title: Administration of SIN-1 induces guinea pig airway hyperresponsiveness through inactivation of airway neutral endopeptidase.
abstract: BACKGROUND
  Peroxynitrite plays an important role in the pathogenesis of airway inflammation. We have already found that peroxynitrite may contribute to decreased beta(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(-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 completely 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(-1).mg tissue(-1); 10(-7) M SIN-1; 15.5+/-4.5 fmol.min(-1).mg tissue(-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.
authors.affiliation: The First Department of Internal Medicine, Osaka City University Medical School, Osaka, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Kanazawa
authors.forename: K
authors.initials: K
authors.lastname: Hirata
authors.forename: J
authors.initials: J
authors.lastname: Yoshikawa
mesh_terms: D000818:Animals; D016535:Bronchial Hyperreactivity / Q000139:chemically induced*; D016084:Bronchoconstriction / Q000187:drug effects; D019332:Endothelin-1 / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D006020:Glycopeptides / Q000494:pharmacology; D006168:Guinea Pigs; D008297:Male; D008981:Molsidomine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D015260:Neprilysin / Q000378:metabolism*; D009566:Nitrates / Q000494:pharmacology; D016877:Oxidants / Q000494:pharmacology; D011480:Protease Inhibitors / Q000494:pharmacology; D012137:Respiratory System / Q000201:enzymology; D013373:Substance P / Q000494:pharmacology; D014132:Trachea / Q000201:enzymology; D014665:Vasodilator Agents / Q000008:administration & dosage
chemical_list: D019332:Endothelin-1; D006020:Glycopeptides; D009566:Nitrates; D016877:Oxidants; D011480:Protease Inhibitors; D014665:Vasodilator Agents; C039642:peroxynitric acid; D013373:Substance P; C002385:linsidomine; D008981:Molsidomine; D015260:Neprilysin; C008890:phosphoramidon