Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.11 (CD10)
 9,792 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Guinea-pig tracheal strips were contracted with cumulative concentrations of bradykinin or substance P in the presence of thiorphan, an inhibitor of endopeptidase 24.11 and of angiotensin-converting enzyme, or in the presence of N-[1-(R,S)-carboxy-3-phenylpropyl]Ala-Ala-Phe-para-aminobenzoate (cFP-AAF-pAB), a selective inhibitor of endopeptidase 24.15. The concentration-effect curve of bradykinin was shifted to the left in the presence of each inhibitor whereas the curve of substance P was sensitive to thiorphan but not to cFP-AAF-pAB. These results show that endopeptidase 24.15 may modulate the contractile effect of bradykinin but not that of substance P in the guinea-pig trachea.
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PMID:Endopeptidase 24.15 modulates bradykinin-induced contraction in guinea-pig trachea. 137 68

Viral infection increases the airway smooth muscle response to substance P. This effect is due to decreased activity of neutral endopeptidase (EC 3.4.24.11), an enzyme that degrades substance P. Inhibition of neutral endopeptidase activity also potentiates substance P-induced 35SO4-labeled macromolecule secretion. Therefore we examined the in vitro effects of substance P on 35SO4-macromolecule secretion from the tracheae of influenza-infected ferrets. Despite a virus-induced loss of neutral endopeptidase activity (demonstrated in muscle bath experiments), there was no difference between control and infected tracheae in either baseline secretion [697 +/- 125 vs. 579 +/- 67 (SE) cpm/15 min; n = 15 tissues) or in the response to 10(-6) M substance P (increased by 218 +/- 63 and 195 +/- 51, respectively) or 10(-5) M substance P (increased by 416 +/- 95 and 354 +/- 54, respectively). Although phosphoramidon (10(-6) M) potentiated the secretory response to substance P, there was again no difference between control and infected tracheae. These data show that although viral infection decreases airway neutral endopeptidase activity, virus-induced hypersecretion is not due to a resulting increase in the secretory response to substance P.
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PMID:Viral infection increases contractile but not secretory responses to substance P in ferret trachea. 137 30

The tachykinins substance P (SP) and neurokinin A (NKA) have been shown to induce airway smooth muscle contraction in mature animals, and the enzyme neutral endopeptidase (NEP) modulates this effect. We evaluated maturation of SP- and NKA-induced tracheal smooth muscle contraction and modulation of their effects by NEP in anesthetized, paralyzed, and artificially ventilated piglets less than 4 days, 2-3 wk, and 10 wk of age. Tracheal smooth muscle tension was measured in vivo from an open tracheal segment by use of a force transducer. Intravenous SP caused a dose-dependent increase in tracheal tension in all three age groups; however, the response in less than 4-day-old piglets was significantly weaker than in 2- to 3- and 10-wk-old piglets. NKA caused a dose-dependent increase in tracheal tension only in 2- to 3- and 10-wk-old piglets. The response of tracheal tension to NKA was weaker than the response to SP in all age groups. Atropine (2 mg/kg) significantly diminished the responses of tracheal tension to SP and NKA, indicating a cholinergic contribution to these responses at all ages. Intravenous thiorphan, a known NEP inhibitor, potentiated the effects of SP only in 2- to 3- and 10-wk-old piglets and did not affect the response of tracheal tension to NKA at any age. Biochemical analyses demonstrated a significant increase in tracheal NEP activity in comparably aged piglets over the first 10 wk of life.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Tracheal smooth muscle responses to substance P and neurokinin A in the piglet. 137 11

We investigated the effects of ozone exposure (3.0 ppm, 2 h) on airway neutral endopeptidase (NEP) activity and bronchial reactivity to substance P in guinea pigs. Reactivity after ozone or air exposure was determined by measuring specific airway resistance in intact unanesthetized spontaneously breathing animals in response to increasing doses of intravenous substance P boluses. The effective dose of substance P (in micrograms) that produced a doubling of baseline specific airway resistance (ED200SP) was determined by interpolation of cumulative substance P dose-response curves. NEP activity was measured in tracheal homogenates made from each animal of other groups exposed to either ozone or room air. By reverse-phase high-pressure liquid chromatography, this activity was characterized by the phosphoramidon-inhibitable cleavage of alanine-p-nitroaniline from succinyl-(Ala)3-p-nitroaniline in the presence of 100 microM amastatin. Mean values of the changes in log ED200SP were 0.27 +/- 0.07 (SE) for the ozone-exposed group and 0.08 +/- 0.04 for the air-exposed group. We found that phosphoramidon significantly increased substance P reactivity in the air-exposed animals (P less than 0.01), but it had no effect in the ozone-exposed group. This finding was associated with a significant reduction in tracheal homogenate NEP activity of ozone-exposed animals compared with controls: mean values were 18.1 +/- 1.9 nmol.min-1.mg protein-1 for the ozone-exposed group and 25.1 +/- 2.4 nmol.min-1.mg protein-1 for air-exposed animals (P less than 0.05). Inhalation of an aerosolized NEP preparation, partially purified from guinea pig kidney, reversed the substance P hyperreactivity produced by ozone exposure.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Aerosolized neutral endopeptidase reverses ozone-induced airway hyperreactivity to substance P. 137 13

Neutral endopeptidase 24.11 contains an active site arginine believed to function in substrate binding. This arginine is thought to form an ionic interaction with the COOH-terminal carboxylate of NEP substrates. The functionality of arginine 102 has been investigated by using site-directed mutagenesis to produce mutants in which this residue was converted to a lysine, glycine, glutamine, or glutamate. All of the mutants exhibited essentially full activity as determined with a synthetic peptide amide, glutaryl-Ala-Ala-Phe-4-methoxy-2-naphthylamide. In contrast, activity was detected only with the wild-type enzyme and the lysine mutant using a synthetic substrate containing a free COOH-terminal carboxylate, dansyl-Gly-Trp-Gly. Inhibition studies with the physiologically active peptide substrates substance P, endothelin, and angiotensin I, as well as substance P free acid, [D-Ala2,Leu5]enkephalin, and [D-Ala2,Leu5]enkephalinamide indicated a lack of importance of arginine 102 in substrate binding. With [D-Ala2,Met5]enkephalin and the chemotactic peptide, N-formyl-Met-Leu-Phe, a significant decrease in affinity is observed with the arginine 102 mutants. These results suggest that the contribution of arginine 102 to substrate binding is dependent upon the strength of other subsite interactions. Examination of dipeptides as inhibitors indicates that the nature and orientation of the P'2 residue is important in determining the strength of the interaction of arginine 102 with its substrates.
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PMID:Analysis of the importance of arginine 102 in neutral endopeptidase (enkephalinase) catalysis. 137 21

We determined the effect of an inhibitor of neutral endopeptidase, acetorphan, on the skin responses to substance P and on the bronchostrictor effects of sodium metabisulphite aerosol in asthmatic subjects. One hour following ingestion of acetorphan (200 mg) or placebo tablets, cutaneous responses to substance P were performed in four subjects. In seven subjects, bronchial challenge with increasing concentrations of sodium metabisulphite solutions was performed and the concentration required to cause a 20% fall in baseline FEV1 determined (PC20). On the acetorphan day, there was a significant increase in the wheal and flare responses to substance P and to the diluent (0.9% NaCl) alone. However, there was no significant effect of acetorphan on the PC20 metabisulphite. We conclude that metabisulphite airway challenge in vivo may not invoke the release of endogenous neuropeptides. However, the degree of inhibition of neuropeptide breakdown by the oral dose of acetorphan used may not have been optimal.
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PMID:Effect of neutral endopeptidase inhibitor on airway function and bronchial responsiveness in asthmatic subjects. 137 94

Aerosol administration of neurokinin A (NKA) or substance P (SP) to conscious guinea pigs produced labored abdominal breathing (dyspnea). Time to onset of dyspnea was inversely related to tachykinin concentration. Aerosol administration of the neutral endopeptidase inhibitor thiorphan significantly potentiated tachykinin-induced dyspnea without affecting responses to leukotriene D4 (LTD4), carbachol, histamine, platelet activating factor or serotonin (5-HT), indicating selectivity for tachykinins rather than a nonspecific effect on agonist reactivity. The rank order of potency for producing dyspnea was LTD4 greater than or equal to NKA (with thiorphan) much greater than SP (with thiorphan) greater than 5-HT = carbachol greater than histamine greater than platelet-activating factor. Pretreatment with propranolol, phentolamine, methysergide, pyrilamine or the peptide leukotriene antagonist, ICI 198,165, did not alter dyspnea induced by NKA or SP. The dose-response curves for NKA and SP were shifted to small degrees (less than 3-fold) to the right by atropine and to the left by indomethacin. Also, pretreatment with capsaicin did not affect responses to NKA or SP, indicating that they do not cause dyspnea by activating capsaicin sensitive C-fibers. These results suggest primarily direct effects of NKA and SP. This model may be useful for in vivo evaluation of tachykinin antagonists.
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PMID:Tachykinin-induced dyspnea in conscious guinea pigs. 137 29

The effects of neutral endopeptidase inhibition (NEP-I) were studied in 6 conscious sheep with heart failure (HF) induced by rapid ventricular pacing for 7 days. Measurements were performed 1 h before and for 6 h after intravenous (i.v.) bolus administration of vehicle and SCH 39370 (1.25 and 5 mg/kg) on separate days. After the higher dose, an index of serum NEP activity decreased from 0.83 +/- 0.05 to 0.13 +/- 0.07 nmol/ml/min (p less than 0.001) at 1 h and then returned to control levels at 6 h. Plasma atrial natriuretic peptide (ANP) and cyclic GMP rose from 328 +/- 28 and 20.2 +/- 4.3 to a peak of 570 +/- 65 pmol/L (p less than 0.001) and 28.7 +/- 6.3 nmol/L (p less than 0.05) respectively. Natriuresis and diuresis were significant and left atrial pressure (LAP) decreased from 21.9 +/- 1.1 to 20.1 +/- 0.8 mm Hg (p less than 0.05). Despite high endogenous ANP levels in HF, NEP-I further increases both ANP and its "second messenger." Its natriuretic and hemodynamic effects are consistent with enhanced ANP activity in renal and vascular tissues, suggesting that NEP-I may be useful for treating HF.
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PMID:Acute hemodynamic, hormonal, and renal effects of neutral endopeptidase inhibition in ovine heart failure. 138 Jun 8

The purpose of this study was to determine whether substance P (SP), neurokinin A (NKA), and neurokinin B (NKB) induce the release of neutrophil chemotactic activity (NCA) from bovine bronchial epithelial cells (BBEC) and whether neutral endopeptidase (NEP), a membrane-bound metalloenzyme that hydrolyzes tachykinins, modulates these effects. BBEC monolayers were exposed to SP, NKA, and NKB in the absence or presence of phosphoramidon (10(-6) M), a selective NEP inhibitor, for 72 h. Using a modified blind-well in vitro neutrophil chemotaxis assay, we found that tachykinin-exposed BBEC culture supernatant fluids induced significant neutrophil chemotaxis compared with supernatants obtained from unstimulated BBEC. Maximal effect was observed after 48 h of incubation and at SP concentration of 10(-13) M [92 +/- 3 (SP) vs. 64 +/- 2 (media) cells/high-power field (HPF), mean +/- SE, n = 7, P less than 0.05]. Release of NCA was mediated by the COOH-terminal of the SP molecule. The rank order of potency of tachykinins in inducing release of NCA was SP greater than NKA = NKB. SP-induced response was significantly potentiated by phosphoramidon (109 +/- 3 vs. 92 +/- 3 cells/HPF, n = 7, P less than 0.05), whereas other proteinase inhibitors had no effect. The released NCA was composed of protein and lipid-soluble components. These data indicate that mammalian tachykinins induce the release of NCA from BBEC and that NEP modulates these effects. We suggest that tachykinins regulate neutrophil recruitment into the lower respiratory tract, in part, by inducing the release of NCA from airway epithelial cells.
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PMID:Bronchial epithelial cells release neutrophil chemotactic activity in response to tachykinins. 138 Nov 52

Kinins and substance P have been implicated in the pathogenesis of inflammatory arthritis by virtue of their abilities to induce vasodilation, edema, and pain. The relative biological potencies of these peptides in vivo would depend at least in part upon their rates of catabolism in the joint. We hypothesized that human synovial lining cells may regulate intraarticular levels of kinins and neuropeptides via degradation by cell surface-associated peptidases. We exposed intact human synovial fibroblasts to kinins and substance P, in the presence or absence of specific peptidase inhibitors, and measured the amount of intact substrate remaining and degradation product(s) generated over time. Aminopeptidase M (AmM; EC 3.4.11.2), neutral endopeptidase-24.11 (NEP-24.11; EC 3.4.24.11), and dipeptidyl(amino)peptidase IV (DAP IV; EC 3.4.14.5) were identified on the cell surface of synovial cells. Bradykinin degradation was due entirely to NEP-24.11 (1.39 +/- 0.29 nmol/min per well). Lysylbradykinin was also degraded by NEP-24.11 (0.80 +/- 0.19 nmol/min per well); however, in the presence of phosphoramidon, AmM-mediated conversion to bradykinin (3.74 +/- 0.46 nmol/min per well) could be demonstrated. The combined actions of NEP-24.11 (0.93 +/- 0.15 nmol/min per well) and DAP IV (0.84 +/- 0.18 nmol/min per well) were responsible for the degradation of substance P. AmM (2.44 +/- 0.33 nmol/min per well) and NEP-24.11 (1.30 +/- 0.45 nmol/min per well) were responsible for the degradation of the opioid peptide, [Leu5]enkephalin. The identity of each of the three peptidases was confirmed via synthetic substrate hydrolysis, inhibition profile, and immunological identification. The profiles of peptidase enzymes identified in cells derived from rheumatoid and osteoarthritic joints were identical. These data demonstrate the human synovial fibroblast to be a rich source of three specific peptidases and suggest that it may play a prominent role in regulating peptide levels in the joint.
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PMID:Cultured human synovial fibroblasts rapidly metabolize kinins and neuropeptides. 138 26


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