Skip to main content
NCBI home page
British Journal of Pharmacology logoLink to British Journal of Pharmacology
. 1996 Jun;118(3):695–703. doi: 10.1111/j.1476-5381.1996.tb15456.x

ATP and nitric oxide: inhibitory NANC neurotransmitters in the longitudinal muscle-myenteric plexus preparation of the rat ileum.

G J Smits 1, R A Lefebvre 1
PMCID: PMC1909708  PMID: 8762096

Abstract

1. The nature of neurotransmitter(s) involved in non-adrenergic non-cholinergic (NANC) relaxations induced by electrical stimulation (10 s trains, 1-8 Hz) was investigated in the precontracted longitudinal muscle-myenteric plexus preparation of the rat ileum. 2. Electrical stimulation of the tissue induced complex responses, consisting of a primary contraction, a primary relaxation, an off-relaxation and a rebound contraction, which were all tetrodotoxin(TTX)-sensitive. 3. Vasoactive intestinal polypeptide (VIP) and carbon monoxide (CO) did not induce relaxations. alpha-Chymotrypsin did not reduce the relaxations induced by electrical stimulation, while zinc protoporphyrin IX had non-specific effects. 4. Nitric oxide (NO) induced concentration-dependent relaxations. NG-nitro-L-arginine methylester (L-NAME) abolished the primary contractions and off-relaxations, while it partially reduced the primary relaxations. 5. ATP induced relaxations and ATP-desensitization of the tissues partially reduced the primary relaxations. Suramin and reactive blue 2 did not consistently influence the primary relaxations. 6. The ATP-induced relaxations were not influenced by L-NAME or TTX. The inhibitory effect of ATP-desensitization and L-NAME did not summate. 7. The cyclic AMP content of the tissue did not increase upon electrical stimulation or after addition of NO or ATP. The cyclic GMP content of the tissue increased upon electrical stimulation and addition of NO, but not after addition of ATP. 8. It is concluded that the relaxation induced by electrical stimulation consists of two types of responses. The off-relaxation is completely nitrergic, while the primary relaxation is mediated by NO, ATP and an as yet unknown transmitter which is not VIP or CO.

Full text

PDF
695

Selected References

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

  1. Abrahamsson H. Non-adrenergic non-cholinergic nervous control of gastrointestinal motility patterns. Arch Int Pharmacodyn Ther. 1986 Apr;280(2 Suppl):50–61. [PubMed] [Google Scholar]
  2. Barthó L., Kóczán G., Pethö G., Maggi C. A. Blockade of nitric oxide synthase inhibits nerve-mediated contraction in the rat small intestine. Neurosci Lett. 1992 Sep 28;145(1):43–46. doi: 10.1016/0304-3940(92)90199-h. [DOI] [PubMed] [Google Scholar]
  3. Barthó L., Lefebvre R. A. Nitric oxide causes contraction in the rat isolated small intestine. Eur J Pharmacol. 1994 Jun 23;259(1):101–104. doi: 10.1016/0014-2999(94)90166-x. [DOI] [PubMed] [Google Scholar]
  4. Barthó L., Lefebvre R. A. Nitric oxide-mediated contraction in enteric smooth muscle. Arch Int Pharmacodyn Ther. 1995 Jan-Feb;329(1):53–66. [PubMed] [Google Scholar]
  5. Belai A., Burnstock G. Evidence for coexistence of ATP and nitric oxide in non-adrenergic, non-cholinergic (NANC) inhibitory neurones in the rat ileum, colon and anococcygeus muscle. Cell Tissue Res. 1994 Oct;278(1):197–200. doi: 10.1007/BF00305792. [DOI] [PubMed] [Google Scholar]
  6. Boeckxstaens G. E., Pelckmans P. A., Bult H., De Man J. G., Herman A. G., van Maercke Y. M. Evidence for nitric oxide as mediator of non-adrenergic non-cholinergic relaxations induced by ATP and GABA in the canine gut. Br J Pharmacol. 1991 Feb;102(2):434–438. doi: 10.1111/j.1476-5381.1991.tb12191.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Briejer M. R., Akkermans L. M., Meulemans A. L., Lefebvre R. A., Schuurkes J. A. 5-HT-induced neurogenic relaxations of the guinea-pig proximal colon: investigation into the role of ATP and VIP in addition to nitric oxide. Naunyn Schmiedebergs Arch Pharmacol. 1995 Feb;351(2):126–135. doi: 10.1007/BF00169326. [DOI] [PubMed] [Google Scholar]
  8. Brizzolara A. L., Crowe R., Burnstock G. Evidence for the involvement of both ATP and nitric oxide in non-adrenergic, non-cholinergic inhibitory neurotransmission in the rabbit portal vein. Br J Pharmacol. 1993 Jul;109(3):606–608. doi: 10.1111/j.1476-5381.1993.tb13614.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Brookes S. J. Neuronal nitric oxide in the gut. J Gastroenterol Hepatol. 1993 Nov-Dec;8(6):590–603. doi: 10.1111/j.1440-1746.1993.tb01658.x. [DOI] [PubMed] [Google Scholar]
  10. Burnstock G. Overview. Purinergic mechanisms. Ann N Y Acad Sci. 1990;603:1–18. doi: 10.1111/j.1749-6632.1990.tb37657.x. [DOI] [PubMed] [Google Scholar]
  11. Dalziel H. H., Westfall D. P. Receptors for adenine nucleotides and nucleosides: subclassification, distribution, and molecular characterization. Pharmacol Rev. 1994 Dec;46(4):449–466. [PubMed] [Google Scholar]
  12. De Beurme F. A., Lefebvre R. A. Influence of alpha-chymotrypsin and trypsin on the non-adrenergic non-cholinergic relaxation in the rat gastric fundus. Br J Pharmacol. 1987 May;91(1):171–177. doi: 10.1111/j.1476-5381.1987.tb08996.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. 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]
  14. Fahrenkrug J., Haglund U., Jodal M., Lundgren O., Olbe L., de Muckadell O. B. Nervous release of vasoactive intestinal polypeptide in the gastrointestinal tract of cats: possible physiological implications. J Physiol. 1978 Nov;284:291–305. doi: 10.1113/jphysiol.1978.sp012541. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. García-Pascual A., Triguero D. Relaxation mechanisms induced by stimulation of nerves and by nitric oxide in sheep urethral muscle. J Physiol. 1994 Apr 15;476(2):333–347. doi: 10.1113/jphysiol.1994.sp020135. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Gordon R. K., Gray R. R., Chiang P. K. Vasoactive intestinal polypeptides induce guinea-pig ileum contraction by causing release of endogenous acetylcholine. Arch Int Pharmacodyn Ther. 1990 May-Jun;305:14–24. [PubMed] [Google Scholar]
  17. Kanada A., Hata F., Suthamnatpong N., Maehara T., Ishii T., Takeuchi T., Yagasaki O. Key roles of nitric oxide and cyclic GMP in nonadrenergic and noncholinergic inhibition in rat ileum. Eur J Pharmacol. 1992 Jun 5;216(2):287–292. doi: 10.1016/0014-2999(92)90372-b. [DOI] [PubMed] [Google Scholar]
  18. Katsoulis S., Schmidt W. E., Clemens A., Schwörer H., Creutzfeldt W. Vasoactive intestinal polypeptide induces neurogenic contraction of guinea-pig ileum. Involvement of acetylcholine and substance P. Regul Pept. 1992 Mar 19;38(2):155–164. doi: 10.1016/0167-0115(92)90054-x. [DOI] [PubMed] [Google Scholar]
  19. Kelm M., Schrader J. Control of coronary vascular tone by nitric oxide. Circ Res. 1990 Jun;66(6):1561–1575. doi: 10.1161/01.res.66.6.1561. [DOI] [PubMed] [Google Scholar]
  20. Kennedy C., Burnstock G. Evidence for two types of P2-purinoceptor in longitudinal muscle of the rabbit portal vein. Eur J Pharmacol. 1985 Apr 23;111(1):49–56. doi: 10.1016/0014-2999(85)90112-8. [DOI] [PubMed] [Google Scholar]
  21. Kennedy C., Leff P. How should P2X purinoceptors be classified pharmacologically? Trends Pharmacol Sci. 1995 May;16(5):168–174. doi: 10.1016/s0165-6147(00)89010-0. [DOI] [PubMed] [Google Scholar]
  22. Kennedy I., Humphrey P. P. Evidence for the presence of two types of P2 purinoceptor in the guinea-pig ileal longitudinal smooth muscle preparation. Eur J Pharmacol. 1994 Aug 22;261(3):273–280. doi: 10.1016/0014-2999(94)90117-1. [DOI] [PubMed] [Google Scholar]
  23. Kusunoki M., Tsai L. H., Taniyama K., Tanaka C. Vasoactive intestinal polypeptide provokes acetylcholine release from the myenteric plexus. Am J Physiol. 1986 Jul;251(1 Pt 1):G51–G55. doi: 10.1152/ajpgi.1986.251.1.G51. [DOI] [PubMed] [Google Scholar]
  24. LOWRY O. H., ROSEBROUGH N. J., FARR A. L., RANDALL R. J. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951 Nov;193(1):265–275. [PubMed] [Google Scholar]
  25. Lefebvre R. A. Nitric oxide in the peripheral nervous system. Ann Med. 1995 Jun;27(3):379–388. doi: 10.3109/07853899509002591. [DOI] [PubMed] [Google Scholar]
  26. Lefebvre R. A. Non-adrenergic non-cholinergic neurotransmission in the proximal stomach. Gen Pharmacol. 1993 Mar;24(2):257–266. doi: 10.1016/0306-3623(93)90301-d. [DOI] [PubMed] [Google Scholar]
  27. Lefebvre R. A., Smits G. J., Timmermans J. P. Study of NO and VIP as non-adrenergic non-cholinergic neurotransmitters in the pig gastric fundus. Br J Pharmacol. 1995 Oct;116(3):2017–2026. doi: 10.1111/j.1476-5381.1995.tb16406.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Leff P., Wood B. E., O'Connor S. E. Suramin is a slowly-equilibrating but competitive antagonist at P2x-receptors in the rabbit isolated ear artery. Br J Pharmacol. 1990 Nov;101(3):645–649. doi: 10.1111/j.1476-5381.1990.tb14134.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Li Y. F., Weisbrodt N. W., Lodato R. F., Moody F. G. Nitric oxide is involved in muscle relaxation but not in changes in short-circuit current in rat ileum. Am J Physiol. 1994 Apr;266(4 Pt 1):G554–G559. doi: 10.1152/ajpgi.1994.266.4.G554. [DOI] [PubMed] [Google Scholar]
  30. Liu S. F., McCormack D. G., Evans T. W., Barnes P. J. Evidence for two P2-purinoceptor subtypes in human small pulmonary arteries. Br J Pharmacol. 1989 Nov;98(3):1014–1020. doi: 10.1111/j.1476-5381.1989.tb14633.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Manzini S., Maggi C. A., Meli A. Pharmacological evidence that at least two different non-adrenergic non-cholinergic inhibitory systems are present in the rat small intestine. Eur J Pharmacol. 1986 Apr 16;123(2):229–236. doi: 10.1016/0014-2999(86)90664-3. [DOI] [PubMed] [Google Scholar]
  32. Matharu M. S., Hollingsworth M. Purinoceptors mediating relaxation and spasm in the rat gastric fundus. Br J Pharmacol. 1992 Jun;106(2):395–403. doi: 10.1111/j.1476-5381.1992.tb14346.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Ny L., Andersson K. E., Grundemar L. Inhibition by zinc protoporphyrin-IX of receptor-mediated relaxation of the rat aorta in a manner distinct from inhibition of haem oxygenase. Br J Pharmacol. 1995 May;115(1):186–190. doi: 10.1111/j.1476-5381.1995.tb16337.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Otterson M. F., Sarr M. G. Normal physiology of small intestinal motility. Surg Clin North Am. 1993 Dec;73(6):1173–1192. doi: 10.1016/s0039-6109(16)46186-4. [DOI] [PubMed] [Google Scholar]
  35. Rand M. J., Li C. G. Nitric oxide as a neurotransmitter in peripheral nerves: nature of transmitter and mechanism of transmission. Annu Rev Physiol. 1995;57:659–682. doi: 10.1146/annurev.ph.57.030195.003303. [DOI] [PubMed] [Google Scholar]
  36. 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]
  37. Rattan S., Chakder S. Inhibitory effect of CO on internal anal sphincter: heme oxygenase inhibitor inhibits NANC relaxation. Am J Physiol. 1993 Oct;265(4 Pt 1):G799–G804. doi: 10.1152/ajpgi.1993.265.4.G799. [DOI] [PubMed] [Google Scholar]
  38. Sanders K. M., Ward S. M. Nitric oxide as a mediator of nonadrenergic noncholinergic neurotransmission. Am J Physiol. 1992 Mar;262(3 Pt 1):G379–G392. doi: 10.1152/ajpgi.1992.262.3.G379. [DOI] [PubMed] [Google Scholar]
  39. Schultzberg M., Hökfelt T., Nilsson G., Terenius L., Rehfeld J. F., Brown M., Elde R., Goldstein M., Said S. Distribution of peptide- and catecholamine-containing neurons in the gastro-intestinal tract of rat and guinea-pig: immunohistochemical studies with antisera to substance P, vasoactive intestinal polypeptide, enkephalins, somatostatin, gastrin/cholecystokinin, neurotensin and dopamine beta-hydroxylase. Neuroscience. 1980;5(4):689–744. doi: 10.1016/0306-4522(80)90166-9. [DOI] [PubMed] [Google Scholar]
  40. Serio R., Mulè F., Adamo E. B., Postorino A. Evidence against purines being neurotransmitters of non-adrenergic, non-cholinergic nerves in rat duodenum. Eur J Pharmacol. 1990 Jul 17;182(3):487–495. doi: 10.1016/0014-2999(90)90046-9. [DOI] [PubMed] [Google Scholar]
  41. Soediono P., Burnstock G. Contribution of ATP and nitric oxide to NANC inhibitory transmission in rat pyloric sphincter. Br J Pharmacol. 1994 Nov;113(3):681–686. doi: 10.1111/j.1476-5381.1994.tb17046.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Tovey K. C., Oldham K. G., Whelan J. A. A simple direct assay for cyclic AMP in plasma and other biological samples using an improved competitive protein binding technique. Clin Chim Acta. 1974 Nov 8;56(3):221–234. doi: 10.1016/0009-8981(74)90133-8. [DOI] [PubMed] [Google Scholar]
  43. Tøttrup A., Knudsen M. A., Hanberg Sørensen F., Glavind E. B. Pharmacological identification of different inhibitory mediators involved in the innervation of the internal anal sphincter. Br J Pharmacol. 1995 May;115(1):158–162. doi: 10.1111/j.1476-5381.1995.tb16333.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Waldman S. A., Murad F. Cyclic GMP synthesis and function. Pharmacol Rev. 1987 Sep;39(3):163–196. [PubMed] [Google Scholar]
  45. Yagasaki O., Nabata H., Yanagiya I. Effects of desensitization to adenosine 5'-triphosphate and vasoactive intestinal polypeptide on non-adrenergic inhibitory responses of longitudinal and circular muscles in the rat ileum. J Pharm Pharmacol. 1983 Dec;35(12):818–820. doi: 10.1111/j.2042-7158.1983.tb02904.x. [DOI] [PubMed] [Google Scholar]
  46. Zagorodnyuk V., Maggi C. A. Electrophysiological evidence for different release mechanism of ATP and NO as inhibitory NANC transmitters in guinea-pig colon. Br J Pharmacol. 1994 Aug;112(4):1077–1082. doi: 10.1111/j.1476-5381.1994.tb13193.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Zenilman M. E. Origin and control of gastrointestinal motility. Surg Clin North Am. 1993 Dec;73(6):1081–1099. doi: 10.1016/s0039-6109(16)46181-5. [DOI] [PubMed] [Google Scholar]

Articles from British Journal of Pharmacology are provided here courtesy of The British Pharmacological Society

RESOURCES