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.
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References
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.
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.
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.
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.
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.
BROOKER, G., PEDONE, C. & BAROVSKY, K. (1983). Selective reduction of forskolin-stimulated cyclic AMP accumulation by inhibitors of protein synthesis. Science, 220, 1169–1170.
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.
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.
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.
EDVINSSON, L. & FREDHOLM, B.B. (1983). Characterization of adenosine receptors in isolated cerebral arteries of cat. Br. J. Pharmac., 80, 631–637.
FURCHGOTT, R.F. (1983). Role of endothelium in responses of vascular smooth muscle. Circ. Res., 53, 557–573.
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.
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.
GORMAN, R.R., BUNTING, S. & MILLER, O.V. (1977). Modulation of human platelet adenylate cyclase by prostacyclin (PGX). Prostaglandins, 13, 377–388.
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.
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.
HOLZMANN, S. (1982a). Relaxant and cAMP-increasing effects of forskolin in bovine coronary arteries. Naunyn Schmiedeberg’s Arch. Pharmac., 321, (Suppl.) R42.
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.
HOLZMANN, S. (1983). Cyclic GMP as a possible mediator of coronary arterial relaxation by nicorandil (SG-75). J. cardiovasc. Pharmac., 5, 364–370.
HOLZMANN, S., KUKOVETZ, W.R. & SCHMIDT, K. (1980). Mode of action of coronary arterial relaxation by prostacyclin. J. Cycl. Nucl. Res., 6, 451–460.
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.
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.
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.
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.
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.
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.
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.
KUKOVETZ, W.R. & HOLZMANN, S. (1983). Mechanism of nitrate-induced vasodilation and tolerance. Z. Kardiol., 72, Suppl. 3, 14–19.
KUKOVETZ, W.R. & HOLZMANN, S. (1984). Der Wirkungs-mechanismus von Molsidomin und Nitraten. Med. Praxis, Sondernummer 1, 12–17.
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.
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.
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.
KUKOVETZ, W.R., HOLZMANN, S., WURM, A. & PÖCH, G. (1979b). Prostacycin increases cAMP in coronary arteries. J. Cycl. Nucl. Res., 5, 469–476.
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 Schmiedebergs’ Arch. Pharmac., 267, 189–194.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
MONCADA, S. & VANE, J.R. (1981). Prostacyclin: its biosynthesis, actions and clinical potential. Phil. Trans. R. Soc., B294, 305–329.
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.
MULLER, M.J. & BAER, H.P. (1982). Forskolin-induced smooth muscle relaxation: involvement of cyclic AMP. Proc. Can. Fed. Biol. Sci., 25, 627.
MULLER, M.J. & BAER, H.P. (1983). Relaxant effects of forskolin in smooth muscle. Naunyn Schmiedeberg’s Arch. Pharmac., 322, 78–82.
OLLINGER, P. & KUKOVETZ, W.R. (1983). [3H]Adenosine binding to bovine coronary arteries and myocardium. Eur. J. Pharmac., 93, 35–43.
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.
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.
RAPOPORT, R.M. & MURAD, F. (1983). Agonist-induced endothelium-dependent in rat thoracic aorta may be mediated through cGMP. Circ. Res., 52, 352–357.
SCHMIDT, K. & BAER, H.P. (1983). Forskolin binding sites in rat liver and brain membranes. Eur. J. Pharmac., 94, 337–340.
SCHRÖR, K. & RÖSEN, P. (1979). Prostacyclin (PGI2) decreases the cyclic AMP levels in coronary arteries. Naunyn Schmiedeberg’s Arch. Pharmac., 306, 101–103.
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.
SCHÜTZ, W. & BRUGGER, G. (1982). Characterization of [3H]-adenosine binding to media membranes of hog carotid arteries. Pharmacology, 24, 26–34.
SEAMON, K.B. & DALY, J.W. (1981a). Forskolin: A unique diterpene activator of cyclic AMP-generating system. J. Cycl. Nucl. Res., 7, 201–224.
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.
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.
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.
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.
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.
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.
WATSON, E.L. & DOWD, F.J. (1983). Forskolin: Effects on mouse parotid gland function. Biochem. biophys. Res. Commun., 111, 21–27.
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.
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Kukovetz, W.R., Holzmann, S. (1984). Cyclic nucleotides in smooth muscle relaxation. In: Paton, W., Mitchell, J., Turner, P. (eds) IUPHAR 9th International Congress of Pharmacology London 1984. Palgrave Macmillan, London. https://doi.org/10.1007/978-1-349-17613-7_15
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