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Suppression of prostanoid formation and regulation of peripheral circulation after surgery using thrombin inhibitor (MD805)

Surgery Today volume 28, pages 618–625 (1998)Cite this article

Abstract

We studied the effects of thrombin generation due to surgical stress on prostanoid formation and peripheral circulation in anesthetized dogs. Three experimental groups were used, consisting of a control group (group 1), a thoracotomized group (group 2), and a thoracotomized group treated with thrombin inhibitor (MD805: a synthetic arginine derivative) (group 3). The plasma concentrations of thrombin-antithrombin III complex (TAT) and prostanoids were measured along with the hemodynamic parameters. The plasma concentrations of TAT and thromboxane B2 significantly increased 1h after a thoracotomy in group 2. However, neither concentration increased after a thoracotomy in group 3. The flow ratio of the brachial and femoral arteries to cardiac output significantly decreased 1h after a thoracotomy in group 2. This study indicates that thromboxane A2 was thus synthesized by the stimulation of endogenous thrombin, while it also reduced the peripheral blood flow after surgery.

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References

  1. Garcia-Szabo RR, Peterson MB, Watkins WD, Bizios R, Kong DL, Malik AB (1983) Thromboxane generation after thrombin. Protective effect of thromboxane synthetase inhibition on lung fluid balance. Circ Res 53:214–222

    PubMed  CAS  Google Scholar 

  2. LeRoy EC, Ager A, Gordon JL (1984) Effects of neutrophil elastase and other proteases on porcine aortic endothelial prostaglandin I2 production, adenine nucleotide release, and responses to vasoactive agents. J Clin Invest 74:1003–1010

    PubMed  Article  CAS  Google Scholar 

  3. Torres-Duarte A, Amezcua JL (1991) Thromboxane and prostacyclin generation by human umbilical veins after thrombin. Prostaglandins 42:571–578

    PubMed  Article  CAS  Google Scholar 

  4. Yang Z, Arnet U, Bauer E, von Segesser L, Siebenmann R, Turina M, Luscher TF (1994) Thrombin-induced endotheliumdependent inhibition and direct activation of platelet-vessel wall interaction. Role of prostacyclin, nitric oxide, and thromboxane A2. Circulation 89:2266–2272

    PubMed  CAS  Google Scholar 

  5. Marsen TA, Simonson MS, Dunn MJ (1995) Thrombin induces the preproendothelin-1 gene in endothelial cells by a protein tyrosine kinase-linked mechanism. Circ Res 76:987–995

    PubMed  CAS  Google Scholar 

  6. Fujikawa H, Kawasaki K, Sekiguchi H, Mito H, Hayashi Y, Funayama H, Shimada K (1996) Endothelin-1 production in coronary circulation in a new canine model of coronary thrombosis. Cardiovasc Res 32:604–612

    PubMed  CAS  Google Scholar 

  7. Beving H, Zhao C, Albage A, Ivert T (1996) Abnormally high platelet activity after discontinuation of acetylsalicylic acid treatment. Blood Coagul Fibrinolysis 7:80–84

    PubMed  Article  CAS  Google Scholar 

  8. Yokoyama I, Kobayashi T, Negita M, Hayashi S, Yasutomi M, Katayama A, Uchida K, Takagi H (1996) Liberation of vasoactive substances and its prevention with thromboxane A2 synthase inhibitor in pig liver transplantation. Transplant Int 9:76–81

    CAS  Google Scholar 

  9. Isozaki H, Okajima K, Hara H, Kobayashi M (1994) The protective effect of thromboxane A2 synthetase inhibitor against ischemic liver injury. Surg Today 24:435–440

    PubMed  Article  CAS  Google Scholar 

  10. Zaugg CE, Hornstein PS, Zhu P, Simper D, Luscher TF, Allegrini PR, Buser PT (1996) Endothelin-1-induced release of thromboxane A2 increases the vasoconstrictor effect of endothelin-1 in postischemic reperfused rat hearts. Circulation 94:742–747

    PubMed  CAS  Google Scholar 

  11. Onizuka M, Miyauchi T, Mitsui K, Suzuki N, Masaki T, Goto K, Hori M (1992) Endothelin-1 mediates regional blood flow during and after pulmonary operations. J Thorac Cardiovasc Surg 104: 1696–1701

    PubMed  CAS  Google Scholar 

  12. Onizuka M, Miyauchi T, Mitsui K, Suzuki N, Ueno H, Goto K, Masaki T, Hori M (1993) Plasma levels of endothelin-1 and thrombin-antithrombin III complex in patients undergoing openchest surgery. J Thorac Cardiovasc Surg 105:559–560

    PubMed  CAS  Google Scholar 

  13. Okamoto S, Hijikata A, Kikumoto R, Tonomura S, Hara H, Ninomiya K, Maruyama A, Sugano M, Tamao Y (1981) Potent inhibition of thrombin by the newly synthesized arginine derivative No. 805. The importance of stereo-structure of its hydrophobic carboxamide portion. Biochem Biophys Res Commun 101:440–446

    PubMed  Article  CAS  Google Scholar 

  14. Nakamura K, Hatano Y, Mori K (1985) Thrombin-induced vasoconstriction in isolated cerebral arteries and the influence of a synthetic thrombin inhibitor. Thromb Res 40:715–720

    PubMed  Article  CAS  Google Scholar 

  15. Powell WS (1980) Rapid extraction of oxygenated metabolites of arachidonic acid from biological samples using octadecylsilyl silica. Prostaglandins 20:947–957

    PubMed  Article  CAS  Google Scholar 

  16. Pelzer H, Schwarz A, Heimburger N (1988) Determination of human thrombin-antithrombin III complex in plasma with an enzyme-linked immunosorbent assay. Thromb Haemostas 59: 101–106

    CAS  Google Scholar 

  17. Snedecor GW, Cochran WG (1989) Statistical Methods, 8th edn. Iowa State University Press, Ames, IA, pp 215–237

    Google Scholar 

  18. Callas DD, Hoppensteadt D, Fareed J (1995) Comparative studies on the anticoagulant and protease generation inhibitory actions of newly developed site-directed thrombin inhibitory durgs. Efegatran, argatroban, hirulog, and hirudin. Semin Thromb Hemostas 21:177–183

    Article  CAS  Google Scholar 

  19. Hijikata-Okunomiya A, Okamoto S, Wanaka K (1990) Effect of a synthetic thrombin-inhibitor MD805 on the reaction between thrombin and plasma antithrombin-III. Thromb Res 59:967–977

    PubMed  Article  CAS  Google Scholar 

  20. Vu TKH, Hung DT, Wheaton VI, Coughlin SR (1991) Molecular cloning of a functional thrombin receptor reveals a novel proteolytic mechanism of receptor activation. Cell 64:1057–1068

    PubMed  Article  CAS  Google Scholar 

  21. Ngaiza JR, Jaffe EA (1991) A 14 amino acid peptide derived from the amino terminus of the cleaved thrombin receptor elevates intracellular calcium and stimulates prostacyclin production in human endothelial cells. Biochem Biophys Res Commun 179:1656–1661

    PubMed  Article  CAS  Google Scholar 

  22. Jakschik BA, Marshall GR, Kourik JL, Needleman P (1974) Profile of circulating vasoactive substances in hemorrhagic shock and their pharmacologic manipulation. J Clin Invest 54:842–852

    PubMed  Article  CAS  Google Scholar 

  23. Halter JB, Pflug AE, Porte D Jr (1977) Mechanism of plasma catecholamine increases during surgical stress in man. J Clin Endocrinol Metab 45:936–944

    PubMed  Article  CAS  Google Scholar 

  24. Cox RH, Bagshaw RJ (1980) Effects of anesthesia on carotid sinus reflex control of arterial hemodynamics in the dog. Am J Physiol 239(Heart Circ Physiol 8):H681-H691

    PubMed  CAS  Google Scholar 

  25. Moncada S, Vane JR (1978) Pharmacology and endogenous roles of prostaglandin endoperoxides, thromboxane A2, and prostacyclin. Pharmacol Rev 30:293–331

    PubMed  CAS  Google Scholar 

  26. Kadowitz PJ, Chapnick BM, Feigen LP, Hyman AL, Nelson PK, Spannhake EW (1978) Pulmonary and systemic vasodilator effects of the newly discovered prostaglandin, PGI2. J Appl Physiol 45:408–413

    PubMed  CAS  Google Scholar 

  27. Gillis C, Bengtsson L, Wilman B, Haegerstrand A (1996) Secretion of prostacyclin, tissue plasminogen activator and its inhibitor by cultured adult human endothelial cells grown on different matrices. Eur J Vasc Endovasc Surg 11:127–133

    PubMed  Article  CAS  Google Scholar 

  28. Cryer HG, Garrison RN, Harris PD, Greenwald BH, Alsip NL (1990) Prostaglandins mediate skeletal muscle arteriole dilation in hyperdynamic bacteremia. Am J Physiol 259(Heart Circ Physiol 28):H728-H734

    PubMed  CAS  Google Scholar 

  29. Gosche JR, Garrison RN (1991) Prostaglandins mediate the compensatory responses to hemorrhage in the small intestine of the rat. J Surg Res 50:584–588

    PubMed  Article  CAS  Google Scholar 

  30. Dusting GJ, Moncada S, Vane JR (1978) Vascular actions of arachidonic acid and its metabolites in perfused mesenteric and femoral beds of the dog. Eur J Pharmacol 49:65–72

    PubMed  Article  CAS  Google Scholar 

  31. De Mey JG, Claeys M, Vanhoutte PM (1982) Endotheliumdependent inhibitory effects of acetylcholine, adenosine triphosphate, thrombin and arachidonic acid in the canine femoral artery. J Pharmacol Ther 222:166–173

    Google Scholar 

  32. Butler MJ, Britton BJ, Wood WG, Mainwaring-Burton R, Irving MH (1977) Plasma catecholamine concentrations during operation. Br J Surg 64:786–790

    PubMed  Article  CAS  Google Scholar 

  33. Wada Y, Zaima M, Mori K, Egawa H, Higashiyama H, Iwata S, Kagawa R, Kataoka M, Ozawa K (1995) Effect of gabexate mesilate on thrombin and plasmin generation after hepatic resection in cirrhotic patients. Eur Surg Res 27:57–62

    PubMed  Article  CAS  Google Scholar 

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Affiliations

  1. Department of Surgery, Institute of Clinical Medicine, University of Tsukuba, 305, Tsukuba, Ibaraki, Japan

    Masataka Onizuka, Shigemi Ishikawa, Osamu Ishibashi, Michiharu Suga, Kiyofumi Mitsui & Toshio Mitsui

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  1. Masataka Onizuka
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  2. Shigemi Ishikawa
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  3. Osamu Ishibashi
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  4. Michiharu Suga
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  5. Kiyofumi Mitsui
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  6. Toshio Mitsui
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Onizuka, M., Ishikawa, S., Ishibashi, O. et al. Suppression of prostanoid formation and regulation of peripheral circulation after surgery using thrombin inhibitor (MD805). Surg Today 28, 618–625 (1998). https://doi.org/10.1007/s005950050194

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  • DOI: https://doi.org/10.1007/s005950050194

Key Words

  • endogenous thrombin
  • prostanoids
  • peripheral circulation
  • surgical stress
  • hemodynamics