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(Chest. 2003;124:1067-1072.)
© 2003 American College of Chest Physicians

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, MD, PhD; Hussein D. Foda, MD and Sami I. Said, MD

* 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{at}mail.som.sunysb.edu


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
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.

Key Words: asthma • knockout mice • nitric oxide • nitric oxide synthase • vasoactive intestinal peptide


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Both vasoactive intestinal peptide (VIP) and nitric oxide (NO) relax airway smooth muscle in several species, including human, and are the likely co-transmitters of the inhibitory nonadrenergic, noncholinergic (iNANC) system.1 Conflicting data exist, however, about the precise contributions of these transmitters to nonadrenergic, noncholinergic (NANC) relaxation, and the interactions between them in different smooth-muscle organs.2 3 4 5 6 7 8 In a study using isolated human airways, endogenous NO released by electrical field stimulation (EFS) produced marked inhibition of cholinergic contractile responses, but VIP did not.7 Another study9 concluded that, in human tracheal segments, the neurogenic bronchodilator response is totally NO mediated, with VIP playing no role in this response, while a third report5 proposed that both NO and VIP are major mediators of NANC relaxation of tracheal smooth muscle in guinea pigs.

Interactions between VIP and NO in different tissues have also been the subject of different interpretations. VIP was found to stimulate the synthesis of NO in GI smooth muscle,10 11 and VIP-induced relaxation of guinea pig ileum was reported to be mediated, in part, by NO.12 A similar conclusion was reached from examination of the relaxation of whole guinea pig lung in response to VIP13 ; however, VIP relaxation of isolated guinea pig tracheal strips was found to be independent of NO synthesis.14

Controversy has also focused on the individual roles of neuronal, endothelial, and inducible NO synthases in the regulation of airway smooth-muscle tone, both in the basal state and in modulating airway constriction. The availability of neuronal NO synthase (nNOS) knockout mice (nNOS-/-) provides a unique opportunity for evaluating the relative importance of NO, especially that generated by nNOS, and VIP as transmitters of the inhibitory NANC. 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 EFS. We also examined the tracheal contractile response to methacholine and its relaxant response to VIP.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Animals
nNOS knockout mice (nNOS-/-), on the background of C57 black/6 mice, aged 4 to 6 weeks and weighing 15 to 20 g, were obtained form Dr. Mark C. Fishman, Massachussetts General Hospital, Boston, MA, through a material transfer agreement. These mutant mice were healthy, fertile, and without histopathologic evidence of abnormalities in the CNS.15 The most evident effect of disturbing the neuronal NOS gene was the development of a grossly dilated stomach, with hypertrophy of the pyloric sphincter. Control wild-type mice, C57 black/6, aged 4 to 6 weeks and weighing 15 to 20 g, were purchased from Taconic (Germantown, NY).

Chemicals
Porcine VIP was obtained from the late Professor Viktor Mutt, Karolinska Institute, Stockholm, Sweden. Thromboxane agonist U-46619 was a gift from Upjohn Company (Ann Arbor, MI). Methacholine chloride, phentolamine HCl, propranolol, atropine, and tetrodotoxin were purchased from Sigma Chemical Company (St. Louis, MO).

Tracheal Strip Preparation
Mice were killed with intraperitoneal pentobarbital (60 mg/kg). The tracheas were removed, freed of connective tissue and vasculature, and cut spirally into 2-mm by 2-cm strips. The strips were suspended in a 5-mL organ bath and were perifused with Krebs solution, equilibrated with 95% O2/5% CO2, and maintained at 37°C. The solution was circulated continuously at 3 mL/min by an infusion pump (Cole-Parmer; Chicago, IL). The lower end of each tracheal strip was fixed to the floor of bath, and the upper end was tied to an isometric force transducer (Harvard Apparatus; Holliston, MA). Changes in tracheal smooth-muscle tension, expressed in grams, were recorded graphically on a chart recorder (Harvard Apparatus). Tissues were allowed to stabilize for 1 h at an initial load of 0.5 g. This load was found to provide the best passive tone for measuring both relaxation and contraction.

Methacholine Dose Response
After stabilization of the tracheal strips, six from control wild-type mice and six from nNOS-/- mice, methacholine in final concentrations of 10- 7 to 5 x 10- 5 mol/L was added in 50-µL volume to tissue baths. The contractile responses of the tissues to 10- 7, 10- 6, 10- 5, and 5 x 10- 5 mol/L concentrations of methacholine were recorded and expressed in grams of tension.

EFS
These studies were performed on 12 tracheal strips (6 strips for each group of mice). The same strips were previously used, on the same day, for the methacholine response studies. EFS was performed as previously described.16 Briefly, each tracheal strip was mounted between two platinum electrodes, 6-mm apart, in the tissue bath. The responses to methacholine confirmed that the tracheal epithelium was not damaged. After the last dose of methacholine, the strips were washed for 30 to 60 min with fresh Krebs solution to equilibrate and wash out the methacholine. The strips were then precontracted with a continuous flow of thromboxane agonist U-46619 at a concentration of 10- 6 mol/L in Krebs solution. We used U-46619 as the exclusive agent to increase tracheal tone because we have found it to provide a stable level of smooth-muscle tension. When the tracheal strip reached a plateau, EFS was applied by an electrical stimulator (Grass S44 Stimulator; Grass Medical Instruments; Quincy, MA), connected to the two platinum electrodes adjoining the tracheal strip. Rectangular electrical impulses were delivered at 60 V, with pulse duration of 2 ms, and frequency of 10, 15, and 20 Hz. Each period of stimulation lasted for 2 min, and consecutive stimulations were separated by at least 30 min. The intensity of the EFS stimulus was increased by increasing the frequency of application (hertz). To confirm that the EFS response was due to activation of NANC system, we repeated the EFS experiment in four different tracheal strips from each group in the presence of {alpha}- and ß-adrenergic and cholinergic muscarinic receptor blockers (10- 5 mol/L phentolamine, 10- 5 mol/L propranolol, and 10- 5 mol/L atropine, respectively). To do so, after the last dose of methacholine, the tracheal strips were washed with fresh Krebs for 30 to 60 min for equilibration, then precontracted continuously with U-46619 at a concentration of 10- 6 mol/L in Krebs solution. EFS was then applied in the presence of the blockers. At the end of all experiments, to confirm that the responses to EFS were neurogenic, EFS was again applied after blockade of nerve transmission by 10- 6 mol/L tetrodotoxin. The relaxation responses of the tissues to EFS are expressed as percentage reversal of contraction induced by the thromboxane agonist.

VIP Dose Response
Tracheal strips from eight wild-type mice and six nNOS knockout mice were studied. These strips were different from those used for EFS studies. Each strip was examined for methacholine response to confirm the viability of the tissues and the presence of epithelium. After the last dose of methacholine, the tracheal strip was washed with flow of Krebs solution from 30 min to 1 h. The strips were precontracted with the thromboxane agonist as above. VIP, in final concentrations of 10- 8 to 10- 6 mol/L, was added in 50-µL volume to the tissue bath. The relaxation responses of the tissues to VIP doses are expressed as percentage of reversal of the precontracted state.

Analysis of Data
All data are presented as mean ± SEM. Tracheal responses of different experimental groups were compared using the unpaired t test. Responses to different levels of stimuli within the same experimental group were analyzed by the Kruskal-Wallis one-way analysis of variance test. In both cases, p < 0.05 was considered significant.17


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
EFS
EFS produced an intensity-dependent relaxation in tracheas from both groups of mice. At 10 Hz, the mean relaxation was 48.16 ± 6.70% in wild-type mice tracheas, vs 6 ± 5.31% in nNOS-/- mice tracheas. At 15 Hz, EFS caused a 88.5 ± 21.9% relaxation in wild-type mice tracheas, compared to 30.8 ± 4.21% in nNOS-/- mice tracheas. At 20 Hz, there was a 107.6 ± 16.37% relaxation in wild-type mice tracheas, compared to 46.3 ± 7.52% in nNOS-/- mice tracheas (p < 0.001) [Fig 1 ; n = 6 for each comparison]. The addition of adrenergic and cholinergic blockers before EFS decreased the relaxation response in both wild-type and nNOS-/- mice tracheas, but the relaxant responses of wild-type mice tracheas to different intensities of EFS were significantly greater than those of nNOS-/- mice tracheas. At 10, 15, and 20 Hz, EFS caused, respectively, 28.25 ± 1.97%, 57.00 ± 2.38%, and 74.00 ± 0.577% relaxation in wild-type tracheas, vs 3.21 ± 1.856%, 20.33 ± 0.88%, and 32.61 ± 1.45% relaxation in nNOS-/- mice tracheas (p < 0.001). Tetrodotoxin, a sodium-channel blocker that prevents nerve conduction, totally abolished the relaxation induced by EFS in both groups of tracheas, supporting the impression that the relaxation was completely neurogenic in origin (data not shown).



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  		Figure 1. Dose response in tracheas from wild-type mice (crossed bars) and from nNOS-/- mice (solid bars) to EFS at 10, 15, and 20 Hz. ***Significant differences between the paired responses at all levels of EFS (p < 0.0001).

 
Response to Methacholine
There was a concentration-dependent contraction in response to methacholine in both groups of tracheas. At 10- 7 mol/L, methacholine increased tension in tracheas from wild-type mice by 0.10 ± 0.04 g, vs 0.15 ± 0.06 g in tracheas from nNOS-/- mice. At 10- 6 mol/L, methacholine increased tension in wild-type mice tracheas by 0.15 ± 0.07 g, compared to 0.28 ± 0.01 g in nNOS-/- mice. Concentrations of 10- 5 mol/L and 5 x 10- 5 mol/L were equipotent, and increased tension in wild-type mice tracheas to 0.32 ± 0.11 g vs 0.39 ± 0.11 g in tracheas from nNOS-/- mice. There was a dose-dependent increase in contraction to methacholine (p < 0.05), except between 10- 5 mol/L and 5 x 10- 5 mol/L. Contractions to methacholine were consistently higher in the nNOS-/- groups relative to the tracheas from wild-type mice, but the differences were not significant (p > 0.05) [Fig 2 ; n = 6 for each comparison].



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  		Figure 2. Dose response in tracheas from wild-type mice (solid squares) and from nNOS-/- mice (triangles) to methacholine. **Significant differences between each methacholine dose (p < 0.05), but no significant difference between paired responses to all concentrations of methacholine (p > 0.05).

 
Response to VIP:
VIP at 10- 8 mol/L induced a relaxation in wild-type mice tracheas of 40.1 ± 13.04% vs 14 ± 5.47% in nNOS-/- mice tracheas. At 10- 7 mol/L, VIP caused a relaxation in wild-type mice tracheas of 65 ± 8.21% vs 26.00 ± 0.51% in nNOS-/- mice tracheas, while at 10- 6 mol/L, VIP caused a relaxation in wild-type mice tracheas of 84.66 ± 10.18% compared with 44.00 ± 8.94% in nNOS-/- mice tracheas (p < 0.001) [Fig 3 ; n = 8 for wild-type mice and n = 6 for nNOS-/- mice]. Thus, relaxations in response to VIP were significantly reduced in nNOS-/- mice tracheal strips compared to those from wild-type mice.



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  		Figure 3. Dose response of tracheas from wild-type mice (crossed bars) and nNOS-/- mice (solid bars) to VIP at three concentrations. ***Significant differences between paired at all concentrations of VIP (p < 0.0001).

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The iNANC (ie, relaxant) neural system is the only neurally mediated bronchodilator pathway in human airways. As such, it has attracted considerable interest among students of airway responses, particularly since its function may be impaired in asthma.16 18 Although the identities of the neurotransmitters of iNANC are still debated, there is evidence that NO5 6 9 19 20 and VIP5 16 21 as well as VIP-like neuropeptides, especially pituitary adenylate cyclase-activating peptide, play major roles in mediating this response.22

In the present study, we took advantage of the availability of nNOS knockout mice. These mice provided us with a unique model to elucidate the relative importance of neuronal NOS and hence also of VIP as transmitters of iNANC.

EFS-induced tracheal relaxation was consistently smaller in magnitude in nNOS-/- mice tracheas compared to corresponding responses of control wild-type mice. This suggests that endogenous NO produced by nNOS is an important and major transmitter of iNANC; however, the significant relaxation induced by EFS in tracheal strips of nNOS-/- mice also suggests that NO is not the sole neurotransmitter of this system, and that additional transmitter(s), including probably VIP and pituitary adenylate cyclase-activating peptide, are co-released with NO by EFS.1 16 18 19 22 These conclusions support earlier reports showing that both NO and VIP act as co-transmitters of neurogenic relaxation of tracheal smooth muscles.5 19

The contractile responses of nNOS-/- mice tracheas to methacholine were consistently, though not significantly, greater than those of wild-type mice tracheas. This finding suggests that nNOS contributes to the normal relaxant state of airway smooth muscle in the mouse. Somewhat different conclusions were reached by other investigators23 24 who examined airway responsiveness in mice with selected targeted deletion of neuronal, inducible, or endothelial NO synthase. Despite such discrepancies, the consensus appears to be that NO, acting physiologically, serves to modulate airway smooth-muscle tone.20 This conclusion has been validated in airways from guinea pigs and other species.5 6 7 8 14 19

NO modulation of airway smooth-muscle contraction and airway hyperresponsiveness may be mediated not only via neuronally generated NO, but also via epithelially derived NO. The latter is believed to be a component of epithelium-derived relaxing factor.25

VIP-induced relaxation also was significantly smaller in tracheal strips of nNOS-/- mice than in tracheas of wild-type mice. This observation supports the following two conclusions: first, VIP-induced relaxation may be mediated in part through the release of NO. Secondly, VIP and NO seem to act cooperatively, if not synergistically, to bring about tracheal smooth-muscle relaxation. Evidence for this type of cooperation has been considered in earlier studies of guinea pig airway13 and GI smooth muscle.10 11

Our data, therefore, suggest these conclusions with respect to neurogenic relaxation of murine airway smooth muscle: (1) NO and VIP are probably the dominant co-transmitters of the iNANC system in mouse tracheas, with NO accounting for approximately 60% of the effect; (2) the relaxant effect of VIP in mouse tracheas may depend to a significant degree on the integrity of the nNOS system; and (3) a defect in neuronal NO release could result in increased airway reactivity.


   Acknowledgements
 
Our thanks to Dr. Mark C. Fishman for providing the nNOS knockout mice.


   Footnotes
 
Abbreviations: EFS = electric field stimulation; iNANC = inhibitory nonadrenergic, noncholinergic; NANC =nonadrenergic, noncholinergic; nNOS = neuronal nitric oxide synthase; NO = nitric oxide; VIP = vasoactive intestinal peptide

This study was supported by National Institutes of Health grants HL-55849 (Dr. Said) and HL64634 (Dr. Foda).

Dr. Hasaneen was supported by postdoctoral scholarship fund from the Egyptian Ministry of Higher Education.

Received for publication November 12, 2002. Accepted for publication March 17, 2003.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Maggi, CA, Giachetti, A, Dey, RD, et al (1995) Neuropeptides as regulators of airway function: vasoactive intestinal peptide and the tachykinins. Physiol Rev 75,277-322[Free Full Text]
  2. Belivisi, MG, Stretton, D, Barnes, PJ Nitric oxide as an endogenous modulator of cholinergic neurotransmission in guinea-pig airways. Eur J Pharmacol 1991;198,219-221[CrossRef][ISI][Medline]
  3. Ellis, JL, Undem, BJ Inhibition by NG-nitro-L-arginine of nonadrenergic-noncholinergic-mediated relaxations of human isolated central and peripheral airways. Am Rev Respir Dis 1992;146,1543-1547[ISI][Medline]
  4. Lei, YH, Barnes, PJ, Rogers, DF Regulation of NANC neural bronchoconstriction in vivo in the guinea-pig: involvement of nitric oxide, vasoactive intestinal peptide and soluble guanylyl cyclase. Br J Pharmacol 1993;108,228-235[ISI]
  5. Li, CG, Rand, MJ Evidence that part of NANC relaxant response of guinea pig trachea to electric field stimulation is mediated by nitric oxide. Br J Pharmacol 1991;102,91-94[ISI]
  6. Tucker, JF, Brave, SR, Charalambous, L, et al L-NG-nitro arginine inhibits non-adrenergic, non-cholinergic relaxations of guinea-pig isolated tracheal smooth muscle. Br J Pharmacol 1990;100,663-664[ISI]
  7. Ward, JK, Belvisi, MG, Fox, AJ, et al Modulation of cholinergic neural bronchoconstriction by endogenous nitric oxide and vasoactive intestinal peptide in human airways in vitro. J Clin Invest 1993;92,736-742[ISI][Medline]
  8. Yu, M, Wang, Z, Robinson, NE, et al Inhibitory nerves distribution and mediation of NANC relaxation by nitric oxide in horse airway. J Appl Physiol 1994;76,339-344[Abstract/Free Full Text]
  9. Belvisi, MG, Stretton, CD, Miura, M, et al Inhibitory NANC nerves in human tracheal smooth muscle: a quest for the neurotransmitter. J Appl Physiol 1992;73,2505-2510[Abstract/Free Full Text]
  10. Grider, JR, Murthy, KS, Jin, JG, et al Stimulation of nitric oxide from muscle cells by VIP: prejunctional enhancement of VIP release. Am J Physiol 1992;262,G774-G778[Medline]
  11. Grider, JR Interplay of VIP and nitric oxide in the regulation of the descending relaxation phase of peristalsis. Am J Physiol 1993;264,G334-G340[ISI][Medline]
  12. He, XD, Goyal, RK Nitric oxide involvement in the peptide VIP-associated inhibitory junctional potential in guinea-pig ileum. J Physiol 1993;461,485-499[Abstract/Free Full Text]
  13. Lilly, CM, Stamler, JS, Gaston, B, et al Modulation of vasoactive intestinal peptide pulmonary relaxation by NO in tracheally superfused guinea pig lungs. Am J Physiol 1993;265,L410-L415[Medline]
  14. Sharaf, HH, Said, SI VIP relaxation of airway, pulmonary artery and aortic vascular smooth muscle is unaffected by blockade of nitric oxide synthase. Am Rev Respir Dis 1992;145,A382[abstract]
  15. Huang, PL, Dawson, TM, Bredt, DS, et al Targeted disruption of the neuronal nitric oxide synthase gene. Cell 1993;75,1273-1286[CrossRef][ISI][Medline]
  16. Matsuzaki, Y, Hamasaki, Y, Said, SI Vasoactive intestinal peptide: a possible transmitter of nonadrenergic relaxation of guinea pig airways. Science 1980;210,1252-1253[Abstract/Free Full Text]
  17. Daniel, WW Biostatistics: a foundation for analysis in health sciences. 4th ed. 1987 John Wiley and Sons. New York, NY:
  18. Barnes, PJ Neural control of human airways in health and disease. Am Rev Respir Dis 1986;134,1289-1314[ISI][Medline]
  19. Said, SI Nitric oxide and vasoactive intestinal peptide: co-transmitters of smooth muscle relaxation. News Physiol Sci 1992;7,181-183[Abstract/Free Full Text]
  20. Kesler, BS, Mazzone, SB, Canning, BJ Nitric oxide-dependent modulation of smooth-muscle tone by airway parasympathetic nerves. Am J Respir Crit Care Med 2002;165,481-488[Abstract/Free Full Text]
  21. Ellis, JL, Farmer, SG The effects of vasoactive intestinal peptide (VIP) antagonists, and VIP and peptide histidine isoleucine antisera on non-adrenergic, non-cholinergic relaxations of tracheal smooth muscle. Br J Pharmacol 1989;96,513-520[ISI]
  22. Vaudry, D, Gonzalez, BJ, Basille, M, et al Pituitary adenylate cyclase-activating polypeptide and its receptors: from structure to functions. Pharmacol Rev 2000;52,269-324[Abstract/Free Full Text]
  23. De Sanctis, GT, Mehta, S, Kobzik, L, et al Contribution of type I NOS to expired gas NO and bronchial responsiveness in mice. Am J Physiol 1997;273,L883-L888[Medline]
  24. De Sanctis, GT, MacLean, JA, Hamada, K, et al Contribution of nitric oxide synthases 1, 2, and 3 to airway hyperresponsiveness and inflammation in a murine model of asthma. J Exp Med 1999;189,1621-1630[Abstract/Free Full Text]
  25. Folkerts, G, Nijkamp, FP Airway epithelium: more than just a barrier. Trends Pharmacol Sci 1998;19,334-241[CrossRef][Medline]



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