Peptidase activities in rats treated chronically with Nω-nitro-l-arginine methyl ester (L-NAME) (original) (raw)
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European Journal of Pharmacology, 2000
Intraplantar injection of staphylococcal enterotoxin B induces long-lasting oedema mediated by both cyclooxygenase and lipoxygenase products as well as by neuropeptides from sensory nerves. This study was undertaken to further clarify the role of peripheral primary Ž . afferent sensory nerves in staphylococcal enterotoxin B 25 mgrpaw -induced plasma extravasation and oedema formation. The Ž . w w Ž . Ž . x x tachykinin NK receptor antagonist S -1-2-3-3,4-dichlorophenyl -1 3-isopropoxyphenylacetyl piperidin-3-yl ethyl -4-phenyl-1 azoni-2 rights reserved.
European Journal of Pharmacology, 2009
Rat airways exposure to Staphylococcal enterotoxin A (SEA) and B (SEB) induces marked neutrophil influx. Since sensory neuropeptides play important roles in cell infiltration, in this study we have investigated its contribution in triggering SEA-and SEB-induced pulmonary neutrophil infiltration. Male Wistar rats were exposed intratracheally with SEA (3 ng/trachea) or SEB (250 ng/trachea). Animals received different in vivo pretreatments, after which the neutrophil counts and levels of substance P and IL-1 in bronchoalveolar lavage fluid were evaluated. Alveolar macrophages and peritoneal mast cells were incubated with SEA and SEB to determine the IL-1 and TNF-α levels. Capsaicin pretreatment significantly reduced SEA-and SEB-induced neutrophil influx in bronchoalveolar lavage fluid, but this treatment was more effective to reduce SEA responses. Treatments with SR140333 (tachykinin NK 1 receptor antagonist) and SR48968 (tachykinin NK 2 receptor antagonist) decreased SEA-induced neutrophil influx, whereas SEB-induced responses were inhibited by SR140333 only. Cyproheptadine (histamine/5-hydroxytriptamine receptor antagonist) and MD 7222 (5-HT 3 receptor antagonist) reduced SEA-and SEB-induced neutrophil influx. The substance P and IL-1 levels in bronchoalveolar lavage fluid of SEA-exposed rats were significantly higher than SEB. In addition, SEA (but not SEB) significantly released mast cell TNF-α. Increased production of TNF-α and IL-1 in alveolar macrophages was observed in response to SEA and SEB. In conclusion, sensory neuropeptides contribute significantly to SEA-and SEB-induced pulmonary neutrophil recruitment, but SEA requires in a higher extent the airways sensory innervation, and participation of mast cells and alveolar macrophage products.
Peptides, 2003
Peripheral tachykinins (TKs) are believed to play a role in the pathogenesis of inflammatory bowel diseases (IBD). In this study we investigated changes induced by central administration of two natural TK receptor agonists, NK 1 (PG-SPI) and NK 3 (PG-KII), on trinitrobenzene sulphonic acid (TNBS)-and dextran sodium sulphate (DSS)-induced experimental colitis in rats. Colitis was induced by instilling a single intracolonic dose of TNBS 50 mg kg −1 (0.5 ml in 50% ethanol) or by oral administration of 5% DSS for 7 days. Each group of rats was intracerebroventricularly injected daily with PG-SPI and PG-KII (0.5, 5, and 50 g kg −1 ). On day 3, TNBS-treated animals were killed and the severity of gut inflammation was evaluated by measuring myeloperoxidase (MPO) activity, interleukin-1 (IL-1) production and by scoring macroscopic and histologic colonic damage. DSS-treated animals were checked daily for the length of survival and for stool consistency and faecal blood. In the TNBS group, PG-SPI and PG-KII increased scores for the severity of colonic damage, stimulated the production of IL-1 and increased granulocyte infiltration into the colon (MPO activity). In the DSS group, PG-SPI and PG-KII decreased the percentage of surviving animals, and increased the number of rats that developed loose stools and blood in the faeces and the MPO activity. These results indicate that centrally injected NK 1 and NK 3 tachykinin receptor agonists play a proinflammatory role in experimentally-induced colitis in rats.
The American Journal of Pathology, 2000
Increasing evidence suggests that tachykinins are involved in the control of pathophysiological states, such as inflammation. The precise localization of tachykinin receptors is of paramount importance in the search for their possible physiological and pathological role; in this study, therefore, we attempted to define cellular sites of substance P (NK-1R) and neurokinin A (NK-2R) receptor expression in the healthy and the inflamed human intestine by in situ hybridization and immunohistochemistry. In the normal ileum and colon, NK-1R and NK-2R were localized to smooth muscle cells of the muscularis mucosae and propria and a few inflammatory cells of the lamina propria; NK-1R expression was also found in the muscular wall of submucosal blood vessels, enteric neurons and, to a lesser degree, in surface epithelial cells. Patients with Crohn's disease and ulcerative colitis showed a dramatic increase in NK-1R density relative to controls, in both the inflamed and the uninvolved mucosa. Up-regulation of NK-1R was particularly evident on epithelial cells lining the mucosal surface and crypts, as well as on endothelial cells of capillaries and venules. Also, a marked increase in NK-2R expression was found in both groups of patients on inflammatory cells of the lamina propria, especially eosinophils. Our findings demonstrate that in the normal human intestine NK-1R and NK-2R are expressed in multiple cell types, which are endowed with different physiological functions; in addition, they demonstrate that both NK-1R and NK-2R are up-regulated in patients with Crohn's disease and ulcerative colitis. Taken together, these observations may have important physiological and pathophysiological implications, and provide the rationale for the use of NK-1R and NK-2R antagonists in the treatment of inflammatory bowel disease. Substance P (SP) and neurokinin A (NKA), the two most thoroughly characterized members of the tachykinin family of neuropeptides, are putative neurotransmitters that exert important physiological functions in both the central nervous system and peripheral tissues. SP and NKA abound in the small and large intestine of a variety of mammalian species, including humans, where they are mainly expressed by intrinsic enteric neurons and extrinsic primary afferent nerve fibers originating from dorsal root ganglia and vagal sensory neurons. 2,3 Additional sources of these two neuropeptides are provided by enterochromaffin cells within the gastrointestinal epithelium 4 and blood-derived or resident immune cells of the lamina propria. In keeping with their co-localization on secretory vesicles, 7 SP and NKA are co-released on application of depolarizing stimuli and when intestinal motility is reflexly activated. 8 Once released, SP and NKA exert their biological effects on target cells by interacting with specific receptors, which have been cloned, characterized, and found to have seven transmembrane spanning sequences and to be coupled to G-proteins and the phosphoinositide-signaling pathway. 9 -13 To date, three distinct receptors have been identified, termed neurokinin-1 receptor (NK-1R), neurokinin-2 receptor (NK-2R), and neurokinin-3 receptor (NK-3R). SP preferentially activates the NK-1R, NKA the NK-2R, and neurokinin B the NK-3R; however, at high ligand concentrations each tachykinin can activate each of the tachykinin receptors. Within the gastrointestinal tract, SP and NKA are involved in the physiological control of several digestive functions, including motility, fluid and electrolyte secretion, blood flow, and tissue homeostasis. In addition, there is mounting evidence that tachykinins play a pivotal role in the regulation of immunoinflammatory responses, Supported by the Italian "Ministero della Ricerca Scientifica e Tecnologica" (grants .n°0401-664 and 0401-610).
Effect of E. coli Nissle 1917 on post-inflammatory visceral sensory function in a rat model
Neurogastroenterology and Motility, 2005
Objective: Visceral hyperalgesia (VH) plays a key role for the manifestation of functional gastrointestinal (GI) disorders. In a subgroup of patients, the initial manifestation is preceded by GI inflammation. Recent studies have demonstrated an improvement of inflammation and symptoms during treatment with Escherichia coli Nissle 1917 (EcN). Aim: We aimed to characterize the effects of EcN on visceral sensitivity in a rat model of post-inflammatory VH. Methods: Male Lewis rats underwent colorectal instillation of trinitrobenzenesulphonic acid (TNBS) plus an equal amount of ethanol (test group) or physiological saline solution (control group). After 28, 35 and 42 days, standardized colorectal distensions were performed and the visceromotor reflex (VMR) of abdominal wall muscles was quantified by electromyographic recording. From day 28 onwards, EcN was administered in drinking water. Results: After TNBS, a significant increase of VMR was observed compared with saline controls over all study days. Administration of EcN reduced the TNBSinduced hyperalgesia [EcN: 863 ± 125 lV vs placebo: 1258 ± 157 lV (P < 0.05)] at day 35, while there were no significant alterations at any other study day.
British Journal of Pharmacology, 1994
1 The possibility that tachykinin NK, receptors are involved in the plasma extravasation evoked by intradermal (i.d.) injection of Phoneutria nigriventer venom (PNV) in rat dorsal skin in vivo has been investigated. 2 Local oedema formation induced by the i.d. injection of test agents was measured by the extravascular accumulation of intravenously (i.v.) injected '251-labelled human serum albumin over a 30 min period. 3 The tachykinin NKI agonist, GR73632 (30 pmol per site), induced local oedema formation which was potentiated by co-injection with the neuropeptide vasodilator, calcitonin gene-related peptide (CGRP, 10 pmol per site). The non-peptide tachykinin NKI receptor antagonist, SR140333 (0.03-1 nmol per site co-injected, i.d.) significantly inhibited (0.3 nmol per site, P<0.05; 1 nmol per site, P<0.001) local oedema formation induced by GR73632 with CGRP but not that induced by histamine (10 nmol per site) with CGRP. 4 PNV (0.03-0.3 ig per site) injected i.d. induced dose-dependent local oedema formation. SR140333 (1 nmol per site, co-injected i.d.) inhibited oedema formation; with complete inhibition observed at doses of 0.03 Mg (P<0.05) and 0.1 ig (P<0.001); and partial inhibition (50%) observed with the highest dose of PNV, 0.3 jg (P<0.05). 5 Local oedema formation induced by PNV was not affected by systemic pretreatment with the bradykinin B2 receptor antagonist, Hoe 140 (80 nmol kg-', i.v.), which was used at a dose which significantly inhibited oedema formation by bradykinin (1 nmol per site). 6 Local oedema formation induced by PNV was significantly inhibited (P<0.01) by co-injection of the histamine HI receptor antagonist, mepyramine (2.5 nmol per site), together with the 5-hydroxytryptamine (5-HT) antagonist, methysergide (2.8 nmol per site). 7 In the presence of all three antagonists (mepyramine 2.5 nmol per site; methysergide, 2.8 nmol per site and SR140333 1 nmol per site), the plasma extravasation induced by PNV was further significantly inhibited (P<0.001, when compared with PNV injected i.d. alone; P<0.05 when compared with PNV co-injected with mepyramine and methysergide and P< 0.01, when compared with PNV co-injected with SR140333). 8 These results suggest that oedema formation evoked by i.d. PNV in rat skin may be partially mediated via a mechanism involving tachykinin NKI receptors and that this effect is independent of histamine and 5-HT.
British Journal of Pharmacology, 2001
1 In the gastrointestinal tract, tachykinin NK 2 receptors are localized both on smooth muscle and nerve ®bres. NK 2 receptor antagonists reduce exaggerated intestinal motility in various diarrhoea models but the site of action contributing to this eect is unknown. In this study we investigated the eects of atropine (1.4 mmol kg 71 , i.v.), hexamethonium (13.5 mmol kg 71 , i.v.), and nepadutant (0.1 mmol kg 71 , i.v.), a selective tachykinin NK 2 receptor antagonist, on distension (0.5 and 1 ml)-, or irritation (acetic acid, 0.5 ml of 7.5% v v 71 )-induced motility in the rat distal colon in vivo. The eects of atropine, hexamethonium or N o -nitro-L-argininemethylester (L-NAME, 1.85 mmol kg 71 , i.v.) on [bAla 8 ]NKA(4-10) (10 nmol kg 71 , i.v.)-induced colonic contractions were also investigated. 2 When the colonic balloon was ®lled with a subthreshold volume (0.5 ml), the intraluminal instillation of acetic acid triggered a high-amplitude phasic colonic motility which was partially reduced by nepadutant and suppressed by either hexamethonium or atropine. Filling of the balloon with 1 ml evoked re¯ex (hexamethonium-sensitive), atropine-sensitive phasic colonic motility: nepadutant had no signi®cant eect on the distension-evoked motility.