Am. J. Respir. Crit. Care Med., Volume 158, Number 6, December 1998, 1784-1789

Effects of Endogenous Superoxide Anion and Nitric Oxide on Cholinergic Constriction of Normal and Hyperreactive Guinea Pig Airways

JACOB DE BOER, F.MAY H. POUW, JOHAN ZAAGSMA, and HERMAN MEURS

Department of Molecular Pharmacology, University Centre for Pharmacy, Groningen, The Netherlands

In a guinea pig model of allergic asthma, we have recently established that a deficiency of nitric oxide (NO) contributes to the increased ex vivo responsiveness of isolated perfused tracheae to methacholine after the early asthmatic reaction at 6 h after inhalational challenge of the animals with ovalbumin aerosol. Because this deficiency could be caused by a reaction of NO with enhanced levels of inflammation-induced superoxide anion (O₂), we examined the effect of endogenous O₂ on the regulation of methacholine-induced constriction by NO of intact perfused tracheal tube preparations from unchallenged (control) guinea pigs and from animals 6 h after ovalbumin challenge. In the presence of the NO synthase (NOS) inhibitor N -nitro-L-arginine methyl ester (L-NAME; 100 µM), tracheae obtained from unchallenged guinea pigs showed a 1.7-fold increase in the maximal response to intraluminally applied methacholine (p < 0.05). By contrast, the maximal airway response to methacholine was significantly decreased in the presence of the O₂ scavenger superoxide dismutase (SOD; 100 U/ml), by approximately 45% (p < 0.01). The SOD-induced decrease in responsiveness to methacholine was reversed by L-NAME. Tracheal preparations obtained at 6 h after allergen challenge showed a 1.8-fold increased responsiveness to intraluminally applied methacholine compared with controls (p < 0.001), which was not further enhanced in the presence of L-NAME. SOD had neither an effect on the increased responsiveness nor did it restore the potentiating effect of L-NAME. These results indicate that (1) in normoreactive tracheal preparations, the regulatory role of NO is partially counteracted by endogenous O₂, and ( 2) the deficiency of NO in hyperreactive tracheae obtained at 6 h after ovalbumin challenge is not caused by its reaction with O₂, but rather to decreased cNOS activity. De Boer J, Pouw FMH, Zaagsma J, Meurs H. Effects of endogenous superoxide anion and nitric oxide on cholinergic constriction of normal and hyperreactive guinea pig airways.

This article has been cited by other articles:

				S. M. Wells, M. C. Buford, C. T. Migliaccio, and A. Holian Elevated Asymmetric Dimethylarginine Alters Lung Function and Induces Collagen Deposition in Mice Am. J. Respir. Cell Mol. Biol., February 1, 2009; 40(2): 179 - 188. [Abstract] [Full Text] [PDF]

				S. M. Wells and A. Holian Asymmetric Dimethylarginine Induces Oxidative and Nitrosative Stress in Murine Lung Epithelial Cells Am. J. Respir. Cell Mol. Biol., May 1, 2007; 36(5): 520 - 528. [Abstract] [Full Text] [PDF]

				A. Samb, C. Taille, A. Almolki, J. Megret, J. M. Staddon, M. Aubier, and J. Boczkowski Heme oxygenase modulates oxidant-signaled airway smooth muscle contractility: role of bilirubin Am J Physiol Lung Cell Mol Physiol, September 1, 2002; 283(3): L596 - L603. [Abstract] [Full Text] [PDF]

				G. Thabut, J. El-Benna, A. Samb, S. Corda, J. Megret, G. Leseche, E. Vicaut, M. Aubier, and J. Boczkowski Tumor Necrosis Factor-alpha Increases Airway Smooth Muscle Oxidants Production through a NADPH Oxidase-like System to Enhance Myosin Light Chain Phosphorylation and Contractility J. Biol. Chem., June 14, 2002; 277(25): 22814 - 22821. [Abstract] [Full Text] [PDF]

				M. Aoki, S. Yamamoto, M. Kobayashi, K. Ohga, H. Kanoh, K. Miyata, K. Honda, and T. Yamada Antiasthmatic Effect of YM976, a Novel PDE4 Inhibitor, in Guinea Pigs J. Pharmacol. Exp. Ther., April 1, 2001; 297(1): 165 - 173. [Abstract] [Full Text]