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 physiological effects of the tachykinin peptides substance P (SP) and neurokinin A (NKA) are limited by their microenvironmental degradation. We used the isolated tracheally superfused guinea pig lung to examine the importance of various degradative enzymes in limiting the physiological effects of exogenously administered and endogenously released tachykinins. When SP and NKA are administered via the airway epithelium, neutral endopeptidase (NEP; EC 3.4.24.11) is the major degradative enzyme as indicated by the effects of NEP inhibitors alone compared to the effects of a NEP inhibitor along with a cocktail of other peptidase inhibitors. The effects of enzyme inhibitors on physiological responses is mirrored in the amounts of peptide recovered from lung perfusates as determined using an enzyme-linked immunosorbent assay. We found similar effects when SP and NKA were released endogenously by the acute infusion of capsaicin. These data indicate that NEP is the predominant degradative enzyme modulating the effects of SP and NKA administered via the airways.
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PMID:Peptidase modulation of the pulmonary effects of tachykinins. 171 94

It was shown in two different provocation models (nasal and bronchial provocation) that substance P (SP) may play an important role in the neurogenic inflammatory response in upper and lower airway disease. (1) Pretreatment with SP augments the antigen challenge response of the nasal mucosa. (2) The baseline bronchoalveolar lavage (BAL) concentrations of SP are elevated 8-fold in allergies (pollen asthma) as compared with normals, even outside of season. (3) The SP concentration in BAL increases significantly (p less than 0.05) after bronchial allergen provocation. These findings support a previous hypothesis of an abnormally elevated activity of nonadrenergic-noncholinergic excitatory nerves and are in accordance with the results of a decreased activity of neutral endopeptidase exaggerating neurogenic inflammatory responses in the airways, including bronchomotor tone hyperresponsiveness.
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PMID:The possible role of substance P in the allergic reaction, based on two different provocation models. 171 96

We studied the effect of substance P (SP) on the electric properties of cultured canine tracheal epithelium and its possible modulation by neutral endopeptidase (NEP) by Ussing's short-circuited technique in vitro. Addition of SP (5 x 10(-6) M) to the mucosal side increased short-circuit current (SCC) from 5.1 +/- 0.9 to 10.3 +/- 2.2 microA/cm2 (mean +/- SE; p less than 0.01), which was accompanied by increases in transepithelial potential difference and conductance. The effect of the mucosal SP on SCC was dose-dependent, with the maximal increase from the baseline value being 5.8 +/- 1.0 microA/cm2 observed at 5 x 10(-5) M. The NEP inhibitor phosphoramidon (10(-5) M) did not affect these responses. On the other hand, SCC was not altered by the addition of SP to the submucosal side. However, it was increased dose-dependently in the presence of phosphoramidon (10(-5) M) but not in the presence of captopril, bestatin or leupeptin. This stimulatory effect of submucosal SP was abolished by furosemide, diphenylamine-2-carboxylate and Cl-free medium, but not by amiloride. These results suggest that SP may selectively stimulate Cl secretion across the airway epithelium and that this effect may be modulated by submucosal NEP.
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PMID:Effect of neutral endopeptidase inhibition on substance-P-induced increase in short-circuit current of canine cultured tracheal epithelium. 171 8

The release of substance P- and neurokinin A-like immunoreactivities (SP-LI and NKA-LI) after tracheal infusion of histamine, methacholine, leukotriene D4, and platelet-activating factor was measured in isolated guinea pig lungs superfused through the trachea. Infusion of each of these agonists was associated with a significant (P less than 0.05) increase in the recovery of both SP-LI and NKA-LI from lung perfusates compared with preinfusion baseline recoveries of these peptides. After infusion of bronchoactive mediators, approximately 4-15 times more NKA-LI than SP-LI was recovered from the lung superfusate. Coincident with the release of neuropeptides, mediator infusion was accompanied by an increase in airway opening pressure (Pao). Addition to the perfusate of the neutral endopeptidase inhibitor thiorphan, 1 microM increased the change in Pao induced by histamine (10(-8) mol, P less than 0.005) and methacholine (10(-8) mol, P less than 0.02) and increased the recovery of NKA-LI (P less than 0.05 for histamine and methacholine). Addition of isoproterenol to the perfusion buffer reduced, but did not abolish, either the Pao response or the increased recovery of NKA-LI (P less than 0.05) observed after histamine infusion. We conclude that bronchoactive agonists have the capacity to release both SP-LI and NKA-LI, and we speculate that NKA contributes to the bronchomotor response observed in response to histamine or methacholine.
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PMID:Release of tachykinins by histamine, methacholine, PAF, LTD4, and substance P from guinea pig lungs. 172 49

1. The effects of the inhaled neuropeptides, neurokinin A (NKA) and substance P (SP) on lung resistance (RL) and airway microvascular permeability were studied in anaesthetized guinea-pigs. 2. Single doses of inhaled NKA (3 x 10(-5), 1 x 10(-4), 3 x 10(-4) M; 45 breaths) and SP (1 x 10(-4), 3 x 10(-4), 1 x 10(-3); 45 breaths) caused a dose-dependent increase in both RL and airway microvascular leakage, assessed as extravasation of the albumin marker, Evans blue dye. 3. NKA at 1 x 10(-4) and 3 x 10(-4) M resulted in a significantly higher increase in RL than SP at the same doses. 4. Inhaled SP (3 x 10(-4) M; 45 breaths) caused significantly higher Evans blue dye extravasation in main bronchi and proximal intrapulmonary airways compared to the same dose of NKA. 5. Pretreatment with the specific inhibitor of neural endopeptidase (NEP24.11), phosphoramidon, caused an approximately 100 fold leftward shift of the RL responses to inhaled NKA and SP. 6. Phosphoramidon significantly potentiated both NKA- and SP-induced airway microvascular leakage at proximal intrapulmonary airways, but not at any other airway level. 7. Inhibition of NEP24.11 potentiate both the SP- or NKA-induced airflow obstruction to a larger extent than the induced airway microvascular leakage, suggesting that NEP24.11 is more important in the modulation of the airflow obstruction observed after these mediators.
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PMID:Differential effects of phosphoramidon on neurokinin A- and substance P-induced airflow obstruction and airway microvascular leakage in guinea-pig. 172 66

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

Neurotensin (NT) endopeptidase (EC 3.4.24.16) has been purified about 800-fold from pig brain by four sequential chromatographic steps depending on ion-exchange and hydrophobic interactions. Two types of preparation were studied: one from a Triton X-100-solubilized membrane fraction, and the other from the soluble fraction containing 90% or more of the total activity in the homogenate. NT endopeptidase activity was monitored by high-precision liquid chromatography of the two peptide products, characterized as NT-(1-10) and NT-(1-8), resulting from cleavage of the Pro10-Tyr11 and Arg8-Arg9 bonds respectively. As purification proceeded, from both membranes and cytosol, the yield of the two products achieved a constant ratio of 5:1 and this ratio was reproduced in repeated purifications. However, a distinct peptidase which hydrolysed exclusively at the Arg8-Arg9 bond was partially resolved from NT endopeptidase by chromatography on hydroxyapatite, and this activity was further purified and assigned to endopeptidase-24.15 (EC 3.4.24.15). SDS/PAGE of both preparations of neurotensin endopeptidase revealed a major band of apparent Mr 75000, and treatment of the membrane-associated form with N-Glycanase gave no evidence that the enzyme was a glycoprotein. The membrane-associated and cytosol forms of NT endopeptidase activities, monitored for both NT-(1-10) and NT-(1-8) products, were compared in their responses to 1,10-phenanthroline, EDTA, dithiothreitol (DTT) and some synthetic site-directed inhibitors of endopeptidase-24.15 or peptidyl dipeptidase A. The effects revealed no significant differences between the two preparations, nor did the reagents discriminate between the activities generating the two NT fragments. The partially purified form of endopeptidase-24.15 was also included in this comparison: while some responses were similar, this peptidase was distinguishable in its activation by DTT and its relative resistance to inhibition by EDTA. Both forms of NT endopeptidase were found to hydrolyse other substrates, including Boc-Phe-Ala-Ala-Phe-4-aminobenzoate, bradykinin and substance P (these at faster rates than neurotensin), as well as dynorphin A-(1-8) and luliberin. The bonds hydrolysed in these neuropeptides, as well as in angiotensins I and II and alpha-neoendorphin, were defined. These studies confirm that NT endopeptidase is distinct from endopeptidase-24.15. They further show that the former is a soluble enzyme, not an integral membrane protein, that it is not peptide-specific and that it might be more appropriately named. enzyme, not an integral membrane protein, that it is not peptide-specific and
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PMID:Purification and properties of a neurotensin-degrading endopeptidase from pig brain. 190 21


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