Skip to main content
NCBI home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1993 Aug;92(2):736–742. doi: 10.1172/JCI116644

Modulation of cholinergic neural bronchoconstriction by endogenous nitric oxide and vasoactive intestinal peptide in human airways in vitro.

J K Ward 1, M G Belvisi 1, A J Fox 1, M Miura 1, S Tadjkarimi 1, M H Yacoub 1, P J Barnes 1
PMCID: PMC294908  PMID: 8349813

Abstract

Human airway smooth muscle possesses an inhibitory nonadrenergic noncholinergic neural bronchodilator response mediated by nitric oxide (NO). In guinea pig trachea both endogenous NO and vasoactive intestinal peptide (VIP) modulate cholinergic neural contractile responses. To identify whether endogenous NO or VIP can modulate cholinergic contractile responses in human airways in vitro, we studied the effects of specific NO synthase inhibitors and the peptidase alpha-chymotrypsin on contractile responses evoked by electrical field stimulation (EFS) at three airway levels. Endogenous NO, but not VIP, was shown to inhibit cholinergic contractile responses at all airway levels but this inhibition was predominantly in trachea and main bronchus and less marked in segmental and subsegmental bronchi. To elucidate the mechanism of this modulation we then studied the effects of endogenous NO on acetylcholine (ACh) release evoked by EFS from tracheal smooth muscle strips. We confirmed that release was neural in origin, frequency dependent, and that endogenous NO did not affect ACh release. These findings show that endogenous NO, but not VIP, evoked by EFS can inhibit cholinergic neural responses via functional antagonism of ACh at the airway smooth muscle and that the contribution of this modulation is less marked in lower airways.

Full text

PDF
736

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Altiere R. J., Szarek J. L., Diamond L. Neural control of relaxation in cat airways smooth muscle. J Appl Physiol Respir Environ Exerc Physiol. 1984 Nov;57(5):1536–1544. doi: 10.1152/jappl.1984.57.5.1536. [DOI] [PubMed] [Google Scholar]
  2. Barnes P. J. Modulation of neurotransmission in airways. Physiol Rev. 1992 Jul;72(3):699–729. doi: 10.1152/physrev.1992.72.3.699. [DOI] [PubMed] [Google Scholar]
  3. Barnes P. J. Neural control of human airways in health and disease. Am Rev Respir Dis. 1986 Dec;134(6):1289–1314. doi: 10.1164/arrd.1986.134.5.1289. [DOI] [PubMed] [Google Scholar]
  4. Belvisi M. G., Miura M., Stretton D., Barnes P. J. Endogenous vasoactive intestinal peptide and nitric oxide modulate cholinergic neurotransmission in guinea-pig trachea. Eur J Pharmacol. 1993 Jan 26;231(1):97–102. doi: 10.1016/0014-2999(93)90689-f. [DOI] [PubMed] [Google Scholar]
  5. Belvisi M. G., Stretton C. D., Miura M., Verleden G. M., Tadjkarimi S., Yacoub M. H., Barnes P. J. Inhibitory NANC nerves in human tracheal smooth muscle: a quest for the neurotransmitter. J Appl Physiol (1985) 1992 Dec;73(6):2505–2510. doi: 10.1152/jappl.1992.73.6.2505. [DOI] [PubMed] [Google Scholar]
  6. Belvisi M. G., Stretton C. D., Yacoub M., Barnes P. J. Nitric oxide is the endogenous neurotransmitter of bronchodilator nerves in humans. Eur J Pharmacol. 1992 Jan 14;210(2):221–222. doi: 10.1016/0014-2999(92)90676-u. [DOI] [PubMed] [Google Scholar]
  7. Belvisi M. G., Stretton D., Barnes P. J. Nitric oxide as an endogenous modulator of cholinergic neurotransmission in guinea-pig airways. Eur J Pharmacol. 1991 Jun 6;198(2-3):219–221. doi: 10.1016/0014-2999(91)90626-2. [DOI] [PubMed] [Google Scholar]
  8. Bogle R. G., Moncada S., Pearson J. D., Mann G. E. Identification of inhibitors of nitric oxide synthase that do not interact with the endothelial cell L-arginine transporter. Br J Pharmacol. 1992 Apr;105(4):768–770. doi: 10.1111/j.1476-5381.1992.tb09053.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Brave S. R., Hobbs A. J., Gibson A., Tucker J. F. The influence of L-NG-nitro-arginine on field stimulation induced contractions and acetylcholine release in guinea pig isolated tracheal smooth muscle. Biochem Biophys Res Commun. 1991 Sep 16;179(2):1017–1022. doi: 10.1016/0006-291x(91)91920-8. [DOI] [PubMed] [Google Scholar]
  10. Bult H., Boeckxstaens G. E., Pelckmans P. A., Jordaens F. H., Van Maercke Y. M., Herman A. G. Nitric oxide as an inhibitory non-adrenergic non-cholinergic neurotransmitter. Nature. 1990 May 24;345(6273):346–347. doi: 10.1038/345346a0. [DOI] [PubMed] [Google Scholar]
  11. Ellis J. L., Farmer S. G. Effects of peptidases on non-adrenergic, non-cholinergic inhibitory responses of tracheal smooth muscle: a comparison with effects on VIP- and PHI-induced relaxation. Br J Pharmacol. 1989 Mar;96(3):521–526. doi: 10.1111/j.1476-5381.1989.tb11848.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Fox A., Morton I. K. An examination of the 5-HT3 receptor mediating contraction and evoked [3H]-acetylcholine release in the guinea-pig ileum. Br J Pharmacol. 1990 Nov;101(3):553–558. doi: 10.1111/j.1476-5381.1990.tb14119.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Gibson A., Mirzazadeh S., Hobbs A. J., Moore P. K. L-NG-monomethyl arginine and L-NG-nitro arginine inhibit non-adrenergic, non-cholinergic relaxation of the mouse anococcygeus muscle. Br J Pharmacol. 1990 Mar;99(3):602–606. doi: 10.1111/j.1476-5381.1990.tb12976.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Gillespie J. S., Liu X. R., Martin W. The effects of L-arginine and NG-monomethyl L-arginine on the response of the rat anococcygeus muscle to NANC nerve stimulation. Br J Pharmacol. 1989 Dec;98(4):1080–1082. doi: 10.1111/j.1476-5381.1989.tb12650.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Greenberg B., Rhoden K., Barnes P. J. Relaxant effects of vasoactive intestinal peptide and peptide histidine isoleucine in human and bovine pulmonary arteries. Blood Vessels. 1987;24(1-2):45–50. doi: 10.1159/000158670. [DOI] [PubMed] [Google Scholar]
  16. Hecker M., Mitchell J. A., Harris H. J., Katsura M., Thiemermann C., Vane J. R. Endothelial cells metabolize NG-monomethyl-L-arginine to L-citrulline and subsequently to L-arginine. Biochem Biophys Res Commun. 1990 Mar 30;167(3):1037–1043. doi: 10.1016/0006-291x(90)90627-y. [DOI] [PubMed] [Google Scholar]
  17. Ichinose M., Inoue H., Miura M., Takishima T. Nonadrenergic bronchodilation in normal subjects. Am Rev Respir Dis. 1988 Jul;138(1):31–34. doi: 10.1164/ajrccm/138.1.31. [DOI] [PubMed] [Google Scholar]
  18. Laitinen A., Partanen M., Hervonen A., Pelto-Huikko M., Laitinen L. A. VIP like immunoreactive nerves in human respiratory tract. Light and electron microscopic study. Histochemistry. 1985;82(4):313–319. doi: 10.1007/BF00494059. [DOI] [PubMed] [Google Scholar]
  19. Lammers J. W., Minette P., McCusker M. T., Chung K. F., Barnes P. J. Nonadrenergic bronchodilator mechanisms in normal human subjects in vivo. J Appl Physiol (1985) 1988 May;64(5):1817–1822. doi: 10.1152/jappl.1988.64.5.1817. [DOI] [PubMed] [Google Scholar]
  20. Li C. G., Rand M. J. Evidence that part of the NANC relaxant response of guinea-pig trachea to electrical field stimulation is mediated by nitric oxide. Br J Pharmacol. 1991 Jan;102(1):91–94. doi: 10.1111/j.1476-5381.1991.tb12137.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Michoud M. C., Amyot R., Jeanneret-Grosjean A., Couture J. Reflex decrease of histamine-induced bronchoconstriction after laryngeal stimulation in humans. Am Rev Respir Dis. 1987 Sep;136(3):618–622. doi: 10.1164/ajrccm/136.3.618. [DOI] [PubMed] [Google Scholar]
  22. Palmer J. B., Cuss F. M., Barnes P. J. VIP and PHM and their role in nonadrenergic inhibitory responses in isolated human airways. J Appl Physiol (1985) 1986 Oct;61(4):1322–1328. doi: 10.1152/jappl.1986.61.4.1322. [DOI] [PubMed] [Google Scholar]
  23. Rand M. J. Nitrergic transmission: nitric oxide as a mediator of non-adrenergic, non-cholinergic neuro-effector transmission. Clin Exp Pharmacol Physiol. 1992 Mar;19(3):147–169. doi: 10.1111/j.1440-1681.1992.tb00433.x. [DOI] [PubMed] [Google Scholar]
  24. Rees D. D., Palmer R. M., Hodson H. F., Moncada S. A specific inhibitor of nitric oxide formation from L-arginine attenuates endothelium-dependent relaxation. Br J Pharmacol. 1989 Feb;96(2):418–424. doi: 10.1111/j.1476-5381.1989.tb11833.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Rees D. D., Palmer R. M., Schulz R., Hodson H. F., Moncada S. Characterization of three inhibitors of endothelial nitric oxide synthase in vitro and in vivo. Br J Pharmacol. 1990 Nov;101(3):746–752. doi: 10.1111/j.1476-5381.1990.tb14151.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Richardson J. B. Nerve supply to the lungs. Am Rev Respir Dis. 1979 May;119(5):785–802. doi: 10.1164/arrd.1979.119.5.785. [DOI] [PubMed] [Google Scholar]
  27. Rubanyi G. M., Vanhoutte P. M. Oxygen-derived free radicals, endothelium, and responsiveness of vascular smooth muscle. Am J Physiol. 1986 May;250(5 Pt 2):H815–H821. doi: 10.1152/ajpheart.1986.250.5.H815. [DOI] [PubMed] [Google Scholar]
  28. Stretton C. D., Mak J. C., Belvisi M. G., Yacoub M. H., Barnes P. J. Cholinergic control of human airways in vitro following extrinsic denervation of the human respiratory tract by heart-lung transplantation. Am Rev Respir Dis. 1990 Nov;142(5):1030–1033. doi: 10.1164/ajrccm/142.5.1030. [DOI] [PubMed] [Google Scholar]
  29. Taylor S. M., Paré P. D., Schellenberg R. R. Cholinergic and nonadrenergic mechanisms in human and guinea pig airways. J Appl Physiol Respir Environ Exerc Physiol. 1984 Apr;56(4):958–965. doi: 10.1152/jappl.1984.56.4.958. [DOI] [PubMed] [Google Scholar]
  30. Tucker J. F., Brave S. R., Charalambous L., Hobbs A. J., Gibson A. L-NG-nitro arginine inhibits non-adrenergic, non-cholinergic relaxations of guinea-pig isolated tracheal smooth muscle. Br J Pharmacol. 1990 Aug;100(4):663–664. doi: 10.1111/j.1476-5381.1990.tb14072.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Ward M. J., Macfarlane J. T., Davies D. A place for ipratropium bromide in the treatment of severe acute asthma. Br J Dis Chest. 1985 Oct;79(4):374–378. doi: 10.1016/0007-0971(85)90071-3. [DOI] [PubMed] [Google Scholar]
  32. Wessler I., Hellwig D., Racké K. Epithelium-derived inhibition of [3H]acetylcholine release from the isolated guinea-pig trachea. Naunyn Schmiedebergs Arch Pharmacol. 1990 Oct;342(4):387–393. doi: 10.1007/BF00169454. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES