Skip to main content
NCBI home page
British Journal of Pharmacology logoLink to British Journal of Pharmacology
. 1989 Apr;96(4):759–766. doi: 10.1111/j.1476-5381.1989.tb11880.x

Selective inhibition of adrenaline-induced human platelet aggregation by the structurally related Paf antagonist Ro 19-3704.

M Schattner 1, A Parini 1, F Fouque 1, B B Vargaftig 1, L Touqui 1
PMCID: PMC1854433  PMID: 2787179

Abstract

1. Two non-lipid antagonists of platelet-activating factor acether (Paf), BN 52021 and WEB 2086, at concentrations which completely blocked Paf-induced platelet aggregation, failed to interfere with aggregation by adrenaline. In contrast, Ro 19-3704, a structurally related antagonist of Paf, inhibited concentration-dependently aggregation induced by adrenaline or by the simultaneous addition of submaximal concentrations of adrenaline and Paf. Reversal of aggregation was obtained when Ro 19-3704 was added to the platelet suspension after adrenaline. 2. Ro 19-3704 was selective for Paf and adrenaline since it failed to interfere with platelet aggregation induced by arachidonic acid or ADP. CV-3988, an antagonist of Paf structurally similar to Ro 19-3704, also inhibited adrenaline-induced aggregation. However, a morpholine analogue (MA) of Paf, which has no anti-Paf activity, failed to interfere with the aggregation induced by adrenaline. This suggests that the effect of Ro 19-3704 and CV-3988 on adrenaline is not simply due to their lipid structure. 3. Experiments on plasma membrane preparations showed that Ro 19-3704 inhibited [3H]-yohimbine binding with an inhibition constant (Ki) of 7 +/- 3 microM. In contrast, BN 52021 and MA did not interfere with [3H]-yohimbine binding. Equilibrium binding experiments showed that Ro 19-3704 increased the apparent KD of [3H]-yohimbine binding from 2.02 +/- 0.15 to 7.3 +/- 0.4 nM. The Paf antagonist Ro 19-3704 interacts specifically with the alpha 2-adrenoceptor and may thus prevent the early steps involved in the mechanism of adrenaline-induced platelet activation.

Full text

PDF
759

Selected References

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

  1. Agrawal D. K., Townley R. G. Effect of platelet-activating factor on beta-adrenoceptors in human lung. Biochem Biophys Res Commun. 1987 Feb 27;143(1):1–6. doi: 10.1016/0006-291x(87)90620-6. [DOI] [PubMed] [Google Scholar]
  2. Braquet P., Touqui L., Shen T. Y., Vargaftig B. B. Perspectives in platelet-activating factor research. Pharmacol Rev. 1987 Jun;39(2):97–145. [PubMed] [Google Scholar]
  3. Casals-Stenzel J. Protective effect of WEB 2086, a novel antagonist of platelet activating factor, in endotoxin shock. Eur J Pharmacol. 1987 Mar 17;135(2):117–122. doi: 10.1016/0014-2999(87)90602-9. [DOI] [PubMed] [Google Scholar]
  4. Charo I. F., Feinman R. D., Detwiler T. C. Interrelations of platelet aggregation and secretion. J Clin Invest. 1977 Oct;60(4):866–873. doi: 10.1172/JCI108841. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Chignard M., Le Couedic J. P., Vargaftig B. B., Benveniste J. Platelet-activating factor (PAF-acether) secretion from platelets: effect of aggregating agents. Br J Haematol. 1980 Nov;46(3):455–464. doi: 10.1111/j.1365-2141.1980.tb05993.x. [DOI] [PubMed] [Google Scholar]
  6. Clare K. A., Scrutton M. C. The role of Ca2+ uptake in the response of human platelets to adrenaline and to 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine (platelet-activating factor). Eur J Biochem. 1984 Apr 2;140(1):129–136. doi: 10.1111/j.1432-1033.1984.tb08075.x. [DOI] [PubMed] [Google Scholar]
  7. Coëffier E., Borrel M. C., Lefort J., Chignard M., Broquet C., Heymans F., Godfroid J. J., Vargaftig B. B. Effects of PAF-acether and structural analogues on platelet activation and bronchoconstriction in guinea-pigs. Eur J Pharmacol. 1986 Nov 19;131(2-3):179–188. doi: 10.1016/0014-2999(86)90571-6. [DOI] [PubMed] [Google Scholar]
  8. Fouque F., Vargaftig B. B. Triggering by Paf-acether and adrenaline of cyclo-oxygenase-independent platelet aggregation. Br J Pharmacol. 1984 Nov;83(3):625–633. doi: 10.1111/j.1476-5381.1984.tb16216.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Grant J. A., Scrutton M. C. Interaction of selective alpha-adrenoceptor agonists and antagonists with human and rabbit blood platelets. Br J Pharmacol. 1980;71(1):121–134. doi: 10.1111/j.1476-5381.1980.tb10917.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Hwang S. B., Lee C. S., Cheah M. J., Shen T. Y. Specific receptor sites for 1-O-alkyl-2-O-acetyl-sn-glycero-3-phosphocholine (platelet activating factor) on rabbit platelet and guinea pig smooth muscle membranes. Biochemistry. 1983 Sep 27;22(20):4756–4763. doi: 10.1021/bi00289a022. [DOI] [PubMed] [Google Scholar]
  11. Johnson P. C., Ware J. A., Salzman E. W. Concurrent measurement of platelet ionized calcium concentration and aggregation: studies with the lumiaggregometer. Thromb Res. 1985 Nov 15;40(4):435–443. doi: 10.1016/0049-3848(85)90280-4. [DOI] [PubMed] [Google Scholar]
  12. Munson P. J., Rodbard D. Ligand: a versatile computerized approach for characterization of ligand-binding systems. Anal Biochem. 1980 Sep 1;107(1):220–239. doi: 10.1016/0003-2697(80)90515-1. [DOI] [PubMed] [Google Scholar]
  13. Mustard J. F., Perry D. W., Ardlie N. G., Packham M. A. Preparation of suspensions of washed platelets from humans. Br J Haematol. 1972 Feb;22(2):193–204. doi: 10.1111/j.1365-2141.1972.tb08800.x. [DOI] [PubMed] [Google Scholar]
  14. Nunez D., Chignard M., Korth R., Le Couedic J. P., Norel X., Spinnewyn B., Braquet P., Benveniste J. Specific inhibition of PAF-acether-induced platelet activation by BN 52021 and comparison with the PAF-acether inhibitors kadsurenone and CV 3988. Eur J Pharmacol. 1986 Apr 16;123(2):197–205. doi: 10.1016/0014-2999(86)90660-6. [DOI] [PubMed] [Google Scholar]
  15. Siess W., Weber P. C., Lapetina E. G. Activation of phospholipase C is dissociated from arachidonate metabolism during platelet shape change induced by thrombin or platelet-activating factor. Epinephrine does not induce phospholipase C activation or platelet shape change. J Biol Chem. 1984 Jul 10;259(13):8286–8292. [PubMed] [Google Scholar]
  16. Timmermans P. B., van Zwieten P. A. alpha 2 adrenoceptors: classification, localization, mechanisms, and targets for drugs. J Med Chem. 1982 Dec;25(12):1389–1401. doi: 10.1021/jm00354a001. [DOI] [PubMed] [Google Scholar]
  17. Touqui L., Hatmi M., Vargaftig B. B. Human platelets stimulated by thrombin produce platelet-activating factor (1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine) when the degrading enzyme acetyl hydrolase is blocked. Biochem J. 1985 Aug 1;229(3):811–816. doi: 10.1042/bj2290811. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Vargaftig B. B., Chignard M., Benveniste J., Lefort J., Wal F. Background and present status of research on platelet-activating factor (PAF-acether). Ann N Y Acad Sci. 1981;370:119–137. doi: 10.1111/j.1749-6632.1981.tb29727.x. [DOI] [PubMed] [Google Scholar]
  19. Vargaftig B. B., Fouque F., Benveniste J., Odiot J. Adrenaline and PAF-acether synergize to trigger cyclooxygenase-independent activation of plasma-free human platelets. Thromb Res. 1982 Nov 15;28(4):557–573. doi: 10.1016/0049-3848(82)90171-2. [DOI] [PubMed] [Google Scholar]

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

RESOURCES