Possible mechanism of bronchoprotection by SIN-1 in anaesthetized guinea pigs: roles of nitric oxide and peroxynitrite

Clin Exp Allergy. 2000 Mar;30(3):445-50. doi: 10.1046/j.1365-2222.2000.00715.x.


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.

MeSH terms

  • Acetylcholine / antagonists & inhibitors
  • Acetylcholine / toxicity
  • Animals
  • Bronchi / drug effects*
  • Bronchoalveolar Lavage Fluid
  • Bronchoconstriction / drug effects
  • Bronchoconstriction / physiology*
  • Bronchodilator Agents / pharmacology*
  • Dose-Response Relationship, Drug
  • Glutathione / pharmacology
  • Guinea Pigs
  • Male
  • Molsidomine / analogs & derivatives*
  • Molsidomine / pharmacology
  • Nebulizers and Vaporizers
  • Nitrates / metabolism*
  • Nitric Oxide / metabolism*
  • Penicillamine / analogs & derivatives
  • Penicillamine / pharmacology
  • Rhodamines / metabolism
  • Time Factors
  • Vasodilator Agents / pharmacology*


  • Bronchodilator Agents
  • Nitrates
  • Rhodamines
  • S-nitro-N-acetylpenicillamine
  • Vasodilator Agents
  • dihydrorhodamine 123
  • peroxynitric acid
  • Nitric Oxide
  • linsidomine
  • Molsidomine
  • Glutathione
  • Penicillamine
  • Acetylcholine