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.