Skip to main content
NCBI home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1990 Oct;86(4):1095–1102. doi: 10.1172/JCI114813

Endogenous prostaglandin endoperoxides and prostacyclin modulate the thrombolytic activity of tissue plasminogen activator. Effects of simultaneous inhibition of thromboxane A2 synthase and blockade of thromboxane A2/prostaglandin H2 receptors in a canine model of coronary thrombosis.

P Golino 1, M Rosolowsky 1, S K Yao 1, J McNatt 1, F De Clerck 1, L M Buja 1, J T Willerson 1
PMCID: PMC296837  PMID: 2145320

Abstract

We tested the hypothesis that simultaneous inhibition of TxA2 synthase and blockade of TxA2/PHG2 receptors is more effective in enhancing thrombolysis and preventing reocclusion after discontinuation of tissue plasminogen activator (t-PA) than either intervention alone. Coronary thrombosis was induced in 35 dogs by placing a copper coil into the left anterior descending coronary artery. Coronary flow was measured with a Doppler flow probe. 30 min after thrombus formation, the animals received saline (controls, n = 10); SQ 29548 (0.4 mg/kg bolus + 0.4 mg/kg per h infusion), a TxA2/PGH2 receptor antagonist (n = 8); dazoxiben (5 mg/kg bolus + 5 mg/kg per h infusion), a TxA2 synthase inhibitor (n = 9); or R 68070 (5 mg/kg bolus + 5 mg/kg per h infusion), a drug that blocks TxA2/PGH2 receptors and inhibits TxA2 synthase (n = 8). Then, all dogs received heparin (200 U/kg) and a bolus of t-PA (80 micrograms/kg) followed by a continuous infusion (8 micrograms/kg per min) for up to 90 min or until reperfusion was achieved. The time to thrombolysis did not change significantly in SQ 29548-treated dogs as compared with controls (42 +/- 5 vs. 56 +/- 7 min, respectively, P = NS), but it was significantly shortened by R 68070 and dazoxiben (11 +/- 2 and 25 +/- 6 min, respectively, P less than 0.001 vs. controls and SQ 29548-treated dogs). R 68070 administration resulted in a lysis time significantly shorter than that observed in the dazoxiben-treated group (P less than 0.01). Reocclusion was observed in eight of eight control dogs, five of seven SQ 29548-treated dogs, seven of nine dazoxiben-treated dogs, and zero of eight R 68070-treated animals (P less than 0.001). TxB2 and 6-keto-PGF1 alpha, measured in blood samples obtained from the coronary artery distal to the thrombus, were significantly increased at reperfusion and at reocclusion in control animals and in dogs receiving SQ 29548. R 68070 and dazoxiben prevented the increase in plasma TxB2 levels, whereas 6-keto-PGF1 alpha levels were significantly increased with respect to control and SQ 29548-treated dogs. Thus, simultaneous inhibition of TxA2 synthase and blockade of TxA2/PGH2 receptors is more effective than either intervention alone in this experimental model in enhancing thrombolysis and preventing reocclusion after t-PA administration.

Full text

PDF
1095

Images in this article

1097Image
on p.1097
1098Image
on p.1098
1098Image
on p.1098
1099Image
on p.1099
1099Image
on p.1099
1099Image
on p.1099

Selected References

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

  1. Aiken J. W., Shebuski R. J., Miller O. V., Gorman R. R. Endogenous prostacyclin contributes to the efficacy of a thromboxane synthetase inhibitor for preventing coronary artery thrombosis. J Pharmacol Exp Ther. 1981 Nov;219(2):299–308. [PubMed] [Google Scholar]
  2. Bertelé V., Falanga A., Tomasiak M., Cerletti C., de Gaetano G. SQ 22536, an adenylate-cyclase inhibitor, prevents the antiplatelet effect of dazoxiben, a thromboxane-synthetase inhibitor. Thromb Haemost. 1984 Feb 28;51(1):125–128. [PubMed] [Google Scholar]
  3. Bunting S., Gryglewski R., Moncada S., Vane J. R. Arterial walls generate from prostaglandin endoperoxides a substance (prostaglandin X) which relaxes strips of mesenteric and coeliac ateries and inhibits platelet aggregation. Prostaglandins. 1976 Dec;12(6):897–913. doi: 10.1016/0090-6980(76)90125-8. [DOI] [PubMed] [Google Scholar]
  4. Campbell W. B., Holland O. B., Adams B. V., Gomez-Sanchez C. E. Urinary excretion of prostaglandin E2, prostaglandin F2 alpha, and thromboxane B2 in normotensive and hypertensive subjects on varying sodium intakes. Hypertension. 1982 Sep-Oct;4(5):735–741. doi: 10.1161/01.hyp.4.5.735. [DOI] [PubMed] [Google Scholar]
  5. Cercek B., Lew A. S., Hod H., Yano J., Reddy N. K., Ganz W. Enhancement of thrombolysis with tissue-type plasminogen activator by pretreatment with heparin. Circulation. 1986 Sep;74(3):583–587. doi: 10.1161/01.cir.74.3.583. [DOI] [PubMed] [Google Scholar]
  6. Collen D., Topol E. J., Tiefenbrunn A. J., Gold H. K., Weisfeldt M. L., Sobel B. E., Leinbach R. C., Brinker J. A., Ludbrook P. A., Yasuda I. Coronary thrombolysis with recombinant human tissue-type plasminogen activator: a prospective, randomized, placebo-controlled trial. Circulation. 1984 Dec;70(6):1012–1017. doi: 10.1161/01.cir.70.6.1012. [DOI] [PubMed] [Google Scholar]
  7. De Clerck F., Beetens J., Van de Water A., Vercammen E., Janssen P. A. R 68 070: thromboxane A2 synthetase inhibition and thromboxane A2/prostaglandin endoperoxide receptor blockade combined in one molecule--II. Pharmacological effects in vivo and ex vivo. Thromb Haemost. 1989 Feb 28;61(1):43–49. [PubMed] [Google Scholar]
  8. De Clerck F., Beetens J., de Chaffoy de Courcelles D., Freyne E., Janssen P. A. R 68 070: thromboxane A2 synthetase inhibition and thromboxane A2/prostaglandin endoperoxide receptor blockade combined in one molecule--I. Biochemical profile in vitro. Thromb Haemost. 1989 Feb 28;61(1):35–42. [PubMed] [Google Scholar]
  9. Dray F., Charbonnel B., Maclouf J. Radioimmunoassay of prostaglandins Falpha, E1 and E2 in human plasma. Eur J Clin Invest. 1975 Jul 29;5(4):311–318. doi: 10.1111/j.1365-2362.1975.tb00459.x. [DOI] [PubMed] [Google Scholar]
  10. Fischer S., Struppler M., Böhlig B., Bernutz C., Wober W., Weber P. C. The influence of selective thromboxane synthetase inhibition with a novel imidazole derivative, UK-38,485, on prostanoid formation in man. Circulation. 1983 Oct;68(4):821–826. doi: 10.1161/01.cir.68.4.821. [DOI] [PubMed] [Google Scholar]
  11. FitzGerald G. A., Brash A. R., Oates J. A., Pedersen A. K. Endogenous prostacyclin biosynthesis and platelet function during selective inhibition of thromboxane synthase in man. J Clin Invest. 1983 Oct;72(4):1336–1343. doi: 10.1172/JCI111089. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. FitzGerald G. A., Reilly I. A., Pedersen A. K. The biochemical pharmacology of thromboxane synthase inhibition in man. Circulation. 1985 Dec;72(6):1194–1201. doi: 10.1161/01.cir.72.6.1194. [DOI] [PubMed] [Google Scholar]
  13. Fitzgerald D. J., Fragetta J., FitzGerald G. A. Prostaglandin endoperoxides modulate the response to thromboxane synthase inhibition during coronary thrombosis. J Clin Invest. 1988 Nov;82(5):1708–1713. doi: 10.1172/JCI113784. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Gold H. K., Coller B. S., Yasuda T., Saito T., Fallon J. T., Guerrero J. L., Leinbach R. C., Ziskind A. A., Collen D. Rapid and sustained coronary artery recanalization with combined bolus injection of recombinant tissue-type plasminogen activator and monoclonal antiplatelet GPIIb/IIIa antibody in a canine preparation. Circulation. 1988 Mar;77(3):670–677. doi: 10.1161/01.cir.77.3.670. [DOI] [PubMed] [Google Scholar]
  15. Golino P., Ashton J. H., Glas-Greenwalt P., McNatt J., Buja L. M., Willerson J. T. Mediation of reocclusion by thromboxane A2 and serotonin after thrombolysis with tissue-type plasminogen activator in a canine preparation of coronary thrombosis. Circulation. 1988 Mar;77(3):678–684. doi: 10.1161/01.cir.77.3.678. [DOI] [PubMed] [Google Scholar]
  16. Golino P., Ashton J. H., McNatt J., Glas-Greenwalt P., Yao S. K., O'Brien R. A., Buja L. M., Willerson J. T. Simultaneous administration of thromboxane A2- and serotonin S2-receptor antagonists markedly enhances thrombolysis and prevents or delays reocclusion after tissue-type plasminogen activator in a canine model of coronary thrombosis. Circulation. 1989 Apr;79(4):911–919. doi: 10.1161/01.cir.79.4.911. [DOI] [PubMed] [Google Scholar]
  17. Granström E., Diczfalusy U., Hamberg M., Hansson G., Malmsten C., Samuelsson B. Thromboxane a2: biosynthesis and effects on platelets. Adv Prostaglandin Thromboxane Leukot Res. 1982;10:15–58. [PubMed] [Google Scholar]
  18. 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]
  19. Hamberg M., Svensson J., Wakabayashi T., Samuelsson B. Isolation and structure of two prostaglandin endoperoxides that cause platelet aggregation. Proc Natl Acad Sci U S A. 1974 Feb;71(2):345–349. doi: 10.1073/pnas.71.2.345. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Hanson S. R., Paxton L. D., Harker L. A. Iliac artery mural thrombus formation. Effect of antiplatelet therapy on 111In-platelet deposition in baboons. Arteriosclerosis. 1986 Sep-Oct;6(5):511–518. doi: 10.1161/01.atv.6.5.511. [DOI] [PubMed] [Google Scholar]
  21. Hantgan R. R., Taylor R. G., Lewis J. C. Platelets interact with fibrin only after activation. Blood. 1985 Jun;65(6):1299–1311. [PubMed] [Google Scholar]
  22. Harfenist E. J., Packham M. A., Mustard J. F. Comparison of the interactions of fibrinogen and soluble fibrin with washed rabbit platelets stimulated with ADP. Thromb Haemost. 1985 Apr 22;53(2):183–187. [PubMed] [Google Scholar]
  23. Marcus A. J., Weksler B. B., Jaffe E. A., Broekman M. J. Synthesis of prostacyclin from platelet-derived endoperoxides by cultured human endothelial cells. J Clin Invest. 1980 Nov;66(5):979–986. doi: 10.1172/JCI109967. [DOI] [PMC free article] [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. Patscheke H. Thromboxane synthase inhibition potentiates washed platelet activation by endogenous and exogenous arachidonic acid. Biochem Pharmacol. 1985 Apr 15;34(8):1151–1156. doi: 10.1016/0006-2952(85)90488-5. [DOI] [PubMed] [Google Scholar]
  26. Salimi A., Oliver G. C., Jr, Lee J., Sherman L. A. Continued incorporation of circulating radiolabeled fibrinogen into preformed coronary artery thrombi. Circulation. 1977 Aug;56(2):213–217. doi: 10.1161/01.cir.56.2.213. [DOI] [PubMed] [Google Scholar]
  27. Schafer A. I., Crawford D. D., Gimbrone M. A., Jr Unidirectional transfer of prostaglandin endoperoxides between platelets and endothelial cells. J Clin Invest. 1984 Apr;73(4):1105–1112. doi: 10.1172/JCI111296. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Sheehan F. H., Braunwald E., Canner P., Dodge H. T., Gore J., Van Natta P., Passamani E. R., Williams D. O., Zaret B. The effect of intravenous thrombolytic therapy on left ventricular function: a report on tissue-type plasminogen activator and streptokinase from the Thrombolysis in Myocardial Infarction (TIMI Phase I) trial. Circulation. 1987 Apr;75(4):817–829. doi: 10.1161/01.cir.75.4.817. [DOI] [PubMed] [Google Scholar]
  29. Verstraete M., Bernard R., Bory M., Brower R. W., Collen D., de Bono D. P., Erbel R., Huhmann W., Lennane R. J., Lubsen J. Randomised trial of intravenous recombinant tissue-type plasminogen activator versus intravenous streptokinase in acute myocardial infarction. Report from the European Cooperative Study Group for Recombinant Tissue-type Plasminogen Activator. Lancet. 1985 Apr 13;1(8433):842–847. doi: 10.1016/s0140-6736(85)92208-1. [DOI] [PubMed] [Google Scholar]
  30. Verstraete M., Bleifeld W., Brower R. W., Charbonnier B., Collen D., de Bono D. P., Dunning A. J., Lennane R. J., Lubsen J., Mathey D. G. Double-blind randomised trial of intravenous tissue-type plasminogen activator versus placebo in acute myocardial infarction. Lancet. 1985 Nov 2;2(8462):965–969. doi: 10.1016/s0140-6736(85)90523-9. [DOI] [PubMed] [Google Scholar]
  31. Willerson J. T., Golino P., Eidt J., Campbell W. B., Buja L. M. Specific platelet mediators and unstable coronary artery lesions. Experimental evidence and potential clinical implications. Circulation. 1989 Jul;80(1):198–205. doi: 10.1161/01.cir.80.1.198. [DOI] [PubMed] [Google Scholar]
  32. Williams D. O., Borer J., Braunwald E., Chesebro J. H., Cohen L. S., Dalen J., Dodge H. T., Francis C. K., Knatterud G., Ludbrook P. Intravenous recombinant tissue-type plasminogen activator in patients with acute myocardial infarction: a report from the NHLBI thrombolysis in myocardial infarction trial. Circulation. 1986 Feb;73(2):338–346. doi: 10.1161/01.cir.73.2.338. [DOI] [PubMed] [Google Scholar]
  33. Yasuda T., Gold H. K., Fallon J. T., Leinbach R. C., Guerrero J. L., Scudder L. E., Kanke M., Shealy D., Ross M. J., Collen D. Monoclonal antibody against the platelet glycoprotein (GP) IIb/IIIa receptor prevents coronary artery reocclusion after reperfusion with recombinant tissue-type plasminogen activator in dogs. J Clin Invest. 1988 Apr;81(4):1284–1291. doi: 10.1172/JCI113446. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES