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Possible mechanism of bronchoprotection by SIN‐1 in anaesthetized guinea pigs: roles of nitric oxide and peroxynitrite
Author(s) -
Kanazawa,
Hirata,
Yoshikawa
Publication year - 2000
Publication title -
clinical and experimental allergy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.462
H-Index - 154
eISSN - 1365-2222
pISSN - 0954-7894
DOI - 10.1046/j.1365-2222.2000.00715.x
Subject(s) - peroxynitrite , nitric oxide , medicine , mechanism (biology) , pharmacology , anesthesia , chemistry , biochemistry , superoxide , epistemology , philosophy , enzyme
Background S‐morpholinosydnonimine (SIN‐1) is thought to generate peroxynitrite. Recent reports suggested that peroxynitrite possessed a potent vascular relaxant activity via guanylate cyclase activation. However, no previous studies have examined the relaxant effect of peroxynitrite on airway smooth muscle. Objective To determine the mechanism of bronchoprotection by SIN‐1, considering in particular the involvement of nitric oxide (NO) and peroxynitrite. Methods Peroxynitrite formation was assayed by monitoring the oxidizing activity of dihydrorhodamine 123, and NO was measured polarographically as a redox current in vitro . We examined the effect of SIN‐1 delivered to the airway by ultrasonic nebulization against bronchoconstriction induced by acetylcholine in anaesthetized guinea pigs. Results SIN‐1 produced peroxynitrite in a time‐ and concentration‐dependent manner, but did not produce NO in vitro . However, when mixed with glutathione (GSH) and bronchoalveolar lavage fluid (BALF), peroxynitrite formation by SIN‐1 was inhibited and SIN‐1 induced the release of NO. SNAP (S‐nitroso‐N‐acetyl‐penicillamine) and SIN‐1 each inhibited acetylcholine‐induced bronchoconstriction in a dose‐dependent manner in vivo . Though GSH alone did not have any effect on baseline airway resistance and acetylcholine‐induced bronchoconstriction, pretreatment with GSH significantly enhanced SNAP‐ and SIN‐1‐induced bronchoprotection. In addition, pretreatment with carboxy‐PTIO, a NO scavenger, completely inhibited bronchoprotective effect of SNAP on acetylcholine‐induced bronchoconstriction, but partially inhibited SIN‐1‐induced bronchoprotection. Conclusion These findings demonstrated that SIN‐1 is a potent peroxynitrite‐releasing compound and caused significant bronchoprotection against acetylcholine. The mechanism of bronchoprotection by SIN‐1 appears to be mediated by peroxynitrite but also at least in part through NO regeneration, which may involve GSH and airway thiols as a consequence of exposure to peroxynitrite.