Skip to main content
PMC home page
British Journal of Pharmacology logoLink to British Journal of Pharmacology
. 1995 May;115(1):163–171. doi: 10.1111/j.1476-5381.1995.tb16334.x

Inhibition of rat colon contractility by prostacyclin (IP-) receptor agonists: involvement of NANC neurotransmission.

Y M Qian 1, R L Jones 1
PMCID: PMC1908760  PMID: 7544196

Abstract

1. The possibility that prostacyclin (IP-) receptor agonists inhibit spontaneous contractions of the rat isolated colon by activating enteric neurones has been investigated. Cicaprost was used as the test agonist because of its high stability, selectivity and potency (IC50 = 3.8 nM). 2. The Na+ channel blockers saxitoxin (STX, 1 nM) and tetrodotoxin (TTX, 1 microM), whilst having little effect on resting spontaneous activity, virtually abolished the inhibitory actions of cicaprost (10 nM) and nicotine (3 microM); inhibitory responses to isoprenaline (20 nM) were not affected. Phentolamine (1 microM), propranolol (1 microM) and atropine (1 microM) had no effect on cicaprost inhibition. These data are compatible with release of inhibitory NANC transmitter(s) by cicaprost. 3. A transmitter role for nitric oxide was investigated. The nitric oxide synthase (NOS) inhibitor N omega-nitro-L-arginine methyl ester (L-NAME, 100 microM) inhibited the actions of both cicaprost (10 nM) and nicotine (3 microM) by 50-60%, but did not affect responses to isoprenaline (20 nM) or sodium nitroprusside (1-5 microM). The enantiomeric D-NAME (100 microM), which has negligible NOS inhibitory activity, had no effect on the action of cicaprost. 4. The involvement of purinergic transmitters was also investigated. Desensitization to the inhibitory action of ATP did not affect cicaprost responses. The P2x/P2y-receptor antagonist, suramin, at 300 microM blocked ATP responses, but not those due to adenosine; it did not affect cicaprost inhibition. The selective adenosine A1-receptor antagonist, DPCPX, used at a sufficiently high concentration (5 microM) to block adenosine A2-receptors, did not affect cicaprost inhibition.(ABSTRACT TRUNCATED AT 250 WORDS)

Full text

PDF

Selected References

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

  1. Bailey S. J., Hourani S. M. Effects of purines on the longitudinal muscle of the rat colon. Br J Pharmacol. 1992 Apr;105(4):885–892. doi: 10.1111/j.1476-5381.1992.tb09073.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Banks B. E., Brown C., Burgess G. M., Burnstock G., Claret M., Cocks T. M., Jenkinson D. H. Apamin blocks certain neurotransmitter-induced increases in potassium permeability. Nature. 1979 Nov 22;282(5737):415–417. doi: 10.1038/282415a0. [DOI] [PubMed] [Google Scholar]
  3. Bianchetti A., Manara L. In vitro inhibition of intestinal motility by phenylethanolaminotetralines: evidence of atypical beta-adrenoceptors in rat colon. Br J Pharmacol. 1990 Aug;100(4):831–839. doi: 10.1111/j.1476-5381.1990.tb14100.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bredt D. S., Hwang P. M., Snyder S. H. Localization of nitric oxide synthase indicating a neural role for nitric oxide. Nature. 1990 Oct 25;347(6295):768–770. doi: 10.1038/347768a0. [DOI] [PubMed] [Google Scholar]
  5. Bruns R. F. Adenosine receptors. Roles and pharmacology. Ann N Y Acad Sci. 1990;603:211–226. doi: 10.1111/j.1749-6632.1990.tb37674.x. [DOI] [PubMed] [Google Scholar]
  6. 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]
  7. Burnstock G., Campbell G., Satchell D., Smythe A. Evidence that adenosine triphosphate or a related nucleotide is the transmitter substance released by non-adrenergic inhibitory nerves in the gut. Br J Pharmacol. 1970 Dec;40(4):668–688. doi: 10.1111/j.1476-5381.1970.tb10646.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Burnstock G. The non-adrenergic non-cholinergic nervous system. Arch Int Pharmacodyn Ther. 1986 Apr;280(2 Suppl):1–15. [PubMed] [Google Scholar]
  9. Collis M. G., Stoggall S. M., Martin F. M. Apparent affinity of 1,3-dipropyl-8-cyclopentylxanthine for adenosine A1 and A2 receptors in isolated tissues from guinea-pigs. Br J Pharmacol. 1989 Aug;97(4):1274–1278. doi: 10.1111/j.1476-5381.1989.tb12589.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. 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]
  11. Den Hertog A., Pielkenrood J., Van den Akker J. Effector mechanisms for alpha,beta-methylene ATP and ATP derivatives in guinea-pig taenia caeci. Eur J Pharmacol. 1985 Mar 26;110(1):95–101. doi: 10.1016/0014-2999(85)90033-0. [DOI] [PubMed] [Google Scholar]
  12. Di Chiara G., North R. A. Neurobiology of opiate abuse. Trends Pharmacol Sci. 1992 May;13(5):185–193. doi: 10.1016/0165-6147(92)90062-b. [DOI] [PubMed] [Google Scholar]
  13. Dong Y. J., Jones R. L., Wilson N. H. Prostaglandin E receptor subtypes in smooth muscle: agonist activities of stable prostacyclin analogues. Br J Pharmacol. 1986 Jan;87(1):97–107. doi: 10.1111/j.1476-5381.1986.tb10161.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Dunn P. M., Blakeley A. G. Suramin: a reversible P2-purinoceptor antagonist in the mouse vas deferens. Br J Pharmacol. 1988 Feb;93(2):243–245. doi: 10.1111/j.1476-5381.1988.tb11427.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Ellis J. L., Farmer S. G. 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 Mar;96(3):513–520. doi: 10.1111/j.1476-5381.1989.tb11847.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Faussone-Pellegrini M. S. Histogenesis, structure and relationships of interstitial cells of Cajal (ICC): from morphology to functional interpretation. Eur J Morphol. 1992;30(2):137–148. [PubMed] [Google Scholar]
  17. Gaion R. M., Trento M. The role of prostacyclin in modulating cholinergic neurotransmission in guinea-pig ileum. Br J Pharmacol. 1983 Oct;80(2):279–286. doi: 10.1111/j.1476-5381.1983.tb10031.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Gough G. R., Maguire M. H., Satchell D. G. Three new adenosine triphosphate analogs. Synthesis and effects on isolated gut. J Med Chem. 1973 Oct;16(10):1188–1190. doi: 10.1021/jm00268a028. [DOI] [PubMed] [Google Scholar]
  19. Goyal R. K., Rattan S., Said S. I. VIP as a possible neurotransmitter of non-cholinergic non-adrenergic inhibitory neurones. Nature. 1980 Nov 27;288(5789):378–380. doi: 10.1038/288378a0. [DOI] [PubMed] [Google Scholar]
  20. Gozes I., Meltzer E., Rubinrout S., Brenneman D. E., Fridkin M. Vasoactive intestinal peptide potentiates sexual behavior: inhibition by novel antagonist. Endocrinology. 1989 Dec;125(6):2945–2949. doi: 10.1210/endo-125-6-2945. [DOI] [PubMed] [Google Scholar]
  21. Grider J. R., Murthy K. S., Jin J. G., Makhlouf G. M. Stimulation of nitric oxide from muscle cells by VIP: prejunctional enhancement of VIP release. Am J Physiol. 1992 Apr;262(4 Pt 1):G774–G778. doi: 10.1152/ajpgi.1992.262.4.G774. [DOI] [PubMed] [Google Scholar]
  22. Gryglewski R. J., Bunting S., Moncada S., Flower R. J., Vane J. R. Arterial walls are protected against deposition of platelet thrombi by a substance (prostaglandin X) which they make from prostaglandin endoperoxides. Prostaglandins. 1976 Nov;12(5):685–713. doi: 10.1016/0090-6980(76)90047-2. [DOI] [PubMed] [Google Scholar]
  23. Hakoda H., Ito Y. Modulation of cholinergic neurotransmission by the peptide VIP, VIP antiserum and VIP antagonists in dog and cat trachea. J Physiol. 1990 Sep;428:133–154. doi: 10.1113/jphysiol.1990.sp018204. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Hata F., Ishii T., Kanada A., Yamano N., Kataoka T., Takeuchi T., Yagasaki O. Essential role of nitric oxide in descending inhibition in the rat proximal colon. Biochem Biophys Res Commun. 1990 Nov 15;172(3):1400–1406. doi: 10.1016/0006-291x(90)91605-r. [DOI] [PubMed] [Google Scholar]
  25. Hoyle C. H., Knight G. E., Burnstock G. Suramin antagonizes responses to P2-purinoceptor agonists and purinergic nerve stimulation in the guinea-pig urinary bladder and taenia coli. Br J Pharmacol. 1990 Mar;99(3):617–621. doi: 10.1111/j.1476-5381.1990.tb12979.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Huizinga J. D., Berezin I., Daniel E. E., Chow E. Inhibitory innervation of colonic smooth muscle cells and interstitial cells of Cajal. Can J Physiol Pharmacol. 1990 Mar;68(3):447–454. doi: 10.1139/y90-063. [DOI] [PubMed] [Google Scholar]
  27. Jones R. L., Wilson N. H., Marr C. G., Muir G., Armstrong R. A. Diphenylmethylazine prostanoids with prostacyclin-like actions on human platelets. J Lipid Mediat. 1993 Mar-Apr;6(1-3):405–410. [PubMed] [Google Scholar]
  28. Lawrence R. A., Jones R. L., Wilson N. H. Characterization of receptors involved in the direct and indirect actions of prostaglandins E and I on the guinea-pig ileum. Br J Pharmacol. 1992 Feb;105(2):271–278. doi: 10.1111/j.1476-5381.1992.tb14245.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Lefebvre R. A., de Beurme F. A., Sas S. Effect of apamin on the responses to VIP, ATP and NANC neurone stimulation in the rat and cat gastric fundus. J Auton Pharmacol. 1991 Apr;11(2):73–83. doi: 10.1111/j.1474-8673.1991.tb00246.x. [DOI] [PubMed] [Google Scholar]
  30. 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]
  31. Lim S. P., Muir T. C. Neuroeffector transmission in the guinea-pig internal anal sphincter: an electrical and mechanical study. Eur J Pharmacol. 1986 Aug 22;128(1-2):17–24. doi: 10.1016/0014-2999(86)90552-2. [DOI] [PubMed] [Google Scholar]
  32. Maas A. J., Den Hertog A. The effect of apamin on the smooth muscle cells of the guinea-pig taenia coli. Eur J Pharmacol. 1979 Sep 15;58(2):151–156. doi: 10.1016/0014-2999(79)90006-2. [DOI] [PubMed] [Google Scholar]
  33. Mackenzie I., Burnstock G. Evidence against vasoactive intestinal polypeptide being the non-adrenergic, non-cholinergic inhibitory transmitter released from nerves supplying the smooth muscle of the guinea-pig taenia coli. Eur J Pharmacol. 1980 Oct 17;67(2-3):255–264. doi: 10.1016/0014-2999(80)90506-3. [DOI] [PubMed] [Google Scholar]
  34. Maggi C. A., Giuliani S. Multiple inhibitory mechanisms mediate non-adrenergic non-cholinergic relaxation in the circular muscle of the guinea-pig colon. Naunyn Schmiedebergs Arch Pharmacol. 1993 Jun;347(6):630–634. doi: 10.1007/BF00166946. [DOI] [PubMed] [Google Scholar]
  35. 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]
  36. McLaughlin D. P., MacDonald A. Evidence for the existence of 'atypical' beta-adrenoceptors (beta 3-adrenoceptors) mediating relaxation in the rat distal colon in vitro. Br J Pharmacol. 1990 Nov;101(3):569–574. doi: 10.1111/j.1476-5381.1990.tb14122.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. McQueen D. S., Iggo A., Birrell G. J., Grubb B. D. Effects of paracetamol and aspirin on neural activity of joint mechanonociceptors in adjuvant arthritis. Br J Pharmacol. 1991 Sep;104(1):178–182. doi: 10.1111/j.1476-5381.1991.tb12404.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Nganele D. M., Hintze T. H. Prostacyclin reduces "preload" in conscious dogs via a vagal reflex mechanism. Am J Physiol. 1987 Dec;253(6 Pt 2):H1477–H1483. doi: 10.1152/ajpheart.1987.253.6.H1477. [DOI] [PubMed] [Google Scholar]
  39. O'Connor S. E., Dainty I. A., Leff P. Further subclassification of ATP receptors based on agonist studies. Trends Pharmacol Sci. 1991 Apr;12(4):137–141. doi: 10.1016/0165-6147(91)90530-6. [DOI] [PubMed] [Google Scholar]
  40. Palmer R. M., Ashton D. S., Moncada S. Vascular endothelial cells synthesize nitric oxide from L-arginine. Nature. 1988 Jun 16;333(6174):664–666. doi: 10.1038/333664a0. [DOI] [PubMed] [Google Scholar]
  41. Palmer R. M., Rees D. D., Ashton D. S., Moncada S. L-arginine is the physiological precursor for the formation of nitric oxide in endothelium-dependent relaxation. Biochem Biophys Res Commun. 1988 Jun 30;153(3):1251–1256. doi: 10.1016/s0006-291x(88)81362-7. [DOI] [PubMed] [Google Scholar]
  42. Pandol S. J., Dharmsathaphorn K., Schoeffield M. S., Vale W., Rivier J. Vasoactive intestinal peptide receptor antagonist [4Cl-D-Phe6, Leu17] VIP. Am J Physiol. 1986 Apr;250(4 Pt 1):G553–G557. doi: 10.1152/ajpgi.1986.250.4.G553. [DOI] [PubMed] [Google Scholar]
  43. 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]
  44. Rueff A., Dray A. Pharmacological characterization of the effects of 5-hydroxytryptamine and different prostaglandins on peripheral sensory neurons in vitro. Agents Actions. 1993;38(Spec No):C13–C15. doi: 10.1007/BF01991122. [DOI] [PubMed] [Google Scholar]
  45. Stürzebecher S., Haberey M., Müller B., Schillinger E., Schröder G., Skuballa W., Stock G., Vorbrüggen H., Witt W. Pharmacological profile of a novel carbacyclin derivative with high metabolic stability and oral activity in the rat. Prostaglandins. 1986 Jan;31(1):95–109. doi: 10.1016/0090-6980(86)90228-5. [DOI] [PubMed] [Google Scholar]
  46. Suthamnatpong N., Hata F., Kanada A., Takeuchi T., Yagasaki O. Mediators of nonadrenergic, noncholinergic inhibition in the proximal, middle and distal regions of rat colon. Br J Pharmacol. 1993 Feb;108(2):348–355. doi: 10.1111/j.1476-5381.1993.tb12808.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Suthamnatpong N., Hosokawa M., Takeuchi T., Hata F., Takewaki T. Nitric oxide-mediated inhibitory response of rat proximal colon: independence from changes in membrane potential. Br J Pharmacol. 1994 Jun;112(2):676–682. doi: 10.1111/j.1476-5381.1994.tb13129.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Xie Z. Q., Hirose T., Hakoda H., Ito Y. Effects of vasoactive intestinal polypeptide antagonists on cholinergic neurotransmission in dog and cat trachea. Br J Pharmacol. 1991 Dec;104(4):938–944. doi: 10.1111/j.1476-5381.1991.tb12530.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. 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]
  50. den Hertog A., Nelemans A., Van den Akker J. The inhibitory action of suramin on the P2-purinoceptor response in smooth muscle cells of guinea-pig taenia caeci. Eur J Pharmacol. 1989 Aug 3;166(3):531–534. doi: 10.1016/0014-2999(89)90370-1. [DOI] [PubMed] [Google Scholar]

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

RESOURCES