Rat big endothelin-1-induced bronchoconstriction and vasoconstriction in the isolated perfused rat lung: role of endothelin converting enzyme and neutral endopeptidase 24.11

1997 ◽  
Vol 355 (5) ◽  
pp. 619-624 ◽  
Author(s):  
Heinz-Dieter Held ◽  
Manfred Raschak ◽  
S. Uhlig
Keyword(s):  
Neutral Endopeptidase ◽  
Converting Enzyme ◽  
Rat Lung ◽  
Endothelin 1 ◽  
Endopeptidase 24.11 ◽  
Endothelin Converting Enzyme

Synthesis and degradation of endothelin-1

2003 ◽  
Vol 81 (6) ◽  
pp. 503-510 ◽  
Author(s):  
P D'Orléans-Juste ◽  
M Plante ◽  
J C Honoré ◽  
E Carrier ◽  
J Labonté
Keyword(s):  
Matrix Metalloproteinase ◽  
Neutral Endopeptidase ◽  
Embryonic Stage ◽  
Converting Enzyme ◽  
Endothelin 1 ◽  
Endothelin Converting Enzyme ◽  
Hydrolysis Of ◽  
Synthesis And Degradation

The endothelin-converting enzyme (ECE) is the main enzyme responsible for the genesis of the potent pressor peptide endothelin-1 (ET-1). It is suggested that the ECE is pivotal in the genesis of ET-1, considering that the knockout of both genes generates the same lethal developments during the embryonic stage. Several isoforms of the ECE have been disclosed, namely ECE-1, ECE-2, and ECE-3. Within each of the first two groups, several sub-isoforms derived through splicing of single genes have also been identified. In this review, the characteristics of each sub-isoform for ECE-1 and 2 will be discussed. It is important to mention that the ECE is, however, not the sole enzyme involved in the genesis of endothelins. Indeed, other moieties, such as chymase and matrix metalloproteinase II, have been suggested to be involved in the production of ET intermediates, such as ET-1 (1–31) and ET-1 (1–32), respectively. Other enzymes, such as the neutral endopeptidase 24–11, is curiously not only involved in the degradation and inactivation of ET-1, but is also responsible for the final production of the peptide via the hydrolysis of ET-1 (1–31). In this review, we will attempt to summarize, through the above-mentioned characteristics, the current wisdom on the role of these different enzymes in the genesis and termination of effect of the most potent pressor peptide reported to date.Key words: endothelin converting enzyme, endothelin-1, isoforms, human, inhibitors, chymase, ET-1 (1–31).

Role of endothelin-converting enzyme, chymase and neutral endopeptidase in the processing of big ET-1, ET-1(1-21) and ET-1(1-31) in the trachea of allergic mice

2002 ◽  
Vol 103 (s2002) ◽  
pp. 353S-356S ◽  
Author(s):  
Benjamin A. DE CAMPO ◽  
Roy G. GOLDIE ◽  
Arco Y. JENG ◽  
Peter J. HENRY
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Response Curve ◽  
Histological Analysis ◽  
Neutral Endopeptidase ◽  
Converting Enzyme ◽  
Rightward Shift ◽  
Endothelin Converting Enzyme ◽  
Mast Cell Chymase

The present study examined the roles of endothelin-converting enzyme (ECE), neutral endopeptidase (NEP) and mast cell chymase as processors of the endothelin (ET) analogues ET-1(1–21), ET-1(1–31) and big ET-1 in the trachea of allergic mice. Male CBA/CaH mice were sensitized with ovalbumin (10µg) delivered intraperitoneal on days 1 and 14, and exposed to aerosolized ovalbumin on days 14, 25, 26 and 27 (OVA mice). Mice were killed and the trachea excised for histological analysis and contraction studies on day 28. Tracheae from OVA mice had 40% more mast cells than vehicle-sensitized mice (sham mice). Ovalbumin (10µg/ml) induced transient contractions (15±3% of the Cmax) in tracheae from OVA mice. The ECE inhibitor CGS35066 (10µM) inhibited contractions induced by big ET-1 (4.8-fold rightward shift of dose-response curve; P<0.05), but not those induced by either ET-1(1–21) or ET-1(1–31). The chymase inhibitors chymostatin (10µM) and Bowman-Birk inhibitor (10µM) had no effect on contractions induced by any of the ET analogues used. The NEP inhibitor CGS24592 (10µM) inhibited contractions induced by ET-1(1–31) (6.2-fold rightward shift; P<0.05) but not ET-1(1–21) or big ET-1. These data suggest that big ET-1 is processed predominantly by a CGS35066-sensitive ECE within allergic airways rather than by mast cell-derived proteases such as chymase. If endogenous ET-1(1–31) is formed within allergic airways, it is likely to undergo further conversion by NEP to more active products.

Potent non-peptidic dual inhibitors of endothelin-converting enzyme and neutral endopeptidase 24.11

1997 ◽  
Vol 7 (8) ◽  
pp. 1059-1064 ◽  
Author(s):  
Stéphane De Lombaert ◽  
Lisa B. Stamford ◽  
Louis Blanchard ◽  
Jenny Tan ◽  
Denton Hoyer ◽  
...  
Keyword(s):  
Neutral Endopeptidase ◽  
Converting Enzyme ◽  
Endopeptidase 24.11 ◽  
Endothelin Converting Enzyme ◽  
Dual Inhibitors

scholarly journals The dual endothelin converting enzyme/neutral endopeptidase inhibitor SLV-306 (daglutril), inhibits systemic conversion of big endothelin-1 in humans

Life Sciences ◽  
2012 ◽  
Vol 91 (13-14) ◽  
pp. 743-748 ◽  
Author(s):  
Alison Seed ◽  
Rhoda E. Kuc ◽  
Janet J. Maguire ◽  
Christopher Hillier ◽  
Fiona Johnston ◽  
...  
Keyword(s):  
Neutral Endopeptidase ◽  
Converting Enzyme ◽  
Endothelin 1 ◽  
Endothelin Converting Enzyme

scholarly journals Mutagenesis of Glu403 to Cys in rabbit neutral endopeptidase-24.11 (neprilysin) creates a disulphide-linked homodimer: analogy with endothelin-converting enzyme

1997 ◽  
Vol 327 (3) ◽  
pp. 925-929 ◽  
Author(s):  
V. Mien HOANG ◽  
E. Clare SANSOM ◽  
J. Anthony TURNER
Keyword(s):  
Three Dimensional ◽  
Neutral Endopeptidase ◽  
Biologically Active ◽  
Dimensional Structure ◽  
Mutant Form ◽  
Converting Enzyme ◽  
Wild Type ◽  
Endopeptidase 24.11 ◽  
Reducing Conditions ◽  
Endothelin Converting Enzyme

Neutral endopeptidase-24.11 (NEP; neprilysin; EC 3.4.24.11) and endothelin-converting enzyme (ECE) are related zinc metallopeptidases involved in the processing of biologically active peptides. Only ECE, however, exists as a disulphide-linked homodimer. The covalent linkage in rat ECE is between Cys412 in each subunit, which is equivalent to Glu403 in rabbit NEP. Here we report that directed mutagenesis of Glu403 to cysteine in rabbit NEP creates a disulphide-linked homodimer, as revealed by transient transfection in COS-1 cells and SDS/PAGE of a membrane fraction. Under reducing conditions, both the mutant (E403C) and the wild-type NEP migrate as a polypeptide of 92 kDa. However, under non-reducing conditions, the Mr of the wild type remains unchanged, whereas that of the mutant is doubled. Co-transfection of wild-type ECE and E403C NEP cDNA did not result in the production of a NEP-ECE heterodimer. Comparison of the kinetic constants for wild-type and E403C mutant NEP with either [D-Ala2,Leu5]enkephalin or 3-carboxypropanoyl-alanyl-alanyl-leucine-4-nitroanilide (Suc-Ala-Ala-Leu-NH-Np) as substrate show a decrease of approx. 50% in Vmax/Km for the mutant form. The IC50 value for inhibition of the mutant by phosphoramidon or thiorphan is increased 3-fold and 5-fold respectively. Although NEP and ECE exhibit only about 40% identity and differ substantially in substrate specificity and some other characteristics, these data indicate that they have considerable similarity in three-dimensional structure, allowing dimer formation in the mutant NEP with the disulphide link probably occurring in a hydrophilic surface loop.

ChemInform Abstract: Potent Non-Peptidic Dual Inhibitors of Endothelin-Converting Enzyme and Neutral Endopeptidase 24.11.

ChemInform ◽  
2010 ◽  
Vol 28 (36) ◽  
pp. no-no
Author(s):  
S. DE LOMBAERT ◽  
L. B. STAMFORD ◽  
L. BLANCHARD ◽  
J. TAN ◽  
D. HOYER ◽  
...  
Keyword(s):  
Neutral Endopeptidase ◽  
Converting Enzyme ◽  
Endopeptidase 24.11 ◽  
Endothelin Converting Enzyme ◽  
Dual Inhibitors
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