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 first inhibitor of angiotensin converting enzyme (ACE) was found in and isolated from the venom of the South American pit viper Bothrops jararaca. This was done after it was discovered that bites of the pit viper inhibit the breakdown of a proinflammatory peptide, bradykinin, in prey. Treatment with newly developed orally active ACE-inhibitors has been reported to cause symptoms such as adverse skin reactions, angioneurotic oedema, coughs and, in asthmatics, rapidly decreasing lung function. In this thesis the ACE-inhibitor MK 422 (active parent diacid of enalapril) was demonstrated to potentiate wheal and flare reactions induced by allergens, bradykinin or capsaicin, and to increase infiltration of "inflammatory cells", like eosinophils and neutrophils, into inflammatory dermal test sites in sensitized guinea pigs. MK 422 also augmented spontaneous and allergen-triggered histamine release in vitro from guinea pig skin and lung tissue. Capsaicin "desensitization" of guinea pig skin markedly reduced the wheal and flare reactions to allergens and attenuated the proinflammatory effect of the ACE-inhibitor. The histamine release in vitro from capsaicin-pretreated skin was also decreased, and no clear potentiating effect of MK 422 was demonstrated. In man, enalapril augmented anti-IgE-induced wheal and flare responses and increased bronchial reactivity to histamine. The drop of circulating eosinophils in venous blood was more pronounced after the provocations performed during enalapril treatment, and plasma substance P tended to increase. The alpha 2-adrenoceptor agonist clonidine, known to attenuate "neurogenic inflammation", reduced the wheal and flare reactions in guinea pig skin and decreased infiltration of neutrophils and eosinophils into inflammatory test sites. Furthermore, clonidine abolished the proinflammatory effect of MK 422 on the allergen- evoked wheal and flare reactions in guinea pig skin without counteracting the blood pressure lowering effect of the ACE-inhibitor. Contrarily, an additive hypotensive effect was demonstrated when clonidine was combined with MK 422. It is suggested that the proinflammatory properties demonstrated by ACE-inhibitors is due to augmentation of "neurogenic inflammation".
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PMID:New aspects on inflammatory reactions and cough following inhibiton of angiotensin converting enzyme. 246 91

Mast cells of human skin, but not lung, adenoids, tonsils, or intestine, release histamine in response to substance P, vasoactive intestinal polypeptide, and somatostatin. The substance P receptor of skin mast cells is not of the NK-1, NK-2 or NK-3 subtypes of smooth muscle. Time course and calcium dependency of release by peptides differed from anti-IgE. With anti-IgE, the molar ratios of histamine:PGD2:LTC4 generated by skin mast cells was 1,000:25:2, whereas with substance P these ratios were 1,000:1:0.1. Similar results were obtained with the other neuropeptides. The ability of peptides to stimulate skin mast cell histamine release suggests a mechanism whereby their release from dermal nerve endings is coupled to changes in microvasculature.
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PMID:Interaction of neuropeptides with human mast cells. 246 22

We describe here a series of experiments which have been undertaken in the course of several years to try and study secretory mechanisms operative in the release of antibodies in the lumen of the intestine. The results of our experiments suggest that there are a number of stimuli that are efficacious in eliciting antibody release in the lumen of the rat intestine. These include the peptide hormones cholecystokinin and substance P, and cholinergic agonists such as pilocarpine. The fact that food has a similar effect indicates that the stimulation of antibody release is a physiological process co-ordinated with the ingestion of foreign antigens. We have also shown that food mediates its effect by means of cholecystokinin. Cholecystokinin promotes the release of antibodies belonging to the IgA, IgG, IgM and IgE isotypes. There is reason to believe that not all the IgA is secretory IgA. Antibody release can be inhibited by the CCK antagonist proglumide and by cholinergic antagonists. The intracellular messengers that participate in this process are changes in cytosolic calcium. It is proposed that the release of antibodies in the gastrointestinal tract is an active secretory process.
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PMID:A study of stimuli operative in the release of antibodies in the rat intestine. 247 91

1. Cells were dispersed from human foreskin using a mixture of collagenase and hyaluronidase and separated into mast cell-depleted (less than 1%) or enriched (greater than 75%) preparations by density-gradient centrifugation. 2. Challenge of gradient fractions with epsilon-chain-specific anti-human IgE stimulated the release of histamine, prostaglandin D2 (PGD2) and leukotriene C4 (LTC4). The release of eicosanoids was significantly correlated with that of histamine, suggesting that they are derived from the mast cell population of the dispersate. In highly purified (76.2 +/- 4.2%) mast cell preparations, maximum net release of histamine, PGD2 and LTC4 was 3432 +/- 725, 84.9 +/- 10.8 and 6.6 +/- 1.2 pmol/10(6) nucleated cells. 3. The non-immunological stimuli substance P, vasoactive intestinal peptide (VIP), somatostatin, compound 48/80, morphine and poly-L-lysine released similar amounts of histamine to anti-IgE, but 12 to 21 fold less PGD2 and LTC4. 4. These studies suggest that IgE-dependent and non-immunological stimuli activate human skin mast cells by different secretory mechanisms, a hypothesis supported by our previous findings of differences in Ca2+ requirements and time-course of histamine release. Activation by the non-immunological mechanism may be of importance in vivo due to the close anatomical association between skin mast cells and dermal nerve-terminals containing neuropeptides.
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PMID:Differential release of histamine and eicosanoids from human skin mast cells activated by IgE-dependent and non-immunological stimuli. 247 53

Rat peritoneal mast cells co-cultured with mouse 3T3 fibroblasts (MC/3T3) are fully responsive to immunologic stimuli. To assess their nonimmunologic activation MC/3T3 were challenged with various peptides. Optimal concentrations of substance P (10(-4) M) and bradykinin (5 x 10(-5) M) induced histamine release of 58.2 +/- 9.3 and 66.8 +/- 6.6%, respectively, while neurotensin (10(-4) M) released only 16.6 +/- 3.7% histamine. Freshly isolated mast cells (F-MC) challenged with the same concentrations of peptides released lower percentages of histamine (substance P 45.6 +/- 5.1%, bradykinin 32.5 +/- 5.3%, neurotensin 11.3 +/- 6.0%). In both MC/3T3 and F-MC, only minute amounts of prostaglandin D2 (PGD2) were produced. In contrast, activation with anti-IgE antibodies and compound 48/80 caused both histamine release and PGD2 generation. Compound 48/80-stimulated MC/3T3 and F-MC released 80.2 +/- 3.4 and 51.8 +/- 6.2% histamine, respectively, and produced 15.4 +/- 2.8 ng/10(6) mast cells and 3.9 +/- 1.4 ng/10(6) mast cells PGD2, respectively. These findings indicate that peptides and bradykinin induce selective release of histamine with no PGD2 production in both F-MC and MC/3T3. Moreover, MC/3T3 preserve their functional characteristics of connective tissue mast cells since they are fully responsive to these peptides as F-MC.
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PMID:Differential release of histamine and prostaglandin D2 in rat peritoneal mast cells activated with peptides. 248 57

Many agents are capable of mast cell activation (MCA). In the lung, exposure to allergens induces IgE-mediated mast cell degranulation. By this process, chemical mediators are released and attract inflammatory cells that infiltrate the airway wall. This immune response is a potent stimulus for the pathologic changes seen in asthma (e.g., bronchospasm, mucosal edema, airway hyperreactivity, and mucus secretion). One neglected component of the asthmatic response is vascular permeability--the hallmark of mast cell degranulation. Like muscle contraction, vascular permeability occurs rapidly in response to an antigen challenge and is prevented by classic antiasthmatic therapy. Studies with antidromic nerve stimulation have indicated a relationship between MCA and the histamine-induced release of the sensory neuropeptide substance P, which causes vasodilation. Mediators released during the immediate hypersensitivity reaction may attract neutrophils and other chemotactic factors involved in the late allergic response, which includes a recrudescence of MCA caused by the release of histamine-releasing factors. Understanding these pathophysiologic events in asthma will be useful in formulating therapy.
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PMID:Asthma and mast cell activation. 264 47

This short review examines two examples of studies into the mechanisms of allergic responses which have particular relevance to inflammation research. The first is the ability of human skin mast cells, but not those derived from lung, adenoids, tonsils or intestine, to release histamine in response to stimulation by neuropeptides including substance P, vasoactive intestinal polypeptide (VIP) and somatostatin. The neuropeptide activation site does not appear to be a classical tachykinin receptor but rather a binding site of low affinity and low specificity capable of interacting with neuropeptides and compounds with similar physicochemical characteristics. In contrast to IgE-dependent activation, neuropeptide stimulation of skin mast cells induces a rapid release of histamine with minimal generation of PGD2 and LTC4. This pseudo-allergic reaction is thought to underlie the weal and flare response in the skin and may have a role in urticaria. The second example describes studies to elucidate the mechanisms of the late asthmatic response by use of a guinea-pig model. As in man, both early and late phase responses in the guinea-pig are inhibited by sodium cromoglycate whereas only the early response is inhibited by the beta-adrenoceptor stimulant drug salbutamol. Examination of bronchoalveolar fluid has shown a temporal relationship between an airways neutrophilia and the late response. However, pharmacological manipulation and the use of an anti-neutrophil serum has shown that these events are not interdependent. The role of the airways eosinophilia requires further investigation.
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PMID:Allergy or inflammation? From neuropeptide stimulation of human skin mast cells to studies on the mechanism of the late asthmatic response. 265 5

The tracheobronchial mucosa of anaesthetized guinea-pigs (normal or sensitized with ovalbumin to produce IgE and IgG antibodies) was superfused (0.02 ml min-1, 5 min) with saline, mediators, and (in sensitized animals) ovalbumin via a catheter atraumatically introduced orally. The intravascular blood pool and amount of macromolecules in excised trachea and adjoining main bronchi were quantified by measuring erythrocytes, that had been labelled in vivo with 99Tcm, and analysing for FITC-dextran, MW = 70,000, that had been given i.v. Extravasation of macromolecules was determined as the analysed total content minus the calculated intravascular content of FITC-dextran. Capsaicin 0.1 nmol extravasated 223 micrograms of FITC-dextran per g wet weight of airway tissue (P less than 0.001). Substance P 0.1 nmol, 41 micrograms g-1 (P greater than 0.05); substance P 0.3 nmol, 142 micrograms g-1 (P less than 0.001); eledoisine 0.1 nmol, 101 micrograms g-1 (P less than 0.01); ovalbumin 0.1 microgram, 179 micrograms g-1 (P less than 0.001); LTC4 0.2 pmol, 180 micrograms g-1 (P less than 0.001); LTD4 0.2 pmol 223 micrograms ml-1 (P less than 0.001). Bronchi and trachea were similarly affected by these agents. Prior superfusion (0.02 ml min-1, 30 min) with terbutaline 0.06 nmol, enprofylline 12 nmol, or lidocaine 6 nmol significantly reduced the effect of capsaicin. Enprofylline also reduced significantly the effect of LTC4. The degree of extravasation in this study was smaller than could be detected by changes in tissue wet to dry weight ratios. The present data support the view that tracheobronchial vascular permeability to macromolecules is subject to physiological and pharmacological control.
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PMID:Leakage of macromolecules from guinea-pig tracheobronchial microcirculation. Effects of allergen, leukotrienes, tachykinins, and anti-asthma drugs. 287 10

The functional and biochemical characterization of rat bone marrow derived mast cells (RBMMC) confirms both species-related differences between rat and mouse bone marrow-derived mast cells (MBMMC) as well as mast cell heterogeneity in a single species. Such RBMMC have the staining characteristics of mucosal mast cells and contain the mucosal mast cell protease. The RBMMC release the preformed granule mediator beta-hexosaminidase both in response to immunologic stimulation with 200 ng Ag (net release 15.8 +/- 3.8%) and in response to 1 microM calcium ionophore A23187 (net release 21.8 +/- 6.8%). However, compound 48/80, substance P, and somatostatin did not induce mast cell degranulation. In experiments with optimal beta-hexosaminidase release, the RBMMC generated similar quantities of the newly formed arachidonic acid metabolites leukotriene C4 and PGD2 when stimulated with either Ag or calcium ionophore A23187. The RBMMC incorporate [35S]sulfate into proteoglycans consisting of 90% chondroitin sulfates and 10% heparin. The chondroitin sulfates were comprised of chondroitin 4 sulfate and chondroitin sulfate diB sulfated disaccharides in a ratio of 4/1. Although we show that RBMMC and MBMMC share a low histamine content, functional IgE receptors and unresponsiveness to cromolyn and selective secretagogues (compound 48/80, substance P, and somatostatin), we also provide evidence that RBMMC differ from MBMMC in their profile of newly generated mediators, preformed granule proteoglycan, and lack of proliferative response to mouse IL-3.
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PMID:Functional and biochemical characterization of rat bone marrow derived mast cells. 297 57

The term hyper-reactivity defines an inadequate reaction of the nose to normal airborne stimuli that are harmless to most of the population. In such cases the nose always shows exactly the same symptoms, irrespective of whether the rhinitis is allergic (IgE- or cell-mediated) or nonspecific (vasomotor). These symptoms include sneezing, nasal obstruction, hypersecretion, and itching of the nose. The vascular supply of the nose consists of capacitance vessels (veins, venules, sinusoids), resistance vessels (arteries, arterioles), and exchange vessels (capillaries of fenestrated types). Drug and mediator effects may be directed to different nasal vessel systems. The autonomic innervation of the nose is complex. Some neuropeptides have been demonstrated, in addition to the classical neurotransmitters of the sympathetic and parasympathetic system. Neuropeptide Y (NPY) is found in adrenergic fibers, vasoactive intestinal peptide (VIP) in cholinergic neurones; substance P (SP), calcitonin-gene-related peptide (CGRP) and neurokinine (NKA) are found in sensory nerves. The possible significance of the different neurotransmitters and mediators in nasal hyperreactivity is discussed.
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PMID:[Current aspects of nasal hyperreactivity]. 306 18


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