Table of Contents Author Guidelines Submit a Manuscript
Table of Contents Alerts

To receive news and publication updates for International Journal of Endocrinology, enter your email address in the box below.

International Journal of Endocrinology
Volume 2011, Article ID 350546, 8 pages
http://dx.doi.org/10.1155/2011/350546
Review Article

The Oxytocin-Oxytocin Receptor System and Its Antagonists as Tocolytic Agents

Nikolaos Vrachnis,1 Fotodotis M. Malamas,2 Stavros Sifakis,3 Efthymios Deligeoroglou,1 and Zoe Iliodromiti1

12nd Department of Obstetrics and Gynecology, Aretaieio Hospital, University of Athens Medical School, 11526 Athens, Greece
21st Department of Obstetrics and Gynecology, Alexandra Hospital, University of Athens Medical School, 11526 Athens, Greece
3Department of Obstetrics and Gynaecology, University Hospital of Heraklion, 71110 Heraklion, Crete, Greece

Received 31 July 2011; Accepted 25 September 2011

Academic Editor: A. Marette

Copyright © 2011 Nikolaos Vrachnis et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. G. Gimpl and F. Fahrenholz, “The oxytocin receptor system: structure, function, and regulation,” Physiological Reviews, vol. 81, no. 2, pp. 629–683, 2001. View at Google Scholar · View at Scopus
  2. C. Viero, I. Shibuya, N. Kitamura et al., “Oxytocin: crossing the bridge between basic science and pharmacotherapy,” CNS Neuroscience and Therapeutics, vol. 16, no. 5, pp. e138–e156, 2010. View at Publisher · View at Google Scholar · View at Scopus
  3. H. J. Lee, A. H. Macbeth, J. H. Pagani, and W. Scott Young, “Oxytocin: the great facilitator of life,” Progress in Neurobiology, vol. 88, no. 2, pp. 127–151, 2009. View at Publisher · View at Google Scholar · View at Scopus
  4. M. L. Boccia, A. P. S. Goursaud, J. Bachevalier, K. D. Anderson, and C. A. Pedersen, “Peripherally administered non-peptide oxytocin antagonist, L368,899®, accumulates in limbic brain areas: a new pharmacological tool for the study of social motivation in non-human primates,” Hormones and Behavior, vol. 52, no. 3, pp. 344–351, 2007. View at Publisher · View at Google Scholar · View at Scopus
  5. J. Yang, “Intrathecal administration of oxytocin induces analgesia in low back pain involving the endogenous opiate peptide system,” Spine, vol. 19, no. 8, pp. 867–871, 1994. View at Google Scholar · View at Scopus
  6. F. Schaller, F. Watrin, R. Sturny, A. Massacrier, P. Szepetowski, and F. Muscatelli, “A single postnatal injection of oxytocin rescues the lethal feeding behaviour in mouse newborns deficient for the imprinted Magel2 gene,” Human Molecular Genetics, vol. 19, no. 24, Article ID ddq424, pp. 4895–4905, 2010. View at Publisher · View at Google Scholar · View at Scopus
  7. V. du Vigneaud, C. Ressler, J. M. Swan, C. W. Roberts, and P. G. Katsoyannis, “The synthesis of oxytocin,” Journal of the American Chemical Society, vol. 76, no. 12, pp. 3115–3121, 1954. View at Google Scholar
  8. H. N. Simhan and S. N. Caritis, “Prevention of preterm delivery,” The New England Journal of Medicine, vol. 357, no. 5, pp. 442–487, 2007. View at Publisher · View at Google Scholar · View at Scopus
  9. R. Smith, “Parturition,” The New England Journal of Medicine, vol. 356, no. 3, pp. 271–283, 2007. View at Publisher · View at Google Scholar · View at Scopus
  10. V. Rimoldi, A. Reversi, E. Taverna et al., “Oxytocin receptor elicits different EGFR/MAPK activation patterns depending on its localization in caveolin-1 enriched domains,” Oncogene, vol. 22, no. 38, pp. 6054–6060, 2003. View at Publisher · View at Google Scholar · View at Scopus
  11. B. M. Sanborn, C. Y. Ku, S. Shlykov, and L. Babich, “Molecular signaling through G-protein-coupled receptors and the control of intracellular calcium in myometrium,” Journal of the Society for Gynecologic Investigation, vol. 12, no. 7, pp. 479–487, 2005. View at Publisher · View at Google Scholar · View at Scopus
  12. K. Riento and A. J. Ridley, “Rocks: multifunctional kinases in cell behaviour,” Nature Reviews Molecular Cell Biology, vol. 4, no. 6, pp. 446–456, 2003. View at Publisher · View at Google Scholar · View at Scopus
  13. M. Molnar and F. Hertelendy, “Signal transduction in rat myometrial cells: comparison of the actions of endothelin-1, oxytocin and prostaglandin F(2α),” European Journal of Endocrinology, vol. 133, no. 4, pp. 467–474, 1995. View at Google Scholar · View at Scopus
  14. M. S. Soloff, Y. J. Jeng, J. A. Copland, Z. Strakova, and S. Hoare, “Signal pathways mediating oxytocin stimulation of prostaglandin synthesis in select target cells,” Experimental Physiology, vol. 85, 2000. View at Google Scholar · View at Scopus
  15. A. Csapo, “Progesterone “block”,” American Journal of Anatomy, vol. 98, pp. 273–291, 1956. View at Google Scholar
  16. S. Mesiano, Y. Wang, and E. R. Norwitz, “Progesterone receptors in the human pregnancy uterus: do they hold the key to birth timing?” Reproductive Sciences, vol. 18, no. 1, pp. 6–19, 2011. View at Publisher · View at Google Scholar
  17. M. Mclean, A. Bisits, J. Davies, R. Woods, P. Lowry, and R. Smith, “A placental clock controlling the length of human pregnancy,” Nature Medicine, vol. 1, no. 5, pp. 460–463, 1995. View at Publisher · View at Google Scholar · View at Scopus
  18. I. Christiaens, D. B. Zaragoza, L. Guilbert, S. A. Robertson, B. F. Mitchell, and D. M. Olson, “Inflammatory processes in preterm and term parturition,” Journal of Reproductive Immunology, vol. 79, no. 1, pp. 50–57, 2008. View at Publisher · View at Google Scholar · View at Scopus
  19. A. Malamitsi-Puchner, N. Vrachnis, E. Samoli, S. Baka, D. Hassiakos, and G. Creatsas, “Elevated second trimester amniotic fluid interferon γ-inducible T-cell α chemoattractant concentrations as a possible predictor of preterm birth,” Journal of the Society for Gynecologic Investigation, vol. 13, no. 1, pp. 25–29, 2006. View at Publisher · View at Google Scholar
  20. A. Malamitsi-Puchner, N. Vrachnis, E. Samoli et al., “Investigation of midtrimester amniotic fluid factors as potential predictors of term and preterm deliveries,” Mediators of Inflammation, vol. 2006, Article ID 94381, 2006. View at Publisher · View at Google Scholar · View at Scopus
  21. N. Vrachnis, N. Vitoratos, Z. Iliodromiti, S. Sifakis, E. Deligeoroglou, and G. Creatsas, “Intrauterine inflammation and preterm delivery,” Annals of the New York Academy of Sciences, vol. 1205, pp. 118–122, 2010. View at Publisher · View at Google Scholar · View at Scopus
  22. P. Mittal, R. Romero, A. L. Tarca et al., “Characterization of the myometrial transcriptome and biological pathways of spontaneous human labor at term,” Journal of Perinatal Medicine, vol. 38, no. 6, pp. 617–643, 2010. View at Publisher · View at Google Scholar · View at Scopus
  23. J. P. Phelan, A. T. Guay, and C. Newman, “Diabetes insipidus in pregnancy: a case review,” American Journal of Obstetrics and Gynecology, vol. 130, no. 3, pp. 365–366, 1978. View at Google Scholar · View at Scopus
  24. A. R. Fuchs, F. Fuchs, and P. Husslein, “Oxytocin receptors and human parturition: a dual role for oxytocin in the initiation of labor,” Science, vol. 215, no. 4538, pp. 1396–1398, 1982. View at Google Scholar · View at Scopus
  25. A. R. Fuchs, F. Fuchs, P. Husslein, and M. S. Soloff, “Oxytocin receptors in the human uterus during pregnancy and parturition,” American Journal of Obstetrics and Gynecology, vol. 150, no. 6, pp. 734–741, 1984. View at Google Scholar · View at Scopus
  26. F. Petraglia, P. Florio, C. Nappi, and A. R. Genazzani, “Peptide signaling in human placenta and membranes: autocrine, paracrine, and endocrine mechanisms,” Endocrine Reviews, vol. 17, no. 2, pp. 156–186, 1996. View at Publisher · View at Google Scholar · View at Scopus
  27. S. Horn, R. Bathgate, C. Lioutas, K. Bracken, and R. Ivell, “Bovine endometrial epithelial cells as a model system to study oxytocin receptor regulation,” Human Reproduction Update, vol. 4, no. 5, pp. 605–614, 1998. View at Publisher · View at Google Scholar · View at Scopus
  28. M. A. Mirando, T. L. Ott, J. L. Vallet, M. Davis, and F. W. Bazer, “Oxytocin-stimulated inositol phosphate turnover in endometrium of ewes is influenced by stage of the estrous cycle, pregnancy, and intrauterine infusion of ovine conceptus secretory proteins,” Biology of Reproduction, vol. 42, no. 1, pp. 98–105, 1990. View at Google Scholar · View at Scopus
  29. J. L. Vallet, G. E. Lamming, and M. Batten, “Control of endometrial oxytocin receptor and uterine response to oxytocin by progesterone and oestradiol in the ewe,” Journal of Reproduction and Fertility, vol. 90, no. 2, pp. 625–634, 1990. View at Google Scholar · View at Scopus
  30. D. C. Wathes, G. E. Mann, J. H. Payne, P. R. Riley, K. R. Stevenson, and G. E. Lamming, “Regulation of oxytocin, oestradiol and progesterone receptor concentrations in different uterine regions by oestradiol, progesterone and oxytocin in ovariectomized ewes,” Journal of Endocrinology, vol. 151, no. 3, pp. 375–393, 1996. View at Google Scholar · View at Scopus
  31. H. H. Zingg, F. Rozen, C. Breton et al., “Gonadal steroid regulation of oxytocin and oxytocin receptor gene expression,” Advances in Experimental Medicine and Biology, vol. 395, pp. 395–404, 1996. View at Google Scholar
  32. R. E. Garfield, S. Sims, and E. E. Daniel, “Gap junctions: their presence and necessity in myometrium during parturition,” Science, vol. 198, no. 4320, pp. 958–960, 1977. View at Google Scholar · View at Scopus
  33. R. E. Garfield and R. H. Hayashi, “Appearance of gap junctions in the myometrium of women during labor,” American Journal of Obstetrics and Gynecology, vol. 140, no. 3, pp. 254–260, 1981. View at Google Scholar · View at Scopus
  34. G. Ambrus and C. V. Rao, “Novel regulation of pregnant human myometrial smooth muscle cell gap junctions by human chorionic gonadotropin,” Endocrinology, vol. 135, no. 6, pp. 2772–2779, 1994. View at Publisher · View at Google Scholar · View at Scopus
  35. F. S. Khan-Dawood, J. Yang, and M. Y. Dawood, “Hormonal regulation of connexin-43 in baboon corpora lutea,” Journal of Endocrinology, vol. 157, no. 3, pp. 405–414, 1998. View at Publisher · View at Google Scholar · View at Scopus
  36. V. Terzidou, “Biochemical and endocrinological preparation for parturition,” Best Practice and Research: Clinical Obstetrics and Gynaecology, vol. 21, no. 5, pp. 729–756, 2007. View at Publisher · View at Google Scholar
  37. F. Petraglia, A. Imperatore, and J. R. G. Challis, “Neuroendocrine mechanisms in pregnancy and parturition,” Endocrine Reviews, vol. 31, no. 6, pp. 783–816, 2010. View at Publisher · View at Google Scholar · View at Scopus
  38. C. P. Plested and A. L. Bernal, “Desensitisation of the oxytocin receptor and other G-protein coupled receptors in the human myometrium,” Experimental Physiology, vol. 86, no. 2, pp. 303–312, 2001. View at Publisher · View at Google Scholar · View at Scopus
  39. F. Conti, S. Sertic, A. Reversi, and B. Chini, “Intracellular trafficking of the human oxytocin receptor: evidence of receptor recycling via a Rab4/Rab5 “short cycle”,” American Journal of Physiology, vol. 296, no. 3, pp. E532–E542, 2009. View at Publisher · View at Google Scholar
  40. S. Phaneuf, G. Asbóth, M. P. Carrasco et al., “Desensitization of oxytocin receptors in human myometrium,” Human Reproduction Update, vol. 4, no. 5, pp. 625–633, 1998. View at Publisher · View at Google Scholar · View at Scopus
  41. S. Phaneuf, B. Rodriguez Linares, R. L. Tamby Raja, I. Z. MacKenzie, and A. Lopez Bernal, “Loss of myometrial oxytocin receptors during oxytocin-induced and oxytocin-augmented labour,” Journal of Reproduction and Fertility, vol. 120, no. 1, pp. 91–97, 2000. View at Google Scholar · View at Scopus
  42. M. Y. Dawood, “Novel approach to oxytocin induction-augmentation of labor: application of oxytocin physiology during pregnancy,” Advances in Experimental Medicine and Biology, vol. 395, pp. 585–594, 1996. View at Google Scholar · View at Scopus
  43. M. Manning, S. Stoev, B. Chini, T. Durroux, B. Mouillac, and G. Guillon, “Peptide and non-peptide agonists and antagonists for the vasopressin and oxytocin V1a, V1b, V2 and OT receptors: research tools and potential therapeutic agents,” Progress in Brain Research, vol. 170, pp. 473–512, 2008. View at Publisher · View at Google Scholar · View at Scopus
  44. G. Pitt, A. Batt, R. Haigh et al., “Non-peptide oxytocin agonists,” Bioorganic and Medicinal Chemistry Letters, vol. 14, no. 17, pp. 4585–4589, 2004. View at Publisher · View at Google Scholar · View at Scopus
  45. A. D. Borthwick, “Oxytocin antagonists and agonists,” Annual Reports in Medicinal Chemistry, vol. 41, pp. 409–421, 2006. View at Publisher · View at Google Scholar · View at Scopus
  46. R. H. Ring, L. E. Schechter, S. K. Leonard et al., “Receptor and behavioral pharmacology of WAY-267464, a non-peptide oxytocin receptor agonist,” Neuropharmacology, vol. 58, no. 1, pp. 69–77, 2010. View at Publisher · View at Google Scholar · View at Scopus
  47. J. G. Westergaard, A. P. Lange, G. T. Pedersen, and N. J. Secher, “Use of oral oxytocics for stimulation of labor in cases of premature rupture of the membranes at term. A randomized comparative study of prostaglandin E2 tablets and demoxytocin resoriblets,” Acta Obstetricia et Gynecologica Scandinavica, vol. 62, no. 2, pp. 111–116, 1983. View at Google Scholar
  48. W. Rath, “Prevention of postpartum haemorrhage with the oxytocin analogue carbetocin,” European Journal of Obstetrics Gynecology and Reproductive Biology, vol. 147, no. 1, pp. 15–20, 2009. View at Publisher · View at Google Scholar
  49. D. Papatsonis, V. Flenady, and H. Liley, “Maintenance therapy with oxytocin antagonists for inhibiting preterm birth after threatened preterm labour,” Cochrane Database of Systematic Reviews, no. 1, Article ID CD005938, 2009. View at Publisher · View at Google Scholar · View at Scopus
  50. R. E. Bittar and M. Zugaib, “Management of preterm labor,” Revista Brasileira de Ginecologia e Obstetricia, vol. 31, no. 8, pp. 415–422, 2009. View at Google Scholar · View at Scopus
  51. Worldwide Atosiban versus Beta-agonists Study Group, “Effectiveness and safety of the oxytocin antagonist atosiban versus beta-adrenergic agonists in the treatment of preterm labour. he Worldwide Atosiban versus Beta-agonists Study Group,” British Journal of Obstetrics and Gynaecology, vol. 108, no. 2, pp. 133–142, 2001. View at Publisher · View at Google Scholar
  52. T. M. Goodwin, G. J. Valenzuela, H. Silver, and G. Creasy, “Dose ranging study of the oxytocin antagonist atosiban in the treatment of preterm labor. Atosiban Study Group,” Obstetrics and Gynecology, vol. 88, no. 3, pp. 331–336, 1996. View at Publisher · View at Google Scholar
  53. J. M. Moutquin, D. Sherman, H. Cohen et al., “Double-blind, randomized, controlled trial of atosiban and ritodrine in the treatment of preterm labor: a multicenter effectiveness and safety study,” American Journal of Obstetrics and Gynecology, vol. 182, no. 5, pp. 1191–1199, 2000. View at Publisher · View at Google Scholar · View at Scopus
  54. M. Kashanian, A. R. Akbarian, and M. Soltanzadeh, “Atosiban and nifedipin for the treatment of preterm labor,” International Journal of Gynecology and Obstetrics, vol. 91, no. 1, pp. 10–14, 2005. View at Publisher · View at Google Scholar · View at Scopus
  55. W. R. Al-Omari, H. B. Al-Shammaa, E. M. Al-Tikriti, and K. W. Ahmed, “Atosiban and nifedipine in acute tocolysis: a comparative study,” European Journal of Obstetrics Gynecology and Reproductive Biology, vol. 128, no. 1-2, pp. 129–134, 2006. View at Publisher · View at Google Scholar
  56. J. King, V. Flenady, S. Cole, and S. Thornton, “Cyclo-oxygenase (COX) inhibitors for treating preterm labour,” Cochrane Database of Systematic Reviews, no. 2, Article ID CD001992, 2005. View at Google Scholar · View at Scopus
  57. K. Duckitt and S. Thornton, “Nitric oxide donors for the treatment of preterm labour,” Cochrane Database of Systematic Reviews, no. 3, Article ID CD002860, 2002. View at Google Scholar · View at Scopus
  58. D. Papatsonis, V. Flenady, S. Cole, and H. Liley, “Oxytocin receptor antagonists for inhibiting preterm labour,” Cochrane Database of Systematic Reviews, no. 3, Article ID CD004452, 2005. View at Google Scholar · View at Scopus
  59. B. Chini, M. Manning, and G. Guillon, “Affinity and efficacy of selective agonists and antagonists for vasopressin and oxytocin receptors: an "easy guide" to receptor pharmacology,” Progress in Brain Research, vol. 170, pp. 513–517, 2008. View at Publisher · View at Google Scholar · View at Scopus
  60. P. Pierzynski, A. Lemancewicz, T. Reinheimer, M. Akerlund, and T. Laudanski, “Inhibitory effect of barusiban and atosiban on oxytocin-induced contractions of myometrium from preterm and term pregnant women,” Journal of the Society for Gynecologic Investigation, vol. 11, no. 6, pp. 384–387, 2004. View at Publisher · View at Google Scholar · View at Scopus
  61. T. M. Reinheimer, G. J. Chellman, J. C. Resendez, J. K. Meyer, and W. H. Bee, “Barusiban, an effective long-term treatment of oxytocin-induced preterm labor in nonhuman primates,” Biology of Reproduction, vol. 75, no. 5, pp. 809–814, 2006. View at Publisher · View at Google Scholar · View at Scopus
  62. T. M. Reinheimer, W. H. Bee, J. C. Resendez, J. K. Meyer, G. J. Haluska, and G. J. Chellman, “Barusiban, a new highly potent and long-acting oxytocin antagonist: pharmacokinetic and pharmacodynamic comparison with atosiban in a cynomolgus monkey model of preterm labor,” Journal of Clinical Endocrinology and Metabolism, vol. 90, no. 4, pp. 2275–2281, 2005. View at Publisher · View at Google Scholar · View at Scopus
  63. T. M. Reinheimer, “Barusiban suppresses oxytocin-induced preterm labour in non-human primates,” BMC Pregnancy and Childbirth, vol. 7, no. 1, article S15, 2007. View at Publisher · View at Google Scholar · View at Scopus
  64. S. Thornton, T. M. Goodwin, G. Greisen, M. Hedegaard, and J. C. Arce, “The effect of barusiban, a selective oxytocin antagonist, in threatened preterm labor at late gestational age: a randomized, double-blind, placebo-controlled trial,” American Journal of Obstetrics and Gynecology, vol. 200, no. 6, pp. 627–e1, 2009. View at Publisher · View at Google Scholar · View at Scopus
  65. G. P. McCafferty, M. A. Pullen, C. Wu et al., “Use of a novel and highly selective oxytocin receptor antagonist to characterize uterine contractions in the rat,” American Journal of Physiology, vol. 293, no. 1, pp. R299–R305, 2007. View at Publisher · View at Google Scholar · View at Scopus
  66. A. D. Borthwick and J. Liddle, “The design of orally bioavailable 2,5-diketopiperazine oxytocin antagonists: from concept to clinical candidate for premature labor,” Medicinal Research Reviews, vol. 31, no. 4, pp. 576–604, 2011. View at Publisher · View at Google Scholar
  67. 2011, http://clinicaltrials.gov/ct2/show/study/NCT00404768.
  68. D. J. Pettibone, M. Guidotti, C. M. Harrell et al., “Progress in the development of oxytocin antagonists for use in preterm labor,” Advances in Experimental Medicine and Biology, vol. 395, pp. 601–612, 1996. View at Google Scholar · View at Scopus
  69. R. M. Freidinger and D. J. Pettibone, “Small molecule ligands for oxytocin and vasopressin receptors,” Medicinal Research Reviews, vol. 17, no. 1, pp. 1–16, 1997. View at Publisher · View at Google Scholar · View at Scopus
  70. C. Serradeil-Le Gal, G. Valette, L. Foulon et al., “SSR126768A (4-Chloro-3-[(3R)-(+)-5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxo-2, 3-dihydro-1H-indol-3-yl]-N-ethyl-N-(3-pyridylmethyl)-benzamide, Hydrochloride): a new selective and orally active oxytocin receptor antagonist for the prevention of Preterm labor,” Journal of Pharmacology and Experimental Therapeutics, vol. 309, no. 1, pp. 414–424, 2004. View at Publisher · View at Google Scholar · View at Scopus
  71. M. Åkerlund, T. Bossmar, R. Brouard et al., “Receptor binding of oxytocin and vasopressin antagonists and inhibitory effects on isolated myometrium from preterm and term pregnant women,” British Journal of Obstetrics and Gynaecology, vol. 106, no. 10, pp. 1047–1053, 1999. View at Google Scholar
  72. M. Steinwall, T. Bossmar, R. Brouard et al., “The effect of relcovaptan (SR 49059), an orally active vasopressin V 1a receptor antagonist, on uterine contractions in preterm labor,” Gynecological Endocrinology, vol. 20, no. 2, pp. 104–109, 2005. View at Publisher · View at Google Scholar · View at Scopus
  73. G. Decaux, A. Soupart, and G. Vassart, “Non-peptide arginine-vasopressin antagonists: the vaptans,” The Lancet, vol. 371, no. 9624, pp. 1624–1632, 2008. View at Publisher · View at Google Scholar · View at Scopus
  74. D. Hayoz, G. Bizzini, B. Noël et al., “Effect of SR 49059, a V1a vasopressin receptor antagonist, in Raynaud's phenomenon,” Rheumatology, vol. 39, no. 10, pp. 1132–1138, 2000. View at Google Scholar · View at Scopus
  75. R. Brouard, T. Bossmar, D. Fournié-Lloret, D. Chassard, and M. Åkerlund, “Effect of SR49059, an orally active V(1a) vasopressin receptor antagonist, in the prevention of dysmenorrhoea,” British Journal of Obstetrics and Gynaecology, vol. 107, no. 5, pp. 614–619, 2000. View at Google Scholar · View at Scopus
  76. A. Shuaib, C. X. Wang, T. Yang, and R. Noor, “Effects of nonpeptide V1 vasopressin receptor antagonist SR-49059 on infarction volume and recovery of function in a focal embolic stroke model,” Stroke, vol. 33, no. 12, pp. 3033–3037, 2002. View at Publisher · View at Google Scholar · View at Scopus