Skip to main content
NCBI home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1977 Oct;74(10):4251–4255. doi: 10.1073/pnas.74.10.4251

Ionophores stimulate prostaglandin and thromboxane biosynthesis*

Howard R Knapp 1, Oswald Oelz 1, L Jackson Roberts 1, Brian J Sweetman 1, John A Oates 1, Peter W Reed 1
PMCID: PMC431917  PMID: 270668

Abstract

The role of calcium in triggering prostaglandin and thromboxane synthesis was studied in several systems with ionophores of different ion specificities. Divalent cationophore A23187 stimulates prostaglandin and thromboxane production by washed human platelets in a concentration-dependent manner (0.3-9 μM). A23187 also induces an antimycin A-insensitive burst in oxygen utilization which is partially blocked by 5 mM aspirin or 10 μM indomethacin. Under our conditions, A23187 (up to 10 μM) does not appear to damage platelet membranes since it does not cause appreciable loss of lactate dehydrogenase or β-glucuronidase. Mono- and divalent cationophore X537A also stimulates platelet thromboxane B2 production and oxygen utilization, but monovalent cationophores nigericin, monensin A, A204, and valinomycin have no effect. The synthesis of prostaglandins E2, D2, and F2α by rat renal medulla mince is stimulated by 1 and 5 μM A23187 without changes in tissue ATP content, lactate output, or K+ efflux. X537A, monensin A, and nigericin (all 5 μM) stimulate both prostaglandin output and K+ efflux from renal medulla, while 5 μM valinomycin or A204 has no effect on either. None of the ionophores stimulates renomedullary prostaglandin production if calcium is omitted from the incubation medium. A23187 also stimulates prostaglandin production by human lymphoma cells, rat stomach and trachea preparations, and guinea pig polymorphonuclear leukocytes. These observations suggest a major role for Ca2+ in stimulating prostaglandin and thromboxane biosynthesis, and also indicate that prostaglandin and/or thromboxane release may partially mediate some of the previously described effects of ionophores on cells and tissues.

Keywords: calcium, platelets, renal medulla, A23187, X537A

Full text

PDF
4251

Selected References

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

  1. Asciak C. P., Domazet Z. 9-Hydroxyprostaglandin dehydrogenase activity in the adult rat kidney. Regional distribution and sub-fractionation. Biochim Biophys Acta. 1975 Feb 20;380(2):338–343. doi: 10.1016/0005-2760(75)90019-3. [DOI] [PubMed] [Google Scholar]
  2. Carr K., Sweetman B. J., Frölich J. C. High performance liquid chromotography of prostaglandins: biological applications. Prostaglandins. 1976 Jan;11(1):3–14. doi: 10.1016/0090-6980(76)90167-2. [DOI] [PubMed] [Google Scholar]
  3. Christ E. J., van Dorp D. A. Comparative aspects of prostaglandin biosynthesis in animal tissues. Biochim Biophys Acta. 1972 Aug 11;270(4):534–545. [PubMed] [Google Scholar]
  4. Danon A., Chang L. C., Sweetman B. J., Nies A. S., Oates J. A. Synthesis of prostaglandins by the rat renal papilla in vitro. Mechanism of stimulation by angiotensin II. Biochim Biophys Acta. 1975 Apr 18;388(1):71–83. doi: 10.1016/0005-2760(75)90063-6. [DOI] [PubMed] [Google Scholar]
  5. Derksen A., Cohen P. Patterns of fatty acid release from endogenous substrates by human platelet homogenates and membranes. J Biol Chem. 1975 Dec 25;250(24):9342–9347. [PubMed] [Google Scholar]
  6. Feinstein M. B., Fraser C. Human platelet secretion and aggregation induced by calcium ionophores. Inhibition by PGE1 and dibutyryl cyclic AMP. J Gen Physiol. 1975 Nov;66(5):561–581. doi: 10.1085/jgp.66.5.561. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Flower R. J. Drugs which inhibit prostaglandin biosynthesis. Pharmacol Rev. 1974 Mar;26(1):33–67. [PubMed] [Google Scholar]
  8. Frölich J. C., Wilson T. W., Sweetman B. J., Smigel M., Nies A. S., Carr K., Watson J. T., Oates J. A. Urinary prostaglandins. Identification and origin. J Clin Invest. 1975 Apr;55(4):763–770. doi: 10.1172/JCI107987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Fukami M. H., Holmsen H., Bauer J. Thrombin-induced oxygen consumption, malonyldialdehyde formation and serotonin secretion in human platelets. Biochim Biophys Acta. 1976 Mar 25;428(1):253–256. doi: 10.1016/0304-4165(76)90126-4. [DOI] [PubMed] [Google Scholar]
  10. Garbers D. L., Wakabayashi T., Reed P. W. Enzyme profile of the cytoplasmic droplet from bovine epididymal spermatozoa. Biol Reprod. 1970 Dec;3(3):327–337. doi: 10.1093/biolreprod/3.3.327. [DOI] [PubMed] [Google Scholar]
  11. Hamberg M., Samuelsson B. Prostaglandin endoperoxides. Novel transformations of arachidonic acid in human platelets. Proc Natl Acad Sci U S A. 1974 Sep;71(9):3400–3404. doi: 10.1073/pnas.71.9.3400. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. 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]
  13. Horton E. W. Hypotheses on physiological roles of prostaglandins. Physiol Rev. 1969 Jan;49(1):122–161. doi: 10.1152/physrev.1969.49.1.122. [DOI] [PubMed] [Google Scholar]
  14. Lands W. E., Samuelsson B. Phospholipid precursors of prostaglandins. Biochim Biophys Acta. 1968 Oct 22;164(2):426–429. doi: 10.1016/0005-2760(68)90168-9. [DOI] [PubMed] [Google Scholar]
  15. Lowe D. A., Richardson N. P., Taylor P., Donatsch P. Increasing intracellular sodium triggers calcium release from bound pools. Nature. 1976 Mar 25;260(5549):337–338. doi: 10.1038/260337a0. [DOI] [PubMed] [Google Scholar]
  16. Malmsten C., Hamberg M., Svensson J., Samuelsson B. Physiological role of an endoperoxide in human platelets: hemostatic defect due to platelet cyclo-oxygenase deficiency. Proc Natl Acad Sci U S A. 1975 Apr;72(4):1446–1450. doi: 10.1073/pnas.72.4.1446. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Markelonis G., Garbus J. Alterations of intracellular oxidative metabolism as stimuli evoking prostaglandin biosynthesis. Prostaglandins. 1975 Dec;10(6):1087–1106. doi: 10.1016/s0090-6980(75)80056-6. [DOI] [PubMed] [Google Scholar]
  18. Mürer E. H. Release reaction and energy metabolism in blood platelets with special reference to the burst in oxygen uptake. Biochim Biophys Acta. 1968 Oct 1;162(3):320–326. doi: 10.1016/0005-2728(68)90118-7. [DOI] [PubMed] [Google Scholar]
  19. Oelz O., Oelz R., Knapp H. R., Sweetman B. J., Oates J. A. Biosynthesis of prostaglandin D2. 1. Formation of prostaglandin D2 by human platelets. Prostaglandins. 1977 Feb;13(2):225–234. doi: 10.1016/0090-6980(77)90004-1. [DOI] [PubMed] [Google Scholar]
  20. Pickett W. C., Cohen P. Mechanism of the thrombin-mediated burst in oxygen consumption by human platelets. J Biol Chem. 1976 Apr 25;251(8):2536–2538. [PubMed] [Google Scholar]
  21. Pickett W. C., Jesse R. L., Cohen P. Initiation of phospholipase A2 activity in human platelets by the calcium ion ionophore A23187. Biochim Biophys Acta. 1976 Jan 18;486(1):209–213. doi: 10.1016/0005-2760(77)90086-8. [DOI] [PubMed] [Google Scholar]
  22. Pressman B. C. Biological applications of ionophores. Annu Rev Biochem. 1976;45:501–530. doi: 10.1146/annurev.bi.45.070176.002441. [DOI] [PubMed] [Google Scholar]
  23. Reed P. W. Effects of divalent cation ionophore A23187 on potassium permeability of rat erythrocytes. J Biol Chem. 1976 Jun 10;251(11):3489–3494. [PubMed] [Google Scholar]
  24. Reed P. W., Lardy H. A. A23187: a divalent cation ionophore. J Biol Chem. 1972 Nov 10;247(21):6970–6977. [PubMed] [Google Scholar]
  25. Roberts L. J., 2nd, Sweetman B. J., Morgan J. L., Payne N. A., Oates J. A. Identification of the major urinary metabolite of thromboxane B2 in the monkey. Prostaglandins. 1977 Apr;13(4):631–647. doi: 10.1016/0090-6980(77)90234-9. [DOI] [PubMed] [Google Scholar]
  26. Schwartz A. Cellular and molecular mechanisms involved in cardiac cell function: effects of an antibiotic ionophore. Acta Med Scand Suppl. 1976;587:71–82. doi: 10.1111/j.0954-6820.1976.tb05869.x. [DOI] [PubMed] [Google Scholar]
  27. Tamarit-Rodriguez J., Hellman B., Sehilin J. Metabolic characteristics of pancreatic beta-cells exposed to calcium-transporting ionophores. Biochim Biophys Acta. 1977 Jan 24;496(1):167–174. doi: 10.1016/0304-4165(77)90124-6. [DOI] [PubMed] [Google Scholar]
  28. Vonkeman H., van Dorp D. A. The action of prostaglandin synthetase on 2-arachidonyl-lecithin. Biochim Biophys Acta. 1968 Oct 22;164(2):430–432. doi: 10.1016/0005-2760(68)90169-0. [DOI] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES