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 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 activity levels of a dynorphin converting enzyme (DCE), a substance P endopeptidase (SPE) and a substance P alpha-amidating enzyme (SP-GLYE) were measured in the cerebrospinal fluid (CSF) of 90 patients with chronic low back pain, sciatica and neurological signs of rhizopathy. The DCE activity was significantly higher in men than in women. Age was related to the DCE activity independent of sex, i.e., older patients had higher enzyme activity. The activities of two substance P converting enzymes were not related to sex or age. Self-reported pain experience and affective covariates (anxiety, depression, hostility, somatization) of pain, and myelography data were not found to be related to the enzyme activity levels once adjustment had been made for sex and age. The activity levels of the enzymes measured here had no predictive value for the long-term outcome of rehabilitation and therapy at the 5-year follow-up of the patients. The sex difference in DCE activity provides further evidence in favor of the role of gender in the psychoendocrine coping with pain distress.
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PMID:Neuropeptide converting enzyme activities in CSF of low back pain patients. 215 Aug 78

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

Neutral endopeptidase exists on the membranes of many cells in the airways. By cleaving and thus inactivating tachykinins released from sensory nerves, NEP limits the actions of these peptides. The selectivity of the enzyme is due, at least in part, to its close association with tachykinin receptors. By cleaving and inactivating the tachykinins, it limits the concentration of tachykinin that reaches the receptor. Decreased NEP activity produced by selective enzyme inhibitors, air pollutants, infections, and oxidants leads to exaggerated neurogenic inflammation. We speculate that the multiple stimuli that enter the airways of healthy individuals normally produce small, nonsymptomatic neurogenic inflammatory responses. However, when NEP activity is decreased, the responses become exaggerated and may contribute to the pathogenesis of diseases such as asthma and bronchitis.
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PMID:Decreased neutral endopeptidases: possible role in inflammatory diseases of airways. 216 84

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

Recently, it has been hypothesized that the N-terminal portion of substance P (SP), SP(1-7), which results from the action of endopeptidase 24.11 (EC3.4.24.11), could be involved in mediating the depressor effects of baroreceptor afferent activation via its action on cells in the nucleus tractus solitarius (NTS). In this study, the binding of a monoclonal antibody to endopeptidase 24.11 was examined immunohistochemically at the level of the caudal medulla of the rat brain. By light microscopy, intense immunoreactivity was seen in the NTS, in fibers bordering the area postrema, and in the area postrema itself. After electron microscopy, endopeptidase 24.11-like immunoreactivity was seen to be associated with the cytoskeleton and plasma membrane in axons, dendrites and glial processes. Antigen was also associated with synaptic vesicles and plasma membranes in presynaptic terminals forming mainly axo-dendritic synapses typical of vagal afferent terminals involved in the baroreceptor reflex. Thus, endopeptidase 24.11 appears to be localized at sites where it could effectively process SP prior to its binding to postsynaptic receptors.
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PMID:Immunocytochemical localization of endopeptidase-24.11 in the nucleus tractus solitarius of the rat brain. 229 Jun 20

Nonadrenergic, noncholinergic contractile responses of guinea pig hilar bronchi to transmural electrical stimulation (TES) have been suggested to be due to release of endogenous tachykinins from capsaicin-sensitive neurons (C-fibers). Thiorphan and phosphoramidon, inhibitors of neutral endopeptidase (NEP, the major enzyme responsible for degrading tachykinins), were found to potentiate contractile responses of this isolated airway segment to TES and exogenously applied capsaicin, substance P and neurokinin A. However, the magnitude of potentiation by either inhibitor was smaller for TES and capsaicin (less than 10-fold leftward shift) than for the substrate agonists (about 100-fold leftward shift). This quantitative difference in potentiation by NEP inhibitors does not appear to be due to an influence of vasoactive intestinal peptide or calcitonin gene-related peptide, two endogenous peptides that might be released concomitantly by TES. Neither peptide caused marked effects on contractile responses to TES or tachykinins when applied to the isolated tissues. Addition of inhibitors of serine proteases, aminopeptidases, acetylcholinesterase and angiotensin-converting enzyme failed to further potentiate responses to TES in the presence of thiorphan. Therefore, the contractile response does not appear to be further modified by the activity of these peptidases. Neuropeptide gamma, but not neuropeptide K, was potentiated by thiorphan. The data suggest that peptides that are not substrates for NEP (for example, neuropeptide K) may also be released by TES from capsaicin-sensitive neurons to cause contraction. This may, at least in part, explain the quantitative difference in potentiation by NEP inhibitors of contractile responses to TES and to exogenously applied NEP-sensitive tachykinins in the guinea pig hilar bronchus.
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PMID:Pharmacologic studies on the differential influence of inhibitors of neutral endopeptidase on nonadrenergic, noncholinergic contractile responses of the guinea pig isolated hilar bronchus to transmural electrical stimulation and exogenously applied tachykinins. 239 13

Synaptic membrane preparations from human striatum and human diencephalon were shown to contain a phosphoramidon-sensitive metalloendopeptidase that appeared identical with endopeptidase-24.11. The activity of endopeptidase-24.11 was determined with an enzymic assay employing [D-Ala2,Leu5]enkephalin as substrate, and its distribution in human brain was similar to that in pig brain, with the striatum containing the highest levels. The choroid plexus and pons also contained substantial activity. A good correlation (r = 0.97) was obtained for the distribution of the endopeptidase in pig brain and pituitary by the enzymic assay and by an immunoradiometric assay specific for pig endopeptidase-24.11. Synaptic membrane preparations from human striatum and diencephalon hydrolysed substance P at the same sites as did preparations of pig striatal synaptic membranes, and hydrolysis was substantially abolished by phosphoramidon. These results suggest that endopeptidase-24.11 is the principal enzyme hydrolysing substance P in human synaptic membrane preparations.
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PMID:The metabolism of neuropeptides. Endopeptidase-24.11 in human synaptic membrane preparations hydrolyses substance P. 240 61


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