Advertisement

Sources of Increased in vivo Cyclooxygenase Product Release Following Whole-Body Irradiation of Rats

  • M. J. Schneidkraut
  • P. A. Kot
  • P. W. Ramwell

Abstract

Ionizing radiation alters cyclooxygenase product synthesis in a time- and dose-related manner. Rats exposed to 10 or 20 Gy whole-body gamma radiation showed a significant increase (p <.05) in urine immunoreactive thromboxane B2 (iTXB2) 4-120 hours after 10 Gy as well as 4 and 12 hours after 20 Gy exposure. Irradiation with 2 Gy had no effect. The source(s) of this radiation-induced increase in iTXB2 excretion was studied by regional shielding. Rats were anesthetized and exposed to sham radiation, 15 Gy whole-body radiation, or a dose of 20 Gy radiation with either the abdomen or thorax shielded. Four hours after exposure, the animals were re-anesthetized and urine samples collected. Unshielded animals exposed to a 15 Gy dose of radiation showed a 2.5-fold (p <.05) increase in iTXB2 excretion. Abdominal shielding attenuated the radiation-induced increase in iTXB2 excretion by 41%, but thoracic shielding prevented the increase in iTXB2 excretion. Thus, the thoracic organs are an important source of the radiation-induced increase in iTXB2 excretion, and the abdominal organs may also contribute to the increased in vivo release of iTXB2. In the next series of experiments, the individual contribution of the kidneys and lungs to the increased excretion of cyclooxygenase products was studied. Rats were subjected to 20 Gy whole-body radiation and 4 hours after exposure, either the kidneys or lungs were isolated and perfused with a cell-free medium. Radiation did not alter urine acidification by the isolated perfused kidney. However, the concentration of urine from irradiated kidneys was 18.3% (p <.05) less than urine from control kidneys. Whole-body gamma radiation also elicited a 2.2-fold (p <.05) and 3.6-fold (p <.05) increase in the excretion of iPGE2 and 6-keto prostaglandin F (i6KPGF) from isolated perfused kidneys. The excretion rate of iTXB2 from perfused kidneys after irradiation was not significantly different from sham-irradiated controls. On the other hand, isolated perfused rat lungs released 100% (p <.05) more iTXB2 following irradiation than lungs from sham-irradiated animals. The release of i6KPGF was also significantly elevated. These studies showed a regional release of cyclooxygenase products following irradiation. The elevated excretion rate of iTXB2 appears to be primarily due to an increased pulmonary release of this arachidonate metabolite.

Keywords

Arachidonic Acid Release Perfuse Kidney Cyclooxygenase Product Sham Radiation Follow Radiation Exposure 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Armstrong, J. M., Boura, A. L. A., Hamberg, M., and Samuelsson, B. A comparison of the vasodepressor effects of the cyclic endoperoxides PGG2 and PGH2 with those of PGD2 and PGE2 in hypertensive and normotensive rats. Eur. J. Pharmacol. 39: 251–258, 1976.PubMedCrossRefGoogle Scholar
  2. 2.
    Angerio, A. D., Fitzpatrick, T. M., Kot, P. A., Ramwell, P. W., and Rose, J. C. Effect of verapamil on the pulmonary vasoconstrictor action of prostaglandin F2ケ and a synthetic PGH2 analogue. Brit. J. Pharmacol. 73: 101–103, 1981.Google Scholar
  3. 3.
    Charo, I. F., Feinmann, R. D., Detwiler, T. C., Smith, J. B., Ingerman, C. M., and Silver, M. J. Prostaglandin endoperoxides and thromboxane A2 an induce platelet aggregation in the absence of secretion. Nature 269: 66–69, 1977.PubMedCrossRefGoogle Scholar
  4. 4.
    Cowan, D. H. Platelet adherence to collagen: Role of prostaglandin-thromboxane synthesis. Brit. J. Haematol. 49: 425–434, 1981.CrossRefGoogle Scholar
  5. 5.
    Dusting, G. J., Chappie, D. J., Hughes, R., Moncada, S., and Vane, J. R. Prostacyclin (PGI2) induces coronary vasodilatation in anaesthetized dogs. Cardiovasc. Res. 12: 720–730, 1978.PubMedCrossRefGoogle Scholar
  6. 6.
    Dusting, G. J., Moncada, S., and Vane, J. R. Vascular actions of arachidonic acid and its metabolites in perfused mesenteric and femoral beds of the dog. Eur. J. Pharmacol. 49: 65–72, 1978.PubMedCrossRefGoogle Scholar
  7. 7.
    Ellis, E. F., Nies, A. S., and Oates, J. A. Cerebral arterial smooth muscle contraction by thromboxane A2. Stroke 8: 480–483, 1977.PubMedCrossRefGoogle Scholar
  8. 8.
    Ellis, E. F., Oelz, O., Roberts, L. J., II, Payne, N. A., Sweetman, B. J., Nies, A. S., and Oates, J. A. Coronary arterial smooth muscle contraction by a substance released from platelets: Evidence that it is thromboxane A2. Science 193: 1135–1137,1976.Google Scholar
  9. 9.
    Fletcher, J. R., and Ramwell, P. W. Hemodynamic evaluation of prostaglandin D2 in the conscious baboon. Adv. Prostaglandin Thromboxane Res. 7: 723–725, 1980.PubMedGoogle Scholar
  10. 10.
    Hamberg, M., Svensson, J., and Samuelsson, B. Thromboxanes: A new group of biologically active compounds derived from prostaglandin endoperoxides. Proc. Natl. Acad. Sci. USA 72: 2994–2998, 1975.PubMedCrossRefGoogle Scholar
  11. 11.
    Kot, P. A., Johnson, M., Ramwell, P. W., and Rose, J. C. Effects of ganglionic and β-adrenergic blockade on cardiovascular responses to the bisenoic prostaglandins and their precursor arachidonic acid. Proc. Soc. Exp. Biol. Med. 149: 953–957, 1975.PubMedGoogle Scholar
  12. 12.
    Rose, J. C., Johnson, M., Ramwell, P. W., and Kot, P. A. Effects of arachidonic acid on systemic arterial blood pressure, myocardial contractility and platelets in the dog. Proc. Soc. Exp. Biol. Med. 147: 652–655, 1974.PubMedGoogle Scholar
  13. 13.
    Rose, J. C., Kot, P. A., Ramwell, P. W., Doykos, M., and O’Neill, W. P. Cardiovascular responses to the prostaglandin endoperoxide analogs in the dog. Proc. Soc. Exp. Biol. Med. 153: 209–212, 1976.PubMedGoogle Scholar
  14. 14.
    Petakau, A. Radiation carcinogenesis from a membrane perspective. Acta Physiol. Scand. Suppl. 492: 81–90, 1980.Google Scholar
  15. 15.
    Hemler, M. E., Cook, H. W., and Lands, W. E. M. Prostaglandin biosynthesis can be triggered by lipid peroxides. Arch. Biochem. Biophys. 193: 340–345, 1979.PubMedCrossRefGoogle Scholar
  16. 16.
    Egan, R. W., Paxton, J., and Kuehl, F. A., Jr. Mechanism for irreversible self-destruction of prostaglandin synthetase. J. Biol. Chem. 251: 7329–7335, 1976.PubMedGoogle Scholar
  17. 17.
    Seregi, A., Serfozo, P., and Mergl, Z. Evidence for the localization of hydrogen peroxide-stimulated cyclooxygenase activity in rat brain mitochondria: A possible coupling with monoamine oxidase. J. Neurochem. 40: 407–413, 1983.PubMedCrossRefGoogle Scholar
  18. 18.
    Taylor, L., Menconi, M. J., and Polgar, P. The participation of hydroperoxides and oxygen radicals in the control of prostaglandin synthesis. J. Biol. Chem. 258: 6855–6857, 1983.PubMedGoogle Scholar
  19. 19.
    Eisen, V., and Walker, D. I. Effect of ionizing radiation on prostaglandin-like activity in tissues. Brit. J. Pharmacol. 57: 527–532, 1976.Google Scholar
  20. 20.
    Pausescu, E. J., Teodosiu, T., and Chirvasie, R. Effects of total exposure to 60Co gamma radiation on cerebral nicotinamide nucleotides and glutathione in dogs. Radiat. Res. 51: 302–309, 1972.PubMedCrossRefGoogle Scholar
  21. 21.
    Nikandrova, T. I., Zhulanova, Z. I., and Romanstev, E. F. Prostaglandinsynthetase activity in the liver, brain, and testis of gamma irradiated Fl (CBA X C57 B1) mice. Radiobiologiia 21: 265–269, 1981.PubMedGoogle Scholar
  22. 22.
    Romantsev, E. F., Zhulanova, Z. I., and Nikandrova, T. I. Prostaglandinsynthetase activity of brain tissues in experimental animals with radiation sickness. Vestn. Akad. Med. Nauk. SSSR. 9: 86–89, 1982.Google Scholar
  23. 23.
    Trocha, P. J., and Catravas, G. N. Prostaglandins, lysosomes, and radiation injury. Adv. Prostaglandins Thromboxane Res. 7: 851–856, 1980.Google Scholar
  24. 24.
    Maclouf, J., Bernard, P., Rigaud, M., Rocquet, G., and Breton, J. C. Alteration of arachidonic acid metabolism with spleen microsomes of irradiated rats. Biochem. Biophys. Res. Comm. 79: 585–591, 1977.PubMedCrossRefGoogle Scholar
  25. 25.
    Steel, L. K., and Catravas, G. N. Radiation-induced changes in production of prostaglandins F2α, E, and thromboxane B2 in guinea pig parenchymal lung tissue. Int. J. Radiat. Biol. 42: 517–530, 1982.CrossRefGoogle Scholar
  26. 26.
    Steel, L. K., Swedler, I. K., and Catravas, G. N. Effects of 60Co radiation on synthesis of prostaglandins F2α, E, and thromboxane B2 in lung airways of guinea pigs. Radiat. Res. 94: 156–165, 1983.PubMedCrossRefGoogle Scholar
  27. 27.
    Allen, J. B., Sagerman, R. H., and Stuart, M. J. Irradiation decreases vascular prostacyclin formation with no concomitant effect on platelet thromboxane production. Lancet 2: 1193–1196, 1981.PubMedCrossRefGoogle Scholar
  28. 28.
    Trocha, P. J., and Catravas, G. N. Prostaglandin levels and lysosomal enzyme activities in irradiated rats. Int. J. Radiat. Biol. 38: 503–511, 1980.CrossRefGoogle Scholar
  29. 29.
    Trocha, P. J., and Catravas, G. N. Effect of radioprotectant WR2721 on cyclic nucleotides, prostaglandins, and lysosomes. Radiat. Res. 94: 239–251, 1983.PubMedCrossRefGoogle Scholar
  30. 30.
    Heinz, T. R., Schneidkraut, M. J., Kot, P. A., Ramwell, P. W., and Rose, J. C. Radiation-induced alterations in cyclooxygenase product synthesis by isolated perfused rat lungs. Prog. Biochem. Pharmacol. 20: 74–83, 1985.PubMedGoogle Scholar
  31. 31.
    Hahn, G. L., Menconi, M. J., Cahill, M., and Polgar, P. The influence of gamma radiation on arachidonic acid release and prostacyclin synthesis. Prostaglandins 25: 783–791, 1983.PubMedCrossRefGoogle Scholar
  32. 32.
    Walker, D. I., and Eisen, V. Effect of ionizing radiation on 15-hydroxy prostaglandin dehydrogenase (PGDH) activity in tissues. Int. J. Radiat. Biol. 36: 399–407, 1979.CrossRefGoogle Scholar
  33. 33.
    Baluda, V. P., Sushkevich, N., Parshkov, E. M., and Lukoyanova, T. I. Influence of gamma rays 60Co and fast neutrons on intravascular platelet aggregation and prostacyclin-like activity of the vascular wall. Buill. Eksp. Biol. Med. 91: 559–562, 1981.CrossRefGoogle Scholar
  34. 34.
    Borowska, A., Sierakowski, S., Mackowiak, J., and Wisniewski, K. A prostaglandin-like activity in small intestine and postirradiation gastrointestinal syndrome. Experientia 35: 1368–1370, 1979.PubMedCrossRefGoogle Scholar
  35. 35.
    Eldor, A., Vlodavsky, I., Hy Am, E., Atzman, R., and Fuks, Z. The effect of radiation on prostacyclin (PGI2) production by cultured endothelial cells. Prostaglandins 25: 263–279, 1983.PubMedCrossRefGoogle Scholar
  36. 36.
    Rubin, D. B., Drab, E. A., Ts’ao, C. H., Gardner, D., and Ward, W. F. Prostacyclin snythesis in irradiated endothelial cells cultured from bovine aorta. J. Appl. Physiol. 58: 592–597, 1985.PubMedGoogle Scholar
  37. 37.
    Sinzinger, H., Cromwell, M., and Firbas, W. Long-lasting depression of rabbit aortic prostacyclin formation by single-dose irradiation. Radiat. Res. 97: 533–536, 1984.PubMedCrossRefGoogle Scholar
  38. 38.
    Sinzinger, R., Firbas, W., and Cromwell, M. Radiation induced alterations in rabbit aortic prostacyclin formation. Prostaglandins 24: 323–329, 1982.PubMedCrossRefGoogle Scholar
  39. 39.
    Ts’ao, C. H., Ward, W. F., and Port, C. D. Radiation injury in rat lung. I. Prostacyclin (PGI2) production, arterial perfusion, and ultrastructure. Radiat. Res. 96: 284–293, 1983.Google Scholar
  40. 40.
    Ziboh, V. A., Mallia, C., Morhart, E., and Taylor, J. R. Induced biosynthesis of cutaneous prostaglandins by ionizing irradiation. Proc. Soc. Exp. Biol. Med. 169: 386–391, 1982.PubMedGoogle Scholar
  41. 41.
    Schneidkraut, M. J., Kot, P. A., Ramwell, P. W., and Rose, J. C. Urinary prostacyclin and thromboxane levels after whole body gamma-irradiation in the rat. Adv. Prostaglandin Thromboxane Leukotriene Res. 12: 107–111, 1983.Google Scholar
  42. 42.
    Schneidkraut, M. J., Kot, P. A., Ramwell, P. W., and Rose, J. C. Thromboxane and prostacyclin synthesis following whole body irradiation in rats. J. Appl. Physiol. 57: 833–838, 1984.PubMedGoogle Scholar
  43. 43.
    Schneidkraut, M. J., Kot, P. A., Ramwell, P. W., and Rose, J. C. Regional release of cyclooxygenase products after radiation exposure of the rat. J. Appl. Physiol. 61: 1264–1269, 1986.PubMedGoogle Scholar
  44. 44.
    Donlon, M., Steel, L., Helgeson, E. A., Shipp, A., and Catravas, G. N. Radiationinduced alterations in prostaglandin excretion in the rat. Life Sci. 32: 2631–2639, 1983.PubMedCrossRefGoogle Scholar
  45. 45.
    Donlon, M., Steel, L., Helgeson, E. A., Wolfe, S W. W., and Catravas, G. N. WR2721 inhibition of radiation-induced prostaglandin excretion in rats. Int. J. Radiat. Biol. 47: 205–212, 1985.CrossRefGoogle Scholar
  46. 46.
    Pearce, J. W., Sonnenberg, H., Veress, A. T., and Ackermann, U. Evidence for a humoral factor modifying the renal response to blood volume expansion in the rat. Can. J. Physiol. Pharmacol. 47: 377–386, 1969.PubMedCrossRefGoogle Scholar
  47. 47.
    Sun, F. F., Taylor, B. M., Sutter, D. M., and Weeks, J. R. Metabolism of prostacyclin. III. Urinary metabolite profile of 6-keto PGF1α in the rat. Prostaglandins 17: 753–759, 1979.Google Scholar
  48. 48.
    Forstermann, U., and Neufang, B. The role of the kidney in the metabolism of prostacyclin by the 15-hydroxyprostaglandin dehydrogenase pathway in vivo. Biochim. Biophys. Acta 793: 338–345, 1984.Google Scholar
  49. 49.
    Bakhle, Y. S. Inhibition by clinically used dyes of prostaglandin inactivation in rat and human lung. Brit. J. Pharmacol. 72: 715–721, 1981.Google Scholar
  50. 50.
    Hellewell, P. G., and Pearson, J. D. Effect of sulphasalazine on pulmonary inactivation of prostaglandin F2α in the pig. Brit. J. Pharmacol. 76: 319–326, 1982.Google Scholar
  51. 51.
    Hoult, J. R. S., and Robinson, C. Selective inhibition of thromboxane B2 accumulation and metabolism in perfused guinea-pig lung. Brit. J. Pharmacol. 78: 85–88, 1983.Google Scholar
  52. 52.
    Levenson, D. J., Simmons, C. E., and Brenner, B. M. Arachidonic acid metabolism, prostaglandins and the kidney. Am. J. Med. 72: 354–374, 1982.PubMedCrossRefGoogle Scholar
  53. 53.
    McGuire, J. C., and Sun, F. F. Metabolism of prostacyclin. Oxidation by rhesus monkey lung 15-hydroxyl prostaglandin dehydrogenase. Arch. Biochem. Biophys. 189: 92–96, 1978.Google Scholar
  54. 54.
    Myatt, L., Jogee, M., Lewis, P. J., and Elder, M. G. Measurement of 13,14 dihydro-6,15 dioxo PGF1α by radioimmunoassay: Application to the study of prostacyclin metabolism. Prog. Lipid Res. 20: 807–810, 1981.PubMedCrossRefGoogle Scholar
  55. 55.
    Robinson, C., and Hoult, J. R. S. Inactivation of prostaglandins in the perfused rat lung. Biochem. Pharmacol. 31: 633–638, 1982.PubMedCrossRefGoogle Scholar
  56. 56.
    Robinson, C., Hoult, J. R. S., Waddell, K. A., Blair, I. A., and Dollery, C. T. Total profiling by GC/NICIMS of the major cyclooxygenase products from antigen and leukotriene-challenged guinea-pig lung. Biochem. Pharmacol. 33: 395–400, 1984.PubMedCrossRefGoogle Scholar
  57. 57.
    Wong, P. Y. K., McGiff, J. C., Cagen, L., Malik, K. U., and Sun, F. F. Metabolism of prostacyclin in the rabbit kidney. J. Biol. Chem. 254: 12–14, 1979.PubMedGoogle Scholar
  58. 58.
    Miller, M. J. S., Spokas, E. G., and McGiff, J. C. Metabolism of prostglandin E2 in the isolated perfused kidney of the rabbit. Biochem. Pharmacol. 31: 2955–2960, 1982.PubMedCrossRefGoogle Scholar
  59. 59.
    Brash, A. R., Jackson, E. K., Saggesse, C. A., Lawson, J. A., Oates, J. A., and Fitzgerald, G. A. Metabolite disposition of prostacyclin in humans. J. Pharmacol. Exp. Therap. 226: 78–87, 1983.Google Scholar

Copyright information

© Plenum Press, New York 1987

Authors and Affiliations

  • M. J. Schneidkraut
    • 1
  • P. A. Kot
    • 1
  • P. W. Ramwell
    • 1
  1. 1.Department of Physiology and BiophysicsGeorgetown University Medical CenterUSA

Personalised recommendations