Aging Clinical and Experimental Research

, Volume 9, Issue 6, pp 391–403 | Cite as

Alterations in β-adrenoceptor mechanisms in the aging heart. Relationship with heart failure

  • N. Ferrara
  • K. Davia
  • P. Abete
  • F. Rengo
  • S. E. Harding
Review Article


In chronic heart failure substantial and characteristic changes occur in the function of the adrenergic nervous system. Studies in isolated left ventricular muscle and in single cardiomyocytes from experimental models of aging and, recently, from humans show an age-related reduced contractile response to β-adrenoceptor stimulation. “β-adrenoceptor desensitization” is thought to be a general and common mechanism to explain the age- and heart failure-related decrease in β-adrenoceptor response. The aim of this review is to compare alterations in β-adrenoceptor mechanisms in physiological cardiovascular aging and chronic heart failure. From an analysis of the overall data on the role of aging in β-adrenoceptor regulation in human and animal hearts, it is possible to conclude that the reduced response to β-agonists is common to all species and all cardiac tissues. Moreover, the age-related changes are limited to β-adrenoceptor-G-protein (s)-adenylyl cyclase system abnormalities, while the type and level of abnormalities change with species and tissues. The modifications shown in the aging heart are not very different from some observed in heart failure. In particular, both in aged and failing hearts we may see that the decrease in β-adrenoceptor responsiveness is related to changes in G-protein function.

Key words

Aging heart failure β-adrenergic receptor β-adrenoceptor desensitization G-protein 


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  1. 1.
    Bristow M.R., Ginsburg R., Minobe W., Cubicciotti R.S., Sageman W.S., Lurie K., Billingham M.E., Harrison D.C., Stinson E.B.: Decreased catecholamine sensitivity and beta-adrenergic receptor density in failing human hearts. N. Engl. J. Med. 307: 205–211, 1982.PubMedGoogle Scholar
  2. 2.
    Bristow M.R., Anderson F.L., Port J.D., Skerl L., Hershberger R.E., Larrabee P., O’Connell J.B., Renlund D.G., Volkman K., Murray J., Feldman A.M.: Differences in beta-adrenergic neuroeffector mechanisms in ischemic versus dilated cardiomyopathy. Circulation 84: 1024–1039, 1991.PubMedGoogle Scholar
  3. 3.
    Frey M.J., Lanoce V., Molinoff P.B., Wilson J.R.: Skeletal muscle beta-receptors and isoproterenol-stimulated vasodilation in canine heart failure. J. Appl. Physiol. 67: 2026–2031, 1989.PubMedGoogle Scholar
  4. 4.
    Harding S.E., Jones S.M., O’Gara P., Del Monte F., Vescovo G., Poole-Wilson P.A.: Isolated ventricular myocytes from failing and non-failing human heart; the relation of age and clinical status of patients to isoproterenol response. J. Mol. Cell. Cardiol. 24: 549–564, 1992.PubMedGoogle Scholar
  5. 5.
    Harding S.E., Brown L.A., Wynne D.G., Davies C.H., Poole-Wilson P.A.: Mechanisms of beta-adrenoceptor desensitisation in the failing human heart. Cardiovasc. Res. 28: 1451–1460, 1994.PubMedGoogle Scholar
  6. 6.
    Davies C.H., Ferrara N., Harding S.E.: Beta-adrenoceptor function changes with age of subject in myocytes from non-failing ventricle. Cardiovasc. Res. 31: 152–156, 1996.PubMedGoogle Scholar
  7. 7.
    Ferrara N., O’Gara P., Wynne D.G., Brown L.A., Del Monte F., Poole-Wilson P.A., Harding S.E.: Decreased contractile responses to isoproterenol in isolated cardiac myocytes from ageing guinea-pigs. J. Mol. Cell. Cardiol. 27: 1141–1150, 1995.PubMedGoogle Scholar
  8. 8.
    Guarnieri T., Filburn C.R., Zitnik G., Roth G.S., Lakatta E.G.: Contractile and biochemical correlates of β-adrenergic stimulation of the aged heart. Am. J. Physiol. 239: H501–H508, 1980.PubMedGoogle Scholar
  9. 9.
    Rodeheffer R.J., Gerstenblith G., Becker L.C., Fleg J.L., Weisfeldt M.L., Lakatta E.G.: Exercise cardiac output is maintained with advancing age in healthy human subjects: cardiac dilatation and increased stroke volume compensate for a diminished heart rate. Circulation 69: 203–213, 1984.PubMedGoogle Scholar
  10. 10.
    White M., Roden R., Minobe W., Khan M.F., Larrabee P., Wollmering M., Port J.D., Anderson F., Campbell D., Feldman A.M., Bristow M.R.: Age-related changes in beta-adrenergic neuroeffector systems in the human heart. Circulation 90: 1225–1238, 1994.PubMedGoogle Scholar
  11. 11.
    Sibley D.R., Strasser R.H., Caron M.G., Lefkowitz R.J.: Homologous desensitization of adenylate cyclase is associated with phosphorylation of the beta-adrenergic receptor. J. Biol. Chem. 260: 3883–3886, 1985.PubMedGoogle Scholar
  12. 12.
    Reithmann C., Werdan K.: Homologous vs. heterologous desensitization of the adenylate cyclase system in heart cells. Eur. J. Pharmacol. 154: 99–104, 1988.PubMedGoogle Scholar
  13. 13.
    Beltrami C.A., Finato N., Rocco M., Feruglio G.A., Puricelli C., Cigola E., Quaini F., Sonnenblick E.H., Olivetti G., Anversa P.: Structural basis of end-stage failure in ischemic cardiomyopathy in humans. Circulation 89: 151–163, 1994.PubMedGoogle Scholar
  14. 14.
    Del Monte F., Harding S.E., Rosano G.M.C., Poole-Wilson P.A.: Contractile properties of hypertrophic and non-hypertrophic human ventricular myocytes. J. Am. Coll. Cardiol.21: 284A (Abstract), 1993.Google Scholar
  15. 15.
    Gerdes A.M., Kellerman S.E., Moore J.A., Muffly K.E., Clark L.C., Reaves P.Y., Malec K.B., Mckeown P.P., Schocken D.D.: Structural remodeling of cardiac myocytes in patients with ischemic cardiomyopathy. Circulation 86: 426–430, 1992.PubMedGoogle Scholar
  16. 16.
    Schaper J., Froede R., Hein S., Buck A., Hashizume H., Speiser B., Friedl A., Bleese N.: Impairment of the myocardial ultrastructure and changes of the cytoskeleton in dilated cardiomyopathy. Circulation 83: 504–514, 1991.PubMedGoogle Scholar
  17. 17.
    Arai M., Alpert N.R., Maclennan D.H., Barton P., Periasamy M.: Alterations in sarcoplasmic reticulum gene expression in human heart failure. A possible mechanism for alterations in systolic and diastolic properties of the failing myocardium. Circ. Res. 72: 463–469, 1993.PubMedGoogle Scholar
  18. 18.
    Beuckelmann D.J., Nabauer M., Erdmann E.: Intracellular calcium handling in isolated ventricular myocytes from patients with terminal heart failure. Circulation 85: 1046–1055, 1992.PubMedGoogle Scholar
  19. 19.
    Grossman W.: Diastolic dysfunction and congestive heart failure. Circulation 81(Suppl. 2): 1–7, 1990.Google Scholar
  20. 20.
    Gwathmey J.K., Copelas L., Mackinnon R., Schoen F.J., Feldman M.D., Grossman W., Morgan J.P.: Abnormal calcium handling in myocardium from patients with end-stage heart failure. Circ. Res. 61: 70–76, 1987.PubMedGoogle Scholar
  21. 21.
    Litwin S.E., Grossman Diastolic dysfunction as a cause of heart failure. J. Am. Coll. Cardiol. 22: 49–55, 1993.Google Scholar
  22. 22.
    Mercadier J.J., Lompre A.M., Duc P., Boheler K.R., Fraysse J.B., Wisnewsky C., Allen P.D., Komajda M., Schwartz K.: Altered sarcoplasmic reticulum Ca2(+)-ATPase gene expression in the human ventricle during end-stage heart failure. J. Clin. Invest. 85: 305–309, 1990.PubMedCentralPubMedGoogle Scholar
  23. 23.
    Anversa P., Hiler B., Ricci R., Guideri G., Olivetti G.: Myocyte cell loss and myocyte hypertrophy in the aging rat heart. J. Am. Coll. Cardiol. 8: 1441–1448, 1986.PubMedGoogle Scholar
  24. 24.
    Eghbali M., Webert K.T.: Collagen type I expression in the heart. Ann. N.Y. Acad. Sci. USA 580: 468–472, 1990.Google Scholar
  25. 25.
    Fraticelli A., Josephson R., Danziger R., Lakatta E., Spurgeon H.: Morphological and contractile characteristics of rat cardiac myocytes from maturation to senescence. Am. J. Physiol. 257: H259–H265, 1989.PubMedGoogle Scholar
  26. 26.
    Olivetti G., Melissari M., Capasso J.M., Anversa P.: Cardiomyopathy of the aging human heart. Myocyte loss and reactive cellular hypertrophy. Circ. Res. 68: 1560–1568, 1991.PubMedGoogle Scholar
  27. 27.
    Lakatta E., Mitchell J.H., Pomerance A., Rowe G.G.: Human aging: changes in structure and function. J. Am. Coll. Cardiol. 10: 42a–47a, 1987.PubMedGoogle Scholar
  28. 28.
    Tomanek R.J., Taunton C.A., Liskop K.S.: Relationship between age, chronic exercise, and connective tissue of the heart. J. Gerontol. 27: 33–38, 1972.PubMedGoogle Scholar
  29. 29.
    Besse S., Assayag P., Delcayre C., Carre F., Cheav S-L., Lecarpentier Y., Swynghedauw B.: Normal and hypertrophied senescent rat heart: mechanical and molecular characteristics. Am. J. Physiol. 265: H183–H190, 1993.PubMedGoogle Scholar
  30. 30.
    Capasso J.M., Malhotra A., Remily R.M., Scheuer J., Sonnenblick E.H.: Effects of age on mechanical and electrical performance of rat myocardium. Am. J. Physiol. 245: H72–H81, 1983.PubMedGoogle Scholar
  31. 31.
    Froehilch J.P., Lakatta E.G., Beard E., Spurgeon H.A., Weisfeldt M.L., Gerstenblith G.: Studies of sarcoplasmic reticulum function and contraction duration in young adult and aged rat myocardium. J. Mol. Cell. Cardiol. 10: 427–438, 1978.Google Scholar
  32. 32.
    Lompre A.M., Lambert F., Lakatta E., Schwartz K.: Expression of sarcoplasmic reticulum Ca2+ATPase and calsequestrin genes in rat heart during ontogenic development and aging. Circ. Res. 69: 1380–1388, 1991.PubMedGoogle Scholar
  33. 33.
    Maciel L.M.Z., Polikar D., Rohrer D., Popovich B.K., Dillman W.H.: Age-induced decreases in the messenger RNA coding Ca2+-ATPase of the rat heart. Circ. Res. 67: 230–234, 1990.PubMedGoogle Scholar
  34. 34.
    Schulman S.P., Lakatta E., Fleg J.L., Lakatta L., Becker L.C., Gerstenblith G.: Age-related decline in left ventricular filling at rest and exercise. Am. J. Physiol. 263: H1932–H1938, 1992.PubMedGoogle Scholar
  35. 35.
    Wei J.Y., Spurgeon H.A., Lakatta E.: Excitation-contraction in rat myocardium: alterations with adult aging. Am. J. Physiol. 246: H784–H791, 1984.PubMedGoogle Scholar
  36. 36.
    Alquist R.F.: A study of the adrenotropic receptors. Am. J. Physiol. 153: 586–600, 1948.Google Scholar
  37. 37.
    Emorine L.J., Marullo S., Briend Sutren M.M., Patey G., Tate K., Klutchko C., Strosberg A.D.: Molecular characterization of the human beta 3-adrenergic receptor. Science 245: 1118–1121, 1989.PubMedGoogle Scholar
  38. 38.
    Frielle T., Collins S., Daniel K.W., Caron M.G., Lefkowitz R.J., Kobilka B.K.: Cloning of the cDNA for the human Beta-1 adrenergic receptor. Proc. Natl. Acad. Sci. USA 84: 7920–7924, 1987.PubMedGoogle Scholar
  39. 39.
    Frielle T., Caron M.G., Lefkowitz R.J.: Properties of the beta 1- and beta 2-adrenergic receptor subtypes revealed by molecular cloning. Clin. Chem. 35: 721–725, 1989.PubMedGoogle Scholar
  40. 40.
    Frielle T., Kobilka B., Lefkowitz R.J., Caron M.G.: Human beta 1- and beta 2-adrenergic receptors: structurally and functionally related receptors derived from distinct genes. Trends Neurosci. 11: 321–324, 1988.PubMedGoogle Scholar
  41. 41.
    Brodde O.E.: Beta-adrenoceptors in cardiac disease (Review). Pharmacol. Ther. 60: 405–430, 1993.PubMedGoogle Scholar
  42. 42.
    Marullo S., Emorine L.J., Strosberg A.D., Delavier-Klutchko C.: Selective binding of ligans to beta1, beta2 or chimerc beta1/beta2-adrenergic receptors involves multiple subsites. Embo Journal 9: 1471–1476, 1990.PubMedGoogle Scholar
  43. 43.
    Altschuld R.A., Starling R.C., Hamlin R.L., Billman G.E., Hensley J., Castillo L.C., Fertel R.H., Hohl C.M., Robitaille P-M.L., Jones L.R., Xiao R-P., Lakatta E.G.: Response of failing canine and human heart cells to beta-2 adrenergic stimulation. Circulation 92: 1612–1618, 1995.PubMedGoogle Scholar
  44. 44.
    Borea P.A., Amerini S., Masini I., Cerbai E., Ledda F., Mantelli L., Varani K., Mugelli A.: Beta 1- and beta 2-adrenoceptors in sheep cardiac ventricular muscle. J. Mol. Cell. Cardiol. 24: 753–763, 1992.PubMedGoogle Scholar
  45. 45.
    Lemoine H., Kaumann A.J.: Regional differences of beta 1- and beta 2-adrenoceptor-mediated functions in feline heart. A beta 2-adrenoceptor-mediated positive inotropic effect possibly unrelated to cyclic AMP. Naunyn Schmiedebergs Arch. Pharmacol. 344: 56–69, 1991.PubMedGoogle Scholar
  46. 46.
    Del Monte F., Kaumann A.J., Poole-Wilson P.A., Wynne D.G., Harding S.E.: Coexistence of functioning b1- and b2-adrenoceptors in single myocytes from human ventricle. Circulation 88: 854–863, 1993.PubMedGoogle Scholar
  47. 47.
    Freissmuth M., Hausleithner V., Nees S., Bock M., Schutz W.: Cardiac ventricular beta 2-adrenoceptors in guinea pigs and rats are localized on the coronary endothelium. Naunyn Schmiedebergs Arch. Pharmacol. 334: 56–62, 1986.PubMedGoogle Scholar
  48. 48.
    Milano C.A., Allen L.F., Rockman H.A., Dolber P.C., McMinn T.R., Chien K.R., Johnson T.D., Bond R.A., Lefkowitz R.J.: Enhanced myocardial function in transgenic mice overexpressing the beta 2-adrenergic receptor. Science 264: 582–586, 1994.PubMedGoogle Scholar
  49. 49.
    Kuznetsov V., Pak E., Robinson R.B., Steinberg S.F.: Beta 2-adrenergic receptor actions in neonatal and adult rat ventricular myocytes. Circ. Res. 76: 40–52, 1995.PubMedGoogle Scholar
  50. 50.
    Xiao R-P., Lakatta E.G.: β1-adrenoceptor stimulation and β2-adrenoceptor stimulation differ in their effects on contraction, cytosolic Ca2+ and Ca2+ current in single rat ventricular cells. Circ. Res. 73: 286–300, 1993.PubMedGoogle Scholar
  51. 51.
    Buxton I.L.O., Brunton L.L.: Direct analysis of beta-adrenergic receptor subtypes in intact adult ventricular myocytes of the rat. Circ. Res. 56: 126–132, 1985.PubMedGoogle Scholar
  52. 52.
    Kitagawa Y., Adachi-Akahane S., Nagao T.: Determination of beta-adrenoceptor subtype on rat isolated ventricular myocytes by use of highly selective beta-antagonists. Br. J. Pharmacol. 116: 1635–1643, 1995.PubMedGoogle Scholar
  53. 53.
    Kaumann A.J., Lemoine H.: Beta2-adrenoceptor-mediated positive inotropic effect of adrenaline in human ventricular myocardium. Naunyn Schmiedebergs Arch. Pharmacol. 335: 403–411, 1987.PubMedGoogle Scholar
  54. 54.
    Kaumann A.J., Hall J.A., Murray K.J., Wells F.C., Brown M.J.: A comparison of the effects of adrenaline and noradrenaline on human heart: the role of beta 1-and beta 2-adrenoceptors in the stimulation of adenylate cyclase and contractile force. Eur. Heart J. 10: 29–37, 1989.PubMedGoogle Scholar
  55. 55.
    Gauthier C., Tavernier G., Charpentier F., Langin D., Le Marec H.: Functional beta3-adrenoceptors in the human heart. J. Clin. Invest. 98: 556–562, 1996.PubMedCentralPubMedGoogle Scholar
  56. 56.
    Kaumann A.J., Sanders L., Hall J.A., Murray K.J., Brown M.J.: Stimulation of β1- and β2-adrenoceptors in human ventricular myocardium from failing hearts hastens the onset of relaxation. Br. J. Pharmacol. 105: 283P (Abstract), 1992.Google Scholar
  57. 57.
    Hall J.A., Kaumann A.J., Brown M.J.: Selective beta 1-adrenoceptor blockade enhances positive inotropic responses to endogenous catecholamines mediated through beta 2-adrenoceptors in human atrial myocardium. Circ. Res. 66: 1610–1623, 1990.PubMedGoogle Scholar
  58. 58.
    Hall J.A., Petch M.C., Brown M.J.: In vivo demonstration of cardiac beta 2-adrenoreceptor sensitization by beta 1-antagonist treatment. Circ. Res. 69: 959–964, 1991.PubMedGoogle Scholar
  59. 59.
    Abrass I.B., Scapace P.J.: Human lymphocytes beta-adrenergic receptors are unaltered with age. J. Gerontol. 36: 298–301, 1981.PubMedGoogle Scholar
  60. 60.
    Doyle V., O’Malley K., Kelly J.G.: Human lymphocytes beta-adrenoceptor density in relation to age and hypertension. J. Cardiovasc. Pharmacol. 4: 738–740, 1982.PubMedGoogle Scholar
  61. 61.
    Landmann R., Bittiger H., Buhler F.R.: High affinity beta2-adrenergic receptors in mononuclear leucocytes: similar density in young and old normal subjects. Life Sci. 29: 1761–1771, 1981.PubMedGoogle Scholar
  62. 62.
    Bohm M., Dorner H., Htun P., Lensche H., Platt D., Erdmann E.: Effects of exercise on myocardial adenylate cyclase and Gi alpha expression in senescence. Am. J. Physiol. 264: H805–H814, 1993.PubMedGoogle Scholar
  63. 63.
    Bazan A., Van De Velde E., Fraeyman N.: Effect of age on beta-receptors, Gs alpha- and Gi alpha-proteins in rat heart. Biochem. Pharmacol. 48: 479–486, 1994.PubMedGoogle Scholar
  64. 64.
    Gudmundsdottir E., Benediktsdottir V.E., Gudbjarnason S.: Combined effects of age and dietary fat on beta 1-receptors and Ca2+ channels in rat hearts. Am. J. Physiol. 260: H66–H72, 1991.PubMedGoogle Scholar
  65. 65.
    Ferrara N., Bohm M., Zolk O., O’Gara P., Harding S.E.: The role of Gi-proteins and β-adrenoceptors in the age-re lated decline of contraction in guinea-pig ventricular myocytes. J. Mol. Cell. Cardiol. 29: 439–448, 1997.PubMedGoogle Scholar
  66. 66.
    Cerbai E., Guerra L., Varani K., Barbieri M., Borea P.A., Mugelli A.: Beta-adrenoceptor subtypes in young and old rat ventricular myocytes: a combined patch-clamp and binding study. Br. J. Pharmacol. 116: 1835–1842, 1995.PubMedGoogle Scholar
  67. 67.
    Brodde O.E., Zerkowski H.R., Schranz D., Broede-Sitz A., Michel-Reher M., Schafer-Beisenbusch E., Piotrowski J.A., Oelert H.: Age-dependent changes in the beta-adrenoceptor-G-protein(s)-adenylyl cyclase system in human right atrium. J. Cardiovasc. Pharmacol. 26: 20–26, 1995.PubMedGoogle Scholar
  68. 68.
    Fowler M.B., Laser J.A., Hopkins G.L., Minobe W., Bristow M.R.: Assessment of the β-adrenergic receptor pathway in the intact failing human heart: progressive receptor down-regulation and subsensitivity to agonist response. Circulation 74: 1290–1302, 1986.PubMedGoogle Scholar
  69. 69.
    Molenaar P., Russell F.D., Shimada T., Summers R.J.: Function, characterization and autoradiographic localization and quantitation of beta-adrenoceptors in cardiac tissues. Clin. Exp. Pharmacol. Physiol. 16: 529–533, 1989.PubMedGoogle Scholar
  70. 70.
    Summers R.J., Molenaar P., Russell F., Elnatan J., Jones C.R., Buxton B.F., Chang V., Hambley J.: Coexistence and localization of beta1- and beta 2-adrenoceptors in the human heart. Eur. Heart J. 10 (Suppl. B): 11–21, 1989.PubMedGoogle Scholar
  71. 71.
    Merlet P., Delforge J., Syrota A., Angevin E., Maziere B., Crouzel C.H., Valette H., Loisance D., Castaigne A., Rande J.L.D.: Positron emission tomography with CGP 12177 to assess beta-adrenergic receptor concentration in idiopathic dilated cardiomyopathy. Circulation 87: 1169–1178, 1993.PubMedGoogle Scholar
  72. 72.
    Delehanty J.M., Himura Y., Elam H., Hood W.B. Jr., Liang C.S.: Beta-adrenoceptor downregulation in pacing-induced heart failure is associated with increased interstitial NE content. Am. J. Physiol. 266: H930–H935, 1994.PubMedGoogle Scholar
  73. 73.
    Brodde O.E., Schuler S., Kretsch R., Brinkmann M., Borst H.G., Hetzer R., Reidmeister J.C., Warnecke H., Zerkowski H.R.: Regional distribution of beta-adrenoceptors in the human heart: coexistence of functional beta1- and beta 2-adrenoceptors in both atria and ventricles in severe congestive cardiomyopathy. J. Cardiovasc. Pharmacol. 8: 1235–1242, 1986.PubMedGoogle Scholar
  74. 74.
    Bristow M.R., Ginsburg R., Umans V., Fowler M., Minobe Rasmussen R., Zera P., Menlove R., Shah P., Jamieson S., Stinson E.B.: B1-and B2-adrenergic receptor subpopulations in nonfailing and failing human ventricular myocardium: Coupling of both receptor subtypes to muscle contraction and selective B1-receptor down-regulation in heart failure. Circ. Res. 59: 297–309, 1986.PubMedGoogle Scholar
  75. 75.
    Lands A.M., Arnold A., Mcauliff J.P., Luduena F.P., Brown T.G.: Differentiation of receptor systems activated by sympathomimetic amines. Nature 214: 597–598, 1967.PubMedGoogle Scholar
  76. 76.
    Anderson F.L., Port J.D., Reid B.B., Larrabee P., Hanson G., Bristow M.R.: Myocardial catecholamine and neuropeptide Y depletion in failing ventricles of patients with idiopathic dilated cardiomyopathy. Correlation with beta-adrenergic receptors down-regulation. Circulation 85: 46–53, 1992.PubMedGoogle Scholar
  77. 77.
    Brodde O.E., Zerkowski H.R., Doetsch N., Motomura S., Khamssi M.: Myocardial beta-adrenoceptor changes in heart failure: concomitant reduction in beta 1- and beta 2-adrenoceptor function related to the degree of heart failure in patients with mitral valve disease. J. Am. Coll. Cardiol. 14: 323–331, 1989.PubMedGoogle Scholar
  78. 78.
    Higginbotham M.B., Morris K.G., Sanders Williams R., Coleman R.E., Cobb F.R.: Physiological basis for the age-related decline in aerobic work capacity. Am. J. Cardiol. 57: 1374–1379, 1986.PubMedGoogle Scholar
  79. 79.
    Port S., Cobb F.R., Coleman R.E., Jones R.H.: Effect of age on the reponse of the left ventricular ejection fraction to exercise. N. Engl. J. Med. 303: 1133–1137, 1980.PubMedGoogle Scholar
  80. 80.
    Stratton J.R., Cerqueira M.D., Schwartz R.S., Levy W.C., Veith R.C., Kahn S.E., Abrass I.B.: Differences in cardiovascular responses to isoproterenol in relation to age and exercise training in healthy men. Circulation 86: 504–512, 1992.PubMedGoogle Scholar
  81. 81.
    Docherty J.R.: Cardiovascular responses in ageing: a review. Pharmacol. Rev. 42: 103–125, 1990.PubMedGoogle Scholar
  82. 82.
    Dobson J.G. Jr., Fenton R.A., Romano F.D.: Increased myocardial adenosine production and reduction of beta-adrenergic contractile response in aged hearts. Circ. Res. 66: 1381–1390, 1990.PubMedGoogle Scholar
  83. 83.
    Sakai M., Danziger R.S., Xiao R.P., Spurgeon H.A., Lakatta E.G.: Contractile response of individual cardiac myocytes to norepinephrine declines with senescence. Am. J. Physiol. 262: H184–H189, 1992.PubMedGoogle Scholar
  84. 84.
    Ziegler M.G., Lake C.R., Kopin I.J.: Plasma noradrenaline increases with age. Nature 261: 333–335, 1976.PubMedGoogle Scholar
  85. 85.
    Galbo H., Richter E.A., Holst J.J., Christensen N.J.: Diminished hormonal responses to exercise in trained rats. J. Appl. Physiol. 43: 953–958, 1977.PubMedGoogle Scholar
  86. 86.
    Reithmann C., Gierschik P., Werdan K., Jakobs K.H.: Hormonal regulation of Gi alpha level and adenylyl cyclase responsiveness. Br. J. Clin. Pharmacol. 30 (Suppl. 1): 118S–120S, 1990.PubMedGoogle Scholar
  87. 87.
    Eschenhagen T., Mende U., Diederich M., Nose M., Schmitz W., Scholz H., Schulte A.M., Esch J., Warnholtz A., Schafer H.: Long-term beta-adrenoceptor-mediated up-regulation of Gi alpha and G(o) alpha mRNA levels and pertussis toxin-sensitive guanine nucleotide-binding proteins in rat heart. Mol. Pharmacol. 42: 773–783, 1992.PubMedGoogle Scholar
  88. 88.
    Muller F.U., Boheler K.R., Eschenhagen T., Schmitz W., Scholz H.: Isoprenaline stimulates gene transcription of the inhibitory G protein alpha-subunit Gi alpha-2 in rat heart. Circ. Res. 72: 696–700, 1993.PubMedGoogle Scholar
  89. 89.
    Clark R.B., Kunkel M.W., Friedman J., Goka T.J., Johnson J.A.: Activation of cAMP-dependent protein kinase is required for heterologous desensitization of adenylyl cyclase in S49 wild-type lymphoma cells. Proc. Natl. Acad. Sci. USA 85: 1442–1446, 1988.PubMedGoogle Scholar
  90. 90.
    Francis G.S., Cohn J.N., Johnson G., Rector T.S., Goldman S., Simon A.: Plasma norepinephrine, plasma renin activity, and congestive heart failure. Relations to survival and the effects of therapy in V-HeFT II. The V-HeFT VA Cooperative Studies Group. Circulation 87: VI40–VI48, 1993.PubMedGoogle Scholar
  91. 91.
    Thomas J.A., Marks B.H.: Plasma norepinephrine in congestive heart failure. Am. J. Cardiol. 41: 233–243, 1978.PubMedGoogle Scholar
  92. 92.
    Francis G.S., Benedict C., Johnstone D.E., Kirlin P.C., Nicklas J., Liang C.S., Kubo S.H., Rudin-Toretsky E., Yusuf S.: Comparison of neuroendocrine activation in patients with left ventricular dysfunction with and without congestive heart failure. A substudy of the Studies of Left Ventricular Dysfunction (SOLVD). Circulation 82: 1724–1729, 1990.PubMedGoogle Scholar
  93. 93.
    Harding S.E., Jones S.M., O’Gara P., Vescovo G., Poole-Wilson P.A.: Reduced beta-agonist sensitivity in single atrial cells from failing human hearts. Am. J. Physiol. 259: H1009–H1014, 1990.PubMedGoogle Scholar
  94. 94.
    Pitschner H.F., Droege A., Mitze M., Schlepper M., Brodde O.E.: Down-regulated beta-adrenoceptors in severely failing human ventricles: uniform regional distribution, but no increased internalization. Basic Res. Cardiol. 88: 179–191, 1993.PubMedGoogle Scholar
  95. 95.
    Steinfath M., Lavicky J., Schmitz W., Scholz H., Doring V., Kalmar P.: Regional distribution of beta 1- and beta 2-adrenoceptors in the failing and nonfailing human heart. Eur. J. Clin. Pharmacol. 42: 607–611, 1992.PubMedGoogle Scholar
  96. 96.
    Harding S.E., Davies C.H., Wynne D.G., Poole-Wilson P.A.: Contractile characteristics and response to agonists in myocytes from failing human heart. Eur. Heart J. 15 (Suppl. D): 35–36, 1994.PubMedGoogle Scholar
  97. 97.
    Bristow M.R., Minobe W., Rasmussen R., Larrabee P., Skerl L., Klein J.W., Anderson F.L., Murray J., Mestroni L., Karwande S.V., Fowler M., Ginsburg R.: Beta-adrenergic neuroeffector abnormalities in the failing human heart are produced by local rather than systemic mechanisms. J. Clin. Invest. 89: 803–815, 1992.PubMedCentralPubMedGoogle Scholar
  98. 98.
    Von Der Leyen H., Mende U., Meyer Neumann J., Nose M., Schmitz Scholz H., Starbatty J., Stein B., Wenzlaff H., Doring V., Kalmar P., Haverich A.: Mechanisms underlying the reduced positive inotropic effects of the phosphodiesterase III inhibitors pimobendan, adibendan and saterinone in failing as compared to nonfailing human cardiac muscle preparations. Naunyn Schmiedebergs Arch. Pharmacol. 344: 90–100, 1991.PubMedGoogle Scholar
  99. 99.
    Maisel A.S., Ziegler M.S., Carter S., Insel P.A., Motulsky H.J.: In vivo regulation of beta-adrenergic receptors on mononuclear leukocytes and heart. Assessment of receptor compartmentation after agonist infusion and acute aortic constriction in guinea pigs. J. Clin. Invest. 82: 2038–2044, 1988.PubMedCentralPubMedGoogle Scholar
  100. 100.
    Barak L.S., Tiberi M., Freedman N.J., Kwatra M.M., Lefkowitz R.J., Caron M.G.: A highly conserved tyrosine residue in G protein-coupled receptors is required for agonist-mediated beta 2-adrenergic receptor sequestration. J. Biol. Chem. 269: 2790–2795, 1994.PubMedGoogle Scholar
  101. 101.
    Ungerer M., Parruti G., Bohm M., Mechthild P., DeBlasi A., Erdmann E., Lohse M.J.: Expression of β-arrestins and β-adrenergic receptor kinases in the failing human heart. Circ. Res. 74: 206–213, 1994.PubMedGoogle Scholar
  102. 102.
    Robishaw J.D., Foster K.A.: Role of G-proteins in the regulation of the cardiovascular system. Annu. Rev. Physiol. 51: 229–244, 1989.PubMedGoogle Scholar
  103. 103.
    Fleming J.W., Wisler P.L., Watanabe A.M.: Signal transduction by G proteins in cardiac tissues. Circulation 85: 420–433, 1992.PubMedGoogle Scholar
  104. 104.
    Xiao R.P., Ji X., Lakatta E.G.: Functional coupling of the beta 2-adrenoceptor to a pertussis toxin-sensitive G protein in cardiac myocytes. Mol. Pharmacol. 47: 322–329, 1995.PubMedGoogle Scholar
  105. 105.
    Kim D., Lewis D.L., Graziadei L., Neer E.J., Bar-Sagi D., Clapham D.: G-protein betagamma-subunits activate the cardiac K+ channel via phospholipase A2. Nature 337: 557–560, 1989.PubMedGoogle Scholar
  106. 106.
    Birnbaumer L.: Receptor-to-effector signaling through G proteins: roles for beta gamma dimers as well as alpha subunits. Cell 71: 1069–1072, 1992.PubMedGoogle Scholar
  107. 107.
    Pitcher J.A., Inglese J., Higgins J.B., Arriza J.L., Casey P.J., Kim C., Benovic J.L., Kwatra M.M., Caron M.g., Lefkowitz R.J.: Role of beta gamma subunits of G proteins in targeting the beta-adrenergic receptor kinase to membrane-bound receptors. Science 257: 1264–1267, 1992.PubMedGoogle Scholar
  108. 108.
    Feldman A.M., Jackson D.D., Bristow M.R., Cates A.E., Van Dop C.: Immunodetectable levels of the inhibitory guanine nucleotide-binding regulatory proteins in failing human heart: discordance with measurements of adenylate cyclase activity and levels of pertussis toxin substrate. J. Mol. Cell. Cardiol. 23: 439–452, 1991.PubMedGoogle Scholar
  109. 109.
    Miyamoto A., Kawana S., Kimura H., Ohshika H.: Impaired expression of Gs alpha protein mRNA in rat ventricular myocardium with aging. Eur. J. Pharmacol. 266: 147–154, 1994.PubMedGoogle Scholar
  110. 110.
    Feldman R.D., Tan C.M., Chorazyczewski J.: G protein alterations in hypertension and aging. Hypertension 26: 725–732, 1995.PubMedGoogle Scholar
  111. 111.
    Bohm M., Gierschik P., Jakobs K.H., Schnabel P., Kemkes B., Erdmann E.: Localization of a “postreceptor” defect in human dilated cardiomyopathy. Am. J. Cardiol. 64: 812–814, 1989.PubMedGoogle Scholar
  112. 112.
    Feldman A.M., Cates A.E, Bristow M.R, Van Dop C.: Altered expression of alpha-subunits of G proteins in failing human hearts. J. Mol. Cell. Cardiol. 21: 359–365, 1989.PubMedGoogle Scholar
  113. 113.
    Schnabel P., Bohm M., Gierschik P., Jakobs K.H., Erdmann E.: Improvement of cholera toxin-catalyzed ADP-ribosylation by endogenous ADP-ribosylation factor from bovine brain provides evidence for an unchanged amount of Gsa in failing human myocardium. J. Mol. Cell. Cardiol. 22: 73–82, 1990.PubMedGoogle Scholar
  114. 114.
    Xiao R.-P., Spurgeon H.A., O’Connor F., Lakatta E.G.: Age-associated changes in β-adrenergic modulation on rat cardiac excitation-contraction coupling. J. Clin. Invest. 94: 2051–2059, 1994.PubMedCentralPubMedGoogle Scholar
  115. 115.
    Bohm M., Gierschik P., Jakobs K.H., Pieske B., Schnabel P., Ungerer M., Erdmann E.: Increase of Gi alpha in human hearts with dilated but not ischemic cardiomyopathy. Circulation 82: 1249–1265, 1990.PubMedGoogle Scholar
  116. 116.
    Fu L.X., Liang Q.M., Waagstein F., Hoebeke J., Sylven C., Jansson E., Sotonyi P., Hjalmarson A.: Increase in functional activity rather than in amount of Gi-alpha in failing human heart with dilated cardiomyopathy. Cardiovasc. Res. 26: 950–955, 1992.PubMedGoogle Scholar
  117. 117.
    Feldman A.M., Cates A.E., Veazey W.B., Hershberger R.E., Bristow M.R., Baughman K.L., Baumgartner A., Van Dop C.: Increase of the 40,000-mol wt pertussis toxin substrate (G protein) in the failing human heart. J. Clin. Invest. 82: 189–197, 1988.PubMedCentralPubMedGoogle Scholar
  118. 118.
    Neumann J., Schmitz Scholz H., Von Meyerinck L., Doring V., Kalmar P.: Increase in myocardial Gi-proteins in heart failure. Lancet 2: 936–937, 1988.PubMedGoogle Scholar
  119. 119.
    Eschenhagen T., Mende U., Nose M., Schmitz W., Scholz H., Warnholtz A., Wustel J.M.: Isoprenaline-induced increase in mRNA levels of inhibitory G-protein alpha-subunits in rat heart. Naunyn-Schmiedebergs Arch. Pharmacol. 343: 609–615, 1991.PubMedGoogle Scholar
  120. 120.
    Brown L.A., Harding S.E.: The effect of pertussis toxin on b-adrenoceptor responses in isolated cardiac myocytes from noradrenaline-treated guinea-pigs and patients with cardiac failure. Br. J. Pharmacol. 106: 115–122, 1992.PubMedGoogle Scholar
  121. 121.
    Eschenhagen T., Mende U., Nose M., Schmitz W., Scholz H., Haverich A., Hirt S., Doring V., Kalm P., Hoppner Seitz H-J.: Increased messenger RNA level of the inhibitory G protein alpha subunit Gi alpha-2 in human end-stage heart failure. Circ. Res. 70: 688–696, 1992.PubMedGoogle Scholar
  122. 122.
    Sytkowsky P.A., Kannel W.B., D’agostino R.B.: Changes in risk factors and the decline in mortality from cardiovascular disease. N. Engl. J. Med. 322: 1635–1641, 1990.Google Scholar
  123. 123.
    Kannel B., Belanger A.J.: Epidemiology of heart failure. Am. Heart J. 121: 951–957, 1991.PubMedGoogle Scholar
  124. 124.
    Uemera K., Pisa Z.: Trends in cardiovascular disease mortality in industrialized countries. World Health Stat. Q. 41: 155–168, 1988.Google Scholar
  125. 125.
    Lefant C.: Report of the task force on research in heart failure. Circulation 90: 1118–1123, 1994.Google Scholar
  126. 126.
    Cohn J.N., Levine T.B., Olivari M.T., Garberg V., Lura D., Francis G.S., Simon A.B., Rector T.: Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure. N. Engl. J. Med. 311: 819–823, 1984.PubMedGoogle Scholar
  127. 127.
    Francis G.S., Rector T.S., Cohn J.N.: Sequential neurohumoral measurements in patients with congestive heart failure. Am. Heart J. 116: 1464–1468, 1988.PubMedGoogle Scholar
  128. 128.
    Bristow M.R., Ginsburg R., Strosberg A., Montgomery W., Minobe W.: Pharmacology and inotropic potential of forskolin in the human heart. J. Clin. Invest. 74: 212–223, 1984.PubMedCentralPubMedGoogle Scholar
  129. 129.
    Baumann G., Felix S., Sattelberger U., Klein G.: Cardiovascular effects of forskolin (HL 362) in patients with idiopathic congestive cardiomyopathy. A comparative study with dobutamine and sodium nitroprusside. J. Cardiovasc. Pharmacol. 16: 93–100, 1990.PubMedGoogle Scholar
  130. 130.
    Heilbrunn S.M., Shah P., Bristow M.R., Valantine H.A., Ginsburg R.: Increased beta-receptor density and improved hemodynamic response to catecholamine stimulation during long-term metoprolol therapy in heart failure from dilated cardiomyopathy. Circulation 79: 483–490, 1989.PubMedGoogle Scholar
  131. 131.
    Waagstein F., Bristow M.R., Swedberg K., Camerini F., Fowler M.B., Silver M.A., Gilbert E.M., Johnson M.R., Goss F.G., Hjalmarson A.: Beneficial effects of metoprolol in idiopathic dilated cardiomyopathy. Metoprolol in Dilated Cardiomyopathy (MDC) Trial Study Group. Lancet 342: 1441–1446, 1993.PubMedGoogle Scholar
  132. 132.
    CIBIS Investigators and Committees.: A randomized trial of beta-blockade in heart failure. The Cardiac Insufficiency Bisoprolol Study (CIBIS). Circulation 90: 1765–1773, 1994.Google Scholar
  133. 133.
    Olsen S.L., Gilbert E.M., Renlund D.G., Taylor D.O., Yanowitz F.D., Bristow M.R.: Carvedilol improves left ventricular function and symptoms in chronic heart failure: a double-blind randomized study. J. Am. Coll. Cardiol. 25: 1225–1231, 1995.PubMedGoogle Scholar
  134. 134.
    Packer M., Bristow M.R., Cohn J.N., Colucci W.S., Fowler M.B., Gilbert E.M., Shusterman N.H.: The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. N. Engl. J. Med. 334: 1349–1355, 1996.PubMedGoogle Scholar
  135. 135.
    Gilbert E.M., Sandoval A., Larrabee P., Renlund D.G., O’Connell J.B., Bristow M.R.: Lisinopril lowers cardiac adrenergic drive and increases beta-receptor density in the failing human heart. Circulation 88: 472–480, 1993.PubMedGoogle Scholar
  136. 136.
    Jakob H., Sigmund M., Eschenhagen T., Mende U., Patten M., Schmitz W., Scholz H., Schulte A.M., Esch J., Steinfath M., Hanrath P.: Effect of captopril on myocardial beta-adrenoceptor density and Gi alpha-proteins in patients with mild to moderate heart failure due to dilated cardiomyopathy. Eur. J. Clin. Pharmacol. 47: 389–394, 1995.PubMedGoogle Scholar
  137. 137.
    Lakatta E.G., Gerstenblith G., Angel C.S., Shock N.W., Weisfeldt M.L.: Diminished inotropic response of aged myocardium to catecholamines. Circ. Res. 36: 262–269, 1975.PubMedGoogle Scholar
  138. 138.
    Besse S.: Is the senescent heart overloaded and already failing? Cardiovasc. Drugs Ther. 8: 581–587, 1994.PubMedGoogle Scholar

Copyright information

© Springer Internal Publishing Switzerland 1997

Authors and Affiliations

  • N. Ferrara
    • 1
    • 3
  • K. Davia
    • 2
  • P. Abete
    • 1
  • F. Rengo
    • 1
  • S. E. Harding
    • 2
  1. 1.Institute of Internal Medicine, Cardiology and Cardiovascular Surgery“Federico II” UniversityNapoliItaly
  2. 2.Department of Cardiac MedicineNational Heart and Lung Institute, Imperial CollegeLondonUK
  3. 3.“Salvatore Maugeri” Foundation, IRCCSRehabilitation Institute of TeleseBeneventoItaly

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