Modulation of the Guanylate Cyclase -cGMP System by Vasodilators and the Role of Free Radicals as Second Messengers

  • Ferid Murad


This brief article will review some of the studies, from this laboratory and others, that have led to our present understanding of the synthesis of cyclic GMP and its role in smooth muscle relaxation and more specifically its role to mediate the effects of several classes of vasodilators. The regulation of the synthesis of cyclic GMP and some of its effects in several model systems have recently been reviewed in some detail. Readers are referred to these reviews (Waldman and Murad, 1987; Murad, 1986; Leitman and Murad, 1987) and the references therein for a more detailed discussion.


Methylene Blue Atrial Natriuretic Peptide Guanylate Cyclase Atrial Natriuretic Factor Soluble Guanylate Cyclase 
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.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Arnold, W.P., Mittal, C.K., Katsuki S., and Murad, F. Nitric oxide activates guanylate cyclase and increases guanosine 3′, 5′-monophosphate levels in various tissue preparations. Proc. Natl. Acad. Sci. USA. 74:3203–3207, 1977.PubMedCrossRefGoogle Scholar
  2. Braughler, J.M., Mittal, C.K. and Murad, F. Purification of soluble guanylate cyclase from rat liver. Proc. Natl Acad. Sci. USA. 76:219–222, 1979.PubMedCrossRefGoogle Scholar
  3. Braughler, J.M., Mittal, C.K. and Murad, F. Effects of thiols, sugars and proteins on nitric oxide activation of guanylate cyclase. J. Biol. Chem. 254:12450–12454, 1979.PubMedGoogle Scholar
  4. Currie, M.J., Geller, D.M., Cole, B.R., Baylon J.G., Yusheng, W., Holmberg, S.W., and Needleman, P.N. Bioactive cardiac substances, potent activity in mammalian atria. Science. 221: 71–73, 1983.PubMedCrossRefGoogle Scholar
  5. DeBold, A. Atrial natriuretic factor of the heart, studies on isolation and properties. Proc. Soc. Exp. Biol. 170:133–138, 1982.Google Scholar
  6. Draznin, M.B., Rapoport, R.M. and Murad, F. Myosin light chain phosphorylation in contraction and relaxation of intact rat thoracic aorta. Intl. Biochem. 18:917–928, 1986CrossRefGoogle Scholar
  7. Fiscus, R.R., Rapoport, R.M., and Murad, F. Endothelium-dependent and nitrovasodilator-induced activation of cyclic GMP-dependent protein kinase in rat aorta. J. Cyclic Nucl. Protein Phosphor. Res. 9:415–425, 1983.Google Scholar
  8. Forstermann, U., Mulsch, A., Bohme, E and Busse, R.B. Stimulation of soluble guanylate cyclase by an acetylcholine-induced endothelium derived factor from rabbit and canine arteries. Cir. Res. 58:531–538, 1986.CrossRefGoogle Scholar
  9. Furchgott, R.F. Role of endothelium in response of vascular smooth muscle. Circ. Res. 53: 557–573, 1983.PubMedCrossRefGoogle Scholar
  10. Gerzer, R., Bohme, E., Hoffman, F., and Schultz, G. Soluble guanylate cyclase from bovine lung contains heme and copper. FEBS Lett. 132:71–74, 1981.PubMedCrossRefGoogle Scholar
  11. Guerrant, R.L., Hughes, J.M., Chang, B., Robertson, C.C., and Murad, F. Activation of intestinal guanylate cyclase by heat stable enterotoxin of Escherichia Coli: Studies of tissue specificity, potential receptors and intermediates. J. Infec. Dis. 142:220–228, 1980CrossRefGoogle Scholar
  12. Hamet, P., Temblay, J., Pong, S.C., Garcia, R., Thiebault, G., Gutkowska, J., Cantin, M., and Genest, J. Effects of natural and synthetic atrial natriuretic factor on cyclic GMP. Biochem. Biophys. Res. Commun. 123:515–527, 1984.PubMedCrossRefGoogle Scholar
  13. Hughes, J., Murad, F., Chang, B., and Guerrant, R. The role of cyclic GMP in the mechanism of action of the heat-stable enterotoxin of E. Coli. Nature. 271:755–756, 1978.PubMedCrossRefGoogle Scholar
  14. Ignarro, L.J., Harbison, R.G., Wood, K.S., and Kadowitz, P.J. Activation of purified soluble guanylate cyclase by endothelium derived relaxing factor form intrapulmonary artery and vein: stimulation by acetylcholine, bradykinin and arachidonic acid. J. Pharmacol. Exp. Therap. 237:893–900, 1986.Google Scholar
  15. Kamisaki, Y., Saheki, S., Nakane, M., Palmieri, J., Kuno, T., Chang, B., Waldman, S.A., and Murad, F. Soluble guanylate cyclase from rat lung exists as a heterodimer. J. Biol Chem. 261:7236–7241, 1986.PubMedGoogle Scholar
  16. Katsuki, S., and Murad, F. Regulation of cyclic 3′, 5′-adenosine monophosphate and cyclic 3′-5′-guanosine monophosphate levels. Molec. Pharmacol. 13:330–341, 1977.Google Scholar
  17. Katsuki, S., Arnold, W. , Mittal, D.K., and Murad, F. Stimulation of guanylate cyclase by sodium nitroprusside, nitroglycerin and nitric oxide in various tissues preparations and comparison to the effects of sodium azide and hydroxylamine. J. Cyclic Nucl Res. 3:23–35, 1977.Google Scholar
  18. Katsuki, S., Arnold, W.P., and Murad, F. Effect of sodium nitroprusside, nitroglycerin and sodium azide on levels of cyclic nucleotides and mechanical activity of various tissues. J. Cyclic Nucl Res. 3:239–247, 1977.Google Scholar
  19. Kimura, H., and Murad, F. Evidence for two different forms of guanylate cyclase in rat heart.J. Biol. Chem. 249:6910–6919, 1974.PubMedGoogle Scholar
  20. Kimura, H., and Murad, F. Two forms of guanylate cyclase in mammalian tissues and possible mechanisms for their regulation. Metabolism. 24:439–445, 1975.PubMedCrossRefGoogle Scholar
  21. Kimura, H., Mittal, C.K. and Murad, F. Activation of guanylate cyclase from rat liver and other tissues with sodium azide. J. Biol. Chem. 250:8016–8022, 1975.PubMedGoogle Scholar
  22. Kimura, H., C.K. Mittal, and Murad, F. Appearance of magnesium guanylate cyclase activity in rat liver with sodium-azide activation. J. Biol. Chem. 251:7769–7773, 1976.PubMedGoogle Scholar
  23. Kobayoshi, S., Kanaide, H., and Nakamura, M. Cytosolic free calcium transients in cultured vascular smooth muscle cells: microflurometric measurements. Science. 229:553–556, 1985.CrossRefGoogle Scholar
  24. Kuno, T., Kamisaki, S.A., Waldman, Garieppy, J., Schoolnik, S.A., and Murad, F. Characterization of the receptor for heat-stable enterotoxin from E. Coli in rat intestine. J. Biol. Chem. 261:1470–1476, 1986.PubMedGoogle Scholar
  25. Kuno, T., J.W. Andresen, Y. Kamisaki, S.A. Waldman, L.Y. Chang, S. Saheki, D.C. Leitman, M. Nakane, and F. Murad. Co-purification of an atrial natriuretic factor receptor and particulate guanylate cyclase from rat lung. J. Biol. Chem. 261:5817–5823, 1986.PubMedGoogle Scholar
  26. Leitman, D.C., and Murad, F. Comparison of binding and cyclic GMP accumulation by atrial natriuretic peptides in endothelial cells. Biochim. Biophys. Acta. 885:74–79, 1986.PubMedCrossRefGoogle Scholar
  27. Leitman, D.C., Anderson, J.W., Kuno, T., Kamisaki, Y., Chang, J., and Murad, F. Identification of multiple binding sites for atrial natriuretic factor by affinity cross-linking in cultured endothelial cells. J. Biol. Chem 261:11650–11655, 1986.PubMedGoogle Scholar
  28. Leitman, D.C. and Murad, F. Atrial natriuretic factor receptor heterogeneity and stimulation of particulate guanylate cyclase and cyclic GMP accumulation. Endocrine and Metal. Clin. in No. Amer. 16:79–105, 1987.Google Scholar
  29. Leitman, D.C., Andresen, J.W., Catalano, R.M. , Waldman, S.A., Tuan, J.J., and Murad, F. Atrial natriuretic peptide binding, crosslinking, and stimulation of cyclic GMP accumulation and particulate guanylate cyclase activity in cultured cells. J. Biol. Chem. 263:3720–3728, 1988.PubMedGoogle Scholar
  30. Maack, T., Suguki, M., Almeida, F.A., Nussenzvieg, Scarborough, R.M., McEnrae, G.A., and Lewicki, J.A. Physiological role of silent receptors of atrial natriuretic factor. Science. 238:675–678, 1987.PubMedCrossRefGoogle Scholar
  31. Mittal, C.K., and Murad, F. Activation of guanylate cyclase with superoxide dismutase and hydroxylradical, a physiological regulator of cyclic GMP formation. Proc. Nat. Acad Sci. 74:4360–4364, 1977.PubMedCrossRefGoogle Scholar
  32. Mittal, C.K., and Murad, F. Properties and oxidative regulation of guanylate cyclase. J.Cyclic Nucl. Res. 3:381–391, 1977.Google Scholar
  33. Mittal, C.K. , Kimura, H., and Murad, F. Purification and properties of a protein required for sodium azide activation of guanylate cyclase. J. Biol. Chem. 252:4348–4390, 1977.Google Scholar
  34. Mittal, C.K., Arnold, W.P., and Murad, F. Characterization of protein inhibitors of guanylate cyclase activation from rat heart and bovine lung. J. Biol. Chem. 253:1266–1271, 1978.PubMedGoogle Scholar
  35. Murad, F. Cyclic guanosine monophosphate as a mediator of vasodilation. J. Clin. Invest. 78:1–5, 1986.PubMedCrossRefGoogle Scholar
  36. Palmer, R.M.J., Feuidge, A.G., and Moncada, S. Nitric oxide release accounts for the biological activity of endothelium derived relaxing factor. Nature. 327:524, 1987.PubMedCrossRefGoogle Scholar
  37. Popescu, L.M., Panoiu, C., Hinescu, M. and Nutu, O. The mechanism of cGMP-induced relaxation in vascular smooth muscle. Eur. J. Pharmacol. 107:393–394, 1985.PubMedCrossRefGoogle Scholar
  38. Rapoport, R.M., Draznin, M., and Murad, F. Sodium nitroprusside-induced protein phosphorylation in intact rat aorta is mimicked by 8-bromo-cyclic GMP. Proc. Nat. Acad. Sci. USA. 79:6470–6474, 1982.PubMedCrossRefGoogle Scholar
  39. Rapoport, R.M., and Murad, F. Agonist-induced endothelial-dependent relaxation in rat thoracic aorta may be mediated through cyclic GMP. Cir. Res. 52:352–357, 1983.CrossRefGoogle Scholar
  40. Rapoport, R.M., and Murad, F. Endothelium-dependent and nitrovasodilator-induced relaxation of vascular smooth muscle: role for cyclic GMP. J. Cyclic Nucl. and Protein Phosphor Res. 9:281–296, 1983.Google Scholar
  41. Rapoport, R.M., Draznin, M.B. and Murad, F. Endothelium dependent relaxation in rat aorta may be mediated through cyclic GMP-dependent protein phosphorylation. Nature. 306:274–276, 1983.CrossRefGoogle Scholar
  42. Rapoport, R.M. Cyclic guanosine monophosphate inhibition of contraction may be mediated through inhibition of phosphotidylinositol hydrolysis in rat aorta. Circ. Res. 58:407–410, 1986.PubMedCrossRefGoogle Scholar
  43. Shenk, D.B., Phelps, M.N., Porter, J.G., Fuller, F., Cordell, B., and Lewicki, J. Purification and subunit composition of atrial natriuretic Peptide receptor. Proc. Nat. Acad Sci. 84:1521–1525, 1987.CrossRefGoogle Scholar
  44. Song, D.L., Kohse, K. and Murad, F. Brain natriuretic factor: Augmentation of cellular cyclic GMP, activation of particulate guanylate cyclase and receptor binding. FEBS Let. 1:125–129, 1988.CrossRefGoogle Scholar
  45. Waldman, S.A., Lewicki, J.A., Brandwein, H.J., and Murad, F. Partial purification and characterization of particulate guanylate cyclase from rat liver after solubilization with tryspin. J. Cyclic. Nucl. Res. 8:359–370, 1982.Google Scholar
  46. Waldman, S.A., Rapoport, R.M., and Murad, F. Atrial natriuretic factor selectively activates particulate guanylate cyclase and elevates cyclic GMP in rat tissues. J. Biol. Chem. 259:14332–14334, 1984.PubMedGoogle Scholar
  47. Waldman, S.A., Kuno, T. Kamisaki, Y., Chang, L.Y., Garieppy, J., O’Hanley, P.D., Schoolnik, G.K., and Murad, F. Intestinal receptor for heat-stable enterotoxin of E. Coli is tightly coupled to a novel form of particulate guanylate cyclase. Inf. and Immun. 51:320–326, 1986.Google Scholar
  48. Waldman, S.A., and Murad F. Cyclic GMP synthesis and function. Phar. Rev. 39:163–196, 1987.Google Scholar
  49. Winquist, R.J., Faison, E.P., Waldman, S.A., Schwartz, K., Murad, F., and Rapoport, R.M. Atrial natriuretic factor elicits an endothelium independent relaxation and activates particulate guanylate cyclase in vascular smooth muscle. Proc. Nat. Acad Sci. 81:7661–7664, 1984.PubMedCrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1989

Authors and Affiliations

  • Ferid Murad
    • 1
  1. 1.Departments of Medicine and PharmacologyStanford UniversityStanfordUSA

Personalised recommendations