Advertisement

Cyclic nucleotides in smooth muscle relaxation

  • W. R. Kukovetz
  • S. Holzmann

Abstract

There is ample evidence to support, although there is also some against, the theory that cyclic AMP (cAMP) mediates the relaxant effects of adenylate cyclase stimulating agents such as β-adrenergic stimulants and adenosine in smooth muscle (see reviews by Hardman, 1981; Kukovetz et al., 1981; Baer et al., 1983). Evidence was also obtained for a similar role of cyclic GMP (cGMP) in relaxation caused by direct stimulants (nitrates) and, more recently, by indirect stimulants of guanylate cyclase, particularly acetylcholine (ACh). This review will mainly deal with relaxation of coronary arterial smooth muscle and will focus on our present knowledge concerning such functions of cyclic nucleotides in the relaxant effects of stimulants of both types of cyclases including relaxation by prostacyclin and forskolin, and also on their involvement in the relaxant effects of phosphodiesterase (PDE) inhibitors. Some consideration will be given to the mechanisms by which cAMP and cGMP achieve relaxation.

Keywords

Vascular Smooth Muscle Adenylate Cyclase Cyclic Nucleotide Guanylate Cyclase Myosin Light Chain Kinase 
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. ADELSTEIN, R.S., CONTI, M.A., HATHAWAY, D.R. & KLEE, C.B. (1978). Phosphorylation of smooth muscle myosin light chain kinase by the catalytic subunit of adenosine 3′,5′-monophosphate-dependent protein kinase. J. biol. Chem., 253, 8347–8350.PubMedGoogle Scholar
  2. ANAND-SRIVASTAVA, M.B., FRANKS, D.J., CATIN, M. & GENEST, J. (1982). Presence of ‘Ra’ and ‘P’-site receptors for adenosine coupled to adenylate cyclase in cultured vascular smooth muscle cells. Biochem. biophys. Res. Commun., 108, 213–219.PubMedCrossRefGoogle Scholar
  3. APPLEMAN, M.M., ARIANO, M.A., TAKEMOTO, D.J. & WHITSON, R.H. (1982). Cyclic Nucleotide Phosphodiesterases. In Handbook of Experimental Pharmacology Vol. 58/I, Cyclic Nucleotides I: Biochemistry. Nathanson, J.A. & Kebabian, J.W. (eds) pp. 261–300, Berlin/Heidelberg/New York: Springer-Verlag.Google Scholar
  4. BAER, H.P., MULLER, M.J. & VRIED, R. (1983). Adenosine receptors in smooth muscle. In Physiology and Pharmacology of Adenosine Derivatives. Daly, J.W., Kuroda, Y., Phillis, J.W., Shimizu, H. & Ui, M. (eds) pp. 77–84, New York: Raven Press.Google Scholar
  5. BERGSTRAND, H., KRISTOFFERSON, I., LUNDQUIST, B., & SCHURMANN, A. (1977). Effects of antiallergic agents, compound 48/80, and some reference inhibitors of the activity of partially purified human lung tissue adenosine cyclic 3′,5′-monophosphate and guanosine cyclic 3′,5′-monophosphate phosphodiesterases. Mol. Pharmac., 13, 38–43.Google Scholar
  6. BROOKER, G., PEDONE, C. & BAROVSKY, K. (1983). Selective reduction of forskolin-stimulated cyclic AMP accumulation by inhibitors of protein synthesis. Science, 220, 1169–1170.PubMedCrossRefGoogle Scholar
  7. CASNELLIE, J.E., IVES, H.E., JAMIESON, J.D. & GREENGARD, P. (1980). Cyclic GMP-dependent protein phosphorylation in intact medial tissue and isolated cells from vascular smooth muscle. J. biol. Chem., 255, 3770–3776.PubMedGoogle Scholar
  8. DEMBINSKA-KIEC, A., RÜCKER, W. & SCHÖNHÖFER, P.S. (1980). Effects of PGI2 and PGI-analogues on cAMP levels in cultured endothelial and smooth muscle cells derived from bovine arteries. Naunyn Schmiedeberg’s Arch. Pharmac., 311, 67–70.CrossRefGoogle Scholar
  9. DUSTING, G.J., MONCADA, S. & VANE, J.R. (1977). Prostacyclin (PGX) is the endogenous metabolite responsible for relaxation of coronary arteries induced by arachidonic acid. Prostaglandins, 13, 3–15.PubMedCrossRefGoogle Scholar
  10. EDVINSSON, L. & FREDHOLM, B.B. (1983). Characterization of adenosine receptors in isolated cerebral arteries of cat. Br. J. Pharmac., 80, 631–637.CrossRefGoogle Scholar
  11. FURCHGOTT, R.F. (1983). Role of endothelium in responses of vascular smooth muscle. Circ. Res., 53, 557–573.PubMedCrossRefGoogle Scholar
  12. FURCHGOTT, R.F. & ZAWADZKI, J.V. (1980). The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature, 288, 373–376.CrossRefGoogle Scholar
  13. GOLDMAN, S.J., DICKINSON, E.S. & SLAKEY, L.L. (1983). Effect of adenosine on synthesis and release of cyclic AMP by cultured vascular cells from swine. J. Cycl. Nucl. Res., 9, 69–78.Google Scholar
  14. GORMAN, R.R., BUNTING, S. & MILLER, O.V. (1977). Modulation of human platelet adenylate cyclase by prostacyclin (PGX). Prostaglandins, 13, 377–388.PubMedCrossRefGoogle Scholar
  15. GRIFFITH, T.M., EDWARDS, D.H., LEWIS, M.J., NEWBY, A.C. & HENDERSON, A.H. (1984). The nature of endothelium-derived vascular relaxant factor. Nature, 308, 645–647.PubMedCrossRefGoogle Scholar
  16. HARDMAN, J.G. (1981). Cyclic nucleotides and smooth muscle contraction: some conceptual and experimental consideration. In Smooth Muscle: an assessment of current knowledge. Bülbring, E., Brading, A.F., Jones, A.W. & Tomita, T. (eds) pp. 249–262, London: Edward Arnold.Google Scholar
  17. HOLZMANN, S. (1982a). Relaxant and cAMP-increasing effects of forskolin in bovine coronary arteries. Naunyn Schmiedeberg’s Arch. Pharmac., 321, (Suppl.) R42.Google Scholar
  18. HOLZMANN, S. (1982b). Endothelium-induced relaxation by acetylcholine associated with larger rises in cyclic GMP in coronary arterial strips. J. Cycl. Nucl. Res., 8, 409–419.Google Scholar
  19. HOLZMANN, S. (1983). Cyclic GMP as a possible mediator of coronary arterial relaxation by nicorandil (SG-75). J. cardiovasc. Pharmac., 5, 364–370.CrossRefGoogle Scholar
  20. HOLZMANN, S., KUKOVETZ, W.R. & SCHMIDT, K. (1980). Mode of action of coronary arterial relaxation by prostacyclin. J. Cycl. Nucl. Res., 6, 451–460.Google Scholar
  21. HOLZMANN, S., SCHMIDT, K., DITTRICH, P. & KUKOVETZ, W.R. (1982). Zum Mechanismus der positiv inotropen und gefäßerweiternden Wirkung von Forskolin aus Coleus forskohlii. Planta Medica, 45, 133.PubMedCrossRefGoogle Scholar
  22. IGNARRO, L.J., BURKE, T.M., WOOD, K.S., WOLIN, M.S. & KADOWITZ, P.J. (1984). Association between cyclic GMP accumulation and acetylcholine-elicited relaxation of bovine intrapulmonary artery. J. Pharmac. exp. Ther., 228, 682–690.Google Scholar
  23. ITO, T., OGAWA, K., ENOMOTO, I., HASHIMOTO, H., KAI, I. & SATAKE, T. (1980). Comparison of the effects of PGI2 and PGE on coronary and systemic hemodynamics and coronary arterial cyclic nucleotide levels in dog. In Advances in Prostaglandin and Thromboxane Research Vol. 7. Samuelsson, B., Ramwell, P.W. & Paoletti, R. (eds) pp. 641–646, New York: Raven Press.Google Scholar
  24. IVES, H.E., CASNELLIE, J.E., GREENGARD, P. & JAMIESON, J.O. (1980). Subcellular localization of cyclic GMP-dependent protein kinase and its substrates in vascular smooth muscle. J. biol. Chem., 255, 3777–3785.PubMedGoogle Scholar
  25. KATSUKI, S., ARNOLD, W., MITTAL, C. & MURAD, F. (1977). Stimulation of guanylate cyclase by sodium nitroprusside, nitroglycerin and nitric oxide in various tissue preparations and comparison to the effects of sodium azide and hydroxylamine. J. Cycl. Nucl. Res., 3, 23–35.Google Scholar
  26. KRAMER, G.L. & WELLS, J.N. (1979). Effects of phosphodiesterase inhibitors on cyclic nucleotide levels and relaxation of pig coronary arteries. Mol. Pharmac., 16, 813–822.Google Scholar
  27. KRAMER, G.L., GARST, J.E., MITCHEL, S.S. & WELLS, J.N. (1977). Selective inhibition of cyclic nucleotide phosphodiesterases by analogues of 1-methyl-3-isobutyl-xanthine. Biochemistry, 16, 3316–3321.PubMedCrossRefGoogle Scholar
  28. KUKOVETZ, W.R. & HOLZMANN, S. (1983). Mechanism of nitrate-induced vasodilation and tolerance. Z. Kardiol., 72, Suppl. 3, 14–19.PubMedGoogle Scholar
  29. KUKOVETZ, W.R. & HOLZMANN, S. (1984). Der Wirkungs-mechanismus von Molsidomin und Nitraten. Med. Praxis, Sondernummer 1, 12–17.Google Scholar
  30. KUKOVETZ, W.R., HOLZMANN, S. & POCH, G. (1982a). Function of cyclic GMP in acetylcholine-induced con- traction of coronary smooth muscle. Naunyn Schmiedeberg’s Arch. Pharmac., 319, 29–33.CrossRefGoogle Scholar
  31. KUKOVETZ, W.R., HOLZMANN, S., STRAKA, M., & SCHMIDT, K. (1982b). Mechanismus der gefäßer-weiternden Wirkung von Molsidomin. In Molsidomin: Neue Aspekte zur Therapie der ischämischen Herzerkrankung. Bassenge, E. & Schmutzler, H. (eds) pp. 32–36, München/Wien/Baltimore: Urban & Schwarzenberg.Google Scholar
  32. KUKOVETZ, W.R., HOLZMANN, S., WURM, A. & PÖCH, G. (1979a). Evidence for cyclic GMP-mediated relaxant effects of nitrocompounds in coronary smooth muscle. Naunyn Schmiedeberg’s Arch. Pharmac., 310, 129–138.CrossRefGoogle Scholar
  33. KUKOVETZ, W.R., HOLZMANN, S., WURM, A. & PÖCH, G. (1979b). Prostacycin increases cAMP in coronary arteries. J. Cycl. Nucl. Res., 5, 469–476.Google Scholar
  34. KUKOVETZ, W.R. & PÖCH, G. (1970). Inhibition of cyclic3′,5′-nucleotide-phosphodiesterase as a possible mode of action of papaverine and similarly acting drugs. Naunyn SchmiedebergsArch. Pharmac., 267, 189–194.CrossRefGoogle Scholar
  35. KUKOVETZ, W.R., PÖCH, G. & HOLZMANN, S. (1981). Cyclic nucleotides and relaxation of vascular smooth muscle. In Vasodilatation. Vanhoutte, P.M. & Leusen, I. (eds) pp. 339–353, New York: Raven Press.Google Scholar
  36. KUKOVETZ, W.R., PÖCH, G. & HOLZMANN, S. (1982c). Adenosine-stimulation of adenylate cyclase as a mechanism of smooth muscle relaxation. Naunyn Schmiedeberg’s Arch. Pharmac., 321, (Suppl) R9.Google Scholar
  37. KUKOVETZ, W.R., PÖCH, G., HOLZMANN, S., WURM, A. & RINNER, I. (1978). Role of cyclic nucleotides in adenosine-mediated regulation of coronary flow. In Advances in Cyclic Nucleotide Research Vol. 9. George, W.J. & Ignaao, L.J. (eds) pp. 397–409, New York: Raven Press.Google Scholar
  38. KUKOVETZ, W.R., PÖCH, G., HOLZMANN, S., WURM, A. & RINNER, I. (1979c). Cyclic nucleotides and coronary flow. In Cyclic Nucleotides and Therapeutic Perspectives. Cehovic, G. & Robison, G.A. (eds) pp. 109–125, Oxford/New York: Pergamon Press.Google Scholar
  39. KUKOVETZ, W.R., PÖCH, G., WURM, A., HOLZMANN, S. & PAIETTA, E. (1976). Effect of phosphodiesteraseinhibition on smooth muscle tone. In Ionic Actions on Vascular Smooth Muscle, Betz, E. (ed.) pp. 124–131, Berlin/Heidelberg/New York: Springer-Verlag.CrossRefGoogle Scholar
  40. KUKOVETZ, W.R., WURM, A., HOLZMANN, S. & PÖCH, G. (1979d). Evidence for an adenylate cyclase-linked adenosine receptor mediating coronary relaxation. In Physiological and regulatory function of adenosine and adenine nucleotides. Baer, H.P. & Drummond, C.I. (eds) pp. 205–213, New York: Raven Press.Google Scholar
  41. KUKOVETZ, W.R., WURM, A., RINNER, I., HOLZMANN, S. & POCH, G. (1977). Stimulation of adenylyl cyclase in coronary smooth muscle by adenosine. In Excitation-Contraction Coupling in Smooth Muscle. Casteels, R., Godfraind, T. & Rüegg, J.C. (eds) pp. 399–406, Amsterdam: Elsevier/North-Holland/Biomedical Press.Google Scholar
  42. LINDNER, E., DOHADWALLA, A.N. & BHATTACHARYA, B.K. (1978). Positive inotropic and blood pressure lowering activity of a diterpene derivative isolated from Coleus forskohlii: Forskolin. Arzneimittelforschung (Drug Res.), 28, 284–289.Google Scholar
  43. LITOSCH, I., HUDSON, T.H., MILLS, T., LI, S.Y. & FAIN, J.N. (1982). Forskolin as an activator of cyclic AMP accumulation and lipolysis in rat adipocytes. Mol. Pharmac., 22, 109–115.Google Scholar
  44. MILLER, O.V., AIKEN, J.W., HEMKER, D.P., SHEBUSKI, R.J. & GORMAN, R.R. (1979). Prostacyclin stimulation of dog arterial cyclic AMP levels. Prostaglandins, 18, 915–925.PubMedCrossRefGoogle Scholar
  45. MISTRY, G. & DRUMMOND, G.I. (1983). Effects of adenosine, its analogs, adrenergic agents, and prostaglandins on heart microvessels. In Regulatory Function of Adenosine. Berne, R.M., Rall, R.W. & Rubio, R. (eds) p. 529, Boston: Martinus Nijhoff Publ.Google Scholar
  46. MONCADA, S. & VANE, J.R. (1981). Prostacyclin: its biosynthesis, actions and clinical potential. Phil. Trans. R. Soc., B294, 305–329.CrossRefGoogle Scholar
  47. MORIWAKI, K., ITOH, Y., HDA, S. & ICHIHARA, K. (1982). Forskolin potentiates adrenocorticotropin-induced cyclic AMP production and steroidgenesis in isolated rat adrenal cells. Life Sci., 30, 2235–2240.PubMedCrossRefGoogle Scholar
  48. MULLER, M.J. & BAER, H.P. (1982). Forskolin-induced smooth muscle relaxation: involvement of cyclic AMP. Proc. Can. Fed. Biol. Sci., 25, 627.Google Scholar
  49. MULLER, M.J. & BAER, H.P. (1983). Relaxant effects of forskolin in smooth muscle. Naunyn Schmiedeberg’s Arch. Pharmac., 322, 78–82.CrossRefGoogle Scholar
  50. OLLINGER, P. & KUKOVETZ, W.R. (1983). [3H]Adenosine binding to bovine coronary arteries and myocardium. Eur. J. Pharmac., 93, 35–43.CrossRefGoogle Scholar
  51. OLSSON, R.A. (1983). Adenosine receptors on vascular smooth muscle. In Regulatory Function of Adenosine. Berne, R.A., Rall, T.W. & Rubio, R. (eds) pp. 33–45, Boston: Martinus Nijhoff Publ.CrossRefGoogle Scholar
  52. POCH, G. & HOLZMANN, S. (1980). Quantitative estimation of overadditive and underadditive drug effects by means of theoretical, additive dose response curves. J. Pharmac. Meth., 4, 179–188; Erratum: J. Pharmac. Meth., 5, 183.CrossRefGoogle Scholar
  53. RAPOPORT, R.M. & MURAD, F. (1983). Agonist-induced endothelium-dependent in rat thoracic aorta may be mediated through cGMP. Circ. Res., 52, 352–357.PubMedCrossRefGoogle Scholar
  54. SCHMIDT, K. & BAER, H.P. (1983). Forskolin binding sites in rat liver and brain membranes. Eur. J. Pharmac., 94, 337–340.CrossRefGoogle Scholar
  55. SCHRÖR, K. & RÖSEN, P. (1979). Prostacyclin (PGI2) decreases the cyclic AMP levels in coronary arteries. Naunyn Schmiedeberg’s Arch. Pharmac., 306, 101–103.CrossRefGoogle Scholar
  56. SCHULTZ, K.D., SCHULTZ, K. & SCHULTZ, G. (1977). Sodium nitroprusside and other smooth musclerelaxants increase cyclic GMP levels in rat ductus deferens. Nature, 265, 750–751.PubMedCrossRefGoogle Scholar
  57. SCHÜTZ, W. & BRUGGER, G. (1982). Characterization of [3H]-adenosine binding to media membranes of hog carotid arteries. Pharmacology, 24, 26–34.PubMedCrossRefGoogle Scholar
  58. SEAMON, K.B. & DALY, J.W. (1981a). Forskolin: A unique diterpene activator of cyclic AMP-generating system. J. Cycl. Nucl. Res., 7, 201–224.Google Scholar
  59. SEAMON, K.B. & DALY, J.W. (1981b). Activation of adenylate cyclase by the diterpene forskolin does not require the guanine nucleotide regulatory protein. J. biol. chem., 256, 9799–9801.PubMedGoogle Scholar
  60. SEAMON, K.B., PADGETT, W. & DALY, J.W. (1981). Forskolin: Unique diterpene activator of adenylate cyclase in membranes and in intact cells. Proc. man. Acad. Sci.U.S.A., 78, 3363–3367.CrossRefGoogle Scholar
  61. SIEGL, A.M., DALY, J.W. & SMITH, J.B. (1982). Inhibition of aggregation and stimulation of cyclic AMP generation in intact human platelets by the diterpene forskolin. Mol. Pharmac., 21, 680–687.Google Scholar
  62. SILVER, P.J. & DiSALVO, J. (1979). Adenosine 3′,5′monophosphate-mediated inhibition of myosin light chain phosphorylation in bovine actomyosin. J. biol. Chem., 254, 9951–9954.PubMedGoogle Scholar
  63. SILVER, P.J., SCHMIDT-SILVER, C. & DiSALVO, J. (1982). β-adrenergic relaxation and cAMP kinase activation in coronary arterial smooth muscle. Am. J. Physiol., 242, H177–H184.Google Scholar
  64. SUTHERLAND, E.W., ROBISON, G.A. & BUCHER, R.W. (1968). Some aspects of the biological role of adenosine 3′,5′-monophosphate (cyclic AMP). Circulation, 37, 279–306.CrossRefGoogle Scholar
  65. WATSON, E.L. & DOWD, F.J. (1983). Forskolin: Effects on mouse parotid gland function. Biochem. biophys. Res. Commun., 111, 21–27.PubMedCrossRefGoogle Scholar
  66. ZSOTÉR, T.T., HENEIN, N.F. & WOLCHINSKY, C. (1977). The effect of sodium nitroprusside on the uptake and efflux of 45Ca from rabbit and rat vessels. Eur. J. Pharmac., 45, 7–12.CrossRefGoogle Scholar

Copyright information

© Macmillan Publishers Limited 1984

Authors and Affiliations

  • W. R. Kukovetz
    • 1
  • S. Holzmann
  1. 1.Department of Pharmacodynamics and ToxicologyUniversity of GrazAustria

Personalised recommendations