title: Inhibition of bronchoprotective effects of beta2-adrenoceptor agonists by peroxynitrite in guinea pig airways.
abstract: Peroxynitrite plays an important role in the pathogenesis of inflammatory diseases, including those affecting the lung. In inflamed airways, simultaneous cellular production of superoxide anion (.O2-) and nitric oxide (NO) may occur, potentially resulting in continuous formation of peroxynitrite. However, because peroxynitrite has a short half-life, its in vivo physiologic effects in the airways may not be sufficiently evaluated with a single administration. Accordingly, this study was designed to use 3-morpholinosydnonimine (SIN-1), a compound that releases peroxynitrite, to determine whether peroxynitrite could alter airway beta2-adrenoceptor (beta2-AR) function in anesthetized guinea pigs. Though SIN-1(10(-)7 M) alone had no effect on pulmonary resistance, pretreatment with SIN-1 significantly attenuated isoprenaline- and salbutamol-induced bronchoprotection against acetylcholine. Pretreatment with SIN-1 also attenuated forskolin-induced bronchoprotection. S-Nitroso-N-acetylpenicillamine (SNAP), a potent NO donor, did not have the same effect as SIN-1. N-Acetylcysteine and glutathione each significantly reversed the inhibitory effect of SIN-1 on isoprenaline-induced bronchoprotection in a dose-dependent manner. These striking findings suggested that peroxynitrite, but not NO, is an important mediator of alteration of beta2-AR function in airway smooth muscle. Additionally, the action of peroxynitrite seems to be directed either at adenylate cyclase activity or at effects downstream of such activity.
authors: First Department of Internal Medicine, Osaka City University Medical School, Osaka, Japan.
authors: H
authors: H
authors: Kanazawa
authors: S
authors: S
authors: Shiraishi
authors: T
authors: T
authors: Okamoto
authors: K
authors: K
authors: Hirata
authors: J
authors: J
authors: Yoshikawa
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000403:Airway Resistance; D000420:Albuterol / Q000494:pharmacology; D000818:Animals; D016084:Bronchoconstriction / Q000187:drug effects / Q000502:physiology*; D005576:Colforsin / Q000494:pharmacology; D006168:Guinea Pigs; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D008981:Molsidomine / Q000031:analogs & derivatives / Q000494:pharmacology; D009566:Nitrates / Q000494:pharmacology*; D010396:Penicillamine / Q000031:analogs & derivatives / Q000494:pharmacology; D018342:Receptors, Adrenergic, beta-1 / Q000502:physiology*
chemical_list: D000318:Adrenergic beta-Agonists; D009566:Nitrates; D018342:Receptors, Adrenergic, beta-1; C110881:S-nitro-N-acetylpenicillamine; D005576:Colforsin; C039642:peroxynitric acid; C002385:linsidomine; D008981:Molsidomine; D010396:Penicillamine; D007545:Isoproterenol; D000109:Acetylcholine; D000420:Albuterol