Skip to main content
NCBI home page
Biochemical Journal logoLink to Biochemical Journal
. 1992 Dec 1;288(Pt 2):345–349. doi: 10.1042/bj2880345

Increases in endothelial cyclic AMP levels amplify agonist-induced formation of endothelium-derived relaxing factor (EDRF).

W F Graier 1, K Groschner 1, K Schmidt 1, W R Kukovetz 1
PMCID: PMC1132017  PMID: 1334403

Abstract

The interaction between intracellular cyclic AMP and agonist-induced endothelium-derived relaxing factor (EDRF) (NO) formation was investigated in pig aortic endothelial cells. Three potent stimulators of adenylate cyclase, namely forskolin, adenosine and isoprenaline, amplified bradykinin- and ATP-induced biosynthesis and release of EDRF. None of the substances by itself affected basal EDRF formation. The effects of forskolin, adenosine and isoprenaline corresponded to an enhanced agonist-induced rise in intracellular free Ca2+ concentration ([Ca2+]i), were mimicked by the membrane-permeable cyclic AMP analogue dibutyryl cyclic AMP and were antagonized by the protein kinase inhibitor N-[2-(methylamino)ethyl]-5-isoquinolinesulphonamide dihydrochloride (H-8). Our data suggest that cyclic AMP-dependent phosphorylation modulates Ca(2+)-signalling and thus the function of endothelial cells. This mechanism may be of particular physiological importance, since it allows a joint regulation of endothelial functions by tissues factors such as bradykinin, which directly affects [Ca2+]i and agonists which affect intracellular cyclic AMP levels.

Full text

PDF
345

Selected References

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

  1. Boulanger C., Schini V. B., Moncada S., Vanhoutte P. M. Stimulation of cyclic GMP production in cultured endothelial cells of the pig by bradykinin, adenosine diphosphate, calcium ionophore A23187 and nitric oxide. Br J Pharmacol. 1990 Sep;101(1):152–156. doi: 10.1111/j.1476-5381.1990.tb12105.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Brock T. A., Dennis P. A., Griendling K. K., Diehl T. S., Davies P. F. GTP gamma S loading of endothelial cells stimulates phospholipase C and uncouples ATP receptors. Am J Physiol. 1988 Nov;255(5 Pt 1):C667–C673. doi: 10.1152/ajpcell.1988.255.5.C667. [DOI] [PubMed] [Google Scholar]
  3. Buchan K. W., Martin W. Modulation of agonist-induced calcium mobilisation in bovine aortic endothelial cells by phorbol myristate acetate and cyclic AMP but not cyclic GMP. Br J Pharmacol. 1991 Oct;104(2):361–366. doi: 10.1111/j.1476-5381.1991.tb12436.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Cade C., Ilozue C. V., Rubanyi G. M., Botelho L. H. Smooth muscle cells contain a factor responsible for decreasing big endothelin and endothelin-1 produced by cultured endothelial cells. J Cardiovasc Pharmacol. 1991;17 (Suppl 7):S71–S75. doi: 10.1097/00005344-199100177-00020. [DOI] [PubMed] [Google Scholar]
  5. Cohen P., Klumpp S., Schelling D. L. An improved procedure for identifying and quantitating protein phosphatases in mammalian tissues. FEBS Lett. 1989 Jul 3;250(2):596–600. doi: 10.1016/0014-5793(89)80803-8. [DOI] [PubMed] [Google Scholar]
  6. Cohen P. The structure and regulation of protein phosphatases. Annu Rev Biochem. 1989;58:453–508. doi: 10.1146/annurev.bi.58.070189.002321. [DOI] [PubMed] [Google Scholar]
  7. Des Rosiers C., Nees S. Functional evidence for the presence of adenosine A2-receptors in cultured coronary endothelial cells. Naunyn Schmiedebergs Arch Pharmacol. 1987 Jul;336(1):94–98. doi: 10.1007/BF00177757. [DOI] [PubMed] [Google Scholar]
  8. Freay A., Johns A., Adams D. J., Ryan U. S., Van Breemen C. Bradykinin and inositol 1,4,5-trisphosphate-stimulated calcium release from intracellular stores in cultured bovine endothelial cells. Pflugers Arch. 1989 Aug;414(4):377–384. doi: 10.1007/BF00585046. [DOI] [PubMed] [Google Scholar]
  9. Graier W. F., Groschner K., Schmidt K., Kukovetz W. R. SK&F 96365 inhibits histamine-induced formation of endothelium-derived relaxing factor in human endothelial cells. Biochem Biophys Res Commun. 1992 Aug 14;186(3):1539–1545. doi: 10.1016/s0006-291x(05)81582-7. [DOI] [PubMed] [Google Scholar]
  10. Graier W. F., Schmidt K., Kukovetz W. R. Bradykinin-induced Ca(2+)-influx into cultured aortic endothelial cells is not regulated by inositol 1,4,5-trisphosphate or inositol 1,3,4,5-tetrakisphosphate. Second Messengers Phosphoproteins. 1991;13(4):187–197. [PubMed] [Google Scholar]
  11. Graier W. F., Schmidt K., Kukovetz W. R. Effect of sodium fluoride on cytosolic free Ca2(+)-concentrations and cGMP-levels in endothelial cells. Cell Signal. 1990;2(4):369–375. doi: 10.1016/0898-6568(90)90067-k. [DOI] [PubMed] [Google Scholar]
  12. Graier W. F., Schmidt K., Kukovetz W. R. Is the bradykinin-induced Ca2+ influx and the formation of endothelium-derived relaxing factor mediated by a G protein? Eur J Pharmacol. 1992 Jan 14;225(1):43–49. doi: 10.1016/0922-4106(92)90037-v. [DOI] [PubMed] [Google Scholar]
  13. Grynkiewicz G., Poenie M., Tsien R. Y. A new generation of Ca2+ indicators with greatly improved fluorescence properties. J Biol Chem. 1985 Mar 25;260(6):3440–3450. [PubMed] [Google Scholar]
  14. Hidaka H., Inagaki M., Kawamoto S., Sasaki Y. Isoquinolinesulfonamides, novel and potent inhibitors of cyclic nucleotide dependent protein kinase and protein kinase C. Biochemistry. 1984 Oct 9;23(21):5036–5041. doi: 10.1021/bi00316a032. [DOI] [PubMed] [Google Scholar]
  15. Hori M., Kitakaze M. Adenosine, the heart, and coronary circulation. Hypertension. 1991 Nov;18(5):565–574. doi: 10.1161/01.hyp.18.5.565. [DOI] [PubMed] [Google Scholar]
  16. Kuhn M., Otten A., Frölich J. C., Förstermann U. Endothelial cyclic GMP and cyclic AMP do not regulate the release of endothelium-derived relaxing factor/nitric oxide from bovine aortic endothelial cells. J Pharmacol Exp Ther. 1991 Feb;256(2):677–682. [PubMed] [Google Scholar]
  17. Legrand A. B., Narayanan T. K., Ryan U. S., Aronstam R. S., Catravas J. D. Effects of adenosine and analogs on adenylate cyclase activity in cultured bovine aortic endothelial cells. Biochem Pharmacol. 1990 Sep 1;40(5):1103–1109. doi: 10.1016/0006-2952(90)90499-b. [DOI] [PubMed] [Google Scholar]
  18. Lückhoff A., Clapham D. E. Inositol 1,3,4,5-tetrakisphosphate activates an endothelial Ca(2+)-permeable channel. Nature. 1992 Jan 23;355(6358):356–358. doi: 10.1038/355356a0. [DOI] [PubMed] [Google Scholar]
  19. Lückhoff A., Mülsch A., Busse R. cAMP attenuates autacoid release from endothelial cells: relation to internal calcium. Am J Physiol. 1990 Apr;258(4 Pt 2):H960–H966. doi: 10.1152/ajpheart.1990.258.4.H960. [DOI] [PubMed] [Google Scholar]
  20. Lückhoff A., Pohl U., Mülsch A., Busse R. Differential role of extra- and intracellular calcium in the release of EDRF and prostacyclin from cultured endothelial cells. Br J Pharmacol. 1988 Sep;95(1):189–196. doi: 10.1111/j.1476-5381.1988.tb16564.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Mackie K., Lai Y., Nairn A. C., Greengard P., Pitt B. R., Lazo J. S. Protein phosphorylation in cultured endothelial cells. J Cell Physiol. 1986 Sep;128(3):367–374. doi: 10.1002/jcp.1041280304. [DOI] [PubMed] [Google Scholar]
  22. Martin W., White D. G., Henderson A. H. Endothelium-derived relaxing factor and atriopeptin II elevate cyclic GMP levels in pig aortic endothelial cells. Br J Pharmacol. 1988 Jan;93(1):229–239. doi: 10.1111/j.1476-5381.1988.tb11426.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Mayer B., Schmidt K., Humbert P., Böhme E. Biosynthesis of endothelium-derived relaxing factor: a cytosolic enzyme in porcine aortic endothelial cells Ca2+-dependently converts L-arginine into an activator of soluble guanylyl cyclase. Biochem Biophys Res Commun. 1989 Oct 31;164(2):678–685. doi: 10.1016/0006-291x(89)91513-1. [DOI] [PubMed] [Google Scholar]
  24. Moncada S., Palmer R. M., Higgs E. A. Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol Rev. 1991 Jun;43(2):109–142. [PubMed] [Google Scholar]
  25. Mülsch A., Bassenge E., Busse R. Nitric oxide synthesis in endothelial cytosol: evidence for a calcium-dependent and a calcium-independent mechanism. Naunyn Schmiedebergs Arch Pharmacol. 1989 Dec;340(6 Pt 2):767–770. doi: 10.1007/BF00169688. [DOI] [PubMed] [Google Scholar]
  26. Schilling W. P., Elliott S. J. Ca2+ signaling mechanisms of vascular endothelial cells and their role in oxidant-induced endothelial cell dysfunction. Am J Physiol. 1992 Jun;262(6 Pt 2):H1617–H1630. doi: 10.1152/ajpheart.1992.262.6.H1617. [DOI] [PubMed] [Google Scholar]
  27. Schmidt K., Mayer B., Kukovetz W. R. Effect of calcium on endothelium-derived relaxing factor formation and cGMP levels in endothelial cells. Eur J Pharmacol. 1989 Nov 7;170(3):157–166. doi: 10.1016/0014-2999(89)90536-0. [DOI] [PubMed] [Google Scholar]
  28. Schmidt K., Werner E. R., Mayer B., Wachter H., Kukovetz W. R. Tetrahydrobiopterin-dependent formation of endothelium-derived relaxing factor (nitric oxide) in aortic endothelial cells. Biochem J. 1992 Jan 15;281(Pt 2):297–300. doi: 10.1042/bj2810297. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Smith R. E., Palmer R. M., Bucknall C. A., Moncada S. Role of nitric oxide synthesis in the regulation of coronary vascular tone in the isolated perfused rabbit heart. Cardiovasc Res. 1992 May;26(5):508–512. doi: 10.1093/cvr/26.5.508. [DOI] [PubMed] [Google Scholar]
  30. Steinberg S. F., Jaffe E. A., Bilezikian J. P. Endothelial cells contain beta adrenoceptors. Naunyn Schmiedebergs Arch Pharmacol. 1984 Apr;325(4):310–313. doi: 10.1007/BF00504374. [DOI] [PubMed] [Google Scholar]

Articles from Biochemical Journal are provided here courtesy of The Biochemical Society

RESOURCES