Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P20366 (substance P)
 21,176 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of the neurokinin-1 (NK1) receptor antagonist RP67580 in modulating inflammatory oedema formation has been investigated in guinea-pig skin. Oedema formation was measured over 30 min by the extravascular accumulation of intravenously-injected 125I-albumin in the anaesthetised guinea-pig. RP67580 was injected intradermally with the agents under test. Intradermal RP67580 (10 nmol/site) inhibits oedema formation induced by substance P (30 pmol) and neurokinin A (100 pmol), but not that induced by bradykinin (10-1000 pmol) or histamine (10 nmol). Substance P-induced oedema formation is similar in control (saline) and mepyramine (histamine H1 receptor antagonist) pretreated guinea-pigs suggesting a minimal involvement of histamine in substance P induced oedema formation in guinea-pig skin. Oedema formation induced by intradermal carrageenin (0.2%) was not inhibited by RP67580 (1-10 nmol). A significant but partial inhibition of oedema formation induced in a passive cutaneous anaphylaxis (PCA) response was observed. The oedema formation in the PCA was inhibited 50% by mepyramine pretreatment but in the presence of mepyramine no further inhibition of the PCA response by RP67580 was observed.
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PMID:Effect of a neurokinin-1 (NK1) receptor antagonist on oedema formation induced by tachykinins, carrageenin and an allergic response in guinea-pig skin. 752 80

We have isolated, partially purified, and characterized the mast cells from human heart tissue. The histamine content of left and right ventricles and septum of hearts obtained from 25 patients undergoing heart transplantation was 5.4 +/- 0.6, 5.3 +/- 0.5, and 5.6 +/- 0.5 micrograms/g of wet tissue, respectively. Ultrastructural study of cardiac mast cells revealed scroll, crystal, and mixed granules, homogeneously dense granules, and lipid bodies in the cytoplasm. A mild collagenase digestion was used to disperse the heart mast cells; the average yield was 3.2 +/- 0.6% (range: 0.8 to 13.6%). The average histamine and tryptase content/heart mast cells was 3.3 +/- 0.2 pg (n = 25) and 24.2 +/- 4.3 micrograms/10(6) cells (n = 11), respectively. Survival of cardiac mast cells after overnight culture was 71.9 +/- 5.4% (n = 23). The purification of human heart mast cells can be brought from less than 0.1 to 12% by a combination of low-speed centrifugation over albumin (2%) solution and Percoll gradient. Viability as shown by trypan blue exclusion was greater than 90%. Heart mast cells released histamine in response to immunologic (anti-IgE, anti-Fc epsilon RI, and C5a) and nonimmunologic stimuli (recombinant human stem cell factor, A23187, and compound 48/80) but did not respond to substance P, FMLP, 12-O-tetradecanoylphorbol-13-acetate, or acetylcholine. There was a linear correlation between the percentage of release caused by anti-IgE and anti-Fc epsilon RI, whereas there was no correlation between the release caused by C5a and anti-IgE-mediated stimuli. Cross-linking with anti-IgE of IgE on heart mast cells induced the release of tryptase (10.1 +/- 2.1 micrograms/10(7) cells; n = 10) and the de novo synthesis of PGD2 (17.3 +/- 4.3 ng/10(6) cells; n = 10) and of leukotriene C4 (19.1 +/- 4.5 ng/10(6) cells; n = 10). There was a linear correlation between the percentage of histamine secretion and tryptase release (r = 0.67; p < 0.001) induced by cross-linking of Fc epsilon RI. similarly, there was a significant correlation between percentage of histamine secretion and PGD2 (r = 0.63; p < 0.001) and LTC4 (r = 0.64; p < 0.001) release. Immunoelectron microscopy demonstrated the presence of chymase in cardiac mast cells. Mast cells isolated from human heart can be a useful model with which to study the role of these cells and their mediators in cardiac anaphylaxis and cardiovascular diseases.
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PMID:Human heart mast cells. Isolation, purification, ultrastructure, and immunologic characterization. 753 85

Neurogenic switching is proposed as a hypothesis for a mechanism by which a stimulus at one site can lead to inflammation at a distant site. Neurogenic inflammation occurs when substance P and other neuropeptides released from sensory neurons produce an inflammatory response, whereas immunogenic inflammation results from the binding of antigen to antibody or leukocyte receptors. There is a crossover mechanism between these two forms of inflammation. Neurogenic switching is proposed to result when a sensory impulse from a site of activation is rerouted via the central nervous system to a distant location to produce neurogenic inflammation at the second location. Neurogenic switching is a possible explanation for systemic anaphylaxis, in which inoculation of the skin or gut with antigen produces systemic symptoms involving the respiratory and circulatory systems, and an experimental model of anaphylaxis is consistent with this hypothesis. Food-allergy-iducing asthma, urticaria, arthritis, and fibromyalgia are other possible examples of neurogenic switching. Neurogenic switching provides a mechanism to explain how allergens, infectious agents, irritants, and possibly emotional stress can exacerbate conditions such as migraine, asthma, and arthritis. Because neurogenic inflammation is known to be triggered by chemical exposures, it may play a role in the sick building syndrome and the multiple chemical sensitivity syndrome. Thus neurogenic switching would explain how the respiratory irritants lead to symptoms at other sites in these disorders.
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PMID:Neurogenic switching: a hypothesis for a mechanism for shifting the site of inflammation in allergy and chemical sensitivity. 762 26

Alteration of intestinal myoelectrical activity is a characteristic feature of food protein-induced intestinal anaphylaxis in the conscious rat. The motility changes induced by antigen challenge were appraised in egg-albumin-sensitized rats, chronically implanted with NiCr electrodes in the duodenojejunal wall. Intraduodenal infusion of egg albumin given to fasted sensitized rats triggered a disruption of the cyclic pattern of small intestinal motility lasting 79.1 +/- 23.3 min. The duration of the challenge effect on intestinal myoelectrical activity was significantly reduced by systemic capsaicin pretreatment (125 mg/kg) but to a lesser extent by perivagal capsaicin. Substance P (SP) antagonists (SP 4-11 and CP 96.345) and atropine were also able to shorten the duration of the antigen-challenge-induced alteration of intestinal motility. It is concluded that SP and capsaicin-sensitive afferent nerve endings play an important role in the intestinal anaphylaxis-induced disturbances of intestinal motility.
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PMID:Involvement of capsaicin-sensitive afferent nerves in the intestinal motor alterations induced by intestinal anaphylaxis in rats. 768 18

The inhibitory effects of emedastine difumarate on histamine release were studied in rat peritoneal mast cells. Emedastine significantly inhibited substance P (SP)-induced histamine release at concentrations above 10(-9) M in the presence of extracellular Ca2+ and at concentrations above 10(-11) M in its absence. At concentrations of 10(-8) M or higher, emedastine significantly inhibited SP-induced Ca2+ release from intracellular Ca stores and SP-induced 45Ca uptake into mast cells. Emedastine also inhibited passive peritoneal anaphylaxis in rats and guinea pigs. We conclude that the clinical antiallergic effects of emedastine involve the inhibition of histamine release and that this inhibition is mediated by the inhibition of Ca2+ release from intracellular Ca stores and the inhibition of Ca2+ influx into mast cells.
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PMID:Inhibitory effects of emedastine difumarate on histamine release. 769 Apr 32

Our previous studies have shown that the inhibition of neutral endopeptidase, an enzyme which degrades tachykinins, increases anaphylactic contraction of guinea pig tracheal smooth muscle. Anaphylactic release of tachykinin-like substances was indicated. To investigate this observation further, we examined the effects of phosphoramidon, an inhibitor of a neutral endopeptidase, on contraction induced by mediators of anaphylaxis. Phosphoramidon significantly increased histamine- and leukotriene D4-induced contractions of tracheal rings from unsensitized animals (by 14 and 48%, respectively), but failed to alter the contractile responses to prostaglandins D2 and F2 alpha. In tracheal rings preincubated with tachykinin antagonist-[D-Pro4, D-Trp7,9]-substance P(4-11), or in capsaicin-desensitized tracheal rings, phosphoramidon did not change histamine- and leukotriene D4-induced contractions. In the second part of the study, performed on tracheal rings obtained from ovalbumin-sensitized guinea pigs, we examined the effects of phosphoramidon on contractile responses to histamine and leukotrienes which are released after antigen challenge. The incubation of tracheal rings with H1-histamine receptor antagonist (diphenhydramine HCl) or leukotriene receptor antagonist (ICI 198.615) prevented a phosphoramidon-dependent increase of antigen-induced contraction. These results indicate that histamine and leukotrienes may be involved in the anaphylactic release of tachykinin-like substances or other neutral endopeptidase substratum.
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PMID:Phosphoramidon augments contraction of guinea pig tracheal smooth muscle induced by histamine and leukotriene-D4. 811 Dec 47

Mast cells play a key role in inflammatory reactions triggered by tissue injury or immune perturbations. Little is known about endogenous molecules and mechanisms capable of modulating inappropriate mast cell activity. N-(2-Hydroxyethyl)hexadecanamide (palmitoylethanolamide), found in peripheral tissues, has been proposed to act as a local autacoid capable of negatively regulating mast cell activation and inflammation-hence the acronym Autacoid Local Inflammation Antagonism (ALIA). Recently, N-(2-hydroxyethyl)hexadecanamide (LG 2110/1) has been reported to down-modulate mast cell activation in vitro by behaving as an agonist at the peripheral cannabinoid CB2 receptor. Here, we have characterized and functionally correlated the anti-inflammatory actions of LG 2110/1 with its ability to control mast cell activation, when given orally in a battery of rodent models of inflammation. LG 2110/1 diminished, in a dose-dependent and correllated manner, the number of degranulated mast cells and plasma extravasation induced by substance P injection in the mouse ear pinna. In addition, LG 2110/1 reduced dose dependently plasma extravasation induced by passive cutaneous anaphylaxis reaction. In adult rats LG 2110/1 decreased, in a dose-dependent manner, carrageenan-induced hindpaw edema and hyperalgesia, but not phospholipase A2-induced hindpaw edema. Further, anti-edema effects were observed when utilizing dextran and formalin, known to also cause mast cell activation. Locally administered LG 2110/1 was likewise effective in minimizing dextran-induced hind paw edema. In contrast, equivalent amounts of palmitic acid plus ethanolamine were ineffective against plasma extravasation provoked by substance P. LG 2110/1 did not decrease plasma extravasation induced by the substance P fragment, substance P-(6-11), known to be inactive on mast cells. These results indicate that orally administered N-(2-hydroxyethyl)hexadecanamide is effective in: (a) directly down-modulating mast cell activation in vivo; (b) suppressing pathological consequences initiated by mast cell activation independently of the activating stimuli; (c) exerting an anti-inflammatory action distinguishable from that of classical steroidal and non-steroidal anti-inflammatory agents. These findings raise the possibility that N-(2-hydroxyethyl)hexadecanamide and related saturated N-acylamides ('ALIAmides') represent novel therapeutic agents useful in the management of inflammatory disease conditions.
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PMID:N-(2-hydroxyethyl)hexadecanamide is orally active in reducing edema formation and inflammatory hyperalgesia by down-modulating mast cell activation. 873 13

The morbidity of allergic airway disease and the number of deaths resulting from it have not declined in the past ten years. The multiplicity of mediators released in the acute allergic reaction and our limited knowledge of the basic mechanisms that drive chronic inflammation have hampered the design of effective therapeutic regimens for this type of disease. In this article, Claude Bertrand and Pierangelo Geppetti summarize recent studies in which new, potent and selective tachykinin and kinin receptor antagonists demonstrate the involvement of tachykinins and kinins in airway anaphylaxis, and review how these antagonists might be of use in treating allergic asthma and rhinitis.
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PMID:Tachykinin and kinin receptor antagonists: therapeutic perspectives in allergic airway disease. 875 84

SR 140333, the first member of a newly developed neurokinin-1 (NK1) receptor antagonist series, inhibited in a dose-dependent manner oedema formation in rat skin when administered i.d. premixed with [Arg6,Sar9,Met(O2)11]substance P(6-11) (NK1 ago), a selective agonist of the NK1 receptor or substance P (SP) (ED50 values = 0.9 +/- 0.3 and 0.8 +/- 0.2 nmol/site, respectively) (n = 9). SR 140333 protected rats from NK1 ago- or SP-induced plasma extravasation with ED50 values of 35 +/- 7 and 43 +/- 6 micrograms/kg, respectively, when given i.v. 15 min before the challenge. In ovalbumin-presensitized rats, SR 140333, premixed with the allergen, inhibited in a dose-dependent manner plasma exudation (ED50 = 0.18 +/- 0.04 nmol/site, i.d.) (n = 15). Intravenous injection of SR 140333 inhibited allergen-induced vascular permeability (ED50 = 87 +/- 14 micrograms/kg). These results therefore show that NK1 plays a major role in the development of cutaneous anaphylaxis and that SR 140333 may be an effective prophylactic drug.
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PMID:Effect of SR 140333, a selective NK1 antagonist, on antigen-induced oedema formation in rat skin. 881 86

Two tachykinin NK2 receptor antagonists, MEN 10.627 c(Met-Asp-Trp-Phe-Dap-Leu) and MEN 10.376 [(Tyr5,Trp6,8,9,Lys10]neurokinin A-(4-10), were used to investigate the role of tachykinins in in vitro guinea-pig lung anaphylaxis. Both antagonists dose-dependently decreased bronchoconstriction and the release of thromboxane and prostaglandin E2 induced by antigen challenge in perfused sensitized lungs, but neither had any effect on the basal release of either eicosanoid. The findings indicated that tachykinins released by sensory nerve fibers may contribute to anaphylactic reactions by increasing arachidonic acid metabolite release.
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PMID:Tachykinin NK2 receptor antagonists decrease eicosanoid release in lung anaphylaxis. 890 45


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