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)

Sinorphan is a powerful inhibitor of enkephalinases or endopeptidases 24-11, enzymes implicated in the degradation of the atrial natriuretic factor (ANF). In healthy volunteers, it increases plasma concentrations of endogenic ANF and increases diuresis and natriuresis. In order to study the tolerance and biological effects of pharmacological increase of plasma concentrations of endogenic ANF in severe congestive cardiac failure, 12 patients (in functional Classes III or IV of the NYHA classification) were given a single oral dose of 10, 20 or 40 mg of Sinorphan. Sinorphan was clinically well tolerated. The diastolic blood pressure decreased slightly (- 10 +/- 9 mmHg) but significantly (p less than 0.05). Systolic blood pressure and heart rate were unchanged. Despite spontaneously high plasma ANF concentrations (on average 15 times higher than normal subjects), Sinorphan induced an additional increase of 80 to 100% of plasma ANF concentration compared to the initial values (p less than 0.01) with no dose-dependent response for the dosages used. The inhibition of plasma endopeptidase activity attained 47% at the 30th minute. Urinary cyclic GMP excretion increased by 30% at the second hour (p less than 0.05). In addition, a statistically non significant tendency to increase diuresis and natriuresis was observed. These results show that Sinorphan increases plasma ANF concentrations by inhibition of its degradation in severe congestive cardiac failure and that this increase seems to be associated with potentially beneficial biological changes. The concept of endopeptidase inhibition should constitute a new therapeutic approach in cardiac failure, a situation in which the ANF seems to exert a favourable effect.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Effect of sinorphan, an endopeptidase inhibitor on severe congestive cardiac insufficiency]. 166 33

Human subcultures (third passage) of glomerular visceral epithelial cells (VEC) isolated from one month old kidney were successfully transfected by two recombinant plasmids containing the cloned oncogenes from the simian virus 40 large T antigen and H-ras gene. One postcrisis cell clone (56/10 A1) was selected, propagated and characterized. One hundred percent of the 56/10 A1 cells (current passage greater than 100th; doubling time 30 hrs) expressed the nuclear T-SV40 antigen assayed by IF; the cells failed to express H-ras (RNA blot analysis). Immortalized cells were morphologically and phenotypically compared to parental cell type (third passage). Phenotypic characterization of the 56/10 A1 cells was achieved using indirect immunofluorescence (IF) and immunogold silver staining coupled to bright field and epipolarization microscopy. Both parental and 56/10 A1 cells displayed positivity for cytokeratin, CALLA and PHM5, whereas von Willebrand factor was not detected in the two cell types. Since we have previously shown that human glomerular epithelial cells in culture synthetize plaminogen activator (PA) related compounds, we investigated the secretion pattern of these products in parental and transfected cells. Zymographic analysis of secreted PA related compounds revealed production of free urokinase (u-PA) and type 1 plasminogen activator inhibitor (PAI-1) complexed to tissular plasminogen activator (t-PA). Finally, in the transfected cells, increased cGMP generation under atrial natriuretic factor (ANF) stimulation agreed with previous work performed on nontransfected human VEC. In conclusion, the establishment of a human permanent cell line which retains most of the phenotypic features of parental glomerular visceral epithelial cells should represent a new tool to study human glomerular cell functions.
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PMID:Stable cell line of T-SV40 immortalized human glomerular visceral epithelial cells. 166 15

The neutral endopeptidase 24.11 (NEP) has been shown to inactivate the atrial natriuretic factor (ANF) by opening the ring structure. To document the role of NEP in the metabolic fate of ANF in vivo, the effects of an infusion of thiorphan (25 micrograms/min/kg), a specific NEP inhibitor, on the kinetics and metabolism of endogenous ANF were studied in conscious rabbits. A bolus of [125I]ANF(99-126) was injected 50 min after the beginning of the infusion of thiorphan. Plasma samples containing the radioactive peptides were separated by reverse-phase HPLC. The parent compound could be separated from at least two other minor metabolites, corresponding to the elution position of [125I]ANF(99-105/106-126), the inactive ring-opened metabolite, and of [125I]ANF(103-126), an N-truncated analog. The generation of the N-truncated metabolite was increased by thiorphan. Thiorphan also induced an increase in plasma ANF (29%) that was closely associated with a 32% reduction in the systemic clearance of [125I]ANF(99-126), whereas no modification in the estimated secretion rate was detected. These results support a role for NEP in the regulation of endogenous ANF plasma levels. These results also suggest that specific inhibition of NEP may result in an increase in the apparent activity of alternative metabolic pathways.
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PMID:Role of the endopeptidase 24.11 in the disposition and metabolism of endogenous atrial natriuretic factor in the rabbit. 167 98

We examined calcium and calmodulin regulation of atrial natriuretic factor stimulation of particulate-membrane guanylate cyclase (ANF-s-GC) in SK-NEP-1 cells. W7 and trifluoropiperazine, but not W5, inhibited whole cellular ANF-stimulated cyclic GMP accumulation (ANF-s-cGMP). EGTA and LaCl3 decreased ANF-s-GC and calmodulin reversed this inhibition. A23187-induced inhibition of ANF-s-cGMP was only partly reversible by IBMX. H7 or staurosporine counteracted the inhibitory effect of A23187. Calcium inhibited basal and ANF-s-GC. These data suggest that at low concentrations of calcium, ANF-s-GC was calcium-calmodulin dependent but high concentrations of calcium inhibited ANF-s-GC through phosphodiesterase, through inhibition of GC, and probably through protein kinase C.
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PMID:Calcium and calmodulin regulate atrial natriuretic factor stimulation of cyclic GMP in a human renal cell line. 168 32

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

To study the effect of atrial natriuretic factor (ANF) on airway ciliary motility, we measured ciliary beat frequency by a photoelectric method in response to ANF in cultured tracheal epithelial cells from rabbits. Addition of ANF but not [Tyr8]ANF-(5-27) decreased ciliary beat frequency in a dose-dependent fashion; the maximal decrease from the baseline value was 24.1 +/- 1.5% (+/- SE, P less than 0.001), and a half-maximal inhibitory concentration (IC50) was 3 x 10(-12) M. Inhibition of neutral endopeptidase activity by phosphoramidon (10(-6) M) or thiorphan (10(-6) M) potentiated the effect of ANF so that the dose-response curve for ANF was shifted to lower concentrations by approximately 0.5 log units (P less than 0.05, in each case). The inhibition of ciliary motility induced by ANF was not affected by the blockade of arachidonic acid metabolism with indomethacin, piroxicam, or nordihydroguaiaretic acid, but it was blocked by methylene blue, a soluble guanylate cyclase inhibitor, and was potentiated by M & B 22948, a guanosine 3',5'-cyclic monophosphate (cGMP) phosphodiesterase inhibitor. The intracellular cGMP levels were increased by ANF, an effect that was further potentiated by phosphoramidon or thiorphan. These results suggest that ANF inhibits ciliary motility presumably through a guanylate cyclase-dependent regulatory pathway and that neutral endopeptidase may play a role in modulating the ANF effect on airway mucociliary transport function.
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PMID:Atrial natriuretic factor inhibits ciliary motility in cultured rabbit tracheal epithelium. 182 49

The effects of a clearance receptor ligand Arg-Ser-Ser-Cys-Phe-Gly-Gly-Arg-Ile-Asp-Arg-Ile-Gly-Ala-Cys-NH2 with a disulfide bridge between the two cycteines [C-ANF(4-23)] and the potent neutral endopeptidase (NEP) inhibitor SQ 28,603 on mean arterial pressure (MAP), plasma atrial natriuretic factor (ANF) concentration and renal excretion of sodium and cyclic GMP were determined in conscious deoxycorticosterone acetate/salt hypertensive rats and normotensive rats. In the hypertensive rats, i.v. infusion of C-ANF(4-23) produced depressor responses of approximately 25 mm Hg, but did not significantly affect plasma ANF concentration or stimulate cyclic GMP excretion. In contrast, SQ 28,603 (300 mumol/kg i.v.) significantly reduced MAP and increased excretion of sodium and cyclic GMP. When C-ANF(4-23) was administered in combination with SQ 28,603, the depressor activity was additive and plasma ANF concentrations were significantly increased. The excretion of cyclic GMP was slightly enhanced, but, was not significantly different from the effects of SQ 28,603 alone. Neither SQ 28,603 nor C-ANF(4-23) affected MAP or plasma ANF in the normotensive rats. Finally, the in vitro hydrolysis of C-ANF(4-23) by NEP was prevented by SQ 28,603, indicating that inhibition of NEP may protect peptides recognized by the clearance receptors as well as the biological receptors for ANF. Therefore, the additive effects of C-ANF(4-23) and SQ 28,603 may be due to blockade of separate pathways which inactivate ANF or to the inhibition of C-ANF(4-23) degradation by NEP.
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PMID:Possible regulation of atrial natriuretic factor by neutral endopeptidase 24.11 and clearance receptors. 182 31

Atrial natriuretic peptide (ANP) is a 28-amino-acid hormone involved in the regulation of fluid balance. In circulation, the proteolytic inactivation of ANP has been demonstrated to involve both membrane metalloendopeptidase and an aprotonin-sensitive activity, probably corresponding to kallikrein [Vanneste, Y., Pauwels, S., Lambotte, L., Michel, A., Dimaline, R. & Deschodt-Lanckman, M. (1990) Biochem. J. 269, 801-806]. In the present study, we focused on the aprotinin-sensitive pathway of ANP metabolism. In order to identify the cleavage sites recognized by kallikrein within the sequence of the hormone, tissue kallikrein was purified to homogeneity from human urine and the degradation of human ANP by the enzyme preparation was studied. Our results demonstrate that both intact and Cys7-Phe8-cleaved ANP, the initial metabolite produced in circulation by the metallo-endopeptidase, are substrates in vitro for purified tissue kallikrein. However, the Cys-Phe-cleaved peptide was degraded approximately fourfold faster than the intact hormone by the purified enzyme. The first degradation step of ANP by tissue kallikrein involves two cleavages occurring at the bonds Arg3-Arg4 and Gly16-Ala17, generating an inactive, open-ring metabolite. Incubation of ANP for a longer period with the enzyme led to the generation of several additional degradation fragments. Ten peaks were separated by HPLC and characterized by amino acid analysis. The results allowed the identification of a total of eight peptide bonds susceptible to hydrolysis by tissue kallikrein in the sequence of ANP: Arg3-Arg4, Ser5-Ser6, Cys7-Phe8, Arg11-Met12, Gly16-Ala17, Gly20-Leu21, Ser25-Phe26 and Arg27-Tyr28. These results indicate that the aprotinin-sensitive activity involved in the metabolism of ANP in circulation could correspond to tissue kallikrein. However, clear identification of ANP as a novel physiological substrate of the enzyme will need further investigation.
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PMID:Hydrolysis of intact and Cys-Phe-cleaved human atrial natriuretic peptide in vitro by human tissue kallikrein. 182 98

Metabolic clearance and the biological effects of exogenous human atrial natriuretic factor (ANF) were assessed in two groups each of eight normal volunteers receiving 2-h iv infusions of ANF (2.5 pmol/kg.min) on the fifth day of dosing with the orally active inhibitor of endopeptidase 24.11, candoxatril (25 mg every 12 h in group 1 and 100 mg every 12 h in group 2), and placebo in balanced randomized, double blind, placebo-controlled, cross-over experiments. Although 4 days of pretreatment with the endopeptidase inhibitor did not affect basal plasma ANF, candoxatril enhanced mean ANF-induced increases in plasma ANF by 27 pmol/L (P = NS) and 42 pmol/L (P less than 0.002) in groups 1 and 2, respectively. Calculated MCRs for ANF were significantly reduced by both doses of candoxatril [group 1, 2.5 +/- 0.4 vs. 4.3 +/- 0.6 L/min (P less than 0.01); group 2, 2.3 +/- 0.4 vs. 5.6 +/- 0.8 L/min (P less than 0.001)]. ANF significantly enhanced urinary sodium excretion above preinfusion values in both study phases in both groups. Candoxatril significantly further augmented natriuresis in group 2 (P less than 0.01), but not group 1. Inulin clearance was minimally enhanced, and para-aminohippuran clearance was slightly decreased by candoxatril in both groups. Neither effect alone was statistically significant, but derived renal filtration fractions were significantly enhanced in both groups [group 1, 15.5 +/- 0.5% vs. 13.9 +/- 0.6% (P less than 0.01); group 2, 19.3 +/- 1.9% vs. 18.0 +/- 2.7% (P less than 0.01)]. Basal and stimulated cGMP concentrations in both plasma and urine were significantly enhanced by candoxatril in the two groups (P less than 0.001 and P less than 0.01, respectively, for combined data). Urinary ANF immunoreactivity was significantly enhanced by candoxatril in both groups (P less than 0.05 and P less than 0.01 in groups 1 and 2, respectively), with a more pronounced effect evident at the higher dose (P less than 0.01). These results show that chronic pretreatment with an endopeptidase inhibitor in normal man causes a dose-related reduction in the metabolic clearance of exogenous ANF, amplifies cGMP, and increases renal filtration and the natriuretic responses to infused ANF.
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PMID:EC 24.11 inhibition in man alters clearance of atrial natriuretic peptide. 182 51


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