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. 1990 Aug;100(4):761–766. doi: 10.1111/j.1476-5381.1990.tb14089.x

The role of prostanoid TP- and DP-receptors in the bronchoconstrictor effect of inhaled PGD2 in anaesthetized guinea-pigs: effect of the DP-antagonist BW A868C.

S Hamid-Bloomfield 1, A N Payne 1, A A Petrovic 1, B J Whittle 1
PMCID: PMC1917592  PMID: 2119842

Abstract

1. In anaesthetized, pump-ventilated guinea-pigs, bolus intravenous injection of prostaglandin D2 (PGD2 5-160 micrograms kg-1) caused a dose-dependent rise in both heart rate and systemic mean arterial blood pressure with only a small monophasic rise in pulmonary inflation pressure (PIP). 2. In contrast, inhaled PGD2 (0.1-1 mg ml-1, 30s) provoked a substantial concentration-dependent biphasic rise in PIP. The bronchoconstrictor action of inhaled PGD2 was accompanied by minimal cardiovascular effects. 3. The 3-benzyl substituted hydantoin BW A868C (0.1-1 mg kg-1 i.v.) a novel prostanoid DP-receptor antagonist, had no significant effect on the cardiovascular or bronchoconstrictor effects of intravenously administered or inhaled PGD2. 4. However, BW A868C (0.1-1 mg kg-1 i.v.) did inhibit the hypotensive actions of the DP-receptor agonist, BW 245C (1-3 micrograms kg-1 i.v.). 5. The prostanoid TP-receptor antagonist BM 13.177 (2.5 mg kg-1 i.v.) strongly inhibited the bronchoconstrictor effect of inhaled PGD2, abolishing the first phase of this response and reducing the peak increase in PIP provoked by PGD2 (0.1 or 1 mg ml-1 for 30 s), by 67 +/- 16% and 44 +/- 5% respectively. 6. A combination of BW A868C (0.1 or 1 mg kg-1 i.v.) with BM 13.177 (2.5 mg kg-1 i.v.) produced no greater inhibition of the bronchoconstrictor effect of inhaled PGD2 than that seen with BM 13.177 (2.5 mg kg-1 i.v.) alone. 7. Neither bilateral vagotomy, nor selective inhibition of arachidonate cyclo-oxygenase with indomethacin or 5-lipoxygenase with the novel acetohydroxamic acid BW A4C, significantly reduced the bronchoconstrictor effect of inhaled PGD2.(ABSTRACT TRUNCATED AT 250 WORDS)

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Selected References

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  1. Beasley R. C., Featherstone R. L., Church M. K., Rafferty P., Varley J. G., Harris A., Robinson C., Holgate S. T. Effect of a thromboxane receptor antagonist on PGD2- and allergen-induced bronchoconstriction. J Appl Physiol (1985) 1989 Apr;66(4):1685–1693. doi: 10.1152/jappl.1989.66.4.1685. [DOI] [PubMed] [Google Scholar]
  2. Beasley R., Varley J., Robinson C., Holgate S. T. Cholinergic-mediated bronchoconstriction induced by prostaglandin D2, its initial metabolite 9 alpha,11 beta-PGF2, and PGF2 alpha in asthma. Am Rev Respir Dis. 1987 Nov;136(5):1140–1144. doi: 10.1164/ajrccm/136.5.1140. [DOI] [PubMed] [Google Scholar]
  3. Black J. L., Armour C. L., Vincenc K. S., Johnson P. R. A comparison of the contractile activity of PGD2 and PGF2 alpha on human isolated bronchus. Prostaglandins. 1986 Jul;32(1):25–31. doi: 10.1016/0090-6980(86)90139-5. [DOI] [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. Eglen R. M., Whiting R. L. The action of prostanoid receptor agonists and antagonists on smooth muscle and platelets. Br J Pharmacol. 1988 Jun;94(2):591–601. doi: 10.1111/j.1476-5381.1988.tb11565.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Finney M. J., Karlsson J. A., Persson C. G. Effects of bronchoconstrictors and bronchodilators on a novel human small airway preparation. Br J Pharmacol. 1985 May;85(1):29–36. doi: 10.1111/j.1476-5381.1985.tb08827.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Fuller R. W., Dixon C. M., Dollery C. T., Barnes P. J. Prostaglandin D2 potentiates airway responsiveness to histamine and methacholine. Am Rev Respir Dis. 1986 Feb;133(2):252–254. doi: 10.1164/arrd.1986.133.2.252. [DOI] [PubMed] [Google Scholar]
  8. Giles H., Leff P., Bolofo M. L., Kelly M. G., Robertson A. D. The classification of prostaglandin DP-receptors in platelets and vasculature using BW A868C, a novel, selective and potent competitive antagonist. Br J Pharmacol. 1989 Feb;96(2):291–300. doi: 10.1111/j.1476-5381.1989.tb11816.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Giles H., Leff P. The biology and pharmacology of PGD2. Prostaglandins. 1988 Feb;35(2):277–300. doi: 10.1016/0090-6980(88)90093-7. [DOI] [PubMed] [Google Scholar]
  10. Hamid-Bloomfield S., Whittle B. J. Antagonism of PGD2 vasodepressor responses in the rat in vivo by the novel, selective antagonist, BW A868C. Br J Pharmacol. 1989 Feb;96(2):307–312. doi: 10.1111/j.1476-5381.1989.tb11818.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Hamid-Bloomfield S., Whittle B. J. Prostaglandin D2 interacts at thromboxane receptor-sites on guinea-pig platelets. Br J Pharmacol. 1986 Aug;88(4):931–936. doi: 10.1111/j.1476-5381.1986.tb16268.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Hardy C. C., Robinson C., Tattersfield A. E., Holgate S. T. The bronchoconstrictor effect of inhaled prostaglandin D2 in normal and asthmatic men. N Engl J Med. 1984 Jul 26;311(4):209–213. doi: 10.1056/NEJM198407263110401. [DOI] [PubMed] [Google Scholar]
  13. Heavey D. J., Lumley P., Barrow S. E., Murphy M. B., Humphrey P. P., Dollery C. T. Effects of intravenous infusions of prostaglandin D2 in man. Prostaglandins. 1984 Dec;28(6):755–767. doi: 10.1016/0090-6980(84)90033-9. [DOI] [PubMed] [Google Scholar]
  14. Holgate S. T., Burns G. B., Robinson C., Church M. K. Anaphylactic- and calcium-dependent generation of prostaglandin D2 (PGD2), thromboxane B2, and other cyclooxygenase products of arachidonic acid by dispersed human lung cells and relationship to histamine release. J Immunol. 1984 Oct;133(4):2138–2144. [PubMed] [Google Scholar]
  15. Jackson W. P., Islip P. J., Kneen G., Pugh A., Wates P. J. Acetohydroxamic acids as potent, selective, orally active 5-lipoxygenase inhibitors. J Med Chem. 1988 Mar;31(3):499–500. doi: 10.1021/jm00398a001. [DOI] [PubMed] [Google Scholar]
  16. Jones R. L. Cardiovascular actions of prostaglandins D and E in the sheep: evidence for two distinct receptors. Adv Prostaglandin Thromboxane Res. 1976;1:221–230. [PubMed] [Google Scholar]
  17. 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]
  18. 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]
  19. 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]
  20. Murray J. J., Tonnel A. B., Brash A. R., Roberts L. J., 2nd, Gosset P., Workman R., Capron A., Oates J. A. Release of prostaglandin D2 into human airways during acute antigen challenge. N Engl J Med. 1986 Sep 25;315(13):800–804. doi: 10.1056/NEJM198609253151304. [DOI] [PubMed] [Google Scholar]
  21. Patterson R., Harris K. E., Greenberger P. A. Effect of prostaglandin D2 and I2 on the airways of rhesus monkeys. J Allergy Clin Immunol. 1980 Apr;65(4):269–273. doi: 10.1016/0091-6749(80)90154-2. [DOI] [PubMed] [Google Scholar]
  22. Payne A. N., Garland L. G., Lees I. W., Salmon J. A. Selective inhibition of arachidonate 5-lipoxygenase by novel acetohydroxamic acids: effects on bronchial anaphylaxis in anaesthetized guinea-pigs. Br J Pharmacol. 1988 Jun;94(2):540–546. doi: 10.1111/j.1476-5381.1988.tb11558.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Payne A. N., de Nucci G. Anaphylaxis in guinea pigs induced by ovalbumin aerosol in vivo and in vitro methods. J Pharmacol Methods. 1987 Mar;17(1):83–90. doi: 10.1016/0160-5402(87)90040-4. [DOI] [PubMed] [Google Scholar]
  24. Robinson C., Hardy C. C., Holgate S. T. Pulmonary synthesis, release, and metabolism of prostaglandins. J Allergy Clin Immunol. 1985 Aug;76(2 Pt 2):265–271. doi: 10.1016/0091-6749(85)90640-2. [DOI] [PubMed] [Google Scholar]
  25. Spannhake E. W., Hyman A. L., Kadowitz P. J. Bronchoactive metabolites of arachidonic acid and their role in airway function. Prostaglandins. 1981 Dec;22(6):1013–1026. doi: 10.1016/0090-6980(81)90028-9. [DOI] [PubMed] [Google Scholar]
  26. Spannhake E. W., Lemen R. J., Wegmann M. J., Hyman A. L., Kadowitz P. J. Effects of arachidonic acid and prostaglandins on lung function in the intact dog. J Appl Physiol Respir Environ Exerc Physiol. 1978 Mar;44(3):397–405. doi: 10.1152/jappl.1978.44.3.397. [DOI] [PubMed] [Google Scholar]
  27. Stegmeier K., Pill J., Müller-Beckmann B., Schmidt F. H., Witte E. C., Wolff H. P., Patscheke H. The pharmacological profile of the thromboxane A2 antagonist BM 13.177. A new anti-platelet and anti-thrombotic drug. Thromb Res. 1984 Aug 15;35(4):379–395. doi: 10.1016/0049-3848(84)90230-5. [DOI] [PubMed] [Google Scholar]
  28. Trist D. G., Collins B. A., Wood J., Kelly M. G., Robertson A. D. The antagonism by BW A868C of PGD2 and BW245C activation of human platelet adenylate cyclase. Br J Pharmacol. 1989 Feb;96(2):301–306. doi: 10.1111/j.1476-5381.1989.tb11817.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Wasserman M. A., DuCharme D. W., Griffin R. L., DeGraaf G. L., Robinson F. G. Bronchopulmonary and cardiovascular effects of prostaglandin D2 in the dog. Prostaglandins. 1977 Feb;13(2):255–269. doi: 10.1016/0090-6980(77)90007-7. [DOI] [PubMed] [Google Scholar]
  30. Whittle B. J., Moncada S., Mullane K., Vane J. R. Platelet and cardiovascular activity of the hydantoin BW245C, a potent prostaglandin analogue. Prostaglandins. 1983 Feb;25(2):205–223. doi: 10.1016/0090-6980(83)90105-3. [DOI] [PubMed] [Google Scholar]

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