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

Atrial natriuretic peptide (ANP), a 28-residue peptide with cardiovascular and renal effects, is rapidly cleared from the circulation. Beside renal clearance, an extra-renal metabolism by the enzyme neutral endopeptidase-24.11 (NEP-24.11) has been proposed, since specific NEP-24.11-inhibitors increase endogenous plasma-ANP. NEP-24.11 is present in rat lung but its significance for ANP hydrolysis within the lung is unclear. The aim of this study was to investigate a possible degradation of rat ANP in a membrane preparation from rat lung. Hydrolysis products of ANP were separated by HPLC and further characterized by a pulmonary artery bioassay, by radioimmunoassay with different antisera, by peptide sequencing and by masspectrometry. Rat pulmonary membranes degraded ANP to one main metabolite lacking biological activity and with poor cross-reactivity to an antiserum recognising the central ring-structure of the peptide. Formation of the hydrolysis product was prevented by the NEP-24.11-inhibitor phosphoramidon (1 microM). Peptide sequencing of the metabolite revealed a cleavage between Cys7 and Phe8, which was confirmed by mass-spectrometry. The metabolite had an HPLC elution time identical to that of the product formed by purified porcine NEP-24.11. These findings suggest that ANP is metabolized and inactivated by endopeptidase-24.11 in rat lungs, the first organ exposed to ANP released from the heart.
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PMID:Degradation and inactivation of rat atrial natriuretic peptide 1-28 by neutral endopeptidase-24.11 in rat pulmonary membranes. 147 9

The effects of a neutral endopeptidase (NEP) inhibitor, SCH 39.370, and a clearance receptor ligand, C-atrial natriuretic factor-(4-23) [C-ANF-(4-23)] on the plasma concentration of atrial natriuretic peptide (ANP) and hemodynamics under basal conditions and during increased circulating ANP levels produced by acute volume loading in conscious rats were studied. Measurements of plasma immunoreactive N-terminal fragment of pro-ANP (IR-NT-ANP) concentrations were used to characterize the endogenous secretion of the biologically active peptide in response to drug infusions and volume expansion. Infusion of SCH 39.370 increased plasma IR-ANP levels dose-dependently in conscious normotensive Wistar rats; maximal increases of 17% (P less than 0.02) after the dose of 3 mg/kg, iv, and 67% (P less than 0.002) after the dose of 10 mg/kg, iv, SCH 39.370 were noted. Similarly, infusion of C-ANF-(4-23) alone (30 micrograms/kg, iv bolus, followed by infusion of 3 micrograms/kg.min for 30 min) increased plasma IR-ANP levels by 37% (P less than 0.001). Given in combination, SCH 39.370 and C-ANF-(4-23) produced a greater increase in plasma IR-ANP concentration (83%; P less than 0.001) than when either substance was infused alone. Neither SCH 39.370 nor C-ANF-(4-23), alone or in combination, had any effect on basal plasma IR-NT-ANP concentrations. The combination reduced mean arterial pressure (8 +/- 2 mm Hg; P less than 0.01) and right atrial pressure (0.67 +/- 0.20 mm Hg; P less than 0.01), while administration of SCH 39.370 or C-ANF-(4-23) alone had no effect on mean arterial pressure, heart rate, or right atrial pressure in conscious rats. Acute volume expansion with 0.9% saline (1.1 ml/100 g BW) resulted in an increase in right atrial pressure (2.7 +/- 0.2 mm Hg; P less than 0.001) as well as in plasma IR-ANP (55%; P less than 0.001) and IR-NT-ANP concentrations (24%; P less than 0.03). Volume expansion in rats pretreated with SCH 39.370 resulted in a greater increase in plasma IR-ANP concentrations than in control animals; the relative ANP increases corresponding to the 2.5-mm Hg increase in right atrial pressure were 1.48-, 1.69-, and 2.28-fold in control, 3 mg/kg SCH 39.370-treated, and 10 mg/kg SCH 39.370-treated groups, respectively. When the relation between changes from control in plasma IR-ANP and right atrial pressure in response to acute volume expansion was analyzed in the presence of C-ANF-(4-23), no difference was noted between control and treated rats.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Basal and volume expansion-stimulated plasma atrial natriuretic peptide concentrations and hemodynamics in conscious rats: effects of SCH 39.370, an endopeptidase inhibitor, and C-ANF-(4-23), a clearance receptor ligand. 153 Nov 29

After i.v. injection of 125I-labeled rat atrial natriuretic factor ([125I] ANF; 99-126) in tracer dose to mice, a saturable binding to lung membranes was evidenced using a filtration assay. Analysis of the membrane-bound radioactivity by high-pressure liquid chromatography indicated that it corresponded to the intact hormone in sinorphan-treated mice. [125I]rANF binding was inhibited completely by i.v. administration of rANF with an ED50 of 1.0 +/- 0.1 nmol/kg, a value obtained in sinorphan-treated mice. SC 416,542, an ANF analog with a four amino acid deletion in its ring, representing a selective ligand of ANF clearance receptors, was as potent as rANF in inhibiting the in vivo binding. By contrast, ANF fragments produced by enkephalinase (EC 3.4-24.11, membrane metalloendopeptidase) were less potent or even inactive in competing with [125I]rANF. It is concluded that [125I]rANF binding to lung membranes in vivo occurs to clearance receptors. [125I]rANF binding was enhanced by more than 2-fold in mice receiving enkephalinase inhibitors such as sinorphan and, although to a lesser extent, aminopeptidase inhibitors; on the other hand inhibitors of a variety of other peptidases were ineffective. These data confirm by a novel approach that enkephalinase plays a key role in the inactivation of circulating ANF. Hence, the in vivo binding test can be used to assess the activity of clearance receptor ligands and peptidase inhibitors, two classes of drugs affecting ANF metabolism, with potential clinical utility in cardiovascular and salt-retaining diseases.
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PMID:Binding of [125I]atrial natriuretic factor to mouse lung membranes in vivo: characterization and effects of peptidase inhibitors. 153 34

Atrial natriuretic peptide (ANP) is rapidly degraded by neutral metalloendopeptidase (EC 3.4.24.11, NEP), with the kidney being a major site of ANP clearance. NEP has been anatomically localized in the rat kidney by in vitro autoradiography and the active site studied by a radioinhibitor binding assay (RIBA) using a newly developed radioinhibitor as a radioligand. SCH47896 is a phenolic derivative of SCH39370, a potent specific inhibitor of NEP, which can be radioiodinated with 125I. NEP catalytic activity in the rat kidney was inhibited by SCH47896 and its di-iodo analog SCH48446. Specific binding of [125I]SCH47896 to renal plasma membranes fitted a single-site model with Kd = 43.3 nM and maximal binding site density = 13.8 pmol/mg protein. Thus, [125I]SCH47896 retains full enzymatic inhibitory activity and full binding to the active site of the NEP. Autoradiographs using [125I]SCH47896 demonstrated maximal binding to deep proximal renal tubules. This binding was displaced in a dose-dependent manner by NEP inhibitors. Renal NEP was inhibited by SCH39370. Inhibition of ANP degradation by NEP in the kidney by the new NEP or atriopeptidase inhibitors may explain their natriuretic and diuretic effect in the absence of changes in plasma ANP levels. These studies will allow investigation of the regulation of NEP and the role inhibition of tissue NEP plays in the actions of the new atriopeptidase inhibitors. Furthermore, this method of radioinhibitor binding is applicable to any enzyme, provided a suitable radioligand can be constructed.
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PMID:Localization and characterization of neutral metalloendopeptidase (EC 3.4.24.11), the degradative enzyme for atrial natriuretic peptide, in rat kidney using a radioiodinated neutral metalloendopeptidase inhibitor. 153 41

Atrial natriuretic peptide (ANP) is a potent vasodilator of hypoxia constricted pulmonary vessels. Chronic infusions of ANP have been shown to limit the anatomical pulmonary vascular remodelling associated with chronic exposure to a 10% oxygen environment. SCH 34826 elevates plasma ANP by inhibition of the enzyme neutral endopeptidase EC 3.4.24.11. We administered by subcutaneous injection 90 mg/kg SCH 34826 twice daily into six male Wistar rats. Six littermate controls received 1 ml of 0.4% aqueous methyl cellulose vehicle. All animals were exposed to a 10% oxygen environment for 2 weeks. Administration of SCH 34826 caused a significant reduction in the hypoxia-induced pulmonary vascular remodelling and right ventricle hypertrophy. Neutral endopeptidase inhibition by drugs such as SCH 34826 could prove useful in conditions characterized by pulmonary hypertension and pulmonary vascular remodelling.
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PMID:Effects of SCH 34826, a neutral endopeptidase inhibitor, on hypoxic pulmonary vascular remodelling. 153 51

The enzyme neutral metalloendopeptidase (E.C. 3.4.24.11), also known as the common acute lymphocytic leukemia antigen, neutral endopeptidase, or enkephalinase, functions as an inactivator of a wide variety of signaling oligopeptides such as substance P, neurokinin A, enkephalins, endothelin, atrial natriuretic factor, and formyl chemotactic peptides. A cDNA clone isolated from a human lung library encodes a fragment of neutral metalloendopeptidase containing an internal 81 base pair deletion when compared with the human placental cDNA for this enzyme. Comparison of the deleted cDNA sequence with the intron-exon structure recently determined as the common acute lymphocytic leukemia antigen reveals that the 81 base pairs corresponds precisely with exon 16. RNA analysis using splice junction oligonucleotides indicates that the 16 del form constitutes a minor but significant fraction of the RNA species present in human lung. Expression of constructs containing "wild type" and "exon 16 del" neutral endopeptidases in COS-7 cells reveals that deletion of this 27 amino acid segment reduces enzymatic activity toward the synthetic substrate glutaryl-alanyl-alanyl-phenyl-alanyl-4-methoxy-2-naphthylamide to barely detectable levels.
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PMID:Exon 16 del: a novel form of human neutral endopeptidase (CALLA). 153 84

We investigated regulation of atrial natriuretic factor (ANF)-stimulated cellular cGMP accumulation (ANF-s-cGMP) in an ANF-responsive human renal cell line, SK-NEP-1. Dose-response data indicated that the EC50 for ANF(99-126) was 1.1 x 10(-9) M. Brain natriuretic peptide (10(-6) M) increased cGMP to a level indistinguishable from that of ANF (10(-6) M). [Met-(O)]ANF was only half as potent as ANF, and atriopeptin I (10(-6) M) did not increase cGMP over basal levels. Preincubation of SK-NEP-1 cells with ANF, but not atriopeptin I (API), for two hours or longer, caused a concentration-dependent down-regulation of ANF-s-cGMP. Phorbol 12-myristate 13-acetate (PMA), a protein kinase C (PKC) activator, and A23187 and its 4-bromo derivative, calcium ionophores, inhibited ANF-s-cGMP in a dose-dependent manner. A23187 inhibition was calcium dependent and promoted net cGMP degradation. Thirty-six hour preincubation with PMA, a procedure used to down-regulate PKC, abolished acute PMA inhibition of ANF-s-cGMP without having an effect on ANF-s-cGMP or on 4-bromo-A23187 inhibition thereof. These data indicate that PKC activation specifically inhibited ANF-s-cGMP but that PKC was not required for ANF-s-cGMP in SK-NEP-1 cells. Thus structurally related ANF peptides, protein kinase C (PKC) activators, calcium ionophores are potential modulators of ANF-s-cGMP in cells from this human renal cell line.
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PMID:Phorbol and calcium decreased atriopeptin response in a human renal cell line. 164 14

Thiorphan, a potent inhibitor of enkephalinase (membrane metalloendopeptidase, atriopeptidase, EC 3.4.24.11) enhanced markedly (+214%) and prolonged the rise in plasma atrial natriuretic factor (ANF) immunoreactivity in anesthetized rats submitted to acute extracellular volume expansion obtained through i.v. injection of a Ringer's solution. These changes were accompanied by marked potentiations of the natriuretic and diuretic responses to the ANF-releasing stimulus, whereas kaliuresis was only slightly affected. Thiorphan also enhanced markedly the biphasic rise in urinary cyclic GMP excretion elicited by volume expansion. All these renal responses to volume expansion in thiorphan-treated rats were significantly reduced by pretreatment with anti-ANF antibodies, suggesting an involvement of the endogenous natriuretic hormone protected against degradation. However, pretreatment with antibradykinin antibodies led to qualitatively similar results, suggesting that the endogenous kinin-generating system in kidney may also participate in the responses to endogenous ANF and their potentiation by the peptidase inhibitor.
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PMID:Thiorphan-induced natriuresis in volume-expanded rats: roles of endogenous atrial natriuretic factor and kinins. 165 39

The renal natriuretic actions of endogenous atrial natriuretic factor are enhanced by neutral endopeptidase inhibition (NEP-I). Recognizing that activation of the renin-angiotensin-aldosterone system in congestive heart failure (CHF) antagonizes the renal actions of atrial natriuretic factor, we hypothesized that angiotensin II antagonism with converting enzyme inhibition would potentiate the renal actions of NEP-I in CHF. To test this hypothesis, the renal responses to a specific NEP-I (SQ 28,603) were assessed in dogs with eight days of experimental CHF produced by rapid ventricular pacing. The renal natriuretic responses to NEP-I in experimental CHF were significant. In the same model of CHF, chronic angiotensin antagonism with converting enzyme inhibition potentiated both renal hemodynamic and excretory responses to NEP-I. The potentiated renal hemodynamic response included significant increases in glomerular filtration rate and filtration fraction. In the CHF group with angiotensin antagonism, an intrarenal infusion of low-dose angiotensin abolished the potentiated renal responses to NEP-I, supporting the concept that intrarenal angiotensin antagonism, rather than improved systemic hemodynamics or potentiation of other peptide systems, mediated the enhanced renal responses to NEP-I in the presence of converting enzyme inhibition.
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PMID:Angiotensin inhibition potentiates the renal responses to neutral endopeptidase inhibition in dogs with congestive heart failure. 165 47

The renal, hormonal and haemodynamic effects of chronic (4 days) dosing with an inhibitor of endopeptidase EC 3.4.24.11 (UK 79300) were assessed in two groups, each of eight normal volunteers, receiving 25 mg every 12 h (group 1) or 100 mg every 12 h (group 2) of UK 79300 in double-blind, balanced-randomized, placebo-controlled, crossover studies. Group 2 (but not group 1) exhibited a significant transient natriuresis (P less than 0.01) and a consequent sustained negative cumulative sodium balance (70 +/- 21 mmol) which was established within 48 h and remained for the duration of dosing with UK 79300. Urine and plasma cyclic guanosine monophosphate (cGMP) levels rose significantly above placebo values (P less than 0.01 and P less than 0.001, respectively) in both groups and the effect was sustained throughout the dosing period. Plasma atrial natriuretic factor (ANF) was slightly enhanced by UK 79300 in group 1 (P less than 0.05) but not significantly increased in group 2. Despite a significant increase in heart rate in both groups (P less than 0.001) and of natriuresis in group 2, there was minimal evidence of renin-aldosterone activation in either group. Trends towards lower systolic pressures, observed in both groups, did not attain statistical significance. These findings suggest chronic treatment with UK 79300 induces an increase in tissue ANF levels, with sustained enhancement of plasma and urine concentrations of ANF second messenger (cGMP) and increased heart rate.
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PMID:Prolonged inhibition of endopeptidase 24.11 in normal man: renal, endocrine and haemodynamic effects. 165 38


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