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)

Male Hartley guinea pigs were treated with the enkephalinase inhibitor thiorphan by inhaled or intravenous administration routes and potentiation of substance P-induced airway obstruction examined. Inhaled thiorphan was several thousand times more potent than intravenous thiorphan. The biologic half-life was less than 5 min for aerosolized thiorphan and greater than 20 min after intravenous administration. The very high potency of aerosolized thiorphan may be a result of its direct targeting to enkephalinase concentrated within the airway epithelium. The short duration of action of inhaled thiorphan may reflect its rapid diffusion from the airway surface.
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PMID:Effects of inhaled or intravenous thiorphan on substance P-induced airway obstruction. 172 51

An endopeptidase was isolated from Xenopus laevis skin secretions. This enzyme, which has an apparent molecular mass of 100 kDa, performs a selective cleavage at the Xaa-Phe, Xaa-Leu, or Xaa-Ile bond (Xaa = Ser, Phe, Tyr, His, or Gly) of a number of peptide hormones, including atrial natriuretic factor, substance P, angiotensin II, bradykinin, somatostatin, neuromedins B and C, and litorin. The peptidase exhibited optimal activity at pH 7.5 and a Km in the micromolar range. No cleavage was produced in vasopressin, ocytocin, minigastrin I, and [Leu5]enkephalin, which include in their sequence an Xaa-Phe, Xaa-Leu, or Xaa-Ile motif. The endopeptidase activity was inhibited by divalent cation chelators and by phosphoramidon only at high concentrations (IC50 = 50 microM), whereas it was insensitive to classical inhibitors of chymotrypsin, angiotensin convertase, and serine and cysteine peptidases, as well as carboxypeptidases. It is hypothesized that this enzyme, which is distinct from neutral endopeptidase (EC 3.4.24.11), constitutes the prototype of a family of related metalloendopeptidases that inactivate peptide substrates by cleavage at the Xaa-Phe, Xaa-Leu, or Xaa-Ile bond.
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PMID:A peptide-hormone-inactivating endopeptidase in Xenopus laevis skin secretion. 172 23

Membrane metalloendopeptidase (MMEP; EC 3.4.24.11; enkephalinase) catalyzes the degradation of endothelins, enkephalins, atrial natriuretic factor, substance P, and other small bioactive peptides. We found that MMEP is present in human endometrium, localized primarily in stromal cells of this tissue, and that the specific activity of MMEP (and immunoreactive MMEP protein) in endometrial tissue is correlated in a highly significant positive manner with the concentration of progesterone in plasma. In estrogen-treated, human endometrial stromal cells in monolayer culture, the specific activity of MMEP increases in response to treatment with progestin; and, this increase is accompanied by increases in immunoreactive MMEP protein, newly synthesized MMEP, and MMEP mRNA.
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PMID:Progesterone-regulated cyclic modulation of membrane metalloendopeptidase (enkephalinase) in human endometrium. 174

A noncholinergic, nonadrenergic nervous system has been described, involving the sensory nerves in the airways. Chemicals, dusts and other irritants stimulate these sensory nerves to release substance P and related neuropeptides. These neuropeptides have the remarkable ability to affect multiple cells in the airways and to provoke many responses including cough, mucus secretion, smooth muscle contraction, plasma extravasation and neutrophil adhesion. This series of effects is termed "neurogenic inflammation." An enzyme exists on the surfaces of all lung cells that contain receptors for these neuropeptides. This enzyme, neutral endopeptidase (NEP), by cleaving and thus inactivating the neuropeptides, limits the concentration of the neuropeptide that reaches the receptor on the cell surface. Thus, neurogenic inflammatory responses are normally mild and presumably protective in nature. However, when NEP is inhibited pharmacologically (with NEP inhibitors) or by cigarette smoke, respiratory viral infection, or by inhalation of the industrial pollutant toluene diisocyanate, neurogenic inflammatory responses are exaggerated. Delivery of exogenous human recombinant NEP inhibits neurogenic inflammation. Finally, evidence is provided that corticosteroids suppress neurogenic plasma extravasation and that this drug can upregulate NEP in human airway tissue. Neutral endopeptidase cleaves multiple peptides. Thus, its selectivity resides, at least in part, on its fixed location on the surfaces of specific cells where it can modulate effects of peptides exposed to the cells' surfaces.
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PMID:Neutral endopeptidase modulates neurogenic inflammation. 188 1

To study the role of tachykinins and neutral endopeptidase (NEP), an enzyme that degrades tachykinins, in the immune response in the airways of guinea pigs sensitized to ovalbumin (OVA), we examined the bronchial contractile response to OVA by inhibiting NEP in vitro. After incubating bronchial tissues with the NEP inhibitors phosphoramidon and thiorphan, we added 10(-5)% (10 micrograms/ml) OVA. Phosphoramidon and thiorphan (10(-5) M) significantly maintained the contraction that followed the peak contraction. In the next stages of the experiment, when the contraction induced by 10(-5)% OVA reached a plateau and began to relax, we added 10(-5) M phosphoramidon. Phosphoramidon inhibited the relaxation and significantly potentiated the contraction. In tissues treated with 10(-5) M capsaicin to deplete tachykinins, phosphoramidon did not potentiate the OVA-induced contraction, but substance P (10(-6) M) caused contraction. These results suggest that the immune response causes the release of tachykinin-like substances from capsaicin-sensitive nerves to induce bronchial contraction in part. To confirm the mediators that cause the release of the tachykinin-like substances from the bronchus, we also examined whether phosphoramidon potentiates the effect of leukotriene C4 (LTC4), serotonin, histamine, and platelet-activating factor on bronchial contraction. When the contractions induced by these agonists reached a plateau and began to relax, we added phosphoramidon. Phosphoramidon inhibited the relaxation and significantly potentiated the contractile response to 10(-5) M LTC4, and it significantly reduced the relaxing rate of the 10(-6) M serotonin-induced contraction. However, it did not change the effect of histamine and platelet-activating factor.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Inhibition of neutral endopeptidase potentiates bronchial contraction induced by immune response in guinea pigs in vitro. 189 4

The effect of peptidase inhibitors on neuropeptide release from peripheral endings of capsaicin-sensitive sensory neurons was studied in cerebral superior sagittal and transverse sinuses of guinea-pig. Capsaicin (1 microM)-evoked release of substance P-like immunoreactivity (SP-LI) was increased in a concentration-dependent manner by thiorphan (0.1-10 microM). Captopril (10 microM) or a mixture of bestatin (10 microM), leupeptin (10 microM) and bacitracin (10 microM) did not affect the capsaicin-evoked SP-LI release. Thiorphan (10 microM) increased also the capsaicin-evoked release of neurokinin A-like immunoreactivity (TK-LI) and calcitonin gene-related peptide-like immunoreactivity (CGRP-LI) by 228% and 172%, respectively, while captopril (10 microM) was without effect. Thiorphan (10 microM), but not captopril (10 microM), enhanced by 239% CGRP-LI release induced by bradykinin (10 microM). In the cerebral venous vessels neutral endopeptidase (EC 3.4.24.11, NEP)-like activity was 58.8 +/- 6.1 pmol/mg protein/min, while angiotensin converting enzyme-like activity was below the detection limit of the assay. A thiorphan-sensitive mechanism, putatively attributable to NEP, plays a major role in the inactivation of peptides released from or acting on capsaicin-sensitive sensory fibres of cerebral venous sinuses of guinea-pig.
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PMID:The effect of thiorphan on release of sensory neuropeptides from guinea-pig cerebral venous sinuses. 206 52

Studies using morphological methods, some contemporary and others traditional, have revealed that part of the distinctive behaviour of the airway mucosa under normal and pathological conditions can be explained by the characteristics of the microvasculature. For example, the terminal arterioles of the airway mucosa are innervated not only by sympathetic and parasympathetic nerves but also by sensory nerves. The sensory nerves release tachykinins such as substance P which dilate arterioles and can increase vascular permeability through an action on postcapillary venules. The increase in vascular permeability produced by these mediators results from gaps in the endothelium that permit the extravasation of plasma proteins into the mucosal connective tissue and even into the airway lumen. The magnitude of the response of postcapillary venules to pro-inflammatory mediators is influenced by numerous factors. Among these are airway infections which can potentiate the response by causing the proliferation of mediator-sensitive venules, by decreasing the breakdown of peptide mediators by neutral endopeptidase, and perhaps by increasing the number of tachykinin receptors on venules.
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PMID:The ultrastructure and permeability of tracheobronchial blood vessels in health and disease. 207 51

Tachykinins, including substance P, are contained in sensory nerves of airways. Sensory nerve stimulation causes release of the tachykinins, thus producing a pattern of responses (smooth muscle contraction, submucosal gland secretion, increased vascular permeability, neutrophil adhesion, and cough) collectively referred to as "neurogenic inflammation". The responses to either exogenously or endogenously-released tachykinins are modulated selectively by neutral endopeptidase (NEP), an enzyme that exists on the membranes of cells that contain tachykinin receptors (e.g. submucosal glands, smooth muscle, postcapillary venous endothelium). By cleaving and thus inactivating the tachykinins, NEP limits their action on receptors. The reduced NEP activity associated with respiratory viral infections and inhaled irritants (e.g. toluene diisocyanate, cigarette smoke) potentiates neurogenic inflammatory responses. Exogenously delivered human recombinant NEP reduces responses to tachykinins. Thus, reduced NEP activity in tissues, by exaggerating inflammatory responses resulting from sensory nerve stimulation, may play an important role in the pathogenesis of inflammatory diseases in airways and in other tissues.
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PMID:Neutral endopeptidase modulation of neurogenic inflammation in airways. 207 58

The airways receive a dense innervation from sensory neurons containing substance P (SP). An anti-SP anti-idiotypic antibody (anti-Id ab) recognizing SP receptors was previously characterized pharmacologically and proved to be useful in immunohistochemistry of the central nervous system. This antibody was used to localize SP binding sites in the guinea-pig trachea by immunohistochemistry. Immunolabelling was considered as specific when it could be prevented by a) preabsorption of the anti-Id ab with a C-terminal specific monoclonal anti-SP antibody, and b) preincubation of the tissue sections with either of the tachykinins, substance P and neurokinin A, in the presence of the inhibitor of neutral endopeptidase, phosphoramidon, and addition of these compounds into the antibody incubation medium. Moreover, immunofluorescence was absent when the acetone-fixed of fresh frozen sections were exposed to the detergent Tween 20 prior to immunohistochemistry, which points to a membrane localization of the detected tissue antigen, as expected for SP receptors. Compared with previous reports on autoradiographic localization of SP receptors in the guinea-pig trachea, the present immunohistochemical approach proved to be superior in enabling discrimination of labelled elements: Trachealis muscle, cylindrical epithelial cells and some roundish, singly lying cells in the epithelium and subepithelial lamina propria displayed specific immunofluorescence. These morphological findings match well with the known pharmacological actions of SP on the guinea-pig trachea.
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PMID:Immunohistochemistry of the guinea-pig trachea using an anti-idiotypic antibody recognizing substance P receptors. 215 58

Thiorphan, a well known inhibitor of 'enkephalinase' (endopeptidase 24.11) potentiated and prolonged the contractile response to substance P (SP) and neurokinin A (NKA) on strips of the guinea-pig isolated urinary bladder and this effect was evident both in presence and absence of the mucosal layer. Thiorphan also enhanced and prolonged the capsaicin-induced contraction in strips from the bladder dome which is thought to be mediated by release of endogenous tachykinins. Exposure to capsaicin produced simultaneous release of SP- and tachykinin-like immunoreactivity both in presence and absence of mucosa. This effect of capsaicin was potentiated by thiorphan. Endopeptidase 24.11 activity was detected in the guinea-pig urinary bladder, being more concentrated in the mucosal than the muscular layer. These findings indicate that endopeptidase 24.11 terminates the activity of tachykinins in the guinea-pig urinary bladder and modulates the intensity of the biological response produced after their release from peripheral endings of sensory nerves.
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PMID:Effect of thiorphan on the response of guinea-pig isolated urinary bladder to exogenous and endogenous tachykinins. 223 60


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