Sympathomimetic vs Non-Sympathomimetic Drugs in the Treatment of Heart Failure

  • G. Baumann
  • S. B. Felix
Conference paper


The syndrome of congestive heart failure is characterized by a reduced stroke volume and peripheral circulatory changes that redistribute blood flow to metabolically active tissues. Conventional inotropic therapy has been limited by the moderate potency and marked toxicity of the glycosides [1] and the ob ligate i.v. route of administration of the catecholamines. Recent studies suggest that the potent effects of the catecholamines are also subject to tolerance after prolonged administration [2–5]. Thus, it is not surprising that considerable effort has been expended on developing new inotropic therapies that produce their effects by novel mechanisms of action and — in addition — exert considerable vasodilator properties at the same time. Whereas conventional therapeutic strategy attempts to improve ventricular performance by eliciting a “contractile reserve” from the failing heart, it now seems apparent it is the peripheral circulatory changes that predominantly govern functional capacity. An inotropic agent’s ability to reverse these peripheral circulatory changes is determined by its inotropic potency, vasodilating capacity, and sustained efficacy. The limitations of conventional therapies have therefore led to the development of new classes of nonglycosidic, nonadrenergic inotropic agents that seem to exert their effects by myocardial phosphodiesterase inhibition, by H2 receptor mediated adenylate cyclase stimulation and by calcium-sensitizing of myocardial contractile proteins. Although these potent ino tropes enhance exercise and aerobic capacity, they are palliative rather than curative agents.


Adenylate Cyclase Inotropic Agent Gestive Heart Failure Inotropic Therapy Adenylate Cyclase System 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Selzer A (1981) Digitalis in cardiac failure: do benefits justify risks? Arch Intern Med 141:18CrossRefPubMedGoogle Scholar
  2. 2.
    Colucci WS, Alexander W, Williams GH et al. (1981) Decreased lymphocyte betaadrenergic receptor density in patients with heart failure and tolerance to the betaadrenergic agonist pirbuterol. N Engl J Med 305:185CrossRefPubMedGoogle Scholar
  3. 3.
    Baumann G, Rieß G, Erhardt WD, Felix STB, Ludwig L, Blümel G, Blömer H (1981) Impaired beta-adrenergic stimulation in the uninvolved ventricle post-acute myocardial infarction: reversible defect due to decline in number and affinity of beta-receptors. Am Heart J 101:569CrossRefPubMedGoogle Scholar
  4. 4.
    Baumann G, Mercader D, Busch U et al. (1983) Effects of H2-receptor agonist impromidine in human myocardium and patients with heart failure due to mitral and aortic valve disease. J Cardiovasc Pharmacol 5:618–625CrossRefPubMedGoogle Scholar
  5. 5.
    Baumann G, Felix STB (1983) Zur pharmakologischen Stellung von Prenalterol. II. Versuch einer kritischen Wertung aus experimenteller und klinischer Sicht. Herz/Kreislauf 2:65Google Scholar
  6. 6.
    Zelis R, Lee G, Mason DT (1974) The influence of experimental edema on metabolically determined blood flow. Circ Res 34:482CrossRefPubMedGoogle Scholar
  7. 7.
    Bristow MR, Ginsburg R, Minobe W et al. (1982) Decreased catecholamine sensi tivity and beta-adrenergic receptor density in failing human hearts. N Engl J Med 307:205CrossRefPubMedGoogle Scholar
  8. 8.
    Zelis R, Delea CS, Coleman H et al. (1970) Arterial sodium content in experimental congestive heart failure. Circulation 41:213CrossRefPubMedGoogle Scholar
  9. 9.
    Watkins L, Burkin LA, Haven E et al. (1976) The renin-angiotensin system in congestive heart failure in conscious dogs. J Clin Invest 57:1606CrossRefPubMedCentralPubMedGoogle Scholar
  10. 10.
    Mason DT, Zelis R, Longhurst J et al. (1977) Cardiocirculatory responses to muscular exercise in congestive heart failure. In: Sonnenblick EH, Lesch M (eds) Exercise and heart disease. Grune and Stratton, New York, p 229Google Scholar
  11. 11.
    LeJemtel TH, Maskin CS, Sinoway L et al. (1983) Fixed vasodilating capacity in exercising leg muscles: a limitation of aerobic capacity in heart failure. Clin Res 31:2 (abstr)Google Scholar
  12. 12.
    Zelis R, Longhurst J, Capone RJ et al. (1974) A comparison of regional blood flow and oxygen utilization during dynamic forearm exercise in normal subjects and patients with congestive heart failure. Circulation 50:137CrossRefPubMedGoogle Scholar
  13. 13.
    Maskin CS, Forman R, Sonnenblick EH et al. (1983) Failure of dobutamine to increase exercise capacity. Am J Cardiol 51:177CrossRefPubMedGoogle Scholar
  14. 14.
    Kugler J, Maskin C, Frishman WH et al. (1982) Regional and systemic metabolic effects of angiotensin converting enzyme inhibition during exercise in patients with severe heart failure. Circulation 66:1258CrossRefGoogle Scholar
  15. 15.
    LeJemtel TH, Kugler J, Maskin CS et al. (1982) Captoril therapy in severe heart failure: delayed improvement in maximal oxygen uptake despite immediate hemodynamic effects. Acta Cardiol [Suppl] (Brux) 28:61Google Scholar
  16. 16.
    Lee AP, Ioe R, Blusey R et al. (1979) Long-term effects of physical training on coronary patients with impaired ventricular function. Circulation 60:1519CrossRefPubMedGoogle Scholar
  17. 17.
    Siegel LA, Keung E, Siskind SJ et al. (1981) Beneficial effects of amrinone-hydralazine combination on resting hemodynamics and exercise capacity in patients with severe congestive heart failure. Circ Res 63:838Google Scholar
  18. 18.
    Siskind SJ, Sonnenblick EH, Forman R et al. (1981) Acute substantial benefits of inotropic therapy with amrinone on exercise hemodynamics and metabolism in se vere congestive heart failure. Circulation 64:966CrossRefPubMedGoogle Scholar
  19. 19.
    Maskin CS, Sinoway L, Chadwick B et al. (1983) Sustained hemodynamic and clinical effects of a new cardiotonic agent WIN 47203 in patients with severe congestive heart failure. Circulation 67:1065CrossRefPubMedGoogle Scholar
  20. 20.
    Wilson JR, Ferraro N (1983) Exercise intolerance in patients with chronic left heart failure: relation to oxygen transport and ventilatory abnormalities. Am J Cardiol 51:1358CrossRefPubMedGoogle Scholar
  21. 21.
    Franciosa JA, Park M, Levine TB (1981) Lack of correlation between exercise capacity and indexes of resting left ventricular performance in heart failure. Am J Cardiol 47:33CrossRefPubMedGoogle Scholar
  22. 22.
    Dyke SH, Urschel CW, Sonnenblick EH et al. (1975) Detection of latent function in acutely ischemic myocardium in the dog. Circ Res 36:490CrossRefPubMedGoogle Scholar
  23. 23.
    Braunwald E, Ross J, Frommer PL et al. (1964) Clinical observations on paired electrical stimulation of the heart. Am J Med 37:700CrossRefPubMedGoogle Scholar
  24. 24.
    Sonnenblick EH, Frishman WH, LeJemtel TH (1979) Dobutamine: a new synthetic cardioactive sympathetic amine. N Engl J Med 300:17CrossRefPubMedGoogle Scholar
  25. 25.
    Scholz H (1984) Inotropic drugs and their mechanism of action. J Am Coll Cardiol 4:389CrossRefPubMedGoogle Scholar
  26. 26.
    Klein G, Wirtzfeld A, Schnelle K, Holzmüller W, Schinz A (1980) Hämodynamische und metabolische Wirkungen von Dobutamin und Prenalterol bei gesunden Probanden. In: Bleifeld W, Gattinge R, Schaper W, Brade W (eds) Internationales Dobutamin Symposium. Urban and Schwarzenberg, MunichGoogle Scholar
  27. 27.
    Williams RJ, Bishop Z (1981) Selectivity of dobutamine for adrenergic receptor subtypes: in vitro analysis by radioligand binding. J Clin Invest 67:1703CrossRefPubMedCentralPubMedGoogle Scholar
  28. 28.
    Unverferth DV, Blauford M, Kates RE et al. (1980) Tolerance to dobutamine after a 72-hour continuous infusion. Am J Med 69:262CrossRefPubMedGoogle Scholar
  29. 29.
    Baumann G, Pfafferott C, Klein G (1988) Acute hemodynamic effects of dopexamine, dobutamine and sodium-nitroprusside in chronic heart failure. Eur Heart J 9:503PubMedGoogle Scholar
  30. 30.
    Baumann G, Felix STB, Rieß G, Loher U, Ludwig L, Blömer H (1984) Apparent superiority of H2-receptor stimulation and simultaneous ß-blockade over conventional treatment with /?-sympathomimetic drugs post-acute myocardial infarction. Agents Actions 15:216–228CrossRefPubMedGoogle Scholar
  31. 31.
    Unverferth DV, Magorien RD, Altschuld R et al. (1983) The hemodynamic and metabolic advantages gained by a 3-day infusion of dobutamine in patients with congestive cardiomyopathy. Am Heart J 106:29CrossRefPubMedGoogle Scholar
  32. 32.
    Leier CV, Huss P, Lewis RP et al. (1982) Drug-induced conditioning in congestive heart failure. Circulation 65:1382CrossRefPubMedGoogle Scholar
  33. 33.
    Kenakin TP, Ferris RM (1983) Effects of in vivo beta-adrenoceptor down regulation on cardiac responses to prenalterol and pirbuterol. J Cardiovasc Pharmacol 5:90CrossRefPubMedGoogle Scholar
  34. 34.
    Awan NA, Evensen MK, Needham KE et al. (1981) Hemodynamic effects of oral pirbuterol in chronic severe congestive heart failure. Circulation 63:96CrossRefPubMedGoogle Scholar
  35. 35.
    Erbel R, Meyer J, Lambertz H et al. (1982) Hemodynamic effects of prenalterol in patients with ischemic heart disease and congestive cardiomyopathy. Circulation 66:361CrossRefPubMedGoogle Scholar
  36. 36.
    Pouleur H, van Eyll CH, Hanet C et al. (1988) Long-term effects of xamoterol on left ventricular function and late remodeling: a study in patients with anterior myocardial infarction and single-vessel disease. Circulation 77:1081CrossRefPubMedGoogle Scholar
  37. 37.
    Baumann G, Busch U, Permanetter B et al. (1986) Occurrence and function of histamine receptors possible significance of H2-receptor stimulation in catecholamine-insensitive myocardial insufficiency. In: Schölmerich P, Holtmeier HJ, Kroneberg HG (eds) Cardiovascular receptors new pharmacologic and clinical aspects. Thieme, Stuttgart, p 169Google Scholar
  38. 38.
    Baumann G, Busch U, Permanetter B et al. (1987) Mögliche Bedeutung einer kardialen H2-Rezeptorstimulation bei Katecholamin-refraktärem Myokardversagen unterschiedlichster Ätiologie. In: Brisse B, Bender F (eds) Autonome Inervation des Herzens. Steinkopff, Darmstadt, p 183Google Scholar
  39. 39.
    Baumann G, Ningel K, Permanetter B (1989) Cardiovascular profile of UDCG 115 BS pimobendane and reversibility of catecholamine subsensitivity in severe con gestive heart failure secondary to idiopathic dilated cardiomyopathy. J Cardiovasc Pharmacol 13:730PubMedGoogle Scholar
  40. 40.
    Brodde OE, Schuler S, Kretsch R et al. (1986) Regional distribution of ß-adrenoceptors in the human heart: coexistence of functional ß1- and ß2-adrenoceptors in both atria and ventricles in severe congestive cardiomyopathy. J Cardiovasc Pharmacol 8:1235CrossRefPubMedGoogle Scholar
  41. 41.
    Stiles GL, Taylor S, Lefkowitz RJ (1983) Human cardiac ß-adrenergic receptors: subtype heterogeneity delineated by direct radioligand binding. Life Sci 33:467CrossRefPubMedGoogle Scholar
  42. 42.
    Heitz A, Schwartz J, Velly J (1983) ß-Adrenoceptors of the human myocardium: determination of ß1 and ß2 subtypes by radioligand. Br J Pharmacol 80:711CrossRefPubMedGoogle Scholar
  43. 43.
    Golf S, Lovstad R, Hnsson V (1985) ß-Adrenoceptor density and relative number of ß-adrenoceptor subtypes in biopsies from human right atrial, left ventricular and right ventricular myocardium. Cardiovasc Res 19:636CrossRefPubMedGoogle Scholar
  44. 44.
    Bristow MR, Ginsburg R, Fowler M et al. (1986) ß1- And ß2-adrenergic receptor subpopulations in normal and failing human ventricular myocardium: coupling of both receptor subtypes to muscle contraction and selective ß1 receptor down-regulation in heart failure. Circ Res 59:297CrossRefPubMedGoogle Scholar
  45. 45.
    Bristow MR, Ginsburg R (1986) ß Receptors are present on myocardial cells in human ventricular myocardium. Am J Cardiol 57:3FCrossRefPubMedGoogle Scholar
  46. 46.
    Baumann G, Felix STB, Sackmann I, Klein G (1989) An open study to assess the effects of dopexamine on urinary output and haemodynamics in patients with chronic cardiac failure and to compare these effects with those produced by dobutamine. Eur Heart J (in press)Google Scholar
  47. 47.
    Baumann G, Gutting M, Pfafferott C et al. (1988) Comparison of acute haemodynamic effects of dopexamine hydrochloride, dobutamine and sodium nitroprusside in chronic heart failure. Eur Heart J 9:503PubMedGoogle Scholar
  48. 48.
    Alousi AA, Farah AE, Lesher GY et al. (1979) Cardiotonic activity of amrinone -WIN 40680 (5-amino-3,4’-bipyridine-6(lH)-one). Circ Res 45:666CrossRefPubMedGoogle Scholar
  49. 49.
    Ross G, Dobestani AI, Patel AL (1981) Effect of amrinone on vascular smooth muscle. Fed Proc 40:659 (abstr)Google Scholar
  50. 50.
    Sonnenblick EH, Mancini DM, LeJemtel TH (1989) New inotropic drugs for the treatment of heart failure: promises and limitations. Am J Cardiol (in press)Google Scholar
  51. 51.
    Levine SD, Jacoby M, Satriano JA et al. (1981) The effects of amrinone on transport and cAMP metabolism in toad urinary bladder. J Pharmacol Exp Ther 216:220PubMedGoogle Scholar
  52. 52.
    Scholz H, Meyer W (1986) Phosphodiesterase inhibiting properties of newer inotropic agents. Circulation [Suppl III] 73:III–108Google Scholar
  53. 53.
    Rapundalo St, Grupp I, Grupp G et al. (1986) Myocardial actions of rnilrinone: characterization of its mechanism of action. Circulation 73 [Suppl III]:III–134Google Scholar
  54. 54.
    Colucci WS, Wright RF, Braunwald E (1986) New positive inotropic agents in the treatment of congestive heart failure (pt 2). N Engl J Med 314:349CrossRefPubMedGoogle Scholar
  55. 55.
    Feldman MD, Copelas L, Gwathmey JK et al. (1987) Pharmacologic evidence of an important cause of contractile dysfunction in patients with end-stage heart failure. Circulation 75:331CrossRefPubMedGoogle Scholar
  56. 56.
    Baumann G, Mercader D, Permanetter B, Busch U, Ningel K, Wirtzfeld A, Blömer H (1985) A new therapeutic approach on congestive heart failure: combined phosphodiesterase inhibition with simultaneous H2-receptor stimulation. In: Ganellin CR, Schwartz JC (eds) Frontiers in histamine research. Pergamon, New York, p 325 (Advances in the biosciences, vol 54)Google Scholar
  57. 57.
    Baumann G, Buschauer A, Permanetter B et al. (1988) New aspects for the treatment of congestive heart failure. Innere Medizin 15:30Google Scholar
  58. 58.
    Naccarelli GV, Gray EL, Dougherty AH et al. (1984) Amrinone: acute electrophysiologic and hemodynamic effects in patients with congestive heart failure. Am J Cardiol 54:600CrossRefPubMedGoogle Scholar
  59. 59.
    Nasrat A, Tepper D, Hertzberg J et al. (1983) Effects of amrinone on atrioventricular conduction in the intact canine heart. J Clin Pharmacol 23:257CrossRefGoogle Scholar
  60. 60.
    Alousi AA, Farah AE, Lesher GY et al. (1979) Cardiotonic activity of amrinone WIN 40680. Circ Res 45:666CrossRefPubMedGoogle Scholar
  61. 61.
    Maskin CS, Forman R, Klein NA et al. (1982) Long-term amrinone therapy in pa tients with severe heart failure. Am J Med 72:113CrossRefPubMedGoogle Scholar
  62. 62.
    Weber KT, Andrews V, Janicki JS et al. (1981) Amrinone and exercise performance in patients with chronic heart failure. Am J Cardiol 48:164CrossRefPubMedGoogle Scholar
  63. 63.
    Siskind SY, Sonnenblick EH, Forman R et al. (1981) Acute substantial benefits of inotropic therapy with amrinone on exercise hemodynamics and metabolism in severe congestive heart failure. Circulation 64:966CrossRefPubMedGoogle Scholar
  64. 64.
    LeJemtel TH, Keung E, Ribner HS et al. (1980) Sustained beneficial effects of oral amrinone on cardiac and renal function in patients with severe congestive heart failure. Am J Cardiol 45:123CrossRefPubMedGoogle Scholar
  65. 65.
    Baumann G, Felix STB, Ningel K, Klein G (1989) Piroximone. Vasodilatation versus inotropy: a group comparative study of hemodynamic responses in chronic congestive heart failure with sodium nitroprusside, piroximone (MDL 19205) and dobutamine. Eur Heart J (in press)Google Scholar
  66. 66.
    Wynne J, Malacoff RF, Benotti JR et al. (1980) Oral amrinone in refractory congestive heart failure. Am J Cardiol 45:1245CrossRefPubMedGoogle Scholar
  67. 67.
    Sterling Winthrop Research Institute (1982) Clinical experience with amrinone: overall summary for NDA amendment. Sterling Winthrop Research Institute, Rensselaer NYGoogle Scholar
  68. 68.
    Baumann G, Permanetter B, Wirtzfeld A (1984) Possible value of H2-receptor agonists for treatment of catecholamine-insensitive congestive heart failure. Pharmacol Ther 24:177CrossRefGoogle Scholar
  69. 69.
    Scholtysik G, Salzmann R, Berthold R et al. (1985) DPI 20106, a novel cardioactive agent. Combination of cAMP-independent positive inotropic, negative chronotropic action potential prolonging and coronary dilatory properties. Naunyn Schmiedeberg’s Arch Pharmacol 329:316CrossRefGoogle Scholar
  70. 70.
    Rüegg JC (1986) Effects of new inotropic agents on Ca2+ sensitivity of contractile proteins. Circulation 73 [Suppl III]:III–78Google Scholar
  71. 71.
    Katz AM (1978) A new inotropic drug: its promise and a caution. N Engl J Med 29:1409CrossRefGoogle Scholar
  72. 72.
    Kirk ES, LeJemtel TH, Nelson GR et al. (1976) Mechanisms of beneficial effects of vasodilators and inotropic stimulation in the experimental failing ischemic heart. Am J Med 65:189CrossRefGoogle Scholar
  73. 73.
    LeJemtel TH, Sonnenblick EH (1984) Should the failing heart be stimulated? N Engl J Med 310:1384CrossRefPubMedGoogle Scholar
  74. 74.
    Baumann G, Rieß G, Felix STB et al. (1981) Catecholamines and ß-adrenergic receptors in the non-ischemic myocardium after coronary occlusion. In: Delius W, Gerlach E, Grobecker X, Kübier W (eds) Catecholamines and the heart, vol 72. Springer, Berlin Heidelberg New York, p 91Google Scholar
  75. 75.
    Baumann G, Felix STB, Schrader J et al. (1981) Cardiac contractile and metabolic effects mediated via the myocardial H2-receptor adenylate cyclase system: characterization of two new specific H2-receptor-agonists, impromidine and dimaprit, in the guinea pig and human myocardium. Res Exp Med (Berl) 179:81–98CrossRefGoogle Scholar
  76. 76.
    Baumann G, Felix STB, Rieß G, Loher U, Ludwig L, Blömer H (1982) Effective stimulation of cardiac contractility and myocardial metabolism by impromidine and dimaprit two new H2-agonistic compounds in the surviving, catecholamineinsensitive myocardium after coronary occlusion. J Cardiovasc Pharmacol 4:542–553CrossRefPubMedGoogle Scholar
  77. 77.
    Baumann G, Rieß G, Erhardt WD, Felix STB, Blömer H (1980) Reduzierte ß-adrenerge Ansprechbarkeit im nicht ischämischen Myokard nach experimentellem Herzinfarkt. Z Kardiol 69:209Google Scholar
  78. 78.
    Baumann G, Schrader J, Gerlach E (1981) Inhibitory action of adenosine on histamine and dopamine-stimulated cardiac contractility and adenylate cyclase in guinea pigs. Circ Res 48:259–266CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1989

Authors and Affiliations

  • G. Baumann
  • S. B. Felix

There are no affiliations available

Personalised recommendations