Kanazawa H, Hirata K, Yoshikawa J
The First Department of Internal Medicine, Osaka City University Medical School, Osaka, Japan.
Clin Exp Allergy. 2000 Mar;30(3):445-50. doi: 10.1046/j.1365-2222.2000.00715.x.
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.
To determine the mechanism of bronchoprotection by SIN-1, considering in particular the involvement of nitric oxide (NO) and peroxynitrite.
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.
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.
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.
S-吗啉代亚硝基胍（SIN-1）被认为可生成过氧亚硝酸盐。最近的报告表明，过氧亚硝酸盐通过激活鸟苷酸环化酶具有强大的血管舒张活性。然而，此前尚无研究探讨过氧亚硝酸盐对气道平滑肌的舒张作用。
确定SIN-1的支气管保护机制，尤其考虑一氧化氮（NO）和过氧亚硝酸盐的参与情况。
通过监测二氢罗丹明123的氧化活性来测定过氧亚硝酸盐的形成，并在体外以氧化还原电流极谱法测量NO。我们研究了通过超声雾化将SIN-1输送至气道对麻醉豚鼠乙酰胆碱诱导的支气管收缩的影响。
SIN-1以时间和浓度依赖的方式产生过氧亚硝酸盐，但在体外不产生NO。然而，当与谷胱甘肽（GSH）和支气管肺泡灌洗液（BALF）混合时，SIN-1的过氧亚硝酸盐形成受到抑制，且SIN-1诱导NO释放。在体内，S-亚硝基-N-乙酰青霉胺（SNAP）和SIN-1均以剂量依赖的方式抑制乙酰胆碱诱导的支气管收缩。虽然单独的GSH对基础气道阻力和乙酰胆碱诱导的支气管收缩没有任何影响，但用GSH预处理可显著增强SNAP和SIN-1诱导的支气管保护作用。此外，用NO清除剂羧基-PTIO预处理可完全抑制SNAP对乙酰胆碱诱导的支气管收缩的支气管保护作用，但部分抑制SIN-1诱导的支气管保护作用。
这些发现表明，SIN-1是一种强效的过氧亚硝酸盐释放化合物，对乙酰胆碱具有显著的支气管保护作用。SIN-1的支气管保护机制似乎是由过氧亚硝酸盐介导的，但至少部分是通过NO再生，这可能涉及GSH和气道硫醇，这是暴露于过氧亚硝酸盐的结果。
