The Development of Postsynaptic Cardiac Autonomic Receptors and Their Regulation of Cardiac Function During Embryonic, Fetal, and Neonatal Life

  • Achilles J. Pappano
Part of the Developments in Cardiovascular Medicine book series (DICM, volume 34)


The appearance and development of autonomic receptors and of the mechanisms by which these receptors permit extrinsic regulation of cardiac performance are the object of much research. Interest in this subject has been stimulated because of the fundamental importance that a knowledge of receptor properties and receptor mechanisms has for an understanding of the biochemical, physiologic, pharmacologic, and pathologic features of cardiac function [1, 2]. Furthermore, a systematic examination of the ontogenetic sequence for incorporation of autonomic receptors, the inception of receptor-initiated reactions, and the modifications in receptor-dependent functions is essential for our understanding of how autonomic transmitters regulate the heartbeat.


Muscarinic Receptor Positive Inotropic Effect Embryonic Chick Embryonic Heart Muscarinic Cholinergic Receptor 
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  1. 1.
    Hulme EC, Berrie CP, Birdsall NJM, Burgen ASV: Interactions of muscarinic receptors with guanine nucleotides and adenylate cyclase. In: Birdsall NJM (ed) Drug receptors and their effectors. London: MacMillan, 1981, pp 23–24.Google Scholar
  2. 2.
    Watanabe AM, Jones LR, Manalan AS, Besch HR Jr: Cardiac autonomic receptors: recent concepts from radiolabeled ligand-binding studies. Circ Res 50: 161–174, 1982.PubMedCrossRefGoogle Scholar
  3. 3.
    Pappano AJ: Ontogenetic development of autonomic neuroeffector transmission and transmitter reactivity in embryonic and fetal hearts. Pharmacol Rev 29: 333, 1977.Google Scholar
  4. 4.
    Pappano AJ: Adrenergic receptors and adrenergic mechanisms in the embryonic and fetal heart. In: Kunos G (ed) Adrenoceptors and catecholamine action. New York: John Wiley and Sons, 1981, pp 69–97.Google Scholar
  5. 5.
    Pappano AJ, Higgins D: Initiation of transmitter secretion by adrenergic neurons and its relation to morphological and functional innervation of the embryonic chick heart. In: Bouman LN, Jongsma HJ (eds) Cardiac rate and rhythm. Vol 17: Developments in cardiovascular medicine. Boston: Martinus Nijhoff, 1982, pp 631–651.CrossRefGoogle Scholar
  6. 6.
    Higgins D: The ontogeny of the response of the chick embryo heart to autonomic transmitters and to neurotransmitter-like drugs. Pharmacol Ther 20: 53–77, 1983.PubMedCrossRefGoogle Scholar
  7. 7.
    Lakatta EG: Age-related alterations in the cardiovascular response to adrenergic mediated stress. Fed Proc 39: 3173–3177, 1980.PubMedGoogle Scholar
  8. 8.
    Sastre A, Gray DB, Lane MA: Muscarinic cholinergic binding sites in the developing avian heart. Dev Biol 5_5: 201–205, 1977.Google Scholar
  9. 9.
    Galper JR, Klein W, Catterall WA: Muscarinic acetylcholine receptors in developing chick heart. J Biol Chem 252: 8692–8699, 1977.PubMedGoogle Scholar
  10. 10.
    Renaud JF, Barhanin J, Cavey D, Fosset M, Lazdunski M: Comparative properties of the in ovo and in vitro differentiation of the muscarinic cholinergic receptor in embryonic heart cells. Dev Biol 78: 184200, 1980.Google Scholar
  11. 11.
    Hosey MM, Fields JZ: Quantitative and qualitative differences in muscarinic cholinergic receptors in embryonic and newborn chick hearts. J Biol Chem 256: 6395–6399, 1981.PubMedGoogle Scholar
  12. 12.
    Roeske WR, Yamamura HI: Maturation of mammalian myocardial muscarinic cholinergic receptors. Life Sci 23: 127–132, 1978.PubMedCrossRefGoogle Scholar
  13. 13.
    Fields JZ, Roeske WR, Morkin E, Yamamura HI: Cardiac muscarinic cholinergic receptors: biochemical identification and characterization. J Biol Chem 253: 3251–3258, 1978.PubMedGoogle Scholar
  14. 14.
    Galper JB, Smith TW: Agonist and guanine nucleotide modulation of muscarinic cholinergic receptors in cultured heart cells. J Biol Chem 255: 95719579, 1980.Google Scholar
  15. 15.
    Hosey MM: Regulation of antagonist binding to cardiac muscarinic receptors. Biochem Biophys Res Commun 107: 314–321, 1982.PubMedCrossRefGoogle Scholar
  16. 16.
    Siegel RE, Fischbach GD: Muscarinic receptors in intact chick heart cells in culture. Soc Neurosci 6: 358, 1980.Google Scholar
  17. 17.
    Halvorsen SW, Nathanson NM: In vivo regulation of muscarinic acetylcholine receptor number and function in embryonic chick heart. J Biol Chem 256: 7941–7948, 1981.PubMedGoogle Scholar
  18. 18.
    Pappano AJ: Sodium-dependent depolarization of non-innervated embryonic chick heart by acetylcholine. J Pharmacol Exp Ther 180: 340–350, 1972.PubMedGoogle Scholar
  19. 19.
    Sperelakis N: Electrical properties of embryonic heart cells. In: De Mello WC (ed) Electrical phenomena in the heart. New York: Academic, 1972, pp 1–61.Google Scholar
  20. 20.
    Carmeliet EE, Horres CR, Lieberman M, Vereecke JS: Developmental aspects of potassium flux and permeability of the embryonic chick heart. J Physiol (Lond) 254: 673–692, 1976.Google Scholar
  21. 21.
    Pappano AJ, Skowronek CA: Reactivity of chick embryo heart to cholinergic agonists during ontogenesis: decline in desensitization at the onset of cholinergic transmission. J Pharmacol Exp Ther 191: 109118, 1974.Google Scholar
  22. 22.
    Loffelholz K, Pappano AJ: Increased sensitivity of sinoatrial pacemaker to acetylcholine and to catecholamines at the onset of autonomic neuroeffector transmission in chick embryo heart. J Pharmacol Exp Ther 191: 479–486, 1974.PubMedGoogle Scholar
  23. 23.
    Roeske WR, Wildenthal K: Responsiveness to drugs and hormones in the murine model of cardiac onto-genesis. Pharmacol Ther 14: 55–66, 1981.PubMedCrossRefGoogle Scholar
  24. 24.
    Biegon RL, Pappano AJ: Dual mechanism for inhibition of calcium-dependent action potentials by acetylcholine in avian ventricular muscle: relationship to cyclic AMP. Circ Res 46: 353–362, 1980.PubMedCrossRefGoogle Scholar
  25. 25.
    Reuter H: Effects of neurotransmitters on the slow inward current. In: Zipes DP, Bailey JC, Elharrar V (eds) The slow inward current and cardiac arrhythmias. Boston: Martinus Nijhoff, 1980, pp 205–219.CrossRefGoogle Scholar
  26. 26.
    Inoue D, Hachisu M, Pappano AJ: Acetylcholine increases K+ conductance in atrial but not in ventricular muscle during direct inhibition of Cat+-dependent action potentials in chick heart. Circ Res 53: 158–167 1983.PubMedCrossRefGoogle Scholar
  27. 27.
    Lane MA, Sastre A, Law M, Salpeter M: Cholinergic and adrenergic receptors on mouse cardiocytes in vitro. Dev Biol 57: 254–269, 1977.PubMedCrossRefGoogle Scholar
  28. 28.
    Pager J, Bernard C, Gargouïl Y: Evolution, au cours de la croissance foetale, des effets de l’acetylcholine au niveau de l’oreillette du Rat. C R Soc Biol (Poiters) 159: 2470–2475, 1965.Google Scholar
  29. 29.
    Nukari-Siltovuori A: Postnatal development of adrenergic and cholinergic sensitivity in the isolated rat atria. Experientia 33: 1611–1612, 1977.PubMedCrossRefGoogle Scholar
  30. 30.
    Pappano AJ, Biegon RL: Mechanisms for muscarinic inhibition of calcium-dependent action potentials and contractions in developing ventricular muscle: the role of cyclic AMP. In: Paes de Carvalho AP, Hoffman BF, Lieberman M (eds) Normal and abnormal conduction of the heartbeat. Mt Kisco NY: Futura, 1983, pp. 327–344.Google Scholar
  31. 31.
    Josephson I, Sperelakis N: On the ionic mechanism underlying adrenergic-cholinergic antagonism in ventricular muscle. J Gen Physiol 79: 69–86, 1982.PubMedCrossRefGoogle Scholar
  32. 32.
    Reuter H: Über die Abhängigkeit der Acetylcholinwirkung von der äusseren Ca-Konzentration bei isolierten Meerschweinchenvorhofen. Experientia 22: 39–40, 1966.PubMedCrossRefGoogle Scholar
  33. 33.
    Hachisu M, Pappano AJ: A comparative study of the blockade of calcium-dependent action potentials by verapamil, nifedipine and nimodipine in ventricular muscle. J Pharmacol Ther 225: 112–130, 1983.Google Scholar
  34. 34.
    Rodbell M: The role of hormone receptors and GTPregulatory proteins in membrane transduction. Nature 284: 17–22, 1980.PubMedCrossRefGoogle Scholar
  35. 35.
    Watanabe AM, McConnaughey MM, Strawbridge RA, Fleming JW, Jones LR, Besch HR Jr: Muscarinic cholinergic receptor modulation of R-adrenergic receptor affinity for catecholamines. J Biol Chem 253: 4833–4836, 1978.PubMedGoogle Scholar
  36. 36.
    Biegon RL, Epstein PM, Pappano AJ: Muscarinic antagonism of the effects of a phosphodiesterase inhibitor (methylisobutylxanthine) in embryonic chick ventricle. J Pharmacol Exp Ther 215: 348–356, 1980.PubMedGoogle Scholar
  37. 37.
    Pappano AJ, Hartigan PM, Coutu MD: Acetylcholine inhibits the positive inotropic effect of cholera toxin in ventricular muscle. Am J Physiol 243: H434 - H441, 1983.Google Scholar
  38. 38.
    Linden J, Vogel S, Sperelakis N.: Sensitivity of Ca-dependent slow action potentials to methacholine is induced by phosphodiesterase inhibitors in embryonic chick ventricles. J Pharmacol Exp Ther 222: 383–388, 1982.PubMedGoogle Scholar
  39. 39.
    Ingbretsen CG: Interaction between alpha and beta adrenergic receptors and cholinergic receptors in isolated perfused rat heart: effects on cAMP-protein kinase and phosphorylase. J Cyclic Nucleotide Res 6: 121–132, 1980.Google Scholar
  40. 40.
    Keely SL Jr, Lincoln TM, Corbin JD: Interaction of acetylcholine and epinephrine on heart cyclic AMP-dependent protein kinase. Am J Physiol 234: H432 - H438, 1978.PubMedGoogle Scholar
  41. 41.
    Linden J, Brooker G: The questionable role of cyclic guanosine 3’: 5’ -monophosphate in heart. Biochem Pharmacol 28: 3351–3360, 1979.PubMedCrossRefGoogle Scholar
  42. 42.
    Lincoln TM, Keely SL: Effects of acetylcholine and nitroprusside on cGMP-dependent protein kinase in the perfused rat heart. J Cyclic Nucleotide Res 6: 8391, 1980.Google Scholar
  43. 43.
    Furchgott RF, Zawadzki JV: The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature (Lond) 288: 373376, 1980.Google Scholar
  44. 44.
    Demey JG, Claeys M, Vanhoutte PM: Endothelium-dependent inhibitory effects of acetylcholine, adenosine triphosphate, thrombin and arachidonic acid in the canine femoral artery. J Pharmacol Exp Ther 222: 166–173, 1982.Google Scholar
  45. 45.
    Chen F-CM, Yamamura HI, Roeske WR: Ontogeny of mammalian myocardial (3-adrenergic receptors. Eur J Pharmacol 58: 255–264, 1979.PubMedCrossRefGoogle Scholar
  46. 46.
    Williams LT, Lefkowitz RJ: Receptor binding studies in adrenergic pharmacology, chap 9, New York: Raven, 1978.Google Scholar
  47. 47.
    Whitsett JA, Pollinger J, Matz S: (3-Adrenergic receptors and catecholamine sensitive adenylate cyclase in developing rat ventricular myocardium: effect of thyroid status. Pediatr Res 16: 463–469, 1982.PubMedCrossRefGoogle Scholar
  48. 48.
    Alexander RW, Galper JB, Neer EJ, Smith TW: Non-co-ordinate development of (3-adrenergic receptors and adenylate cyclase in chick heart. Biochem J 204: 825–830, 1982.PubMedGoogle Scholar
  49. 49.
    Whitsett JA, Darovec-Beckerman C: Developmental aspects of beta adrenergic receptors and catecholamine-sensitive adenylate cyclase in rat myocardium. Pediatr Res 15: 1363–1369, 1981.PubMedCrossRefGoogle Scholar
  50. 50.
    Chen F-CM, Yamamura HI, Roeske WR: Adenylate cyclase and beta adrenergic receptor development in the mouse heart. J Pharmacol Exp Ther 222: 7–13, 1982.PubMedGoogle Scholar
  51. 51.
    Ignarro LJ, Shideman FE: Appearance and concentrations of catecholamines and their biosynthesis in the embryonic and developing chick. J Pharmacol Exp Ther 159: 38–48, 1968.PubMedGoogle Scholar
  52. 52.
    Higgins D, Pappano AJ: Development of transmitter secretory mechanisms by adrenergic neurons in the embryonic chick heart ventricle. Devel Biol 87: 148162, 1981.Google Scholar
  53. 53.
    Wacholtz MC, Sha’afi RI: Alprenol binding and cyclic AMP production in embryonic chick red cells during erythropoiesis. Membr Biochem 3: 259–270, 1980.PubMedCrossRefGoogle Scholar
  54. 54.
    Higgins D, Pappano AJ: Developmental changes in the sensitivity of the chick embryo ventricle to [3adrenergic agonist during adrenergic innervation. Circ Res 48: 245–253, 1981.PubMedCrossRefGoogle Scholar
  55. 55.
    Baker SP, Potter LT: Cardiac 43-adrenoceptors during normal growth of male and female rats. Br J Pharmacol 68: 65–70, 1980.PubMedCrossRefGoogle Scholar
  56. 56.
    Bhalla RC, Sharma RV, Ramanathan S: Ontogenetic development of isoproterenol subsensitivity of myocardial adenylate cyclase and 3-adrenergic receptors in spontaneously hypertensive rats. Biochim Biophys Acta 632: 497–506, 1980.PubMedCrossRefGoogle Scholar
  57. 57.
    Lau C, Slotkin TA: Maturation of sympathetic neurotransmission in the rat heart. II. Enhanced development of presynaptic and postsynaptic components of noradrenergic synapses as a result of neonatal hyperthyroidism. J Pharmacol Exp Ther 212: 126–130, 1980.PubMedGoogle Scholar
  58. 58.
    Lau C, Slotkin TA: Maturation of sympathetic neurotransmission in the rat heart. VIII. Slowed development of noradrenergic synapses resulting from hypothyroidism. J Pharmacol Exp Ther 220: 629–636, 1982.PubMedGoogle Scholar
  59. 59.
    Tsai JS, Chen A: Effect of L-triiodothyronine on (-)3H-dihydroalprenolol binding and cyclic AMP response to (-) adrenaline in cultured heart cells. Nature 275: 138–140, 1978.PubMedCrossRefGoogle Scholar
  60. 60.
    Sperelakis N: Changes in membrane electrical properties during development of the heart. In: Zipes DP, Bailey JC, Elharrar V (eds) The slow inward current and cardiac arrhythmias. Boston: Martinus Nijhoff, 1980, pp 221–262.CrossRefGoogle Scholar
  61. 61.
    Shigenobu K, Sperelakis N: Calcium current channels induced by catecholamines in chick embryonic hearts whose fast sodium channels are blocked by tetrodotoxin or elevated potassium. Circ Res 31: 93 2952, 1972.Google Scholar
  62. 62.
    Hagiwara S, Takahashi K: Surface density of calcium ions and calcium spikes in the barnacle muscle fiber membrane. J Gen Physiol 50: 583–601, 1967.PubMedCrossRefGoogle Scholar
  63. 63.
    Brown HF, McNaughton PA, Noble D, Noble SJ: Adrenergic control of cardiac pacemaker currents. Philos Trans R Soc Lond 270: 527–537, 1975.CrossRefGoogle Scholar
  64. 64.
    Tsien RW, Giles W, Greengard P: Cyclic AMP mediates the effects of adrenaline on cardiac Purkinje fibers. Nature 240: 181–183, 1972.Google Scholar
  65. 65.
    Pappano AJ, Carmeliet EE: Epinephrine and the pacemaking mechanism at plateau potentials in sheep cardiac Purkinje fibers. Pflugers Arch 382: 17–26, 1979.PubMedCrossRefGoogle Scholar
  66. 66.
    Standen NB: The postnatal development of adrenoceptor responses to agonists and electrical stimulation in rat isolated atria. Br J Pharmacol 64: 83–89, 1978.PubMedCrossRefGoogle Scholar
  67. 67.
    Mackenzie E, Standen NB: The postnatal develop ment of adrenoceptor responses in isolated papillary muscles from rat. Pflugers Arch 383: 185–187, 1980.PubMedCrossRefGoogle Scholar
  68. 68.
    Seidler FJ, Slotkin TA: Presynaptic and postsynaptic contributions to ontogeny of sympathetic control of heart rate in the pre-weanling rat. Br J Pharmacol 65: 431–434, 1979.PubMedCrossRefGoogle Scholar
  69. 69.
    Ishii K, Shigenobu K, Kasuya Y: Postjunctional supersensitivity in young rat heart produced by immunological and chemical sympathectomy. J Pharmacol Exp Ther 220: 209–215, 1982.PubMedGoogle Scholar
  70. 70.
    Azuma J, Sawamura A, Harada H, Tanimoto T, Ishiyama T, Morita Y, Yamamura Y, Sperelakis N: Cyclic adenosine-monophosphate modulation of contractility via slow Ca2+ channels in chick heart. J Mol Cell Cardiol 13: 577–587, 1981.PubMedCrossRefGoogle Scholar
  71. 71.
    Poison JB, Goldberg ND, Shideman FE: Norepinephrine-and isoproterenol-induced changes in cardiac contractility and cyclic adenosine 3’:5’-monophosphate levels during early development of the embryonic chick. J Pharmacol Exp Ther 200: 630637, 1977.Google Scholar
  72. 72.
    Renaud J-F, Sperelakis N, Le Douarin G: Increase of cyclic AMP levels induced by isoproterenol in cultured and non-cultured chick embryonic hearts. J Mol Cell Cardiol 10: 281–286, 1978.PubMedCrossRefGoogle Scholar
  73. 73.
    Marsh JD, Barry WH, Neer EJ, Alexander RW, Smith TW: Desensitization of chick embryo ventricle to the physiological and biochemical effects of isoproterenol. Circ Res 47: 493–51, 1980.PubMedCrossRefGoogle Scholar
  74. 74.
    Bobik A, Campbell JH, Carson V, Campbell GR: Mechanism of isoprenaline-induced refractoriness of the 13-adrenoceptor-adenylate cyclase system in chick embryo cardiac cells. J Cardiovasc Pharmacol 3: 54 1553, 1981.Google Scholar
  75. 75.
    Hosey MM, Green RD: Effects of isoproterenol on cyclic AMP and cyclic AMP-dependent protein kinase in developing chick myocardium. Biochim Biophys Acta 500: 152–161, 1977.PubMedCrossRefGoogle Scholar
  76. 76.
    Haddox MK, Roeske WR, Russell DH: Independent expression of cardiac type I and II cyclic AMP-dependent protein kinase during murine embryogenesis and postnatal development. Biochim Biophys Acta 585: 527–534, 1979.PubMedCrossRefGoogle Scholar
  77. 77.
    Claycomb WC: Biochemical aspects of cardiac muscle differentiation: possible control of deoxyribonucleic acid synthesis and cell differentiation by adrenergic innervation and cyclic adenosine 3’:5’monophosphate. J Biol Chem 251: 6082–6089, 1976.PubMedGoogle Scholar
  78. 78.
    Au TLS, Collins GA, Walker MJA: Rate, force and cyclic adenosine 3’,5’-monophosphate responses to (-)-adrenaline in neonatal rat heart tissue. Br J Pharmacol 69: 601–608, 1980.PubMedCrossRefGoogle Scholar
  79. 79.
    Clark JB, Vinicor F, Carr L, Clark CM Jr: Adenylyl cyclase responsiveness to guanyl nucleotides in the developing rat heart. Pediatr Res 14: 291–295, 1980.PubMedCrossRefGoogle Scholar
  80. 80.
    Rockson SG, Homcy CJ, Quinn P, Manders WT Haber E, Vatner SF: Cellular mechanisms of impaired adrenergic responsiveness in neonatal dogs. J Clin Invest 67: 319–327, 1981.Google Scholar
  81. 81.
    Hodach RJ, Hodach AE, Fallon JF, Folts JD, Bruyere HJ, Gilbert EF: The role of (3-adrenergic activity in the production of cardiac and aortic arch anomalies in chick embryos. Teratology 12: 33–46, 1975.PubMedCrossRefGoogle Scholar
  82. 82.
    Official B, Rychter Z, Rychterovâ V: The action of isoproterenol on the chick embryo heart. J Mol Cell Cardion 8: 533–544, 1976.CrossRefGoogle Scholar
  83. 83.
    Janatovâ T, Oslâdal B, Dusek J: The effect of intraamnial administration of isoprenaline and dibutyryl cAMP on the chick embryonic heart. Physiol Bohemoslovaca 30: 432, 1981.Google Scholar
  84. 84.
    Oslâdal B, Krause E-G, Beyerdorfer I, Pelough V, Wollenberger A: Effect of intra-amnial administration of a cardiotoxic dose of isoproterenol on cyclic AMP levels in the chick embryo heart. J Mol Cell Cardiol 11: 1183–1187, 1979.CrossRefGoogle Scholar
  85. 85.
    Yamada S, Yamamura HI, Roeske WR: Ontogeny of a,-adrenergic receptors in the mammalian myocardium. Eur J Pharmacol 68: 217–221, 1980.PubMedCrossRefGoogle Scholar
  86. 86.
    Yamada S, Yamamura HI, Roeske WR: The regulation of cardiac a.1-adrenergic receptors by guanine nucleotides and by muscarinic cholinergic agonists. Eur J Pharmacol 63: 239–241, 1980.PubMedCrossRefGoogle Scholar
  87. 87.
    Scholz H: Effects of beta-and alpha-adrenoreceptor activators and adrenergic transmitter releasing agents on the mechanical activity of the heart. Handbook Exp Pharmacol 54: 651–733, 1980.CrossRefGoogle Scholar
  88. 88.
    Benfey BG, Carolin T: Effect of phenylephrine on cardiac contractility and adenyl cyclase activity. Can J Physiol Pharmacol 49: 508–512, 1971.PubMedCrossRefGoogle Scholar
  89. 89.
    Higgins D: The development of the adrenergic innervation of the chick embryo ventricle. PhD thesis, University of Connecticut, Storrs, 1980.Google Scholar
  90. 90.
    Rosen MR, Hordof AJ, Ilvento JP, Danilo P Jr: Effects of adrenergic amines on electrophysiological properties and automaticity of neonatal and adult canine Purkinje fibers. Circ Res 40: 390–400, 1977.PubMedCrossRefGoogle Scholar
  91. 91.
    Hauswirth O, Wehner HD, Ziskoven R: a-Adrenergic receptors and pacemaker current in cardiac Purkinje fibers. Nature (Lond) 263: 155–156, 1976.CrossRefGoogle Scholar

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© Springer Science+Business Media Dordrecht 1984

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  • Achilles J. Pappano

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