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)

To investigate the role of neuropeptides in allergic inflammation, we examined the effect of peptides on eosinophil chemotaxis. Eosinophils were purified from the blood of allergic and normal subjects using a discontinuous Percoll density gradients. Chemotaxis was induced by platelet-activating factor (PAF) and leukotriene B4, and was assayed by a modified Boyden's chamber technique. Four neuropeptides were examined in this study: substance P (SP), neurokinin A, calcitonin gene-related peptide (CGRP), and cholecystokinin octapeptide. Peptides alone (10 nM to 10 microM) were not chemotactic for eosinophils. However, when eosinophils were pre-treated with peptides (100 nM) at 37 degrees C for 30 min, chemotactic response to PAF (10 nM) was significantly enhanced (p < 0.01) in allergic subjects; % control by SP, neurokinin A, CGRP and cholecystokinin octapeptide was 269 +/- 42, 243 +/- 32, 227 +/- 21, and 251 +/- 42, respectively (n = 8). Similar results were obtained in leukotriene B4-induced eosinophil chemotaxis. In contrast, no enhancement was observed in normal subjects. Potentiating effect of SP and CGRP on PAF-induced eosinophil chemotaxis in allergic subjects was significantly attenuated by SP antagonist [D-Pro2,D-Trp7,9]-SP and human CGRP (8-37) receptor antagonist, respectively. Neutral endopeptidase inhibitors (phosphoramidon, leupeptin, and bestatin) failed to significantly augment the PAF-induced eosinophil chemotaxis when the cells were pretreated with various peptides and neutral endopeptidase inhibitors. The C-terminal fragment of SP (SP6-11) had an effect similar to that of the intact SP molecule, whereas no potentiating effect by the N-terminal of SP (SP1-9) was observed. These results suggest that neuropeptides may play a significant role in eosinophil infiltration by priming cells in allergic inflammation.
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PMID:Neuropeptides modulate human eosinophil chemotaxis. 138 21

The depressor, natriuretic and cyclic GMP responses to several species of brain natriuretic peptide (BNP) were compared to atrial natriuretic peptide (ANP) 99-126 in conscious spontaneously hypertensive rats (SHR) and in conscious cynomolgus monkeys treated with vehicle or the selective neutral endopeptidase (NEP 3.4.24.11) inhibitor N-[2-(mercaptomethyl)-1-oxo-3-phenylpropyl]-beta- alanine (SQ 28,603). In the conscious SHR, the natriuretic and cyclic GMP responses to 3 nmol/kg i.v. rat BNP-32 greater than rat ANP 99-126 greater than pig BNP-26 and were significantly potentiated by 100 mumol/kg i.v. SQ 28,603. Human BNP-32 was inactive in the SHR treated with either vehicle or SQ 28,603. In contrast, 1 nmol/kg i.v. of human BNP-32 stimulated renal and depressor responses in the conscious monkeys that were greater than or equal to those elicited by human ANP 99-126, whereas 3 nmol/kg i.v. rat BNP-32 reduced mean arterial pressure without affecting renal function. Furthermore, SQ 28,603 (100 mumol/kg, i.v.) significantly enhanced the cumulative losses of sodium and cyclic GMP stimulated by each of these peptides. In conclusion, the renal and depressor activities of BNP are highly species specific and are significantly potentiated by an inhibitor of NEP 3.4.24.11 in conscious SHR and monkeys. Therefore, protection of endogenous BNP may contribute importantly to the activity of NEP 3.4.24.11 inhibitors in cardiorenal disorders such as hypertension and congestive heart failure.
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PMID:Potentiation of brain natriuretic peptides by SQ 28,603, an inhibitor of neutral endopeptidase 3.4.24.11, in monkeys and rats. 138 30

Neutral endopeptidase 24.11, also known as the common acute lymphoblastic leukemia antigen, is a zinc metallopeptidase involved in the inactivation of biologically active peptides, such as the enkephalins and atrial natriuretic peptide. The highly potent radiolabeled inhibitor 2-((3-[125I]iodo-4-hydroxy)phenylmethyl)-4-N-[3-(hydroxyamino-3-oxo-1- phenylmethyl)propyl]amino-4-oxobutanoic acid ([125I]RB104; Ki = 30 pM) has been developed for the enzyme. [125I]RB104 is highly specific, its Ki for another widely distributed zinc peptidase, angiotensin-converting enzyme, being 15 microM. In binding studies using rat brain slices, [125I]RB104 was shown to have a high affinity (Kd = 300 +/- 20 pM) and high specific binding at the Kd concentration (90%). With rat brain homogenates the Kd of [125I]RB104 was 26.8 +/- 0.9 pM, close to the kinetically derived Kd, 7.0 +/- 0.8 pM. Using the inhibitor, we have developed a simple, rapid, and quantitative technique to detect low nanogram quantities of the endopeptidase directly from tissue extracts after SDS/PAGE. The method has been used to show the presence of low quantities of the enzyme in rabbit bone marrow. Apart from its sensitivity, "inhibitor gel electrophoresis" using [125I]RB104 has the advantage over immunohistochemical methods of being able to label the enzyme in all tissues and species. It will therefore be of great value in determining the exact role of this important regulatory peptidase in a number of biological systems. Moreover, this one-step characterization of neutral endopeptidase 24.11 could be extended to other zinc metallopeptidases such as angiotensin-converting enzyme or collagenases, and inhibitors with affinities as high as RB104 could open the way to visualization of zinc metallopeptidases in different tissues by electron microscopy.
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PMID:Development of [125I]RB104, a potent inhibitor of neutral endopeptidase 24.11, and its use in detecting nanogram quantities of the enzyme by "inhibitor gel electrophoresis". 138 73

Candoxatril is a novel, orally active inhibitor of neutral endopeptidase EC 3.4.24.11, the enzyme that degrades atrial natriuretic peptide (ANP). The acute and chronic (10 days treatment) hemodynamic and hormonal effects of candoxatril (150 mg twice daily) in 12 patients with moderately severe congestive heart failure were investigated in a randomized, placebo-controlled, double-blind study. On study day 1, candoxatril acutely increased plasma ANP levels, suppressed aldosterone and decreased right atrial and pulmonary capillary wedge pressures. After 10 days of treatment, basal ANP was increased and basal aldosterone was decreased. Body weight was reduced, most likely reflecting chronic natriuretic or diuretic effects, or both, and there was a trend toward increased cardiac index and reduced preload values. On study day 10, the acute effects of candoxatril were similar to those on day 1 (i.e., ANP was further increased, aldosterone was suppressed, and right and left ventricular filling pressures were decreased). Thus, candoxatril may offer a new and effective therapeutic approach in the treatment of heart failure.
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PMID:Effectiveness of endopeptidase inhibition (candoxatril) in congestive heart failure. 138 91

The atrial natriuretic factor (ANF) is a vasodilating and natriuretic peptide. In experimental and human cardiac failure, plasma ANF concentrations are increased. The ANF is a good marker of functional and haemodynamic severity and of the prognosis of cardiac failure. In this syndrome, messenger RNA of ANF is expressed not only in the atria but also in the ventricles which also secrete the peptide. Attenuation of the natriuretic response is observed in cardiac failure. It may be related to an abnormality situated after the receptor and second messenger, cyclic GMP and/or the reduction of renal perfusion pressure which occurs in cardiac failure. The therapeutic perspectives of ANF in cardiac failure are limited by the necessity of continuous intravenous or parenteral administration. Inhibitors of the enzyme degrading the peptide, neutral endopeptidase, are under evaluation in clinical trials which are at a preliminary stage for the moment.
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PMID:[Atrial natriuretic factor and cardiac insufficiency]. 138 3

1. Regional haemodynamic responses to atrial natriuretic peptide (ANP, 0.5 nmol kg-1) or proendothelin-1 [1-38] (1.0 nmol kg-1) were assessed in the same conscious Long Evans rats before and 20 min after administration of the novel neutral endopeptidase (NEP) inhibitor, SQ 28,603 (50 mg kg-1, i.v.). In a separate experiment, responses to endothelin-1 (0.5 nmol kg-1), angiotensin I (0.25 nmol kg-1) and angiotensin II (0.12 nmol kg-1) were measured before and after administration of SQ 28,603. 2. SQ 28,603 alone had no significant cardiovascular effects but caused significant prolongation of the hypotensive, tachycardic and renal and mesenteric vasoconstrictor effects of ANP. However, the early vasodilator and late vasoconstrictor responses in the hindquarters were not affected significantly. 3. SQ 28,603 caused significant attenuation of the pressor effects of proendothelin-1 [1-38] but the associated bradycardia was unchanged. SQ 28,603 caused a significant inhibition of the renal and mesenteric vasoconstrictor effects of proendothelin-1 and also inhibited the initial vasodilator and subsequent vasoconstrictor responses in the hindquarters vascular bed. 4. SQ 28,603 had no significant effects on the haemodynamic responses to endothelin-1, angiotensin I, or angiotensin II. 5. The results are consistent with SQ 28,603 not only inhibiting NEP that is involved in the degradation of ANP, but also suppressing activity of the enzyme involved in the conversion of proendothelin-1 [1-38] to endothelin-1.
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PMID:Effects of the neutral endopeptidase inhibitor, SQ 28,603, on regional haemodynamic responses to atrial natriuretic peptide or proendothelin-1 [1-38] in conscious rats. 138 23

The CD10/neutral endopeptidase (NEP) gene was identified in murine genomic DNA using a human CD10 cDNA probe. It is transcribed most abundantly in kidneys resulting in RNA transcripts of 3.4, 6.0, and 6.2 kb. The activity of the murine CD10/NEP shows identical kinetic parameters, Km and Ki, to those observed for this enzyme in other species. Two mAbs raised against rabbit NEP detect a 100 kDa protein by Western blot analysis; the antigen immunoprecipitated from extracts of lung shows specific NEP activity. CD10/NEP, as analyzed by Western blot and enzymatic activity, is expressed at high levels in kidney and lung, and at lower levels in liver, brain, thymus, spleen, and bone marrow. Analysis of bone marrow subpopulations indicate that the majority of CD10/NEP is associated with cells adherent to plastic and with subpopulations that do not express the surface markers AA4.1, B220, Mac-1, and Gr-1. These results suggest that CD10 is primarily associated with the stromal elements in murine bone marrow. A bone marrow stromal line, BMS 2.2, also expresses high levels of CD10/NEP. This peptidase activity on the surface of stromal cells may influence lymphopoiesis or other hematopoietic processes through the hydrolysis of regulatory peptides in the microenvironment.
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PMID:Characterization of murine CD10, an endopeptidase expressed on bone marrow adherent cells. 139 Apr 35

1. We have studied the contractile activity of the 39 amino acid precursor of endothelin-1 (ET-1), big endothelin-1 (big ET-1), on human isolated bronchi. The contribution of the metalloproteases, neutral endopeptidase (NEP) and angiotensin converting enzyme (ACE), in the presence or absence of the epithelium lining, by use of specific inhibitors, was also evaluated on the effects of big ET-1. 2. Big ET-1 elicited a potent contraction of human isolated bronchus. The -log EC50 value for big ET-1 was 7.53 +/- 0.08 (n = 11) and Emax 78.5 +/- 3.8% (% of ACh 3mM). 3. Incubation of human isolated bronchi with the NEP inhibitor phosphoramidon (10(-5) M) induced a rightward shift of the concentration-response curve induced by big ET-1 (10(-9) M to 3 x 10(-7) M). Similar results were observed when human bronchi were incubated with thiorphan (10(-5) M), but the shift to the right was significantly less (P less than 0.01) than that observed in the case of phosphoramidon (-0.35 +/- 0.05 vs -0.67 +/- 0.07 log unit). 4. The two inhibitors of angiotensin I converting enzyme (ACE), captopril or enalapril diacid, did not affect the concentration-response curve for contraction induced by big ET-1. 5. When the epithelium was removed, a leftward shift of the concentration-response curve of big ET-1 (10(-9) M to 3 x 10(-7) M) was observed. Incubation of human isolated bronchi with phosphoramidon or thiorphan (10-5M) or with enalapril diacid or captopril did not modify the leftward shift of the concentration-response curve for big ET-1 after epithelium removal.6. These results suggest that big ET-1 elicits potent contractile activity in the human isolated bronchus and that its effect is the consequence of the conversion to ET-1 by a phosphoramidon-sensitive metalloprotease which, although different from NEP and ACE, appears to be similar to the endothelinconverting enzyme (ECE) described in other studies in animals.
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PMID:Contractile activity of big endothelin-1 on the human isolated bronchus. 139 87

We have characterized a T lymphocyte endopeptidase activity that hydrolyses succinyl-alanine-alanine-phenylalanine-paranitroanilide (Suc-Ala-Ala-Phe-pNa). Hydrolysis of this substrate by intact Jurkat T cells was markedly enhanced when exogenous aminopeptidase N was added to the incubation medium. It thus appears that the release of paranitroaniline from Suc-Ala-Ala-Phe-pNA results from the combination of two distinct enzymatic activities: (i) an endopeptidase activity that cleaves the substrate at the alanyl bond and (ii) an aminopeptidase activity that ultimately cleaves the phenylalanyl bond. This cleavage was further confirmed by HPLC analysis. Specific endopeptidase 24.11 inhibitors were shown to inhibit the endopeptidase activity. These features are reminiscent of the characteristics of neutral endopeptidase (NEP, also known as endopeptidase 24.11, CALLA or CD10). Anti-CD10 monoclonal antibodies (mAbs) recognized the CD10+ B cell line Raji, but not Jurkat cells as assessed by FACS analysis. This is probably due to a lack of sensitivity of this method, the level of NEP activity in Jurkat T cells being 3-5% of that measured in B cell lines. Anti-CD10 mAbs immunoprecipitated endopeptidase 24.11 activities in both Jurkat T cells and Raji B cells, demonstrating that T lymphocytes express a CALLA-related endopeptidase. We also demonstrate that T and B cell endopeptidases have the same molecular weight, that T cells express less functional CALLA mRNA than B cells and that there are at least two shorter transcripts (1.8 and 0.8 kb) in both T and B cells.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Jurkat T cells express a functional neutral endopeptidase activity (CALLA) involved in T cell activation. 139 81

The purpose of the study was to determine the extent that peptidergic afferent and efferent pathways contribute to vagally induced vasodilation in the trachea of the dog. The change in vascular resistance of the tracheal branch of the cranial thyroid artery and the trachealis responses were determined in 28 anesthetized, paralyzed, and mechanically ventilated dogs. After propranolol (2 mg/kg) and phentolamine (1.5 mg/kg), stimulation of the superior laryngeal nerves (NS; 15 Hz, 7 V, 2 ms, 30 s) caused a decrease in vascular resistance of 11.7 +/- 0.8% and a tracheal contraction of 5.2 +/- 4.7 cmH2O. Atropine (1.5 mg/kg) reduced the fall in vascular resistance to 4.7 +/- 0.8% (P less than 0.01), whereas tracheal contraction was abolished. Thiorphan (1.5 mg), a neutral endopeptidase inhibitor, augmented the decrease in vascular resistance (8.8 +/- 0.6%; P less than 0.01) to NS. After hexamethonium (0.5 mg/kg), NS still caused a small decrease in TVR (2.9 +/- 0.9%; P less than 0.05), which was abolished by capsaicin. In atropinized dogs, capsaicin reduced the fall in vascular resistance after NS; the residual vasodilation was virtually abolished by hexamethonium. Acetylcholine (10(-3) mg/kg) decreased vascular resistance (15.7 +/- 3.0%), and the effect was abolished by atropine. We conclude that there is noncholinergic nonadrenergic vagally induced tracheal vasodilation that is peptidergic. The peptidergic vasodilation appears to be mediated by both afferent and efferent pathways.
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PMID:A peptidergic component to vagally induced tracheal vasodilation in the dog. 140 22


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