Human colonic anti-secretory activity of the potent NK(1) antagonist, SR140333: assessment of potential anti-diarrhoeal activity in food allergy and inflammatory bowel disease.

1. This in vitro study was designed to determine the potential use of the NK(1) antagonist, SR140333 as an anti-diarrhoeal treatment for food allergy or inflammatory bowel disease. The effect of various immune and neuronal stimuli on human colonic substance P (SP) release and the effect of SR140333 on subsequently stimulated mucosal ion transport was investigated.

The role of IL-4 in Heligmosomoides polygyrus-induced alterations in murine intestinal epithelial cell function.

IL-4 and IL-13 promote gastrointestinal worm expulsion, at least in part, through effects on nonlymphoid cells, such as intestinal epithelial cells. The role of IL-4/IL-13 in the regulation of intestinal epithelial function during Heligmosomoides polygyrus (Hp) infection was investigated in BALB/c mice infected with Hp or treated with a long-lasting formulation of recombinant mouse IL-4/alphaIL-4 complexes (IL-4C) for 7 days. Separate groups of BALB/c mice were drug-cured of initial infection and later reinfected and treated with anti-IL-4R mAb, an antagonist of IL-4 and IL-13 receptor binding, or with a control mAb.

Potent NK1 antagonism by SR-140333 reduces rat colonic secretory response to immunocyte activation.

The potent neurokinin receptor 1 (NK1) antagonist SR-140333 has previously been shown to reduce castor oil-induced secretion in animal models. The importance of tachykinins in neuroimmune control of secretion and the effect of SR-140333 on key points in this pathway were elucidated in the present study to determine the type of intestinal dysfunction best targeted by this antagonist. Rat colonic secretion and substance P (SP) release were determined in vitro with the use of Ussing chamber and enzyme immunoassay techniques.

Antisecretory and relaxatory effects of tachykinin antagonists in the guinea-pig intestinal tract.

Existing models used to study the mechanism of action and antagonism of tachykinergic effects on intestinal contraction and secretion suffer from technical problems and have not been fully characterized using specific tachykinin antagonists. Contraction of ileal segments by substance P, colonic circular muscle by beta-alanine-neurokinin A, and longitudinal muscle by senktide were used as models for neurokinin-induced contraction in the guinea-pig. Guinea-pig colonic epithelial tissue was stimulated by substance P and senktide to assess NK1- and NK3-mediated secretion.

Progressive alterations in circular smooth muscle contractility in TNBS-induced colitis in rats.

The present study was designed to investigate inflammation-induced changes in smooth muscle responses to acetylcholine and the tachykinins that may contribute to the abnormal motility associated with inflammatory bowel disease. Colitis was induced in male Sprague-Dawley rats by intrarectal administration of trinitrobenzenesulphonic acid in ethanol. After either 4 h (acute) or 7 days (chronic) the distal colon was taken for in vitro measurement of smooth muscle tension and histological assessment.

Hyperthermia prevents functional, histological and biochemical abnormalities induced during ileitis.

Inflammatory bowel disease is associated with altered intestinal motility and epithelial damage. Hyperthermia induces heat shock protein expression, components of a basic cellular defence mechanism, and consequently prevents ischaemic damage. Here we investigate whether hyperthermia may prevent altered smooth muscle function as well as underlying inflammation in a model of inflammatory bowel disease.

Mechanism of tachykinin NK3 receptor-mediated colonic ion transport in the guinea pig.

The guinea pig colon was used to elucidate the mechanism of tachykinin-induced secretion. Increased short-circuit current was observed in response to natural and synthetic tachykinins with rank orders of potency of substance P > neurokinin A = neuropeptide K>> neuropeptide gamma; and senktide (tachykinin NK3 receptor agonist)> Sar-substance P (tachykinin NK1 receptor agonist)> betaAlaneurokinin A (tachykinin NK2 receptor agonist)). A functional role of tachykinin NK1 receptors was confirmed as substance P and neurokinin A responsiveness was blocked by the tachykinin NK1 receptor antagonist GR82334.

The response of rat colonic mucosa to 5-hydroxytryptamine in health and following restraint stress.

The present study characterized the rat colonic secretory response to 5-hydroxytryptamine (5-HT) and determined alterations in this response following stress. 5-HT stimulated rat colonic short-circuit current in a concentration-dependent fashion (pD2 = 5.19).

Effect of mizolastine on visceral sensory afferent sensitivity and inflammation during experimental colitis.

In the present study the effect of mizolastine (CAS 108612-45-9, SL85.0324-00) a novel potent histamine H1-receptor antagonist, on 2,4,6-trinitrobenzene sulphonic acid (TNBS)-induced colitis, a rat model of inflammatory bowel disease, was investigated to determine whether mizolastine has anti-inflammatory properties. Treatment with TNBS resulted in increased nociception in response to rectal balloon distension and caused intestinal damage, tissue oedema and inflammation.

Tachykinergic neurotransmission is enhanced in small intestinal circular muscle in a rabbit model of inflammation.

Previous electrophysiological studies have shown that tachykinin-mediated excitatory junction potentials are enhanced in a ricin model of inflammatory bowel disease. The present study extends these findings by investigating the contractile response to stimulation of noncholinergic nerves and tachykinin agonists. According to rank order potencies, the rabbit ileal circular muscle was neurokinin (NK)1 preferring, and the response to these agonists was down-regulated by acetylcholine and up-regulated by nitric oxide.

Role of sensory afferents in the myoelectric response to acute enteric inflammation in the rabbit.

The role of sensory afferents in inflammation-induced alterations in myoelectric activity in vivo was investigated in the rabbit small intestine. Isolated ileal loops were implanted with serosal electrodes and exposed to ricin or vehicle after pretreatment with 125 mg/kg of subcutaneous (125 mg over 3 days) or intraluminal (640 microM) capsaicin. After 5 h of myoelectric recording, the loops were prepared for histology and for ex vivo generation of eicosanoids.

Interleukin-4 modulates cholinergic neural control of mouse small intestinal longitudinal muscle.

Interleukin-4 contributes to expulsion of certain gastrointestinal parasites and causes intestinal mucosal mastocytosis. Because mast cell-derived mediators are spasmogenic, potentially causing parasitic expulsion, we investigated the effect of interleukin-4 on smooth muscle and the mast cell and mediator dependency of this effect. BALB/c, mast cell-deficient W/Wv mice, 5-lipoxygenase-efficient mice, and their littermate controls were injected with interleukin-4-anti-interleukin-4 antibody complexes that chronically increase serum interleukin-4 levels.

Post-synaptic 5-HT4 receptor modulation of tachykinergic excitation of rat oesophageal tunica muscularis mucosae.

Interaction between the 5-HT4 receptor and cholinergic-dependent and -independent contraction of the rat oesophageal muscularis mucosae was determined. Substance P- (in the presence of atropine) and carbachol-precontracted tissue was relaxed by tryptamines and the substituted benzamides with the following rank order of potency: 5-HT > 5-methoxytryptamine > cisapride > (R)-zacopride > lintopride > metoclopramide, consistent with 5-HT4 receptor activation. The response to 5-HT was not antagonized by tetrodotoxin, methysergide or ondansetron; but was shifted to the right by GR113808 ([1-[2-[methylsulphonyl)amino]ethyl]-4-piperidinyl]methyl-1-H- indole-3-carboxylate) in substance P- and carbachol-precontracted tissue, confirming 5-HT4-mediated relaxation.

Induction of the heat shock response prevents tissue injury during acute inflammation of the rat ileum.

Objectives: To determine if prior total body hyperthermia protected against subsequent acute ileitis induced by the cytotoxic lectin, ricin, in rats. The time course of heat shock mRNA and protein expression in the ileum was determined. The effects of heat stress on small intestinal mucosal integrity, arachidonic acid metabolism, and neutrophilic infiltrate were compared in heated and nonheated rats receiving vehicle or ricin intraluminally.

Cytokine regulation of host defense against parasitic gastrointestinal nematodes: lessons from studies with rodent models.

Studies with rodents infected with Trichinella spiralis, Heligmosomoides polygyrus, Nippostronglyus brasiliensis, and Trichuris muris have provided considerable information about immune mechanisms that protect against parasitic gastrointestinal nematodes. Four generalizations can be made: 1. CD4+ T cells are critical for host protection; 2.

Local TH1 and TH2 responses to parasitic infection in the intestine: regulation by IFN-gamma and IL-4.

Control of parasitic infections is dependent on the production of cytokines that activate mechanisms which limit invasion, reproduction or survival of the parasite. In contrast, conditions that induce inappropriate cytokine responses facilitate the spread of infection and ultimately exacerbate the level of disease. Measurement of local cytokine responses to different gastrointestinal parasites, such as the intracellular protozoan, Cryptosporidium parvum, and luminal dwelling nematodes like Nippostrongylus brasiliensis and Heligmosomoides polygyrus, reveal stereotype response patterns.

Effects of antibiotics on epithelial ion transport in the rabbit distal colon in-vitro.

One side-effect of the therapeutic use of antimicrobial agents is respiratory paralysis as a result of inhibition of skeletal neuromuscular transmission; cholinergic neuro-effector motor transmission in the gastrointestinal tract is inhibited by the same classes of antimicrobial agent. Study of the effects of several classes of antibiotic compound on intestinal motility has suggested that antibiotic-induced alterations of intestinal motility may be related to the onset of diarrhoea or the development of antibiotic-associated colitis. These compounds may, however, also initiate or exacerbate diarrhoea by altering control of epithelial function, a possibility that has not previously been rigorously investigated.

Neural control of mouse small intestinal longitudinal muscle: interactions with inflammatory mediators.

The present study was undertaken to investigate neural control of mouse small intestinal longitudinal muscle. Electrical field stimulation evoked acetylcholine- and neurokinin A-mediated contractile responses, whereas nitric oxide-mediated neurotransmission resulted in relaxation. The inflammatory mediators, histamine and leukotriene D4, contracted the longitudinal muscle preparation.

Changes in enteric neural regulation of smooth muscle in a rabbit model of small intestinal inflammation.

In vitro electrophysiological studies of ileal circular muscle from rabbits with ricin-induced inflammation were performed to investigate whether altered neural control or myogenic activity contributes to previously described changes in in vivo myoelectric activity. Ricin treatment increased mean slow-wave amplitude but not frequency or resting membrane potential. Prolonged electrical field stimulation evoked a hyperpolarization during the stimulus train and a depolarization on cessation of stimulation.

Effects of rotavirus on epithelial transport in rabbit small intestine.

The present study investigated changes in small intestinal epithelial transport in rabbits infected with rotavirus. The crypt depth-villus height ratio was increased in infected ileal tissue as a result of a significant increase in crypt depth and patchy shortening of the villi. Similar villus damage was seen in the jejunum.

A novel in vitro technique to study extrinsic neural control of rabbit colonic muscle and epithelial function.

A novel in vitro technique capable of simultaneously measuring distal colonic epithelial potential difference and muscle contraction is described. Under basal conditions, oscillations in both muscle tone and potential difference were observed. Pelvic nerve stimulation was shown to evoke strong "duration" contractile responses in both the longitudinal and circular muscle layers.

Comparison of the effects of loperamide and loperamide oxide on absorptive processes in rat small intestine.

Mucosal loperamide inhibited the absorption of glycine by everted sacs of rat small intestine over 10-, 30- or 60-min incubation periods, but loperamide oxide was without effect. In stripped intestinal sheets, loperamide inhibited the rise in short-circuit current associated with Na(+)-linked glucose absorption, but this effect was not observed with loperamide oxide. It is concluded that although there is evidence that loperamide oxide is converted to loperamide in the intestinal lumen, the rate at which free loperamide appears is not sufficient to inhibit absorptive processes.

Defective stimulation of cyclic AMP by prostaglandin E2 in colonic epithelial cells in colitis.

The present study investigated the effect of vasoactive intestinal peptide and prostaglandin E2 on cyclic adenosine monophosphate levels in isolated colonocytes during experimental colitis. Intra-rectal trinitrobenzenesulfonic acid induced a colitis-like inflammation in the rabbit distal colon. Basal levels of cyclic adenosine monophosphate were similar in control and colitic colonocytes.

Defective modulation of colonic secretomotor neurons in a rabbit model of colitis.

The present in vitro study was conducted to investigate possible alterations in the control of colonic electrolyte transport in an experimental model of colitis. Intrarectal administration of trinitrobenzenesulfonic acid induced a colitis-like inflammation in the rabbit distal colon. Responses to amiloride and residual short-circuit current after this treatment were unchanged, suggesting that the absorptive and secretory mechanisms remained intact.

Local and systemic actions of loperamide on fluid transport and transmural potential difference across rat small intestine.

The ability of loperamide to influence intestinal fluid transport was assessed using a dual loop preparation. Loperamide was applied to the lumen of the oral, but not the aboral loop, yet basal and prostaglandin-stimulated fluid transport was affected in both, indicating that the drug can act systemically in addition to any local actions. Loperamide had both pro-absorptive and anti-absorptive effects, the latter only occurring when basal fluid absorption was high.