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- Title
Administration of SIN–1 Induces Guinea Pig Airway Hyperresponsiveness through Inactivation of Airway Neutral Endopeptidase.
- Authors
Kanazawa, Hiroshi; Hirata, Kazuto; Yoshikawa, Junichi
- Abstract
Background: Peroxynitrite plays an important role in the pathogenesis of airway inflammation. We have already found that peroxynitrite may contribute to decreased β[sub 2] –adrenoceptor responses in airway smooth muscle. However, it is not known whether peroxynitrite can alter neutral endopeptidase (EC 3.4.24.11; NEP) activity in the airways. This study was designed to determine whether peroxynitrite induces airway hyperresponsiveness to substance P (SP) and endothelin–1 (ET–1) through the inactivation of airway NEP. Methods: We examined whether the administration of S–morpholinosydnonimine (SIN–1), a compound that releases peroxynitrite, increased bronchoconstrictor responses to SP and ET–1 in anesthetized guinea pigs. In addition, we assayed NEP activity in the airways of SIN–1–exposed guinea pigs. Results: Though SIN–1 (10[sup –7] M) alone had no effect on pulmonary resistance, pretreatment with SIN–1 significantly enhanced SP– and ET–1–induced bronchoconstriction. Pretreatment with phosphoramidon, an NEP inhibitor, also enhanced SP– and ET–1–induced bronchoconstriction. However, simultaneous administration of phosphoramidon and SIN–1 had no additive effect on SP– and ET–1–induced bronchoconstriction. Peroxynitrite formation by SIN–1 was completeley inhibited by N–acetylcysteine (NAC) and glutathione (GSH) in vitro, and pretreatment with NAC and GSH significantly reversed the potentiation by SIN–1 of SP–induced bronchoconstriction. In addition, the NEP activity of the trachea after SIN–1 exposure was significantly reduced compared to the level in control guinea pigs (solvent for SIN–1: 30.0±4.2 fmol·min[sup –1] ·mg tissue[sup –1] ; 10[sup –7] M SIN–1; 15.5±4.5 fmol·min[sup –1] ·mg tissue[sup –1] , p<0.05). Conclusions: These findings suggest that peroxynitrite induces airway hyperresponsiveness to SP and ET–1 through the inactivation of airway NEP, and that peroxynitrite is an important mediator of the alterations in airway functions.
- Subjects
AIRWAY (Anatomy); ENDOPEPTIDASES; PEPTIDASE; ENDOTHELINS; PEPTIDES
- Publication
International Archives of Allergy & Immunology, 1999, Vol 120, Issue 4, p317
- ISSN
1018-2438
- Publication type
Article
- DOI
10.1159/000024285