Skip to main content
NCBI home page
British Journal of Pharmacology logoLink to British Journal of Pharmacology
. 1996 Mar;117(6):1171–1180. doi: 10.1111/j.1476-5381.1996.tb16712.x

Evidence for human thromboxane receptor heterogeneity using a novel series of 9,11-cyclic carbonate derivatives of prostaglandin F2 alpha.

A H Krauss 1, D F Woodward 1, L L Gibson 1, C E Protzman 1, L S Williams 1, R M Burk 1, T S Gac 1, M B Roof 1, F Abbas 1, K Marshall 1, J Senior 1
PMCID: PMC1909759  PMID: 8882612

Abstract

1. The pharmacological activity of a novel series of 9,11-cyclic carbonate derivatives of prostaglandin F2 alpha (PGF2 alpha) was investigated in various isolated smooth muscle preparations possessing different prostanoid receptor subtypes as well as in human platelets. Since subdivision of thromboxane (TP-) receptors into vascular/smooth muscle and platelet subtypes is a controversial subject, our studies included a human smooth muscle preparation (myometrium) in addition to the widely used rat aorta and human platelets as TP-receptor preparations. 2. Two members of that series, AGN191976 and AGN192093 were found to be highly potent and selective thromboxane-mimetics. AGN191976 and AGN192093 contracted isolated tissues of the rat thoracic aorta with EC50 values of 0.32 +/- 0.08 and 1.30 +/- 0.53 nM, respectively. Both agonists were at least 10 times more potent than the benchmark TP-agonist, U-46619, in this preparation, whilst being at least 500 times less potent at other prostanoid receptors (DP, EP1, EP3, FP, IP) in vitro. 3. In human myometrial strips from pregnant and non-pregnant donors, both AGN191976 and AGN192093 were potent contractile agonists. The rank order of potency in myometrium of AGN191976 > AGN192093 > U-46619 correlated well with that in the rat aorta. In human platelet-rich plasma (PRP), however, AGN191976 had potent proaggregatory activity (EC50 = 16.3 +/- 1.4 nM), which is a TP-receptor-mediated event, whereas AGN192093 was a much weaker agonist (EC50 = 37.9 +/- 2.0 microM). AGN192093 did not behave as an antagonist in the platelets, since it did not antagonize platelet aggregation induced by ADP, arachidonic acid, U-46619 or AGN191976. In human washed platelets, the activity profile of AGN191976 (EC50 = 4.15 +/- 0.52 nM) and AGN192093 (no aggregation up to 10 microM) was similar to that obtained in PRP. 4. The involvement of TP-receptors was verified with the potent TP-antagonist, SQ29548. SQ29548 (0.1 microM in myometrium; 1 microM in aorta; 1 microM and 10 microM in platelets) antagonized responses to U-46619, AGN191976 and AGN192093 as expected. 5. In conclusion, AGN191976 and AGN192093, both 9,11-cyclic carbonate derivatives of PGF2 alpha, were found to be highly potent and selective thromboxane-mimetics in rat vascular and human myometrial smooth muscle. However, only AGN 191976 was a potent agonist at TP-receptors in human platelets. The differential activity of AGN192093 on TP-receptor-mediated events in platelets and smooth muscle provides further evidence for a subdivision of TP-receptors. AGN192093 appears to be a useful tool for the pharmacological distinction of TP-receptor subtypes.

Full text

PDF
1171

Selected References

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

  1. Armstrong R. A., Jones R. L., Peesapati V., Will S. G., Wilson N. H. Competitive antagonism at thromboxane receptors in human platelets. Br J Pharmacol. 1985 Mar;84(3):595–607. doi: 10.1111/j.1476-5381.1985.tb16139.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Banerjee M., Kang K. H., Morrow J. D., Roberts L. J., Newman J. H. Effects of a novel prostaglandin, 8-epi-PGF2 alpha, in rabbit lung in situ. Am J Physiol. 1992 Sep;263(3 Pt 2):H660–H663. doi: 10.1152/ajpheart.1992.263.3.H660. [DOI] [PubMed] [Google Scholar]
  3. Coleman R. A., Humphrey P. P., Kennedy I., Levy G. P., Lumley P. Comparison of the actions of U-46619, a prostaglandin H2-analogue, with those of prostaglandin H2 and thromboxane A2 on some isolated smooth muscle preparations. Br J Pharmacol. 1981 Jul;73(3):773–778. doi: 10.1111/j.1476-5381.1981.tb16814.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Coleman R. A., Sheldrick R. L. Prostanoid-induced contraction of human bronchial smooth muscle is mediated by TP-receptors. Br J Pharmacol. 1989 Mar;96(3):688–692. doi: 10.1111/j.1476-5381.1989.tb11869.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Duncan A. M., Anderson L. L., Funk C. D., Abramovitz M., Adam M. Chromosomal localization of the human prostanoid receptor gene family. Genomics. 1995 Feb 10;25(3):740–742. doi: 10.1016/0888-7543(95)80022-e. [DOI] [PubMed] [Google Scholar]
  6. Furci L., Fitzgerald D. J., Fitzgerald G. A. Heterogeneity of prostaglandin H2/thromboxane A2 receptors: distinct subtypes mediate vascular smooth muscle contraction and platelet aggregation. J Pharmacol Exp Ther. 1991 Jul 1;258(1):74–81. [PubMed] [Google Scholar]
  7. Harris D. N., Michel I. M., Goldenberg H. J., Hartl K. S., Allen G. T., Steinbacher T. E., Schumacher W. A., Han W. C., Hall S. E., Floyd D. M. Pharmacological characterization of potent, long-acting thromboxane receptor antagonists, SQ 33,261 and SQ 33,552. J Pharmacol Exp Ther. 1992 Apr;261(1):131–137. [PubMed] [Google Scholar]
  8. Hirata M., Hayashi Y., Ushikubi F., Yokota Y., Kageyama R., Nakanishi S., Narumiya S. Cloning and expression of cDNA for a human thromboxane A2 receptor. Nature. 1991 Feb 14;349(6310):617–620. doi: 10.1038/349617a0. [DOI] [PubMed] [Google Scholar]
  9. Jones R. L., Peesapati V., Wilson N. H. Antagonism of the thromboxane-sensitive contractile systems of the rabbit aorta, dog saphenous vein and guinea-pig trachea. Br J Pharmacol. 1982 Jul;76(3):423–438. doi: 10.1111/j.1476-5381.1982.tb09236.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Jones R. L., Wilson N. H., Lawrence R. A. EP 171: a high affinity thromboxane A2-mimetic, the actions of which are slowly reversed by receptor blockade. Br J Pharmacol. 1989 Apr;96(4):875–887. doi: 10.1111/j.1476-5381.1989.tb11898.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Katsura M., Miyamoto T., Hamanaka N., Kondo K., Terada T., Ohgaki Y., Kawasaki A., Tsuboshima M. In vitro and in vivo effects of new powerful thromboxane antagonists (3-alkylamino pinane derivatives). Adv Prostaglandin Thromboxane Leukot Res. 1983;11:351–357. [PubMed] [Google Scholar]
  12. Kennedy I., Coleman R. A., Humphrey P. P., Levy G. P., Lumley P. Studies on the characterisation of prostanoid receptors: a proposed classification. Prostaglandins. 1982 Nov;24(5):667–689. doi: 10.1016/0090-6980(82)90036-3. [DOI] [PubMed] [Google Scholar]
  13. Kitanaka J., Hashimoto H., Sugimoto Y., Sawada M., Negishi M., Suzumura A., Marunouchi T., Ichikawa A., Baba A. cDNA cloning of a thromboxane A2 receptor from rat astrocytes. Biochim Biophys Acta. 1995 Mar 16;1265(2-3):220–223. doi: 10.1016/0167-4889(94)00225-4. [DOI] [PubMed] [Google Scholar]
  14. Kosakai K., Wakabayashi S., Sato T., Mochizuki S., Tomiyama A., Zhou Q., Satake N., Shibata S. Pharmacologic properties of KT2-962 (6-isopropyl-3-[4-(p- chlorobenzenesulfonylamino)-butyl]-azulene-1-sulfonic acid sodium salt); a new TXA2/prostaglandin endoperoxide receptor antagonist. J Cardiovasc Pharmacol. 1993 Mar;21(3):441–447. doi: 10.1097/00005344-199303000-00014. [DOI] [PubMed] [Google Scholar]
  15. Lefer A. M., Smith E. F., 3rd, Araki H., Smith J. B., Aharony D., Claremon D. A., Magolda R. L., Nicolaou K. C. Dissociation of vasoconstrictor and platelet aggregatory activities of thromboxane by carbocyclic thromboxane A2, a stable analog of thromboxane A2. Proc Natl Acad Sci U S A. 1980 Mar;77(3):1706–1710. doi: 10.1073/pnas.77.3.1706. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Lumley P., White B. P., Humphrey P. P. GR32191, a highly potent and specific thromboxane A2 receptor blocking drug on platelets and vascular and airways smooth muscle in vitro. Br J Pharmacol. 1989 Jul;97(3):783–794. doi: 10.1111/j.1476-5381.1989.tb12017.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Mais D. E., DeHoll D., Sightler H., Halushka P. V. Different pharmacologic activities for 13-azapinane thromboxane A2 analogs in platelets and blood vessels. Eur J Pharmacol. 1988 Apr 13;148(3):309–315. doi: 10.1016/0014-2999(88)90108-2. [DOI] [PubMed] [Google Scholar]
  18. Mais D. E., Saussy D. L., Jr, Chaikhouni A., Kochel P. J., Knapp D. R., Hamanaka N., Halushka P. V. Pharmacologic characterization of human and canine thromboxane A2/prostaglandin H2 receptors in platelets and blood vessels: evidence for different receptors. J Pharmacol Exp Ther. 1985 May;233(2):418–424. [PubMed] [Google Scholar]
  19. Masuda A., Mais D. E., Oatis J. E., Jr, Halushka P. V. Platelet and vascular thromboxane A2/prostaglandin H2 receptors. Evidence for different subclasses in the rat. Biochem Pharmacol. 1991 Jul 15;42(3):537–544. doi: 10.1016/0006-2952(91)90316-w. [DOI] [PubMed] [Google Scholar]
  20. McKenniff M., Rodger I. W., Norman P., Gardiner P. J. Characterisation of receptors mediating the contractile effects of prostanoids in guinea-pig and human airways. Eur J Pharmacol. 1988 Aug 24;153(2-3):149–159. doi: 10.1016/0014-2999(88)90601-2. [DOI] [PubMed] [Google Scholar]
  21. Morrow J. D., Minton T. A., Roberts L. J., 2nd The F2-isoprostane, 8-epi-prostaglandin F2 alpha, a potent agonist of the vascular thromboxane/endoperoxide receptor, is a platelet thromboxane/endoperoxide receptor antagonist. Prostaglandins. 1992 Aug;44(2):155–163. doi: 10.1016/0090-6980(92)90077-7. [DOI] [PubMed] [Google Scholar]
  22. Namba T., Sugimoto Y., Hirata M., Hayashi Y., Honda A., Watabe A., Negishi M., Ichikawa A., Narumiya S. Mouse thromboxane A2 receptor: cDNA cloning, expression and northern blot analysis. Biochem Biophys Res Commun. 1992 May 15;184(3):1197–1203. doi: 10.1016/s0006-291x(05)80009-9. [DOI] [PubMed] [Google Scholar]
  23. Narumiya S., Okuma M., Ushikubi F. Binding of a radioiodinated 13-azapinane thromboxane antagonist to platelets: correlation with antiaggregatory activity in different species. Br J Pharmacol. 1986 Jun;88(2):323–331. doi: 10.1111/j.1476-5381.1986.tb10208.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Nicolaou K. C., Magolda R. L., Smith J. B., Aharony D., Smith E. F., Lefer A. M. Synthesis and biological properties of pinane-thromboxane A2, a selective inhibitor of coronary artery constriction, platelet aggregation, and thromboxane formation. Proc Natl Acad Sci U S A. 1979 Jun;76(6):2566–2570. doi: 10.1073/pnas.76.6.2566. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Norel X., Labat C., Gardiner P. J., Brink C. Inhibitory effects of BAY u3405 on prostanoid-induced contractions in human isolated bronchial and pulmonary arterial muscle preparations. Br J Pharmacol. 1991 Nov;104(3):591–595. doi: 10.1111/j.1476-5381.1991.tb12474.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Nüsing R. M., Hirata M., Kakizuka A., Eki T., Ozawa K., Narumiya S. Characterization and chromosomal mapping of the human thromboxane A2 receptor gene. J Biol Chem. 1993 Nov 25;268(33):25253–25259. [PubMed] [Google Scholar]
  27. Ogletree M. L., Harris D. N., Greenberg R., Haslanger M. F., Nakane M. Pharmacological actions of SQ 29,548, a novel selective thromboxane antagonist. J Pharmacol Exp Ther. 1985 Aug;234(2):435–441. [PubMed] [Google Scholar]
  28. Qian Y. M., Jones R. L., Chan K. M., Stock A. I., Ho J. K. Potent contractile actions of prostanoid EP3-receptor agonists on human isolated pulmonary artery. Br J Pharmacol. 1994 Oct;113(2):369–374. doi: 10.1111/j.1476-5381.1994.tb16997.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Raychowdhury M. K., Yukawa M., Collins L. J., McGrail S. H., Kent K. C., Ware J. A. Alternative splicing produces a divergent cytoplasmic tail in the human endothelial thromboxane A2 receptor. J Biol Chem. 1994 Jul 29;269(30):19256–19261. [PubMed] [Google Scholar]
  30. Senior J., Marshall K., Sangha R., Baxter G. S., Clayton J. K. In vitro characterization of prostanoid EP-receptors in the non-pregnant human myometrium. Br J Pharmacol. 1991 Mar;102(3):747–753. doi: 10.1111/j.1476-5381.1991.tb12244.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Senior J., Sangha R., Baxter G. S., Marshall K., Clayton J. K. In vitro characterization of prostanoid FP-, DP-, IP- and TP-receptors on the non-pregnant human myometrium. Br J Pharmacol. 1992 Sep;107(1):215–221. doi: 10.1111/j.1476-5381.1992.tb14489.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Swayne G. T., Maguire J., Dolan J., Raval P., Dane G., Greener M., Owen D. A. Evidence for homogeneity of thromboxane A2 receptor using structurally different antagonists. Eur J Pharmacol. 1988 Aug 2;152(3):311–319. doi: 10.1016/0014-2999(88)90726-1. [DOI] [PubMed] [Google Scholar]
  33. Takahara K., Murray R., FitzGerald G. A., Fitzgerald D. J. The response to thromboxane A2 analogues in human platelets. Discrimination of two binding sites linked to distinct effector systems. J Biol Chem. 1990 Apr 25;265(12):6836–6844. [PubMed] [Google Scholar]
  34. Takahashi K., Nammour T. M., Fukunaga M., Ebert J., Morrow J. D., Roberts L. J., 2nd, Hoover R. L., Badr K. F. Glomerular actions of a free radical-generated novel prostaglandin, 8-epi-prostaglandin F2 alpha, in the rat. Evidence for interaction with thromboxane A2 receptors. J Clin Invest. 1992 Jul;90(1):136–141. doi: 10.1172/JCI115826. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Toda N., Nakajima M., Okamura T., Miyazaki M. Interactions of thromboxane A2 analogs and prostaglandins in isolated dog arteries. J Cardiovasc Pharmacol. 1986 Jul-Aug;8(4):818–825. doi: 10.1097/00005344-198709010-00025. [DOI] [PubMed] [Google Scholar]
  36. Toh H., Ichikawa A., Narumiya S. Molecular evolution of receptors for eicosanoids. FEBS Lett. 1995 Mar 13;361(1):17–21. doi: 10.1016/0014-5793(95)00129-w. [DOI] [PubMed] [Google Scholar]
  37. Tymkewycz P. M., Jones R. L., Wilson N. H., Marr C. G. Heterogeneity of thromboxane A2 (TP-) receptors: evidence from antagonist but not agonist potency measurements. Br J Pharmacol. 1991 Mar;102(3):607–614. doi: 10.1111/j.1476-5381.1991.tb12220.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Ushikubi F., Nakajima M., Hirata M., Okuma M., Fujiwara M., Narumiya S. Purification of the thromboxane A2/prostaglandin H2 receptor from human blood platelets. J Biol Chem. 1989 Oct 5;264(28):16496–16501. [PubMed] [Google Scholar]
  39. al Jarad N., Hui K. P., Barnes N. Effects of a thromboxane receptor antagonist on prostaglandin D2 and histamine induced bronchoconstriction in man. Br J Clin Pharmacol. 1994 Jan;37(1):97–100. doi: 10.1111/j.1365-2125.1994.tb04249.x. [DOI] [PMC free article] [PubMed] [Google Scholar]

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

RESOURCES