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. 1983;15(Suppl 1):133S–139S. doi: 10.1111/j.1365-2125.1983.tb02124.x

Beneficial effects of UK 37248, a thromboxane synthetase inhibitor, in experimental endotoxic shock in the rat

Perry V Halushka, James A Cook, W Curtis Wise
PMCID: PMC1427698  PMID: 6337604

Abstract

1 The effects of pretreatment with the thromboxane synthetase inhibitor UK 37248 (dazoxiben) administered 30 min before intravenous endotoxin (S. enteriditis) in the rat was investigated.

2 Plasma prostaglandins and thromboxanes were determined via radioimmunoassay. Endotoxaemia was associated with significant elevations above control values (<200 pg/ml) in plasma thromboxane B2 (TXB2), prostaglandin E (PGE) and 6-keto-prostaglandin F1α (6-keto-PGF1α). Within 30 min after endotoxin administration plasma immunoreactive (i) iTXB2 was 875±90pg/ml (n=9), iPGE was 1670±271 (n=9) and i6-keto-PGF1α was 1191±209 pg/ml (n=10). By 4 h plasma iTXB2 was 1743±328 pg/ml (n=5), iPGE was 2589±494 pg/ml (n=9) and i6-keto-PGF1α was 4251±984 pg/ml (n=10). UK 37248 pretreatment resulted in a significant (P<0.001) decrease in plasma iTXB2 at 30 min and 4 h to 193±28 pg/ml (n=5) and 421±57 pg/ml (n=5), respectively. Unexpectedly UK 37248 also significantly decreased plasma i6-keto PGF1α at 30 min and 4 h to 360±75 pg/ml (n=10) (P<0.005) and 1920±513 pg/ml (n=10) (P<0.05), respectively. iPGE plasma levels were not significantly changed in the UK 37248-pretreated rats 30 min (2210±370 pg/ml (n=9) or 4 h 3529±1093 pg/ml (n=13) after endotoxin compared to the vehicle-treated rats.

3 UK 37248 significantly (P<0.05) reduced the endotoxin mortality rate at 24 h from 69% (n=13) to 30% (n=13). UK 37248 also reduced splanchnic infarction from 90% (n=20) to 6% (n=16).

4 UK 37248 significantly improved the endotoxin-induced thrombocytopaenia, disseminated intravascular coagulation, hypoglycaemia and lysosomal labilization.

5 We conclude that UK 37248 provides significant beneficial effects in experimental endotoxic shock in the rat.

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Selected References

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

  1. Bartele V., Cerletti C., Schiepatti A., di Minno G., de Gaetano G. Inhibition of thromboxane synthetase does not necessarily prevent platelet aggregation. Lancet. 1981 May 9;1(8228):1057–1058. doi: 10.1016/s0140-6736(81)92224-8. [DOI] [PubMed] [Google Scholar]
  2. Brobmann G. F., Ulano H. B., Hinshaw L. B., Jacobson E. D. Mesenteric vascular responses to endotoxin in the monkey and dog. Am J Physiol. 1970 Nov;219(5):1464–1467. doi: 10.1152/ajplegacy.1970.219.5.1464. [DOI] [PubMed] [Google Scholar]
  3. Bult H., Beetens J., Herman A. G. Blood levels of 6-oxo-prostaglandin F 1 alpha during endotoxin-induced hypotension in rabbits. Eur J Pharmacol. 1980 Apr 11;63(1):47–56. doi: 10.1016/0014-2999(80)90115-6. [DOI] [PubMed] [Google Scholar]
  4. Bult H., Beetens J., Vercruysse P., Herman A. G. Blood levels of 6-keto-PGF1alpha, the stable metabolite of prostacyclin during endotoxin-induced hypotension. Arch Int Pharmacodyn Ther. 1978 Dec;236(2):285–286. [PubMed] [Google Scholar]
  5. 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]
  6. Coalson J. J., Benjamin B., Archer L. T., Beller B., Gilliam C. L., Taylor F. B., Hinshaw L. B. Prolonged shock in the baboon subjected to infusion of E. coli endotoxin. Circ Shock. 1978;5(4):423–437. [PubMed] [Google Scholar]
  7. Cook J. A., Wise W. C., Halushka P. V. Elevated thromboxane levels in the rat during endotoxic shock: protective effects of imidazole, 13-azaprostanoic acid, or essential fatty acid deficiency. J Clin Invest. 1980 Jan;65(1):227–230. doi: 10.1172/JCI109655. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Cook J. A., Wise W. C., Halushka P. V. Thromboxane A2 and prostacyclin production by lipopolysaccharide-stimulated peritoneal macrophages. J Reticuloendothel Soc. 1981 Nov;30(5):445–450. [PubMed] [Google Scholar]
  9. Cook J. A., Wise W. C., Knapp D. R., Halushka P. V. Essential fatty acid deficient rats: a new model for evaluating arachidonate metabolism in shock. Adv Shock Res. 1981;6:93–105. [PubMed] [Google Scholar]
  10. Demling R. H., Smith M., Gunther R., Flynn J. T., Gee M. H. Pulmonary injury and prostaglandin production during endotoxemia in conscious sheep. Am J Physiol. 1981 Mar;240(3):H348–H353. doi: 10.1152/ajpheart.1981.240.3.H348. [DOI] [PubMed] [Google Scholar]
  11. Fishman W. H., Kato K., Anstiss C. L., Green S. Human serum beta-glucuronidase; its measurement and some of its properties. Clin Chim Acta. 1967 Mar;15(3):435–447. doi: 10.1016/0009-8981(67)90008-3. [DOI] [PubMed] [Google Scholar]
  12. Fletcher J. R., Ramwell P. W. The effects of prostacyclin (PGI2) on endotoxin shock and endotoxin-induced platelet aggregation in dogs. Circ Shock. 1980;7(3):299–308. [PubMed] [Google Scholar]
  13. Frölich J. C., Ogletree M., Peskar B. A., Brigham K. L. Pulmonary hypertension correlated to pulmonary thromboxane synthesis. Adv Prostaglandin Thromboxane Res. 1980;7:745–750. [PubMed] [Google Scholar]
  14. Grimm L. J., Knapp D. R., Senator D., Halushka P. V. Inhibition of platelet thromboxane synthesis by 7-(1-imidazolyl) heptanoic acid: dissociation from inhibition of aggregation. Thromb Res. 1981 Nov 15;24(4):307–317. doi: 10.1016/0049-3848(81)90004-9. [DOI] [PubMed] [Google Scholar]
  15. Halushka P. V., Wise W. C., Cook J. A. Protective effects of aspirin in endotoxic shock. J Pharmacol Exp Ther. 1981 Aug;218(2):464–469. [PubMed] [Google Scholar]
  16. Harris R. H., Zmudka M., Maddox Y., Ramwell P. W., Fletcher J. R. Relationship of TXB2 and 6-keto PGF1 alpha to the hemodynamic changes during baboon endotoxic shock. Adv Prostaglandin Thromboxane Res. 1980;7:843–849. [PubMed] [Google Scholar]
  17. Hawiger J., Niewiarowski S., Gurewich V., Thomas D. P. Measurement of fibrinogen and fibrin degradation products in serum by staphylococcal clumping test. J Lab Clin Med. 1970 Jan;75(1):93–108. [PubMed] [Google Scholar]
  18. JANOFF A., WEISSMANN G., ZWEIOFACH B. W., THOMAS L. Pathogenesis of experimental shock. IV. Studies on lysosomes in normal and tolerant animals subjected to lethal trauma and endotoxemia. J Exp Med. 1962 Oct 1;116:451–466. doi: 10.1084/jem.116.4.451. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Krausz M. M., Utsunomiya T., Feuerstein G., Wolfe J. H., Shepro D., Hechtman H. B. Prostacyclin reversal of lethal endotoxemia in dogs. J Clin Invest. 1981 Apr;67(4):1118–1125. doi: 10.1172/JCI110125. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. LeDuc L. E., Needleman P. Regional localization of prostacyclin and thromboxane synthesis in dog stomach and intestinal tract. J Pharmacol Exp Ther. 1979 Oct;211(1):181–188. [PubMed] [Google Scholar]
  21. Lefer A. M., Tabas J., Smith E. F., 3rd Salutary effects of prostacyclin in endotoxic shock. Pharmacology. 1980;21(3):206–212. doi: 10.1159/000137434. [DOI] [PubMed] [Google Scholar]
  22. Moncada S., Bunting S., Mullane K., Thorogood P., Vane J. R., Raz A., Needleman P. Imidazole: a selective inhibitor of thromboxane synthetase. Prostaglandins. 1977 Apr;13(4):611–618. doi: 10.1016/0090-6980(77)90232-5. [DOI] [PubMed] [Google Scholar]
  23. Moncada S., Vane J. R. Pharmacology and endogenous roles of prostaglandin endoperoxides, thromboxane A2, and prostacyclin. Pharmacol Rev. 1978 Sep;30(3):293–331. [PubMed] [Google Scholar]
  24. Needleman P., Raz A., Ferrendelli J. A., Minkes M. Application of imidazole as a selective inhibitor thromboxane synthetase in human platelets. Proc Natl Acad Sci U S A. 1977 Apr;74(4):1716–1720. doi: 10.1073/pnas.74.4.1716. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Pennington D. G., Hyman A. L., Jaques W. E. Pulmonary vascular response to endotoxin in intact dogs. Surgery. 1973 Feb;73(2):246–255. [PubMed] [Google Scholar]
  26. Smith E. F., 3rd, Tabas J. H., Lefer A. M. Beneficial actions of imidazole in endotoxin shock. Prostaglandins Med. 1980 Apr;4(4):215–225. doi: 10.1016/0161-4630(80)90016-6. [DOI] [PubMed] [Google Scholar]
  27. Vermylen J., Defreyn G., Carreras L. O., Machin S. J., Van Schaeren J., Verstraete M. Thromboxane synthetase inhibition as antithrombotic strategy. Lancet. 1981 May 16;1(8229):1073–1075. doi: 10.1016/s0140-6736(81)92241-8. [DOI] [PubMed] [Google Scholar]
  28. Wise W. C., Cook J. A., Eller T., Halushka P. V. Ibuprofen improves survival from endotoxic shock in the rat. J Pharmacol Exp Ther. 1980 Oct;215(1):160–164. [PubMed] [Google Scholar]
  29. Wise W. C., Cook J. A., Halushka P. V., Knapp D. R. Protective effects of thromboxane synthetase inhibitors in rats in endotoxic shock. Circ Res. 1980 Jun;46(6):854–859. doi: 10.1161/01.res.46.6.854. [DOI] [PubMed] [Google Scholar]

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