Skip to main content
NCBI home page
British Journal of Clinical Pharmacology logoLink to British Journal of Clinical Pharmacology
. 1989 Nov;28(5):573–579. doi: 10.1111/j.1365-2125.1989.tb03544.x

Differential effect of aspirin on thromboxane and prostaglandin biosynthesis in man.

J M Ritter 1, J R Cockcroft 1, H S Doktor 1, J Beacham 1, S E Barrow 1
PMCID: PMC1380018  PMID: 2590611

Abstract

1. Effects of a single intravenous dose of aspirin (600 mg) on bradykinin-stimulated prostaglandin (PG) and on thromboxane (TX) biosynthesis were determined in nine healthy male volunteers. Plasma concentrations of 6-oxo-PGF1 alpha and 13,14-dihydro-15-oxo-PGF2 alpha were measured in samples obtained during repeated 10 min intravenous infusions of bradykinin before and up to 6 h after the dose of aspirin. TXB2 was measured in serum from blood allowed to clot at 37 degrees C. 2. Aspirin inhibited bradykinin stimulated PG and platelet TX biosynthesis 0.5 h after the dose. Serum TXB2 remained low, whereas PG synthesis recovered within 6 h. 3. Effects of intravenous sodium salicylate (600 mg) were studied identically in eight subjects. Prostanoid biosynthesis was not inhibited. 4. Biosynthesis of prostacyclin and TXA2 under basal conditions was studied in eight subjects by measuring 2,3-dinor-6-oxo-PGF1 alpha and 2,3-dinor-TXB2 in hourly urine samples obtained during and after intravenous infusion of aspirin and, on a separate occasion, of vehicle. 5. Aspirin infusion reduced urinary excretion of both metabolites greater than 90%, but excretion of 2,3-dinor-6-oxo-PGF1 alpha recovered more rapidly than did that of 2,3-dinor-TXB2. 6. We conclude that cyclo-oxygenase is rapidly synthesised in bradykinin-responsive tissues in vivo and that this reflects similarly rapid enzyme biosynthesis in tissues that produce PGI2 under basal conditions.

Full text

PDF
573

Selected References

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

  1. Barrow S. E., Cockcroft J., Dollery C. T., Hickling N. E., Ritter J. M. Identification of 13,14-dihydro-15-oxo-prostaglandin F2 alpha in the circulation during infusions of bradykinin and prostaglandin E2 in man. Br J Pharmacol. 1987 May;91(1):245–250. doi: 10.1111/j.1476-5381.1987.tb09005.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Barrow S. E., Dollery C. T., Heavey D. J., Hickling N. E., Ritter J. M., Vial J. Effect of vasoactive peptides on prostacyclin synthesis in man. Br J Pharmacol. 1986 Jan;87(1):243–247. doi: 10.1111/j.1476-5381.1986.tb10177.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Burch R. M., Knapp D. R., Halushka P. V. Vasopressin stimulates thromboxane synthesis in the toad urinary bladder: effects of imidazole. J Pharmacol Exp Ther. 1979 Sep;210(3):344–348. [PubMed] [Google Scholar]
  4. Cerletti C., Gambino M. C., Garattini S., de Gaetano G. Biochemical selectivity of oral versus intravenous aspirin in rats. Inhibition by oral aspirin of cyclooxygenase activity in platelets and presystemic but not systemic vessels. J Clin Invest. 1986 Jul;78(1):323–326. doi: 10.1172/JCI112569. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Charo I. F., Shak S., Karasek M. A., Davison P. M., Goldstein I. M. Prostaglandin I2 is not a major metabolite of arachidonic acid in cultured endothelial cells from human foreskin microvessels. J Clin Invest. 1984 Sep;74(3):914–919. doi: 10.1172/JCI111509. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Chiabrando C., Benigni A., Piccinelli A., Carminati C., Cozzi E., Remuzzi G., Fanelli R. Antibody-mediated extraction/negative-ion chemical ionization mass spectrometric measurement of thromboxane B2 and 2,3-dinor-thromboxane B2 in human and rat urine. Anal Biochem. 1987 May 15;163(1):255–262. doi: 10.1016/0003-2697(87)90121-7. [DOI] [PubMed] [Google Scholar]
  7. Dejana E., Cerletti C., de Gaetano G. Interaction of salicylate and other non-steroidal anti-inflammatory drugs with aspirin on platelet and vascular cyclo-oxygenase activity. Thromb Res Suppl. 1983;4:153–159. doi: 10.1016/0049-3848(83)90371-7. [DOI] [PubMed] [Google Scholar]
  8. Ferreira S. H., Moncada S., Vane J. R. Indomethacin and aspirin abolish prostaglandin release from the spleen. Nat New Biol. 1971 Jun 23;231(25):237–239. doi: 10.1038/newbio231237a0. [DOI] [PubMed] [Google Scholar]
  9. FitzGerald G. A., Oates J. A., Hawiger J., Maas R. L., Roberts L. J., 2nd, Lawson J. A., Brash A. R. Endogenous biosynthesis of prostacyclin and thromboxane and platelet function during chronic administration of aspirin in man. J Clin Invest. 1983 Mar;71(3):676–688. doi: 10.1172/JCI110814. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Granström E., Kindahl H. Species differences in circulating prostaglandin metabolites. Relevance for the assay of prostaglandin release. Biochim Biophys Acta. 1982 Dec 13;713(3):555–569. doi: 10.1016/0005-2760(82)90316-2. [DOI] [PubMed] [Google Scholar]
  11. Hamberg M. Inhibition of prostaglandin synthesis in man. Biochem Biophys Res Commun. 1972 Nov 1;49(3):720–726. doi: 10.1016/0006-291x(72)90470-6. [DOI] [PubMed] [Google Scholar]
  12. Hamberg M., Svensson J., Samuelsson B. Thromboxanes: a new group of biologically active compounds derived from prostaglandin endoperoxides. Proc Natl Acad Sci U S A. 1975 Aug;72(8):2994–2998. doi: 10.1073/pnas.72.8.2994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Heavey D. J., Barrow S. E., Hickling N. E., Ritter J. M. Aspirin causes short-lived inhibition of bradykinin-stimulated prostacyclin production in man. Nature. 1985 Nov 14;318(6042):186–188. doi: 10.1038/318186a0. [DOI] [PubMed] [Google Scholar]
  14. Higgs G. A., Salmon J. A., Henderson B., Vane J. R. Pharmacokinetics of aspirin and salicylate in relation to inhibition of arachidonate cyclooxygenase and antiinflammatory activity. Proc Natl Acad Sci U S A. 1987 Mar;84(5):1417–1420. doi: 10.1073/pnas.84.5.1417. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. MacIntyre D. E., Pearson J. D., Gordon J. L. Localisation and stimulation of prostacyclin production in vascular cells. Nature. 1978 Feb 9;271(5645):549–551. doi: 10.1038/271549a0. [DOI] [PubMed] [Google Scholar]
  16. Marcus A. J. Aspirin and thromboembolism--a possible dilemma. N Engl J Med. 1977 Dec 8;297(23):1284–1285. doi: 10.1056/NEJM197712082972312. [DOI] [PubMed] [Google Scholar]
  17. Moncada S. Eighth Gaddum Memorial Lecture. University of London Institute of Education, December 1980. Biological importance of prostacyclin. Br J Pharmacol. 1982 May;76(1):3–31. doi: 10.1111/j.1476-5381.1982.tb09186.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Moncada S., Gryglewski R., Bunting S., Vane J. R. An enzyme isolated from arteries transforms prostaglandin endoperoxides to an unstable substance that inhibits platelet aggregation. Nature. 1976 Oct 21;263(5579):663–665. doi: 10.1038/263663a0. [DOI] [PubMed] [Google Scholar]
  19. Nowak J., Murray J. J., Oates J. A., FitzGerald G. A. Biochemical evidence of a chronic abnormality in platelet and vascular function in healthy individuals who smoke cigarettes. Circulation. 1987 Jul;76(1):6–14. doi: 10.1161/01.cir.76.1.6. [DOI] [PubMed] [Google Scholar]
  20. Patrono C., Ciabattoni G., Pinca E., Pugliese F., Castrucci G., De Salvo A., Satta M. A., Peskar B. A. Low dose aspirin and inhibition of thromboxane B2 production in healthy subjects. Thromb Res. 1980 Feb 1;17(3-4):317–327. doi: 10.1016/0049-3848(80)90066-3. [DOI] [PubMed] [Google Scholar]
  21. Pedersen A. K., FitzGerald G. A. Dose-related kinetics of aspirin. Presystemic acetylation of platelet cyclooxygenase. N Engl J Med. 1984 Nov 8;311(19):1206–1211. doi: 10.1056/NEJM198411083111902. [DOI] [PubMed] [Google Scholar]
  22. Peto R., Gray R., Collins R., Wheatley K., Hennekens C., Jamrozik K., Warlow C., Hafner B., Thompson E., Norton S. Randomised trial of prophylactic daily aspirin in British male doctors. Br Med J (Clin Res Ed) 1988 Jan 30;296(6618):313–316. doi: 10.1136/bmj.296.6618.313. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Ritter J. M., Barrow S. E., Smith P. L., Taylor K. M., Dollery C. T. Predominance of locally-produced prostaglandin E2 over prostacyclin in skin incisions in man. Prostaglandins. 1987 Dec;34(6):867–875. doi: 10.1016/0090-6980(87)90067-0. [DOI] [PubMed] [Google Scholar]
  24. Ritter J. M., Farquhar C., Rodin A., Thom M. H. Low dose aspirin treatment in late pregnancy differentially inhibits cyclo-oxygenase in maternal platelets. Prostaglandins. 1987 Nov;34(5):717–722. doi: 10.1016/0090-6980(87)90294-2. [DOI] [PubMed] [Google Scholar]
  25. Roberts L. J., 2nd, Sweetman B. J., Oates J. A. Metabolism of thromboxane B2 in man. Identification of twenty urinary metabolites. J Biol Chem. 1981 Aug 25;256(16):8384–8393. [PubMed] [Google Scholar]
  26. Rosenkranz B., Fischer C., Meese C. O., Frölich J. C. Effects of salicylic and acetylsalicylic acid alone and in combination on platelet aggregation and prostanoid synthesis in man. Br J Clin Pharmacol. 1986 Mar;21(3):309–317. doi: 10.1111/j.1365-2125.1986.tb05195.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Rosenkranz B., Fischer C., Weimer K. E., Frölich J. C. Metabolism of prostacyclin and 6-keto-prostaglandin F1 alpha in man. J Biol Chem. 1980 Nov 10;255(21):10194–10198. [PubMed] [Google Scholar]
  28. Roth G. J., Majerus P. W. The mechanism of the effect of aspirin on human platelets. I. Acetylation of a particulate fraction protein. J Clin Invest. 1975 Sep;56(3):624–632. doi: 10.1172/JCI108132. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Seymour R. A., Rawlins M. D. Efficacy and pharmacokinetics of aspirin in post-operative dental pain. Br J Clin Pharmacol. 1982 Jun;13(6):807–810. doi: 10.1111/j.1365-2125.1982.tb01870.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Smith J. B., Willis A. L. Aspirin selectively inhibits prostaglandin production in human platelets. Nat New Biol. 1971 Jun 23;231(25):235–237. doi: 10.1038/newbio231235a0. [DOI] [PubMed] [Google Scholar]
  31. TRINDER P. Rapid determination of salicylate in biological fluids. Biochem J. 1954 Jun;57(2):301–303. doi: 10.1042/bj0570301. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Vane J. R. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nat New Biol. 1971 Jun 23;231(25):232–235. doi: 10.1038/newbio231232a0. [DOI] [PubMed] [Google Scholar]
  33. Vesterqvist O. Rapid recovery of in vivo prostacyclin formation after inhibition by aspirin. Evidence from measurements of the major urinary metabolite of prostacyclin by GC-MS. Eur J Clin Pharmacol. 1986;30(1):69–73. doi: 10.1007/BF00614198. [DOI] [PubMed] [Google Scholar]
  34. Warren J. B., Ritter J. M., Hickling N. E., Barrow S. E. Bradykinin-stimulated prostaglandin synthesis in conscious rabbits. Br J Pharmacol. 1987 Dec;92(4):895–900. doi: 10.1111/j.1476-5381.1987.tb11395.x. [DOI] [PMC free article] [PubMed] [Google Scholar]

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

RESOURCES