Adrenergic and muscarinic receptor regulation and therapeutic implications in heart failure

  • Wilhelm Schmitz
  • Peter Boknik
  • Bettina Linck
  • Frank U. Müller
Chapter
Part of the Developments in Molecular and Cellular Biochemistry book series (DMCB, volume 17)

Abstract

In end-stage heart failure the expression of different myocardial regulatory proteins involved in the β-adrenergic cAMP signalling pathway is altered. The downregulation of β1-adrenoceptors and their uncoupling from the effector as well as an increased expression of the inhibitory GTP-binding protein seem to be the most important alterations. Since catecholamine levels are elevated in these patients and since some alterations can be ‘restored’ after treatment with β-adrenoceptor antagonists it was hypothesized that excessive β-adrenergic stimulation could be involved in these alterations.

In this article the changes of β-adrenergic receptors, GTP-binding proteins, sarcoplasmic reticulum Ca2+-ATPase and of phospholamban found in heart failure are addressed with its possible therapeutic implications.

Key words

heart failure adrenergic receptor muscarinic receptor G-protein phosphodiesterase inhibitor angiotensin converting enzyme inhibitor β-adrenoceptor antagonist 

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References

  1. 1.
    Bristow MR, Hershberger RE, Port JD, Minobe W, Rasmussen R: β1-and β2-adrenergic receptor-mediated adenylate cyclase stimulation in nonfailing and failing human ventricular myocardium. Mol Pharm 35: 295–303, 1989Google Scholar
  2. 2.
    Daly PA, Sole MJ: Myocardial catecholamines and the pathophysiology of heart failure. Circulation 82(suppl 1): I–35–143, 1990Google Scholar
  3. 3.
    Schmitz W, Scholz H, Erdmann E: Effects of alpha- and beta-adrenergic agonists, phosphodiesterase inhibitors and adenosine on isolated human heart muscle preparations. Trends Pharmacol Sci 8: 447–450, 1987CrossRefGoogle Scholar
  4. 4.
    Eschenhagen T: G proteins and the heart. Cell Bioi Int 17(8): 723–749, 1993CrossRefGoogle Scholar
  5. 5.
    Bristow MR, Anderson FL, Port DP, Skerl L, Hershberger KS, Larabee P, O Connell JB, Reniund DG, Volkman K, Murray J, Feldman AM: Differences in b-adrenergic neuroeffector mechanisms in ischemic versus idiopathic dilated cardiomyopathy. Circulation 84: 1024–1039, 1991PubMedGoogle Scholar
  6. 6.
    Böhm M, Gierschik P, Jakobs K-H, Pieske B, Schnabel P, Ungerer M, Erdmann E: Increase of Giα in human hearts with dilated but not ischemic cardiomyopathy. Circulation 82: 1249–1265, 1990PubMedCrossRefGoogle Scholar
  7. 7.
    Brodde OE: β1- and β2-adrenoceptors in the human heart: Properties, function, and alterations in chronic heart failure. Pharmacol Rev 43: 203–242, 1991PubMedGoogle Scholar
  8. 8.
    Steinfath M, Geertz B, Schmitz W, Scholz H, Haverich A, Beil I, Hanrath P, Reupcke C, Sigmund M, Lo HB: Distinct down-regulation of cardiac β1- and β2-adrenoceptors in different human heart diseases. Naunyn-Schmiedeberg’s Arch Pharmacol 343: 217–220, 1991CrossRefGoogle Scholar
  9. 9.
    Swedberg K, Eneroth P, Kjekshus J, Wilhelmsen L: Hormones regulating cardiovascular function in patients with severe congestive heart failure and their relation to mortality. Circulation 82: 1730–1736, 1990PubMedCrossRefGoogle Scholar
  10. 10.
    Ungerer M, Bohm M, Elce JS, Erdmann E, Lohse MJ: Altered expression of 13adrenergic receptor kinase and β1-adrenergic receptors in the failing human heart. Circulation 87: 454–463, 1993PubMedGoogle Scholar
  11. 11.
    Linder ME, Gilman AG: G proteins. Scientific American July 1992: 36–43Google Scholar
  12. 12.
    Yatani A, Okabe K, Polakis P, Halenbeck R, McCormick F, Brovvn AM: ras p21 and GAP inhibit coupling of muscarinic receptors to atrial K+ channels. Cell 61: 769–776, 1990PubMedCrossRefGoogle Scholar
  13. 13.
    Fleming JW, Wisler PL, Watanabe AM: Signal transduction by G proteins on cardiac tissues. Circulation 85: 420–433, 1992PubMedGoogle Scholar
  14. 14.
    Brown AM: A cellular logic for G-protein coupled ion channel pathways. FASEB J 5: 2175–2179, 1991PubMedGoogle Scholar
  15. 15.
    Katz AM: Physiology of the heart. 2nd ed.. Raven Press, New York, 1992Google Scholar
  16. 16.
    Feldman MD, Copelas L, Gwathmey JK, Phillips P, Warren SE, Schoen FJ, Grossman W, Morgan JP: Deficient production of cyclic AMP: pharmacologic evidence of an important cause of contractile dysfunction in patients with endstage heart failure. Circulation 75: 331–339, 1987PubMedCrossRefGoogle Scholar
  17. 17.
    Feldman AM, Cates AE, Veazey WB, Hershberger RE, Bristow MR, Baughman KL; Baumgartner WA, van Dop C: Increase in the 40,000-mol wt pertussis toxin substrate (G-protein) in the failing human heart. J Clin Invest 82: 189–197, 1988PubMedCrossRefGoogle Scholar
  18. 18.
    Schnabel P, Böhm M, Gierschik P, Jakobs KH, Erdmann E: Improvement of cholera toxin-catalysed ADP-ribosylation by endogenous ADP-ribosylation factor from bovine brain provides evidence for an unchanged amount of Gsα in failing human myocardium. J Mol Cell Cardiol 22: 73–82, 1990PubMedCrossRefGoogle Scholar
  19. 19.
    Neumann J, Schmitz W, Scholz H, von Meyerinck L, Döring V, Kalmár P: Increase of myocardial Gi-proteins in human heart failure. Lancet II: 936–937, 1988Google Scholar
  20. 20.
    Böhm M, Eschenhagen T, Gierschik P, Larisch K, Lensche H, Mende U, Schmitz W, Schnabel P, Scholz H, Steinfath M, Erdmann E: Radioimmunological quantification of Gi alpha in right and left ventricles from patients with ischaemic and dilated cardiomyopathy and predominant left ventricular failure. J Mol Ceil Cardiol 26: 133–149, 1994CrossRefGoogle Scholar
  21. 21.
    Eschenhagen T, Mende U, Nose M, Schmitz W, Scholz H, Haverich A, Hirt S, Doring V, Kalmár P, Höppner W, Seitz HJ: Increased messenger RNA level of the inhibitory G-protein a subunit Giα-2 in human end-stage heart failure. Circ Res 70: 688–696, 1992PubMedGoogle Scholar
  22. 22.
    Mende U, Eschenhagen T, Geertz B, Schmitz W, Scholz H, Schulte am Esch J, Sempell R, Steinfath M: Isoprenaline-induced increase in the 40/41 kDa pertussis toxin substrates and functional consequences on contractile response in rat heart. Naunyn-Schmiedeberg’s Arch Pharmacol 345: 44–50, 1992CrossRefGoogle Scholar
  23. 23.
    Eschenhagen T, Mende U, Diederich M, Nose M, Schmitz W, Scholz H, Schulte am Esch J, Warnholtz A, Schöfer H: Long-term β-adrenoceptor mediated upregulation of Giα and Goα mRNA levels and pertussis toxin-sensitive guanine nucleotide-binding proteins in rat heart. Mol Pharm 42: 773–783, 1992Google Scholar
  24. 24.
    Müller FU, Boheler KR, Eschenhagen T, Schmitz W, Scholz H: Isoprenaline stimulates gene transcription of the inhibitory G-protein α-subunit Giα-2 in rat heart. Circ Res 72: 696–700, 1993PubMedGoogle Scholar
  25. 25.
    Motomura S, Deighton NM, Zerkowski HR, Doetsch N, Michel MC, Brodde OE: Chronic beta 1-adrenoceptor antagonist treatment sensitizes beta 2-adrenoceptors, but desensitizes M2-muscarinic receptors in the human right atrium. Br J Pharmacol 101 (2): 363–369, 1990PubMedGoogle Scholar
  26. 26.
    Jakob H, Sigmund M, Beck F, Hanrath P, Eschenhagen T, Geertz B, Scholz H, Steinfath M: Reduction of Giα in myocardial biopsies of patients with heart failure under metoprolol treatment. Circulation 90: 1-413, 1994Google Scholar
  27. 27.
    Eschenhagen T, Mende U, Nose M, Schmitz W, Scholz H, Warnholtz A, Wustel JM: Isoprenaline-induced increase in mRNA levels of inhibitory G-protein α-subunits in rat heart. Naunyn-Schmiedeberg’s Arch Pharmacol 343:609–615, 1991CrossRefGoogle Scholar
  28. 28.
    Müller FU, Eschenhagen T, Reidemeister A, Schmitz W, Scholz H: In vivo β-adrenergic stimulation leads to biphasic regulation of Giα-2 gene transcriptional activity in rat heart. J Mol Cell Cardiol 26: 869–875, 1994PubMedCrossRefGoogle Scholar
  29. 29.
    Gwathmey JK, Copelas L, Makinnon R, Shoen FJ, Feldman MD, Grossman W, Morgan JP: Abnormal intracellular calcium handling in myocardium from patients with end-stage heart failure. Circ Res 61: 70–76, 1987PubMedGoogle Scholar
  30. 30.
    Limas CJ, Olivari M-T, Goldenberg TB, Benditt DG, Simon A: Calcium uptake by cardiac sarcoplasmic reticulum in human dilated cardiomyopathy. Cardiovasc Res 21: 601–605, 1987PubMedCrossRefGoogle Scholar
  31. 31.
    Movsesian MA, Bristow MR, Krall J: Calcium uptake by cardiac sarcoplasmic reticulum from patients with dilated cardiomyopathy. Circ Res 65: 1141–1144, 1989PubMedGoogle Scholar
  32. 32.
    Movsesian MA, Colyer J, Wang JH, Krall J: Phospholamban-mediated stimulation of Ca2+ uptake in cardiac sarcoplasmic reticulum from normal and failing human hearts. J Clin Invest 85: 1698–1702, 1990PubMedCrossRefGoogle Scholar
  33. 33.
    Brandl CJ, Green NM, Korczak B, MacLennan DH: Two Ca2+-AT-Pase genes: homologies and mechanistic implications of deduced amino acid sequences. Cell 44: 597–607, 1986PubMedCrossRefGoogle Scholar
  34. 34.
    Burk SE, Lytton J, MacLennan DH, Shull GE: cDNA cloning, functional expression, and mRNA tissue distribution of a third organellar Ca2+ pump. J Biol Chem 264: 18561–18568, 8919Google Scholar
  35. 35.
    MacLennan DH, Brandle CH, Korczak B, Green NM: Amino-acid sequence of a Ca2+ Mg2+-dependent ATPase from rabbit muscle sarcoplasmic reticulum, deduced from ist complementary DNA sequence. Nature 316: 696–700, 1985PubMedCrossRefGoogle Scholar
  36. 36.
    Jones LR: Sarcolemmal enzymes mediating β-adrenergic effects in the heart. In: F. A. Bronner, A. E. Shamoo, AE (eds). Current topics in membranes and transport; regulation of calcium transport across muscle membranes. Academic Press, New York, 1985, pp 11–41Google Scholar
  37. 37.
    Mercadier J-J, Lompré AM, Duc P, Boheler KR, Frays J-P, Wisnewsky C, Allen PD, 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, 1990PubMedCrossRefGoogle Scholar
  38. 38.
    Arai M, Alpert NR, MacLennan DH, 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, 1993PubMedGoogle Scholar
  39. 39.
    Movsesian MA, Karimi M, Green K, Jones LR: Ca2+-transporting ATPase, phospholamban and calsequestrin levels in nonfailing and failing human heart. Circulation 90: 653–657, 1994PubMedGoogle Scholar
  40. 40.
    Hasenfuss G, Reinicke H, Studer R, Meyer M Pieske B, Holtz J, Holubarsch C, Posival H, Just H, Drexler H: Relation between myocardial function and expression of sarcoplasmic reticulum Ca2+-ATPase in failing and nonfailing myocardium. Circ Res 75: 434–442, 1994PubMedGoogle Scholar
  41. 41.
    Luo W, Grupp IL, Harrer J, Ponniah S, Grupp G, Duffy JJ, Doetschman T, Kranias EG: Targeted ablation of the phospholamban gene is associated with markedly enhanced myocardial contractility and loss of β-agonist stimulation. Circ Res 75: 401–409, 1994PubMedGoogle Scholar
  42. 42.
    Danielsen W, von der Leyen H, Meyer W, Neumann J, Schmitz W, Scholz H, Starbatty J, Stein B, Döring V, Kalmár P: Basal and isoprenaline-stimulated cAMP content in failing versus nonfailing human cardiac preparations. J Cardiovasc Pharmacol 14: 171–173, 1989CrossRefGoogle Scholar
  43. 43.
    Böhm M, Reiger B, Schwinger RH, Erdmann E: cAMP concentrations, cAMP dependent protein kinase activity, and phospholamban in nonfailing and failing myocardium. Cardiovasc Res 28(11): 1713–1719, 1994PubMedCrossRefGoogle Scholar
  44. 44.
    Shenolikar S, Nairn AC: Protein phosphatases: recent progress. In: P. Greengard and G. A. Robison (eds). Advances in second messenger and phosphoprotein research. Raven Press, New York, 1991, pp 1–121Google Scholar
  45. 45.
    Neumann J, Eschenhagen T, Jones LR, Linck B, Schmitz W, Scholz H, Zimmermann N: Increased expression of cardiac phosphatases in patients with endstage heart failure. 1995 (submitted)Google Scholar
  46. 46.
    Deighton NM, Motomura S, Borquez D, Zerkowski H-R, Doetsch N, Brodde O-E: Muscarinic cholinoceptors in the human heart: demonstration, subclassification, and distribution. Naunyn-Schmiedebergs’s Arch Pharmacol 341: 14–21, 1990Google Scholar
  47. 47.
    Kohl C, Schmitz W, Scholz H: Positive inotropic effect of carbachol and inositol phosphate levels in mammalian atria after pretreatment with pertussis toxin. J Pharmacol Exp Ther 254: 894–899, 1990PubMedGoogle Scholar
  48. 48.
    Brückner R, Fenner A, Meyer W, Nobis T-M, Schmitz W, Scholz H: Cardiac effects of adenosine and adenosine analogs in guinea-pig atrial and ventricular preparations: evidence against a role of cyclic AMP and cyclic GMP: J Pharmacol Exp Ther 234: 766–774, 1985PubMedGoogle Scholar
  49. 49.
    Brown AM, Birnbaumer L: Ionic channels and their regulation by G protein subunits. Annu Rev Physiol 52: 197–213, 1990PubMedCrossRefGoogle Scholar
  50. 50.
    Gilman AG: G proteins and dual control of adenylate cyclase. Cell 36: 577–579, 1984PubMedCrossRefGoogle Scholar
  51. 51.
    Gupta RC, Neumann J, Boknik P, Watanabe AM: M2-specific muscarinic cholinergic receptor-mediated inhibition of cardiac regulatory protein phosphorylation. Am J Physiol 266: H1138–H1144, 1994PubMedGoogle Scholar
  52. 52.
    Neumann J, Boknik P, Bodor GS, Jones LR, Schmitz W, Schoiz H: Effects of adenosine receptor and muscarinic cholinergic receptor agonists on cardiac protein phosphorylation. J Pharmacol Exp Ther 269:1310–1318: 1994PubMedGoogle Scholar
  53. 53.
    Mery PF, Lohmann SM, Walter U, Fischmeister R: Ca2+ current is regulated by cyclic GMP-dependent protein kinase in mammalian cardiac myocytes. Proc Natl Acad Sci USA 88: 1197–1201, 1991PubMedCrossRefGoogle Scholar
  54. 54.
    Mery PF, Pavoine C, Belhassen L, Pecker F, Fischmeister R: Nitric oxide regulates cardiac Ca2+ current. Involvement of cGMP-inhibited and cGMP-stimulated phosphodiesterases through guanylyl cyclase activation. J Biol Chem 268: 26286–26295, 1993PubMedGoogle Scholar
  55. 55.
    Ahmad Z, Green FJ, Subuhi HS, Watanabe AM: Autonomic regulation of type 1 protein phosphatase in cardiac muscle. J Biol Chem 264:3859–3863, 1989PubMedGoogle Scholar
  56. 56.
    Neumann J, Kaspareit G, Scholz H: Fluoride ion attenuates the negative inotropic effects of muscarinic M2 and adenosine receptor agonists. Eur J Pharmacol, in press, 1995Google Scholar
  57. 57.
    Herzig S, Meier A, Pfeiffer M, Neumann J: Stimulation of protein phosphatases as a mechanism of the muscarinic-receptor-mediated inhibition of cardiac L-type Ca2+ channels. Pflüger’s Arch — Eur J Physiol 429: 531–538, 1995CrossRefGoogle Scholar
  58. 58.
    Böhm M, Ungerer M, Erdmann E: Adenosine receptors in the human heart: Pharmacological characterization in nondiseased and cardiomyopathic tissue. Drug Develop Res 28: 268–276, 1993CrossRefGoogle Scholar
  59. 59.
    von der Leyen H, Mende U, Meyer W, Neumann J, Nose M, Schmitz W, Scholz H, Starbatty J, Stein B, Wenzlaff H, Doring V, Kalmár P, Haverich A: Mechanism underlying the reduced positive inotropic effects of the phosphodiesterase inhibitors pimobendan, adibendan and saterinone in failing as compared to nonfailing human cardiac muscle preparations. Naunyn-Schmiedeberg’s Arch Pharmacol 344: 90–100, 1991CrossRefGoogle Scholar
  60. 60.
    Schmitz W, Eschenhagen T, Mende U, Muller FU, Neumann J, Scholz H: Phosphodiesterase inhibition and positive inotropy in failing human myocardium. In: G. Hasenfuss, Ch. Holubarsch, H. Just and N. R. Alpert (eds). Cellular and Molecular Alterations in the Failing Human Heart. Steinkopff Verlag, Darmstadt, 1992, pp 65–71Google Scholar
  61. 61.
    Bethke T, Klimkievvicz A, Kohl C, von der Leyen H, Mehl H, Mende U, Meyer W, Neumann J, Schmitz W, Scholz H, Starbatty J, Stein B, Wenzlaff H, Döring V, Kalmar P, Haverich A: Effects of isomazole on force of contraction and phosphodiesterase isoenzymes in nonfailing and failing human hearts. J Cardiovasc Pharmacol 18: 386–397, 1991PubMedCrossRefGoogle Scholar
  62. 62.
    Bethke T, Eschenhagen T, Klimkie\,vicz A, Kohl C, von der Leyen H, Mehl H, Mende U, Neumann J, Rossvvag S, Schmitz W, Scholz H, Starbatty J, Stein B, Wenzlaff H, Döring V, Kalmár P, Haverich A: Phosphodiesterase inhibition by enoximone in preparations from failing and nonfailing human hearts. Arzneimittel Forsch 42: 437–445, 1992Google Scholar
  63. 63.
    Levine TB, Francis GS, Goldsmith SR, Simon AB, Cohn JN: Activity of the sympathetic nervous system and renin-angiotensin system assesed by plasma hormone levels and their relation to hemodynamic abnormalities in congestive heart failure. Am J Cardiol 49: 1659–1666, 1982PubMedCrossRefGoogle Scholar
  64. 64.
    Gage J, Rutman H, Lucido D, LeJemtel TH: Additive effects of dobutamine and amrinone on myocardial contractility and ventricular performance in patients with severe heart failure. Circulation 74: 367–373, 1986PubMedCrossRefGoogle Scholar
  65. 65.
    Colucci WS: Observations on the intracoronary administration of milrinone and dobutamine to patients with congestive heart failure. Am J Cardiol 63: 17–22, 1989CrossRefGoogle Scholar
  66. 66.
    Gilbert EM, Port JD, Hershberger RE, Bristow MP: Clinical significance of alterations in the β-adrenergic receptor-adenylate cyclase complex in heart failure. Heart Failure 5: 91–98, 1989Google Scholar
  67. 67.
    Packer M, Medina M, Yushak M: Hemodynamic and clinical limitations of longterm inotropic therapy with amrinone in patients with severe chronic heart failure. Circulation 70: 1038–1047, 1984PubMedCrossRefGoogle Scholar
  68. 68.
    Uretsky BF, Jessup M, Konstam MA, Dec GW, Leier CV, Benotti J, Muralli S, Herrmann HC, Sandberg JA: Multicenter trial of oral enoximone in patients with moderate to moderately severe congestive heart failure. Circulation 82: 774–780, 1990PubMedCrossRefGoogle Scholar
  69. 69.
    The CONSENSUS Trial Study Group: Effects of enalapril on mortality in severe congestive heart failure: results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med 316: 1429–1435, 1987CrossRefGoogle Scholar
  70. 70.
    Packer M, Carver JR, Rodeheffer RJ, Ivanhoe RJ, DiBianco R, Zeldis SM, Hendrix GH, Bommer WJ, Elkayam U, Kukin ML, Mallis GI, Sollano JA, Shannon J, Tandon PK, Demets DL: Effect of oral milrinone on mortality in severe chronic heart failure. N Engl J Med 325: 1468–1475, 1991PubMedCrossRefGoogle Scholar
  71. 71.
    Packer M: Pathophysiology of chronic heart failure. Lancet 340: 88–92, 1992PubMedCrossRefGoogle Scholar
  72. 72.
    Rüegg JC, Solaro RJ: Calcium-sensitizing positive inotropic drugs. In: J.K. Gwathmey, G.M. Briggs and P.D. Allen (eds). Heart Failure: Basic Science and Clinical Aspects. Marcell Dekker, Inc., New York, 1993, pp 457–473Google Scholar
  73. 73.
    captopril Multicenter Research Group: A placebo-controlled trial of captopril in refractory chronic congestive heart failure. J Am Coll Cardiol 2: 755–763, 1983CrossRefGoogle Scholar
  74. 74.
    The SOLVD Investigators: Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med 325: 293–302, 1991CrossRefGoogle Scholar
  75. 75.
    The SOLVD Investigators: Effect on enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. N Engl J Med 327: 685–691, 1992CrossRefGoogle Scholar
  76. 76.
    The SAVE Investigators: Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 327: 669–677, 1992CrossRefGoogle Scholar
  77. 77.
    The AIRE Investigators: Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure. Lancet 3452: 821–882, 1993Google Scholar
  78. 78.
    Fowler MB, Laser JA, Hopkins GL, Minobe W, Bristow MR: Assessment of the β-adrenergic receptor pathway in the intact failing human heart: progressive receptor downregulation and subsenssitivity to agonist response. Circulation 74: 1290–1302, 1986PubMedCrossRefGoogle Scholar
  79. 79.
    Gilbert EM, Sandoval A, Larrabee P, Reniund DG, O Connell JB, Bristow MR: Lisinopril lowers cardiac adrenergic drive and increases β-adrenoceptor density in the failing human heart. Circulation 88:472–480, 1993PubMedGoogle Scholar
  80. 80.
    Jakob H, Sigmund M, Eschenhagen T, Mende U, Patten M, Schmitz W, Scholz H, Schulte am Esch J, Steinfath M, Hanrath P, Völker H: Effect of captopril on myocardial β-adrenoceptor density and Giα-proteins in patients with mild to moderate heart failure due to dilated cardiomyopathy. Eur J Clin Pharmacol 47: 389–394, 1994Google Scholar
  81. 81.
    Hjalmarson A, Waagstein F: New therapeutic strategies in chronic heart failure: Challenge of long-term beta-blockade. Eur Heart J 12(Suppl F): 63–69, 1991PubMedGoogle Scholar
  82. 82.
    Eichhorn EJ: The paradox of beta-adrenergic blockade for the management of congestive heart failure. Am J Med 92:527–538, 1992PubMedCrossRefGoogle Scholar
  83. 83.
    Metoprolol in Dilated Cardiomyopathy (MDC) Trial Study Group: Waagstein F, Bristow MR, Swedberg K, Camerini F, Fowler MB, Silver MA, Gilbert EM, Johnson MR, Goss FG, Hjalmarson A: Beneficial effects of metoprolol in idiopathic dilated cardiomyopathy. Lancet 342:1441–1446, 1993PubMedCrossRefGoogle Scholar
  84. 84.
    Fisher ML, Gottlieb SS, Plotnick GD, Greenberg NL, Patten RD, Bennett SK, Hamilton BP: Beneficial effects of metoproiol in heart failure associated with coronary artery disease: a randomized trial. J Am Coll Cardiol 23: 943–950, 1994PubMedCrossRefGoogle Scholar
  85. 85.
    A randomized trial of beta-blockade in heart failure. The Cardiac Insufficiency Bisoprolol Study (CIBIS). CIBIS Investigators and Committees. Circulation 90(4): 1765–1773, 1994Google Scholar
  86. 86.
    Bristow MR, O Connell JB, Gilbert EM, French WJ, Leatherman G, Kantrowitz NE, Orie J, Smucker ML, Marshall G, Kelly P et al. for the Bucindolol Investigators: Dose-response of chronic beta-blocker treatment in heart failure from either idiopathic dilated or ischemic cardiomyopathy. Circulation 89(4): 1632–1642, 1994PubMedGoogle Scholar
  87. 87.
    Eichhorn EJ, Heesch CM, Risser RC, Marcoux L, Hatfield B: Predictors of systolic and diastolic improvement in patients with dilated cardiomyopathy treated with metoprolol. J Am Coll Cardiol 25(1): 154–162, 1995PubMedCrossRefGoogle Scholar
  88. 88.
    Eichhorn EJ, McGhie I, Bedotto JB, Corbett JR, Malloy CR, Hatfield BA, Deitchman D, Willard JE, Grayburn PA: Effects of bucindolol on neurohumoral activation in congestive heart failure. Am J Cardiol 676: 67–73, 1991CrossRefGoogle Scholar
  89. 89.
    Chadda K, Goldstein S, Byington R, Curb JD: Effect of propranolol after acute myocardial infarction in patients with congestive heart failure. Circulation 73: 503–510, 1986PubMedCrossRefGoogle Scholar
  90. 90.
    Katz AM: Cell death in the failing heart: role of an unnatural growth response to overload. Clin Cardiol, in press, 1995Google Scholar
  91. 91.
    Müller FU, Bokník P, Horst A, Knapp J, Linck B, Schmitz W, Vahlensieck U, Böhm M, Deng MC, Scheld HH: The cAMP response element binding protein (CREB) is expressed and phosphorylated in the human heart. Circulation, in press, 1995Google Scholar

Copyright information

© Kluwer Academic Publishers 1996

Authors and Affiliations

  • Wilhelm Schmitz
    • 1
  • Peter Boknik
    • 1
  • Bettina Linck
    • 1
  • Frank U. Müller
    • 1
  1. 1.Institut für Pharmakologie und ToxikologieWestfälische Wilhelms-UniversitätMünsterGermany

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