oxygen consumption than that of the former animals.
Animals↗
Gastrointestinal transit in an animal model of human diabetes type 2: relationship to gut neuroendocrine peptide contents.
Gastrointestinal transit (GIT) was determined in obese diabetic mice (ob/ob, Umeå/Bom). Blood glucose level, and insulin concentration in the serum and pancreas extracts as well as neuroendocrine peptide contents were measured in several segments of the gut. GIT was significantly slower in the obese diabetic mice, but was not correlated with the blood glucose level, serum insulin, or pancreatic insulin content. GIT was correlated with duodenal secretin content and colonic vasoactive intestinal peptide (VIP) content, but not with the content of other neuroendocrine peptides in different segments investigated. The antral gastrin content in obese diabetic mice was significantly higher than in controls. The concentration of secretin in obese diabetic mice was higher than in controls. Whereas the contents of peptide YY (PYY) and somatostatin were higher in obese diabetic mice, the contents of substance P and VIP were lower. The increased content of duodenal secretin and decreased content of colonic VIP may be among the factors that cause slow GIT in obese diabetic mice. The changes in the colonic contents of PYY, VIP and somatostatin may cause low intestinal secretion and, together with slow GIT, give rise to constipation, which is a common symptom in diabetes.
Animals↗
Enumeration and presumptive identification of bacteria from the small intestine of sheep.
Microflora of the small intestine of sheep was examined. Samples of tissue and digesta were taken from four sites along the small intestine (3, 8, 13, and 18 m from the pylorus) and maintained under anaerobic conditions. The pH of the digesta taken at the 3rd, 8th, 13th, and 18th m sections were 5.44, 6.37, 7.24, and 6.79. Digesta and tissue samples were diluted serially and plated within the anaerobic glove box on complex medium containing rumen fluid. In addition, each sample was plated on the same medium and incubated aerobically. As determined by growth under anaerobic conditions, viable counts of the digesta ranged from 5 X 10(4) to 7 X 10(6) cells/g, whereas counts for the tissue ranged from 2 X 10(2) to 4 X 10(4) cells/g. Viable counts determined aerobically for the digesta ranged from 1 X 10(4) to 5 X 10(6) cells/g, whereas the counts for the tissue ranged from 5 X 10 to 6 X 10(4) cells/g. Tentative identification of 50 isolates from samples of tissue and digesta in the 13th m section revealed a predominance of streptococcal organisms and rod shaped organism morphologically similar to Propionibacterium. An indigenous population of acid-tolerant bacteria with the ability to ferment simple sugars and starch was in the small intestine.
Animals↗