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Laboratory and Animal Investigations |

Nitric Oxide and Vasoactive Intestinal Peptide as Co-transmitters of Airway Smooth-Muscle Relaxation*: Analysis in Neuronal Nitric Oxide Synthase Knockout Mice

Nadia A. Hasaneen; Hussein D. Foda; Sami I. Said
Author and Funding Information

*From the Medical Service and Research Service, VA Medical Center, Northport, and State University of New York at Stony Brook, Stony Brook, NY.

Correspondence to: Sami I. Said, MD, Pulmonary and Critical Care Medicine, SUNY at Stony Brook, Health Sciences Center, Stony Brook, NY 11794-8172; e-mail: ssaid@mail.som.sunysb.edu



Chest. 2003;124(3):1067-1072. doi:10.1378/chest.124.3.1067
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Background: Both vasoactive intestinal peptide (VIP) and nitric oxide (NO) relax airway smooth muscle and are potential co-transmitters of neurogenic airway relaxation. The availability of neuronal NO synthase (nNOS) knockout mice (nNOS−/−) provides a unique opportunity for evaluating NO.

Objective: To evaluate the relative importance of NO, especially that generated by nNOS, and VIP as transmitters of the inhibitory nonadrenergic, noncholinergic (NANC) system.

Study design: In this study, we compared the neurogenic (tetrodotoxin-sensitive) NANC relaxation of tracheal segments from nNOS−/− mice and control wild-type mice (nNOS+/+), induced by electrical field stimulation (EFS). We also examined the tracheal contractile response to methacholine and its relaxant response to VIP.

Results: EFS (at 60 V for 2 ms, at 10, 15, or 20 Hz) dose-dependently reduced tracheal tension, and the relaxations were consistently smaller (approximately 40%) in trachea from nNOS−/− mice than from control wild-type mice (p < 0.001). VIP (10− 8 to 10−6 mol/L) induced concentration-dependent relaxations that were approximately 50% smaller in nNOS−/− tracheas than in control tracheas. Methacholine induced concentration-dependent contractions that were consistently higher in the nNOS−/− tracheas relative to wild-type mice tracheas (p > 0.05).

Conclusion: Our data suggest that, in mouse trachea, NO is probably responsible for mediating a large (approximately 60%) component of neurogenic NANC relaxation, and a similar (approximately 50%) component of the relaxant effect of VIP. The results imply that NO contributes significantly to neurogenic relaxation of mouse airway smooth muscle, whether due to neurogenic stimulation or to the neuropeptide VIP.

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