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)

We examined the role of substance P (SP) and neurokinin A (NKA) in the postmortem bronchoconstriction in guinea pig lungs using isolated lungs superfused via the trachea. Airway opening pressure (Pao) during superfusion was monitored and the superfusate collected for analysis of SP- and NKA-like immunoreactivities (SP-LI and NKA-LI, respectively). Peak Pao (39.0 +/- 3.9 cmH2O) was reached 10 min after starting superfusion; Pao decreased slowly thereafter, reaching only 9.9 +/- 2.2% of the peak value 2 h after starting superfusion (P less than 0.005); 12.6 +/- 2.6 and 34.0 +/- 9.7 fmol of SP-LI and NKA-LI, respectively, were found in the fraction corresponding to 10-20 min of superfusion. Recovered immunoreactivities decreased to 5.2 +/- 0.3 and 9.3 +/- 1.8 fmol of SP-LI and NKA-LI, respectively, in the fraction corresponding to 110-120 min of superfusion (P less than 0.05). Inhibition of neutral endopeptidase with thiorphan resulted in significantly greater increases in Pao (P less than 0.005) and augmentation of the recovery of SP-LI and NKA-LI (P less than 0.05 and P less than 0.001, respectively). Capsaicin treatment of animals 7-10 days before the removal of their lungs abolished the increase in Pao during superfusion and resulted in a significant decrease in the amount of SP-LI and NKA-LI recovered. Our data confirm that tachykinin release occurs during postmortem bronchoconstriction in guinea pig lungs and, furthermore, that tachykinin degradation by NEP modulates the intensity of this response.
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PMID:Tachykinin recovery during postmortem bronchoconstriction in guinea pig lungs. 170 33

To determine the roles of endogenously released tachykinins (substance P, neurokinins A and B) in human bronchial tissues, and to determine the roles of enkephalinase (neutral endopeptidase, E.C. 3.4.24.11) in regulating the effects of the tachykinins, we studied the effects of substance P and capsaicin, which releases tachykinins, on human bronchial smooth muscle contraction in the presence or absence of enkephalinase inhibitor phosphoramidon in vitro. Substance P alone caused human bronchial smooth muscle contraction at 10(-6) M or more. Phosphoramidon (10(-7) to 10(-5) M) potentiated the substance P-induced contraction in a dose-dependent fashion, and phosphoramidon shifted the dose-response curve to lower concentrations. Capsaicin (10(-5) or 10(-4) M) alone caused bronchial smooth muscle contraction in four tissues from nine patients. After the contraction by capsaicin reached a plateau, phosphoramidon (10(-5) M) increased and prolonged the contraction significantly. Furthermore, pretreatment of bronchial tissues with phosphoramidon (10(-5) M) potentiated capsaicin-induced contraction in all tissues from five patients. Phosphoramidon (10(-5) M) shifted the dose-response curve to capsaicin to lower concentrations more than 1 log unit. Captopril did not alter the contractile response to substance P, suggesting that angiotensin-converting enzyme does not regulate the contractile response to substance P in human bronchial smooth muscle in vitro. These results suggest that enkephalinase regulates the contractile effects of exogenous substance P and endogenous substances, probably tachykinins, released by capsaicin in the human bronchus.
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PMID:Enkephalinase inhibitor potentiates substance P- and capsaicin-induced bronchial smooth muscle contractions in humans. 171 Aug 81

Glucocorticoids inhibit plasma extravasation induced in the rat tracheal mucosa by substance P and other tachykinins released from sensory nerves. This study was performed to determine whether this antiinflammatory effect of glucocorticoids is mediated by the tachykinin-degrading enzymes neutral endopeptidase (NEP) and kininase II (angiotensin converting enzyme, ACE). In addition, we studied the effect of dexamethasone on a nonpeptide inflammatory mediator, platelet-activating factor (PAF), which is not degraded by NEP or ACE. Adult male pathogen-free F344 rats were treated for 2 d with dexamethasone (0.5 mg/kg per d i.p.), or with the vehicle used to dissolve the steroid. The magnitude of plasma extravasation produced by an intravenous injection of substance P (5 micrograms/kg) or PAF (10 micrograms/kg) was then assessed by using Monastral blue pigment as an intravascular tracer. The role of NEP and ACE activities in the changes produced by dexamethasone was investigated by examining the effect of the selective inhibitors of these enzymes, phosphoramidon and captopril. Dexamethasone reduced the substance P-induced extravasation by 57% but did not affect the PAF-induced extravasation. The suppressive effect of dexamethasone on substance P-induced extravasation was completely reversed by simultaneously inhibiting NEP and ACE activities, but the inhibition of these enzymes had no effect on PAF-induced extravasation, regardless of whether the rats were pretreated with dexamethasone or not. These results suggest that NEP and ACE mediate a selective inhibitory effect of glucocorticoids on neurogenic plasma extravasation.
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PMID:Neutral endopeptidase and kininase II mediate glucocorticoid inhibition of neurogenic inflammation in the rat trachea. 171 45

Neutral endopeptidase (NEP; EC 3.4.24.11) is well recognized as a regulatory peptidase for substance P (SP)-induced responses in various tissues. To determine whether NEP regulates SP-induced activation of human neutrophils, we examined the effect of the NEP inhibitor phosphoramidon on SP-induced superoxide generation and chemotaxis in human blood neutrophils. SP (10(-6)-10(-4) M) induced superoxide generation and chemotaxis in the neutrophils dose dependently. The NEP inhibitor enhanced the SP-induced responses. Thus, phosphoramidon (10(-6) M) shifted the dose-response curves of SP-induced superoxide generation and chemotaxis of the neutrophils to the left by 0.5-0.6 log. Phosphoramidon prevented the hydrolysis of SP by the neutrophils, the NEP activity of the neutrophils being assessed as 125 +/- 13 pmol of SP/min/10(6) cells. The N-terminal peptide SP (up to 3 x 10(-4) M), which was a major degrading product by NEP of the neutrophils, did not activate the neutrophils. We conclude that NEP modulates SP-induced activation of human neutrophils.
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PMID:Neutral endopeptidase modulates substance P-induced activation of human neutrophils. 171 1

We studied the effects of neutral endopeptidase (NEP) and angiotensin-converting enzyme (ACE) inhibition on the airway responses and the recovery of endogenously released substance P- and neurokinin A-like immunoreactivities (SP-LI and NKA-LI) after tracheal injection of capsaicin in isolated guinea pig lungs superfused through the trachea. Capsaicin in doses from 10(-10) to 10(-7) mol induced a dose-dependent increase in airway opening pressure and release of SP-LI and NKA-LI. Airway opening pressure changes and the recovery of SP-LI and NKA-LI were significantly greater in lungs superfused with the NEP inhibitor SCH 32615 than in control lungs. ACE inhibition with captopril did not increase the mechanical response or the recovery of SP-LI compared with lungs not receiving captopril. In lungs from guinea pigs pretreated with high doses of capsaicin 7-10 days before study, a regimen designed to deplete endogenous tachykinins, there was a significant decrease in the content and release of NKA-LI and SP-LI. There were no detectable airway effects of acute capsaicin infusion even after doses of 10(-5) mol. Because NEP is important in modulating the airway effects of endogenously released tachykinins after tracheal infusion of capsaicin, but ACE is not, it seems likely that tracheal administration of capsaicin releases tachykinins from epithelial rather than endothelial loci.
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PMID:Capsaicin-induced release of tachykinins: effects of enzyme inhibitors. 171 6

We have previously shown that neutral endopeptidase (NEP; EC 3.4.24.11) regulates neuropeptide-induced responses. Recently, Pierart et al. reported that NEP degraded purified interleukin-1 (IL-1) using thymocyte proliferation assay. Since IL-1 is an important cytokine in the immune response and inflammation, we have assessed whether NEP hydrolyzes recombinant human IL-1 beta using three assay systems (bioassay, immunoassay, and HPLC analysis). NEP on the NALM-6 cells (both intact cells and the solubilized plasma membrane fraction) efficiently hydrolyzed Met5-enkephalin and substance P. However, NEP did not significantly decrease the amount of rhIL-1 beta assessed by the growth inhibitory activity of a human melanoma, by the immunoassay, or by the direct analysis on HPLC. Therefore, we conclude that NEP does not significantly hydrolyze rhIL-1 beta. Our results suggest that, in contrast to the regulatory role of NEP in neuropeptide-induced responses, NEP is not a regulatory enzyme for IL-1-induced responses.
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PMID:Neutral endopeptidase (EC 3.4.24.11) does not hydrolyze recombinant human interleukin-1 beta. 171 45

We have compared the contractile responses of substance P (SP) and neurokinin A (NKA) to that of the non degradable muscarinic agonist, carbachol, in small and large human airways in vitro. We have also investigated the effects of the neutral endopeptidase (NEP) inhibitor, thiorphan (100 microM) on these responses. NKA contracted large and small airways to a different extent (56% vs 92% of carbachol maximal contraction, respectively). NKA was significantly less potent in large vs small bronchi (EC50 = 150 +/- 15 vs 12 +/- 5 nM respectively, p less than 0.05). SP had a lower contractile effect in large (26% carbachol maximum) and small airways (59%) with EC50 values higher than 0.5 microM. The enkephalinase inhibitor thiorphan shifted the concentration-response curve to NKA to the left in large (EC50 = 35.2 +/- 8.2 nM) and small bronchi (EC50 = 2.8 +/- 1.3 nM, p less than 0.02). This shift was associated with an increase in the maximal contraction to NKA (75% in large vs 123% in small bronchi). The amplitude of contraction to SP was also potentiated in large (45%) and in smaller bronchi (101%). In conclusion, we have demonstrated that NKA has a significantly greater constrictor effect than a cholinergic agent in more peripheral human airways in vitro. This suggests that non cholinergic constrictor pathways are more likely to be important in more peripheral airways.
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PMID:Effect of tachykinins in small human airways. 171 42

The common acute lymphoblastic leukemia antigen (CALLA, CD10), which is expressed on early lymphoid progenitors and neutrophils, is the zinc metalloprotease, neutral endopeptidase 24.11 (NEP, "enkephalinase"). The CD10 cell surface enzyme is known to hydrolyze a variety of biologically active peptides including met-enkephalin, formyl-met-leu-phe (f-MLP), and substance P. These three CD10/NEP substrates induce the migration and aggregation of neutrophils, suggesting that each of the peptides can function as a mediator of neutrophil inflammatory responses. Recently, inhibition of CD10/NEP was found to reduce the concentration of metenkephalin needed to activate human and invertebrate granulocytes by several orders of magnitude. Herein we show that f-MLP and substance P induce rapid changes in neutrophil morphology, migration, and adhesion molecule expression, including upregulation of Mo1 (CD11b/CD18) and shedding of LAM-1 (also known as LECAM-1, Leu8, or TQ-1, the human homologue of murine gp100MEL14). Importantly, these coordinated changes are potentiated by inhibition of cell surface CD10/NEP enzymatic activity. Neutrophil cell surface CD10/NEP enzymatic activity is also shown to be regulated by the activation state of the cell during the time period in which the enzyme has its most pronounced effects. These results suggest that in neutrophils, CD10/NEP functions to control responsiveness to multiple inflammatory peptides.
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PMID:CD10 (CALLA)/neutral endopeptidase 24.11 modulates inflammatory peptide-induced changes in neutrophil morphology, migration, and adhesion proteins and is itself regulated by neutrophil activation. 171 72

A novel ligand, [4,5-3H-Leu10]substance P ([3H]SP), with high specific activity (137 Ci/mmole) was utilized to investigate the properties of NK (neurokinin)-1 receptors on guinea pig lung membranes (GPLM) and compared them to NK-1 receptors on rat submaxillary glands (RSGM). In the presence of a neutral endopeptidase inhibitor, thiorphan (100 microM), [3H]SP bound with high specificity (greater than 95%), rapidly (k1 = 0.116 nM-1 x min-1) and in a reversible (k-1 = 0.012 min-1) manner to a single class of high-affinity (Kd = 0.16 nM) and saturable (Bmax = 256 fmol/mg protein) receptors. High specific binding with higher density (5-fold) was also detected in RSGM, albeit with a lower affinity (Kd = 1.36 nM). Guanyl-5'-yl-imidodiphosphate and guanosine-5'-O-3-thiotriphosphate inhibited binding to GPLM (and RSGM) in a concentration-related manner. In GPLM, this effect was mediated by a reduction in affinity, mainly via enhancement of ligand dissociation rates and appearance of a lower affinity state (Kd = 3.4 nM). Preincubation of GPLM with sulfhydryl modifying agents (p-chloromercuriphenyl sulfonic acid and N-ethylmaleimide) reduced receptor density and affinity in a time- and concentration-dependent manner. Competition experiments with tachykinins and analogs illustrated a rank order of potency of: SP greater than or equal to [Sar9,Met(O2)11]SP greater than SP-methyl ester greater than or equal to physalaemin greater than SP(6-11) much greater than kassinin greater than neurokinin A = eledoisin much greater than neurokinin B greater than Nle10-NKA(4-10), clearly demonstrating that these receptors are of NK-1 type. Moreover, analysis of over 30 peptide and non-peptide hormones and antagonists demonstrated exquisite selectivity (greater than 10,000-fold) towards NK-1-selective agonists (vs. other ligands. A highly significant (P less than .005) linear correlation (r = 0.924) exists between agonist affinities in GPLM and RSGM. Combined, the data suggest that [3H]SP labels a nearly homogeneous population of high-affinity, G-protein coupled NK-1 receptors on GPLM and RSGM, with very high degree of selectivity.
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PMID:Binding of the novel ligand [4,5-3H-Leu10]substance P to high-affinity NK-1 receptors on guinea pig lung membranes: modulation by GTP analogs and sulfhydryl modifying agents. 171 78

Neurogenic inflammation, due to release of neuropeptides from sensory nerves, has been demonstrated in airways of several species, particularly rodents, and may contribute to the inflammatory response in asthmatic airways. Tachykinins (substance P and neurokinin A) and calcitonin-gene-related peptide released from airway sensory nerves may cause bronchoconstriction, vasodilatation, plasma exudation and mucus secretion. Sensory nerves may become sensitised by inflammatory products and triggered by mediators such as bradykinin, resulting in exaggerated inflammation. The effects of tachykinins may be further amplified by loss of the major degrading enzyme, neutral endopeptidase, from epithelial cells. Several strategies for reducing neurogenic inflammation are possible.
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PMID:Neurogenic inflammation in airways. 171 92


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