Skip to main content
PMC home page
British Journal of Pharmacology logoLink to British Journal of Pharmacology
. 1996 Aug;118(8):1965–1970. doi: 10.1111/j.1476-5381.1996.tb15631.x

Neural 5-HT4 receptors in the human isolated detrusor muscle: effects of indole, benzimidazolone and substituted benzamide agonists and antagonists.

S M Candura 1, E Messori 1, G P Franceschetti 1, G D'Agostino 1, D Vicini 1, M Tagliani 1, M Tonini 1
PMCID: PMC1909897  PMID: 8864530

Abstract

1. In strips of human isolated detrusor muscle, the 5-hydroxytryptamine (5-HT) receptor (5-HT4) that mediates facilitation of neuromuscular cholinergic transmission was further characterized by using 5-HT and a series of ligands known for their 5-HT4 agonist (5-methoxytryptamine: 5-MeOT, cisapride, (R,S)-zacopride, BIMU 8) or antagonist (RS 23597, GR 125487, DAU 6285) properties. 2. In the presence of methysergide (1 microM) and ondansetron (3 microM) to isolate pharmacologically the 5-HT4 receptors, 5-HT (0.3 nM-1 microM), 5-MeOT (10 nM -30 microM), BIMU 8 (10 nM-3 microM), cisapride (0.1-10 microM) and (R,S)-zacopride (0.1-30 microM) potentiated cholinergic contractions to electrical field stimulation in a concentration-dependent manner. RS 23597 (10 nM-10 microM), a competitive 5-HT4 receptor antagonist in other systems, also showed agonist properties. The following rank order of potency as an agonist was obtained: 5-HT (pEC50 = 8.0) > RS 23597 (7.0) = BIMU 8 (6.9) > or = cisapride (6.6) > 5-MeOT (6.0) > or = (R,S)-zacopride (5.7). Relative to 5-HT (intrinsic activity = 1), 5-MeOT acted as a full agonist (1.03), while BIMU 8 (0.76), (R,S)-zacopride (0.61), RS 23597 (0.60) and cisapride (0.41) behaved as partial agonists. 3. The potentiation by 5-HT was competitively antagonized by the selective 5-HT4 receptor antagonist GR 125487 (0.3-3 nM) with a pA2 estimate of 9.75 (Schild slope of 1.09), and by DAU 6285 (1 microM; pK3 = 6.45). Additionally, GR 125487 (3 nM) antagonized the responses to 5-MeOT (pKB = 9.72) and reversed the potentiation induced by RS 23597. As an antagonist, RS 23597 (10, 30 and 100 nM) inhibited the response to 5-HT. In addition, 30 and 100 nM RS 23597 reduced the 5-HT response maximum by 30 and 50%, respectively. The pKB value calculated at 10 nM was 8.0. 4. Thus, in the human isolated detrusor muscle, the 5-HT4 receptors mediating facilitation of cholinergic neuromuscular transmission are activated by indoleamines (5-HT, 5-MeOT), substituted benzamide (cisapride, (R,S)-zacopride), benzoate (RS 23597) and benzimidazolone (BIMU 8) derivatives. The activities (in terms of both potency and efficacy) of most agonists, as well as the affinity estimates of the antagonists GR 125487 and DAU 6285, are comparable to those found in other peripheral tissues. Exceptions are RS 23597, which acted either as a partial agonist or as an antagonist of the response to 5-HT1 and 5-MeOT that showed an unusually low potency. The latter findings may be ascribed to differences in the efficiency of receptor coupling mechanisms and/or in the molecular structure (i.e. splice variants) of the 5-HT4 receptor.

Full text

PDF
1965

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. Anderson K. E. Pharmacology of lower urinary tract smooth muscles and penile erectile tissues. Pharmacol Rev. 1993 Sep;45(3):253–308. [PubMed] [Google Scholar]
  3. Andrade R., Nicoll R. A. Novel anxiolytics discriminate between postsynaptic serotonin receptors mediating different physiological responses on single neurons of the rat hippocampus. Naunyn Schmiedebergs Arch Pharmacol. 1987 Jul;336(1):5–10. doi: 10.1007/BF00177743. [DOI] [PubMed] [Google Scholar]
  4. 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]
  5. Bockaert J., Fozard J. R., Dumuis A., Clarke D. E. The 5-HT4 receptor: a place in the sun. Trends Pharmacol Sci. 1992 Apr;13(4):141–145. doi: 10.1016/0165-6147(92)90051-7. [DOI] [PubMed] [Google Scholar]
  6. Bockaert J., Sebben M., Dumuis A. Pharmacological characterization of 5-hydroxytryptamine4(5-HT4) receptors positively coupled to adenylate cyclase in adult guinea pig hippocampal membranes: effect of substituted benzamide derivatives. Mol Pharmacol. 1990 Mar;37(3):408–411. [PubMed] [Google Scholar]
  7. Boyd I. W., Rohan A. P. Urinary disorders associated with cisapride. Adverse Drug Reactions Advisory Committee. Med J Aust. 1994 May 2;160(9):579–580. [PubMed] [Google Scholar]
  8. Chen H. I. Evidence for the presynaptic action of 5-hydroxytryptamine and the involvement of purinergic innervation in the rabbit lower urinary tract. Br J Pharmacol. 1990 Sep;101(1):212–216. doi: 10.1111/j.1476-5381.1990.tb12115.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Cohen M. L. Canine, but not rat bladder contracts to serotonin via activation of 5HT2 receptors. J Urol. 1990 May;143(5):1037–1040. doi: 10.1016/s0022-5347(17)40178-9. [DOI] [PubMed] [Google Scholar]
  10. Corsi M., Pietra C., Toson G., Trist D., Tuccitto G., Artibani W. Pharmacological analysis of 5-hydroxytryptamine effects on electrically stimulated human isolated urinary bladder. Br J Pharmacol. 1991 Nov;104(3):719–725. doi: 10.1111/j.1476-5381.1991.tb12494.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Craig D. A., Clarke D. E. Pharmacological characterization of a neuronal receptor for 5-hydroxytryptamine in guinea pig ileum with properties similar to the 5-hydroxytryptamine receptor. J Pharmacol Exp Ther. 1990 Mar;252(3):1378–1386. [PubMed] [Google Scholar]
  12. Dumuis A., Sebben M., Bockaert J. The gastrointestinal prokinetic benzamide derivatives are agonists at the non-classical 5-HT receptor (5-HT4) positively coupled to adenylate cyclase in neurons. Naunyn Schmiedebergs Arch Pharmacol. 1989 Oct;340(4):403–410. doi: 10.1007/BF00167041. [DOI] [PubMed] [Google Scholar]
  13. 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]
  14. Eglen R. M., Bley K., Bonhaus D. W., Clark R. D., Hegde S. S., Johnson L. G., Leung E., Wong E. H. RS 23597-190: a potent and selective 5-HT4 receptor antagonist. Br J Pharmacol. 1993 Sep;110(1):119–126. doi: 10.1111/j.1476-5381.1993.tb13780.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Eglen R. M., Bonhaus D. W., Johnson L. G., Leung E., Clark R. D. Pharmacological characterization of two novel and potent 5-HT4 receptor agonists, RS 67333 and RS 67506, in vitro and in vivo. Br J Pharmacol. 1995 Aug;115(8):1387–1392. doi: 10.1111/j.1476-5381.1995.tb16628.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. 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]
  17. 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]
  18. Etienne M., Verlinden M., Brassinne A. Treatment with cisapride of the gastrointestinal and urological sequelae of spinal cord transection: case report. Paraplegia. 1988 Jun;26(3):162–164. doi: 10.1038/sc.1988.26. [DOI] [PubMed] [Google Scholar]
  19. GADDUM J. H. Theories of drug antagonism. Pharmacol Rev. 1957 Jun;9(2):211–218. [PubMed] [Google Scholar]
  20. Gerald C., Adham N., Kao H. T., Olsen M. A., Laz T. M., Schechter L. E., Bard J. A., Vaysse P. J., Hartig P. R., Branchek T. A. The 5-HT4 receptor: molecular cloning and pharmacological characterization of two splice variants. EMBO J. 1995 Jun 15;14(12):2806–2815. doi: 10.1002/j.1460-2075.1995.tb07280.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Hanson P., Soler J. M. Effet du cisapride sur les vessies neurologiques. Acta Belg Med Phys. 1989 Jul-Sep;12(3):81–88. [PubMed] [Google Scholar]
  22. Hindmarsh J. R., Idowu O. A., Yeates W. K., Zar M. A. Pharmacology of electrically evoked contractions of human bladder [proceedings]. Br J Pharmacol. 1977 Sep;61(1):115P–115P. [PMC free article] [PubMed] [Google Scholar]
  23. Holt S. E., Cooper M., Wyllie J. H. On the nature of the receptor mediating the action of 5-hydroxytryptamine in potentiating responses of the mouse urinary bladder strip to electrical stimulation. Naunyn Schmiedebergs Arch Pharmacol. 1986 Dec;334(4):333–340. doi: 10.1007/BF00569366. [DOI] [PubMed] [Google Scholar]
  24. Klarskov P., Hørby-Petersen J. Influence of serotonin on lower urinary tract smooth muscle in vitro. Br J Urol. 1986 Oct;58(5):507–513. doi: 10.1111/j.1464-410x.1986.tb05456.x. [DOI] [PubMed] [Google Scholar]
  25. Maggi C. A., Patacchini R., Santicioli P., Turini D., Barbanti G., Beneforti P., Rovero P., Meli A. Further studies on the motor response of the human isolated urinary bladder to tachykinins, capsaicin and electrical field stimulation. Gen Pharmacol. 1989;20(5):663–669. doi: 10.1016/0306-3623(89)90104-3. [DOI] [PubMed] [Google Scholar]
  26. Messori E., Rizzi C. A., Candura S. M., Lucchelli A., Balestra B., Tonini M. 5-Hydroxytryptamine receptors that facilitate excitatory neuromuscular transmission in the guinea-pig isolated detrusor muscle. Br J Pharmacol. 1995 Jun;115(4):677–683. doi: 10.1111/j.1476-5381.1995.tb14986.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Pillans P. I., Wood S. M. Cisapride increases micturition frequency. J Clin Gastroenterol. 1994 Dec;19(4):336–338. doi: 10.1097/00004836-199412000-00017. [DOI] [PubMed] [Google Scholar]
  28. Reeves J. J., Bunce K. T., Humphrey P. P. Investigation into the 5-hydroxytryptamine receptor mediating smooth muscle relaxation in the rat oesophagus. Br J Pharmacol. 1991 May;103(1):1067–1072. doi: 10.1111/j.1476-5381.1991.tb12301.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Ruggieri M. R., Whitmore K. E., Levin R. M. Bladder purinergic receptors. J Urol. 1990 Jul;144(1):176–181. doi: 10.1016/s0022-5347(17)39405-3. [DOI] [PubMed] [Google Scholar]
  30. Saxena P. R., Heiligers J., Mylecharane E. J., Tio R. Excitatory 5-hydroxytryptamine receptors in the cat urinary bladder are of the M- and 5-HT2-type. J Auton Pharmacol. 1985 Jun;5(2):101–107. doi: 10.1111/j.1474-8673.1985.tb00110.x. [DOI] [PubMed] [Google Scholar]
  31. Schiavone A., Giraldo E., Giudici L., Turconi M., Sagrada A. DAU 6285: a novel antagonist at the putative 5-HT4 receptor. Life Sci. 1992;51(8):583–592. doi: 10.1016/0024-3205(92)90227-g. [DOI] [PubMed] [Google Scholar]
  32. Schuurkes J. A., Van Nueten J. M., Van Daele P. G., Reyntjens A. J., Janssen P. A. Motor-stimulating properties of cisapride on isolated gastrointestinal preparations of the guinea pig. J Pharmacol Exp Ther. 1985 Sep;234(3):775–783. [PubMed] [Google Scholar]
  33. Todd J. K., Mack A. J. A study of human bladder detrusor muscle. Br J Urol. 1969 Aug;41(4):448–454. doi: 10.1111/j.1464-410x.1969.tb09946.x. [DOI] [PubMed] [Google Scholar]
  34. 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]
  35. Tonini M., Rizzi C. A., Manzo L., Onori L. Novel enteric 5-HT4 receptors and gastrointestinal prokinetic action. Pharmacol Res. 1991 Jul;24(1):5–14. doi: 10.1016/1043-6618(91)90059-7. [DOI] [PubMed] [Google Scholar]
  36. Varrault A., Bockaert J. Differential coupling of 5-HT1A receptors occupied by 5-HT or 8-OH-DPAT to adenylyl cyclase. Naunyn Schmiedebergs Arch Pharmacol. 1992 Oct;346(4):367–374. doi: 10.1007/BF00171076. [DOI] [PubMed] [Google Scholar]
  37. Villalón C. M., den Boer M. O., Heiligers J. P., Saxena P. R. Further characterization, by use of tryptamine and benzamide derivatives, of the putative 5-HT4 receptor mediating tachycardia in the pig. Br J Pharmacol. 1991 Jan;102(1):107–112. doi: 10.1111/j.1476-5381.1991.tb12140.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Waikar M. V., Ford A. P., Clarke D. E. Evidence for an inhibitory 5-HT4 receptor in urinary bladder of rhesus and Cynomolgus monkeys. Br J Pharmacol. 1994 Jan;111(1):213–218. doi: 10.1111/j.1476-5381.1994.tb14046.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. 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]
  40. de Groot G. H., de Pagter G. F. Effects of cisapride on constipation due to a neurological lesion. Paraplegia. 1988 Jun;26(3):159–161. doi: 10.1038/sc.1988.25. [DOI] [PubMed] [Google Scholar]

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

RESOURCES