Skip to main content
NCBI home page
British Journal of Pharmacology logoLink to British Journal of Pharmacology
. 1995 May;115(1):172–176. doi: 10.1111/j.1476-5381.1995.tb16335.x

Differences in response to 5-HT4 receptor agonists and antagonists of the 5-HT4-like receptor in human colon circular smooth muscle.

F S Tam 1, K Hillier 1, K T Bunce 1, C Grossman 1
PMCID: PMC1908740  PMID: 7647972

Abstract

1. In isolated circular smooth muscle strips of human colon 5-hydroxytryptamine (5-HT) produced a concentration-related inhibition of spontaneous motility. 2. The azabicycloalkyl benzimidazolones, BIMU 8 and BIMU 1, which have 5-HT4 receptor stimulant properties, inhibited motility with EC50 values of 0.76 microM and 3.19 microM respectively and their Emax values were not significantly different from 5-HT (EC50, 0.13 microM). 3. The 5-HT4 receptor antagonist, DAU 6285 (1-10 microM), displaced the 5-HT concentration-response curve to the right in a parallel concentration-dependent manner without depressing the maximum. The Schild plot was linear and the slope did not differ significantly from unity giving a pA2 value of 6.32. 4. The high affinity selective 5-HT4 receptor antagonist, GR 113808, at a concentration of 3 nM displaced the 5-HT concentration-response curve in a parallel manner giving an apparent pKB estimate of 8.9 +/- 0.24. However, higher concentrations of 10-100 nM GR 113808 did not result in a further significant displacement of the 5-HT concentration-response curve and there was no suppression of Emax. 5. GR 113808 (10 nM) also caused a parallel displacement of the concentration-response curve to the 5-HT4 receptor agonist, 5-methoxytryptamine (5-MeOT) giving apparent pKB values ranging from 8.3-9.3. 6. GR 113808 (3-100 nM) failed to displace 5-HT or 5-MeOT concentration-response curves in tissue strips from 3 patients out of a total of 10 patients studied in whom the response to 5-HT and 5-MeOT was normal.(ABSTRACT TRUNCATED AT 250 WORDS)

Full text

PDF
172

Selected References

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

  1. ARUNLAKSHANA O., SCHILD H. O. Some quantitative uses of drug antagonists. Br J Pharmacol Chemother. 1959 Mar;14(1):48–58. doi: 10.1111/j.1476-5381.1959.tb00928.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Baxter G. S., Clarke D. E. Benzimidazolone derivatives act as 5-HT4 receptor ligands in rat oesophagus. Eur J Pharmacol. 1992 Mar 3;212(2-3):225–229. doi: 10.1016/0014-2999(92)90333-y. [DOI] [PubMed] [Google Scholar]
  3. Baxter G. S., Craig D. A., Clarke D. E. 5-Hydroxytryptamine4 receptors mediate relaxation of the rat oesophageal tunica muscularis mucosae. Naunyn Schmiedebergs Arch Pharmacol. 1991 May;343(5):439–446. doi: 10.1007/BF00169544. [DOI] [PubMed] [Google Scholar]
  4. Borman R. A., Burleigh D. E. Evidence for the involvement of a 5-HT4 receptor in the secretory response of human small intestine to 5-HT. Br J Pharmacol. 1993 Nov;110(3):927–928. doi: 10.1111/j.1476-5381.1993.tb13901.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Buchheit K. H., Gamse R., Pfannkuche H. J. SDZ 205-557, a selective, surmountable antagonist for 5-HT4 receptors in the isolated guinea pig ileum. Naunyn Schmiedebergs Arch Pharmacol. 1992 Apr;345(4):387–393. doi: 10.1007/BF00176615. [DOI] [PubMed] [Google Scholar]
  6. Dumuis A., Bouhelal R., Sebben M., Bockaert J. A 5-HT receptor in the central nervous system, positively coupled with adenylate cyclase, is antagonized by ICS 205 930. Eur J Pharmacol. 1988 Jan 27;146(1):187–188. doi: 10.1016/0014-2999(88)90503-1. [DOI] [PubMed] [Google Scholar]
  7. Dumuis A., Bouhelal R., Sebben M., Cory R., Bockaert J. A nonclassical 5-hydroxytryptamine receptor positively coupled with adenylate cyclase in the central nervous system. Mol Pharmacol. 1988 Dec;34(6):880–887. [PubMed] [Google Scholar]
  8. Dumuis A., Gozlan H., Sebben M., Ansanay H., Rizzi C. A., Turconi M., Monferini E., Giraldo E., Schiantarelli P., Ladinsky H. Characterization of a novel 5-HT4 receptor antagonist of the azabicycloalkyl benzimidazolone class: DAU 6285. Naunyn Schmiedebergs Arch Pharmacol. 1992 Mar;345(3):264–269. doi: 10.1007/BF00168685. [DOI] [PubMed] [Google Scholar]
  9. Dumuis A., Sebben M., Monferini E., Nicola M., Turconi M., Ladinsky H., Bockaert J. Azabicycloalkyl benzimidazolone derivatives as a novel class of potent agonists at the 5-HT4 receptor positively coupled to adenylate cyclase in brain. Naunyn Schmiedebergs Arch Pharmacol. 1991 Mar;343(3):245–251. doi: 10.1007/BF00251122. [DOI] [PubMed] [Google Scholar]
  10. Eglen R. M., Alvarez R., Johnson L. G., Leung E., Wong E. H. The action of SDZ 205,557 at 5-hydroxytryptamine (5-HT3 and 5-HT4) receptors. Br J Pharmacol. 1993 Feb;108(2):376–382. doi: 10.1111/j.1476-5381.1993.tb12812.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Eglen R. M., Swank S. R., Walsh L. K., Whiting R. L. Characterization of 5-HT3 and 'atypical' 5-HT receptors mediating guinea-pig ileal contractions in vitro. Br J Pharmacol. 1990 Nov;101(3):513–520. doi: 10.1111/j.1476-5381.1990.tb14113.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Elswood C. J., Bunce K. T., Humphrey P. P. Identification of putative 5-HT4 receptors in guinea-pig ascending colon. Eur J Pharmacol. 1991 Apr 17;196(2):149–155. doi: 10.1016/0014-2999(91)90421-l. [DOI] [PubMed] [Google Scholar]
  13. Gale J. D., Grossman C. J., Whitehead J. W., Oxford A. W., Bunce K. T., Humphrey P. P. GR113808: a novel, selective antagonist with high affinity at the 5-HT4 receptor. Br J Pharmacol. 1994 Jan;111(1):332–338. doi: 10.1111/j.1476-5381.1994.tb14064.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Grossman C. J., Kilpatrick G. J., Bunce K. T. Development of a radioligand binding assay for 5-HT4 receptors in guinea-pig and rat brain. Br J Pharmacol. 1993 Jul;109(3):618–624. doi: 10.1111/j.1476-5381.1993.tb13617.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Kaumann A. J. Blockade of human atrial 5-HT4 receptors by GR 113808. Br J Pharmacol. 1993 Nov;110(3):1172–1174. doi: 10.1111/j.1476-5381.1993.tb13937.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Lorrain J., Grosset A., O'Connor S. E. 5-HT4 receptors, present in piglet atria and sensitive to SDZ 205-557, are absent in papillary muscle. Eur J Pharmacol. 1992 Dec 8;229(1):105–108. doi: 10.1016/0014-2999(92)90293-d. [DOI] [PubMed] [Google Scholar]
  17. Medhurst A. D., Kaumann A. J. Characterization of the 5-HT4 receptor mediating tachycardia in piglet isolated right atrium. Br J Pharmacol. 1993 Nov;110(3):1023–1030. doi: 10.1111/j.1476-5381.1993.tb13916.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Reeves J. J., Bunce K. T., Humphrey P. P., Gunning S. J. Further characterisation of the 5-HT receptor mediating smooth muscle relaxation in rat oesophagus. Br J Pharmacol. 1989 Dec;98 (Suppl):800P–800P. [PubMed] [Google Scholar]
  19. Rizzi C. A., Coccini T., Onori L., Manzo L., Tonini M. Benzimidazolone derivatives: a new class of 5-hydroxytryptamine4 receptor agonists with prokinetic and acetylcholine releasing properties in the guinea pig ileum. J Pharmacol Exp Ther. 1992 May;261(2):412–419. [PubMed] [Google Scholar]
  20. Tam F. S., Hillier K., Bunce K. T. Characterization of the 5-hydroxytryptamine receptor type involved in inhibition of spontaneous activity of human isolated colonic circular muscle. Br J Pharmacol. 1994 Sep;113(1):143–150. doi: 10.1111/j.1476-5381.1994.tb16186.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Tonini M., Candura S. M., Onori L., Coccini T., Manzo L., Rizzi C. A. 5-hydroxytryptamine4 receptor agonists facilitate cholinergic transmission in the circular muscle of guinea pig ileum: antagonism by tropisetron and DAU 6285. Life Sci. 1992;50(21):PL173–PL178. doi: 10.1016/0024-3205(92)90453-v. [DOI] [PubMed] [Google Scholar]
  22. Tonini M., Messori E., Franceschetti G. P., Rizzi C. A., Castoldi A. F., Coccini T., Candura S. M. Characterization of the 5-HT receptor potentiating neuromuscular cholinergic transmission in strips of human isolated detrusor muscle. Br J Pharmacol. 1994 Sep;113(1):1–2. doi: 10.1111/j.1476-5381.1994.tb16163.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Waikar M. V., Hegde S. S., Ford A. P., Clarke D. E. Pharmacological analyses of endo-6-methoxy-8-methyl-8-azabicyclo[3.2.1]oct-3-yl-2,3-dihydro-2-oxo-1 H- benzimidazole-1-carboxylate hydrochloride (DAU 6285) at the 5-hydroxytryptamine4 receptor in the tunica muscularis mucosae of rat esophagus and ileum of guinea pig: role of endogenous 5-hydroxytryptamine. J Pharmacol Exp Ther. 1993 Feb;264(2):654–661. [PubMed] [Google Scholar]
  24. Wardle K. A., Sanger G. J. The guinea-pig distal colon--a sensitive preparation for the investigation of 5-HT4 receptor-mediated contractions. Br J Pharmacol. 1993 Dec;110(4):1593–1599. doi: 10.1111/j.1476-5381.1993.tb14006.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Zerkowski H. R., Broede A., Kunde K., Hillemann S., Schäfer E., Vogelsang M., Michel M. C., Brodde O. E. Comparison of the positive inotropic effects of serotonin, histamine, angiotensin II, endothelin and isoprenaline in the isolated human right atrium. Naunyn Schmiedebergs Arch Pharmacol. 1993 Apr;347(4):347–352. doi: 10.1007/BF00165383. [DOI] [PubMed] [Google Scholar]

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

RESOURCES