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.
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September 2002
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September 01 2002
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
Benjamin A. DE CAMPO;
Benjamin A. DE CAMPO
*Department of Pharmacology, The University of Western Australia, 35 Stirling Highway, Crawley, Western Australia 6009, Australia
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Roy G. GOLDIE;
Roy G. GOLDIE
*Department of Pharmacology, The University of Western Australia, 35 Stirling Highway, Crawley, Western Australia 6009, Australia
†Western Australian Institute for Medical Research, B Block, Hospital Avenue, Nedlands, Western Australia 6009, Australia
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Arco Y. JENG;
Arco Y. JENG
‡Novartis Institute for Biomedical Research, Summit, NJ, U.S.A.
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Peter J. HENRY
*Department of Pharmacology, The University of Western Australia, 35 Stirling Highway, Crawley, Western Australia 6009, Australia
†Western Australian Institute for Medical Research, B Block, Hospital Avenue, Nedlands, Western Australia 6009, Australia
Dr P. Henry, Department of Pharmacology, The University of Western Australia, 35 Stirling Highway, Crawley, Western Australia 6009, Australia (e-mail [email protected]).
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Publisher: Portland Press Ltd
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© 2002 The Biochemical Society and the Medical Research Society
2002
Clin Sci (Lond) (2002) 103 (s2002): 353S–356S.
Citation
Benjamin A. DE CAMPO, Roy G. GOLDIE, Arco Y. JENG, Peter J. HENRY; 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. Clin Sci (Lond) 1 September 2002; 103 (s2002): 353S–356S. doi: https://doi.org/10.1042/CS103S353S
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