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Mechanism of Action of Inotropic Agents in Heart Failure

  • K. Chatterjee
Part of the Update in Intensive Care and Emergency Medicine book series (UICM, volume 6)

Abstract

In 1785 William Withering in his accounts of Foxglove, reported the beneficial effects of digitalis in dropsy [1]. Thus, the use of drugs with positive inotropic effects in the management of heart failure was introduced in the clinical practice. Catecholamines with positive inotropic effects appeared several decades after the introduction of digitalis and presently a large number of such catecholamines are available for the clinical use and a growing number of such agents are undergoing clinical investigation. Non-glycoside, non-catecholamine inotropic agents have also been developed and enthusiasm continues to introduce newer inotropic agents with novel modes of action in the management of both acute and chronic heart failure. The background for this increasing interest in developing inotropic agents is based on the fact that the inotropic agents have the potential to correct one important functional abnormality, that is, the reduced contractile function that frequently initiates heart failure. Although the principle goal for the use of inotropic agents is to enhance contractile function, it needs to be realized that the modes of action and the relative potencies of various inotropic agents are not similar and understanding the mechanism of action of these various inotropic agents and their hemodynamic effects has direct clinical relevance in their use in the management of patients with heart failure.

Keywords

Chronic Heart Failure Systemic Vascular Resistance Hemodynamic Effect Inotropic Agent Positive Inotropic Effect 
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.

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References

  1. 1.
    Withering W (1941) An account of the foxglove and some of its medical uses with practical remarks on dropsy and other diseases. In: Willius FA, Keys TE (eds) Classics of cardiology. Henry Schuman, New York, p 231Google Scholar
  2. 2.
    Wohlfahrt B, Noble MIM (1982) The cardiac excitation-contraction coupling. Pharmacol Ther 16: 1CrossRefGoogle Scholar
  3. 3.
    Chapman RA (1983) Control of cardiac contractility at the cellular level. Am J Physiol 245: H535PubMedGoogle Scholar
  4. 4.
    Fabiato A, Fabiato F (1979) Calcium and cardiac excitation-contraction coupline. Annu Rev Physiol 41: 473PubMedCrossRefGoogle Scholar
  5. 5.
    Colucci WS, Wright RF, Braunwald E (1986) New positive inotropic agents in the treatment of congestive heart failure. Mechanisms of action and recent clinical development. N Engl J Med 314: 290PubMedCrossRefGoogle Scholar
  6. 6.
    Colucci WS, Wright RF, Braunwald E (1986) New positive inotropic agents in the treatment of congestive heart failure. Mechanisms of action and recent clinical developments. N Engl J Med 314: 349PubMedCrossRefGoogle Scholar
  7. 7.
    Katz AM (1986) Discussion section. Article by Endoh M, Yanagisawa T, Taira N, Blinks JR: Effects of new inotropic agents on cyclic nucleotide metabolism and calcium transients in canine ventricular muscle. Circulation 73 (Suppl III): 117Google Scholar
  8. 8.
    Allen DG, Blinks JR (1978) Calcium transients in aquorin-injection frog cardiac muscle. Nature 273: 509PubMedCrossRefGoogle Scholar
  9. 9.
    Smith TW, Antman EM, Friedman PL, et al (1984) Digitalis glycosides: Mechanisms and manifestations of toxicity. Prog Cardiovasc Dis 26: 413PubMedCrossRefGoogle Scholar
  10. 10.
    Smith TW, Antman EM, Friedman PL, et al (1984) Digitalis glycosides: Mechanisms and manifestations of toxicity ( Part III ). Prog Cardiovasc Dis 27: 21PubMedCrossRefGoogle Scholar
  11. 11.
    Braunwald E (1985) Effects of digitalis on the normal and failing heart. J Am Coll Cardiol 5: 51AGoogle Scholar
  12. 12.
    Sonnenblick EH, Williams JF Jr, Glick G, et al (1966) Studies on Digitalis XV: Effects of cardiac glycosides on myocardial force-velocity relations in the failing heart. Circulation 34: 532PubMedGoogle Scholar
  13. 13.
    Spann JF Jr, Buccino RA, Sonnenblick EH, Braunwald E (1967) Contractile state of cardiac muscle obtained from cats with experimentally produced ventricular hypertrophy at heart failure. Circ Res 21: 341PubMedGoogle Scholar
  14. 14.
    Mahler F, Karliner JS, O’Rourke RA (1974) Effects of chronic digoxin administration on left ventricular performance in the normal conscious dog. Circulation 50: 720PubMedGoogle Scholar
  15. 15.
    Crawford MH, Karliner JS, O’Rourke RA, Amon KW (1976) Effects of chronic digoxin administration on left ventricular performance in normals subjects. Echocardiographic study. Am J Cardiol 38: 843PubMedCrossRefGoogle Scholar
  16. 16.
    Mason DT, Braunwald E (1964) Studies on digitalis X. Effects of ouabain on forearm vascular resistance and venous tone in normal subjects and in patients in heart failure. J Clin Invest 43: 532PubMedCrossRefGoogle Scholar
  17. 17.
    Shanbour LL, Jacobson ED (1972) Digitalis and the mesenteric circulation. Am J Dig Dis 17: 826PubMedCrossRefGoogle Scholar
  18. 18.
    Ross J Jr, Braunwald E, Waldhausen JA (1960) Studies of digitalis II: Extracardiac effects on venous return and on the capacity of peripheral vascular bed. J Clin Invest 39: 936Google Scholar
  19. 19.
    Sugar KB, Hanson EC, Powell WJ (1977) Neurogenic vasoconstrictor effects during acute global ischemia in dogs. J Clin Invest 60: 1248CrossRefGoogle Scholar
  20. 20.
    DeMots H, Rahimtoola SH, McAnulty JH, Porter GA (1978) Effects of ouabain on coronary and systemic vascular resistance and myocardial oxygen consumption in patients without heart failure. Am J Cardiol 41: 88PubMedCrossRefGoogle Scholar
  21. 21.
    Garan H, Smith TW, Powell WJ Jr (1974) The central nervous system as a site of action for the coronary vasoconstrictor effect of digoxin. J Clin Invest 54: 1365PubMedCrossRefGoogle Scholar
  22. 22.
    Arnold SB, Byrd RC, Meister W, et al (1980) Long-term digitalis therapy improves left ventricular function in heart failure. N Engl J Med 303: 1443PubMedCrossRefGoogle Scholar
  23. 23.
    Covit AB, Schaer GL, Sealy JE, et al (1983) Suppression of the renin-angiotensin by intravenous digoxin in chronic congestive heart failure. Am J Med 75: 445PubMedCrossRefGoogle Scholar
  24. 24.
    Watanabe AM (1985) Digitalis and the autonomic nervous system. J Am Coll Cardiol 5: 35AGoogle Scholar
  25. 25.
    Nakamura M (1985) Digitalis induced augmentation of cardiopulmonary baroreflex control of forearm vascular resistance. Circulation 71: 11PubMedCrossRefGoogle Scholar
  26. 26.
    Gillis RA, Quest JA (1980) The role of the nervous system in the cardiovascular effects of digitalis. Pharmacol Rev 31: 19Google Scholar
  27. 27.
    Ahlquist RP (1984) A study of adrenotropic receptors. Am J Physiol 153: 586Google Scholar
  28. 28.
    Watanabe AM (1983) Recent advances in knowledge about beta-adrenergic receptors: Application to clinical cardiology. J Am Coll Cardiol 1: 82PubMedCrossRefGoogle Scholar
  29. 29.
    Colucci WS (1984) Alpha-adrenergic receptors in cardiovascular medicine. In: Karliner JS, Haft JI (eds) Receptor science in cardiology. Futura Publications Mt Kisco NY, p 43Google Scholar
  30. 30.
    Goldberg M, Robertson D (1984) Evidence for the existence of vascular alpha2-adrenoreceptors in humans. Hypertension 6: 551PubMedGoogle Scholar
  31. 31.
    Langer SZ (1974) Presynaptic regulation of catecholamine release. Biochem Pharmacol 23: 1793PubMedCrossRefGoogle Scholar
  32. 32.
    Bruckner R, Meyer W, Mugge A, et al (1984) Alpha-adrenoceptor mediated positive isotropic effect on phenylephrine in isolated human ventricular myocardium. Eur J Pharmacol 99: 345PubMedCrossRefGoogle Scholar
  33. 33.
    Lefkowitz RJ, Stadel JM, Caron MG (1983) Adenylate cyclase-coupled beta adrenergic receptors: Structure and mechanisms of activation and desensitization. Annu Rev Biochem 52: 159PubMedCrossRefGoogle Scholar
  34. 34.
    Francis GS (1983) The role of isotropic agents in the management of heart failure. In: Cohn JN (ed) Drug treatment of heart failure, Chap VII. York Medical Books, New York, p 125Google Scholar
  35. 35.
    Innes IR, Nickerson M (1975) Norepinephrine, epinephrine and the sympathomimetic amines. In: Goodman LS, Gilman A (eds) Pharmacological basis of therapeutics, 5th edn, Macmillan, New York, p 477Google Scholar
  36. 36.
    Goldberg LI, Rajfer SI (1985) Dopamine receptors. Applications in clinical cardiology. Circulation 72: 245PubMedCrossRefGoogle Scholar
  37. 37.
    Goldberg LI (1972) Gardiovascular and renal actions of dopamine Potential applications. Pharmacol Rev 24: 1PubMedGoogle Scholar
  38. 38.
    Goldberg LI, HGsieh YY, Resnekov L (1977) Newer catecholamines for treatment of heart failure and shock: An update on dopamine and a first look at dobutamine. Prog Cardiovasc Dis 4: 327CrossRefGoogle Scholar
  39. 39.
    Rajfer SI, Anton AH, Rossen J, Goldberg LI (1984) Beneficial hemodynamic effects of oral levodopa in heart failure: Relationship to the generation of dopamine. N Engl J Med 310: 1357PubMedCrossRefGoogle Scholar
  40. 40.
    Daly PA, Chatterjee K, Viquerat CE, et al (1985) RO13–6438, a new inotrope-vasodilator: Systemic and coronary hemodynamic effects in congestive heart failure. Am J Cardiol 55: 1539PubMedCrossRefGoogle Scholar
  41. 41.
    DeMarco T, Daly PA, Chatterjee K: Levodopa in chronic heart failure: Systemic and coronary hemodynamic and neurohumoral effects: Am J Cardiol (in press)Google Scholar
  42. 42.
    Brown RA, Dixon J, Farmer JB, et al (1985) Dopexamine: A novel agonist at peripheral dopamine receptors and beta2-adrenoreceptors. Br J Pharmacol 85: 599PubMedGoogle Scholar
  43. 43.
    Dawson JR, Thompson DS, Signy M, et al (1985) Acute hemodynamic and metabolic effects of dopexamine, a new dopaminergic receptor agonist in patients with chronic heart failure. Br Heart J 54: 313PubMedCrossRefGoogle Scholar
  44. 44.
    DeMarco T, Kwasman M, Lau D, Chatterjee K: Dopexamine hydrochloride in chronic heart failure: Improved cardiac performance without increased metabolic cost. Am J Cardiology (In press)Google Scholar
  45. 45.
    Fennell WH, Taylor AA, Young JB, et al (1983) Propylbutyldopamine: Hemodynamic effects in conscious dogs, normal human volunteers and patients with heart failure. Circulation 67: 829PubMedCrossRefGoogle Scholar
  46. 46.
    Francis GS, Parks R, Cohn JN (1983) The effects of bromocriptine in patients with congestive heart failure. Am Heart J 106: 100PubMedCrossRefGoogle Scholar
  47. 47.
    Leon CA, Suarez JM, Aranoff RD, et al (1984) Fenoldopam: Efficacy of a new orally active dopamine analog in heart failure. Circulation 70 (Suppl II): 307Google Scholar
  48. 48.
    Francis GS, Wilson BC, Rector TS (1988) Hemodynamic, renal, and neurohumoral effects of a selective oral DA, receptor agonist (fenoldopam) in patients with congestive heart failure. Am J Cardiol 116 (2): 473–479Google Scholar
  49. 49.
    Dei Gas L, Manca C, Bermardini B, et al (1982) Noninvasive evaluation of the effects of oral ibopamine (SB 7505) on cardiac and renal function in patients with congestive heart failure. J Cardiovasc Pharmacol 4: 436CrossRefGoogle Scholar
  50. 50.
    Dei Cas L, Bolognesi R, Cucchini F, et al (1983) Hemodynamic effects of ibopamine in patients with idiopathic congestive cardiomyopathy. J Cardiovasc Pharmacol 5: 249CrossRefGoogle Scholar
  51. 51.
    Rajfer SI, Rossen JD, Douglas FL, Goldberg LI, Karrison T (1986) Effects of long-term therapy with oral ibopamine on resting hemodynamics and exercise capacity in patients with heart failure: Relationship to the generation of N-methyldopamine and to plasma nor-epinephrine levels. Circulation 73: 740PubMedCrossRefGoogle Scholar
  52. 52.
    Cantelli I, Lolli C, Bomba E, Brunelli D, Bracchetti D (1986) Sustained oral treatment with ibopamine in patients with chronic congestive heart failure. Current Ther Res 9: 900Google Scholar
  53. 53.
    Ruffolo RR Jr, Spradlin TA, Pollock GD, et al (1981) Alpha and beta adrenergic effects of the stereoisomers of dobutamine. J Pharmacol Exp Ther 219: 447PubMedGoogle Scholar
  54. 54.
    Chatterjee J, Bendersky R, Parmley WW (1982) Dobutamine in heart failure. Eur Heart J 3: 107PubMedGoogle Scholar
  55. 55.
    Liang G, Hood WB (1979) Dobutamine infusion in conscious dogs with and without autonomic nervous system inhibition: Effects on systemic hemodynamics, regional blood flows, and cardiac metabolism. J Pharmacol Exp Ther 211: 698–705PubMedGoogle Scholar
  56. 56.
    Colucci WS, Wright RF, Jaski BE, Fifer MA, Braunwald E (1986) Milrinone and dobutamine in severe heart failure: Differing hemodynamic effects and individual patient responsiveness. Circulation 73 (Suppl III): 175Google Scholar
  57. 57.
    Bristow MR, Ginsburg R, Minobe W, et al (1982) Decreased catecholamine sensitivity and beta-adrenergic receptor density in failing human hearts. N Engl J Med 307: 205PubMedCrossRefGoogle Scholar
  58. 58.
    Unverferth DV, Magorien RD, Altschuld R, et al (1983) The hemodynamic and metabolic advantages gained by a three-day infusion of dobutamine in patients with congestive cardiomyopathy. Am Heart J 106: 29PubMedCrossRefGoogle Scholar
  59. 59.
    Bendersky R, Chatterjee K, Parmley WW, et al (1981) Dobutamine in chronic ischemic heart failure: Alterations in left ventricular function and coronary hemodynamics. Am J Cardiol 48: 554PubMedCrossRefGoogle Scholar
  60. 60.
    Sharma B, Goodwin JF (1978) Beneficial effect of salbutamol on cardiac function in severe congestive cardiomyopathy: Effect on systolic and diastolic function of the left ventricle. Circulation 58: 449PubMedGoogle Scholar
  61. 61.
    Bourdillon PDV, Dawson JR, Foale RA, et al (1982) Salbutamol in the treatment of heart failure. Br Heart J 43: 206CrossRefGoogle Scholar
  62. 62.
    Mifune J, Kuramoto K, Ueda K, et al (1982) Hemodynamic effects of salbutamol, an oral long-acting beta stimulant in patients with congestive heart failure. Am Heart J 104: 1011PubMedCrossRefGoogle Scholar
  63. 63.
    Rude RE, Turi Z, Brown EJ, et al (1981) Acute effects of oral pirbuterol on congestive heart failure. Circulation 64: 139PubMedCrossRefGoogle Scholar
  64. 64.
    Awan NA, Needham K, Evenson MK, et al (1981) Therapeutic efficacy of oral pirbuterol in severe chronic congestive heart failure. Acute hemodynamic and long-term ambulatory evaluation. Am Heart J 102: 555PubMedCrossRefGoogle Scholar
  65. 65.
    Leier CV, Nelson S, Huss P, et al (1982) Intravenous pirbuterol. Clin Pharmacol Ther 31: 89PubMedCrossRefGoogle Scholar
  66. 66.
    Colucci WS, Alexander RW, Williams GH, et al (1981) Decreased lymphocyte beta-adrenergic-receptor density in patients with heart failure and tolerance to the beta-adrenergic agonist, pirbuterol. N Engl J Med 305: 185PubMedCrossRefGoogle Scholar
  67. 67.
    Manders WT, Watner SF, Braunwald E (1980) Cardio-selective beta adrenergic stimulation with prenalterol in the conscious dog. J Pharmacol Exp Ther 215: 266PubMedGoogle Scholar
  68. 68.
    Kirlin PC, Pitt B (1981) Hemodynamic effects of intravenous prenalterol in severe heart failure. Am J Cardiol 47: 670PubMedCrossRefGoogle Scholar
  69. 69.
    Wahr D, Swedberg K, Rabbino M, et al (1984) Intravenous and oral prenalterol in congestive heart failure. Effects on systemic and coronary hemodynamics and myocardial catecholamine balance. Am J Med 76: 999PubMedCrossRefGoogle Scholar
  70. 70.
    Nuttal A, Snow HM (1982) The cardiovascular effects of ICI 118, 587: A beta-adrenoreceptor partial agonist. Br J Pharmacol 77: 381Google Scholar
  71. 71.
    Bhatia JSS, Swedberg K, Chatterjee K (1986) Acute hemodynamic and metabolic effects of ICI 118, 587 ( Corwin), a selective partial beta agonist, in patients with dilated cardiomyopathy. Am Heart J 111: 692PubMedCrossRefGoogle Scholar
  72. 72.
    Kino M, Hirota Y, Yamamoto S, et al (1983) Cardiovascular effects of a newly synthesized cardiotonic agent (TA-064) on normal and diseased hearts. Am J Cardiol 51: 802PubMedCrossRefGoogle Scholar
  73. 73.
    Ozaki N, Bito K, Kinoshita M, Kawakita S (1983) Effects of a cardiotonic agent, TA-064, on isolated canine cerebral, coronary, femoral, mesenteric and renal arteries. J Cardiovasc Pharmacol 5: 818PubMedCrossRefGoogle Scholar
  74. 74.
    Nelson S, Leier CV (1981) Butopamine in normal human subjects. Curr Therap Res 30: 405Google Scholar
  75. 75.
    Thompson MJU, Huss P, Unverferth DV, et al (1980) Hemodynamic effects of intravenous butopamine in congestive heart failure. Clin Pharmacol Ther 28: 324PubMedCrossRefGoogle Scholar
  76. 76.
    Goldstein RE, Skelton CL, Levey GS, et al (1971) Effects of chronic heart failure on the capacity of glucagon to enhance contractility and adenyl cyclase activity of human papillary muscles. Circulation 44: 638PubMedGoogle Scholar
  77. 77.
    Daly JW (1984) Forskolin, adenylate cyclase, and cell physiology: An overview. Adv Cyclic Nucleotide Prot Phosphoryl Res 17: 81Google Scholar
  78. 78.
    Matsue S, Murakami E, Takekoshi N, et al (1983) Hemodynamic effects of dibutyryl cyclic AMP in congestive heart failure. Am J Cardiol 51: 1364CrossRefGoogle Scholar
  79. 79.
    Strada SJ, Thompson WJ (1984) Cyclic nucleotide phosphodiesterases. Adv Cyclic Nucleotide Prot Phosphoryl Res 16: 1Google Scholar
  80. 80.
    Still JA, Sullivan SF (1981) Aminophylline. Anesth Analg 60: 587Google Scholar
  81. 81.
    Mancini D, LeJemtel T, Sonnenblick E (1985) Intravenous use of amrinone for the treatment of the failing heart. Am J Cardiol 56: 8BGoogle Scholar
  82. 82.
    Benotti JR, Grossman W, Braunwald E, et al (1978) Hemodynamic assessment of amrinone: A new inotropic agent. N Engl J Med 299: 1373PubMedCrossRefGoogle Scholar
  83. 83.
    Cody RJ, Muller FB, Kubo SH, et al (1986) Identification of the direct vasodilator effect of milrinone with an isolated limb preparation in patients with chronic congestive heart failure. Circulation 73: 124PubMedCrossRefGoogle Scholar
  84. 84.
    Simonton CA, Chatrerjee K, Cody RJ, et al (1985) Milrinone in congestive heart failure: Acute and chronic hemodynamic and clinical evaluation. J Am Coll Cardiol 6: 453PubMedCrossRefGoogle Scholar
  85. 85.
    Kubo SH, Cody RJ, Chatterjee K, et al (1985) Acute dose-range study of milrinone in congestive heart failure. Am J Cardiol 55: 726PubMedCrossRefGoogle Scholar
  86. 86.
    Crawford MH, Richards KL, Sodums MT, Kennedy GT (1984) Positive inotropic and vasodilator effects of MDL 17043 in patients with reduced left ventricular performance. Am J Cardiol 53: 1051PubMedCrossRefGoogle Scholar
  87. 87.
    Kereiakes D, Chatterjee K, Parmley WW, et al (1984) Intravenous and oral MDL 17043 (a new inotrope-vasodilator agent) in congestive heart failure: Hemodynamic and clinical evaluation in 38 patients. J Am Coll Cardiol 4: 884PubMedCrossRefGoogle Scholar
  88. 88.
    Uretsky BF, Generalovich T, Reddy PS, et al (1984) Acute hemodynamic effect of oral MDL 17043 in severe congestive heart failure. Am J Cardiol 54: 357PubMedCrossRefGoogle Scholar
  89. 89.
    Petein M, Levine B, Cohn JN (1984) Hemodynamic effects of a new inotropic agent, piroximone (MDL 19,205) in patients with chronic heart failure. J Am Coll Cardiol 4: 364PubMedCrossRefGoogle Scholar
  90. 90.
    Dage RC, Roebel LE, Hsieh CP, Woodward JK (1984) Cardiovascular properties of a new cardiotonic agent, MDL 19, 205. J Cardiovasc Pharmacol 6: 35PubMedCrossRefGoogle Scholar
  91. 91.
    Daly PA, Chatterjee K, Viquerat CE, et al (1985) RO13–6438, a new inotrope-vasodilator: Systemic and coronary hemodynamic effects in congestive heart failure. Am J Cardiol 55: 1539PubMedCrossRefGoogle Scholar
  92. 92.
    Renard M, Jacobs P, Dechamps P, et al (1983) Hemodynamic and clinical response to three-day infusion of sulmazol (AR LI15BS) in severe congestive heart failure. Chest 84: 408PubMedCrossRefGoogle Scholar
  93. 93.
    Mancini D, Sonnenblick EH, Latts JR, et al (1984) Hemodynamic and clinical benefits of CI-914, a new cardiotonic agent. Circulation 70 (Suppl II): 307Google Scholar
  94. 94.
    Endoh M, Yamashita S, Taira N (1982) Positive inotropic effect of amrinone in relation to cyclic nucleotide metabolism in the canine ventricular muscle. J Pharmacol Exp Ther 221: 775PubMedGoogle Scholar
  95. 95.
    Ludmer PL, Wright RF, Arnold MO, et al (1986) Separation of the direct myocardial and vasodilator actions of milrinone administratered by an intracoronary infusion technique. Circulation 73: 130PubMedCrossRefGoogle Scholar
  96. 96.
    Dage RC, Kariya T, Hsieh PC, et al (1987) Pharmacology of enoximone. Am J Cardiol 60: 10CCrossRefGoogle Scholar
  97. 97.
    Janicki JS, Shroff SG, Weber KT (1987) Physiologic response to the inotropic and vasodilator properties of enoximone. Am J Cardiol 60: 15CGoogle Scholar
  98. 98.
    Kereiakes DJ, Viquerat C, Lanzer P, et al (1984) Mechanisms of improved left ventricular function following intravenous MDL, 17093 in patients with severe chronic heart failure. Am Heart J 108: 1278PubMedCrossRefGoogle Scholar

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© Springer-Verlag Berlin Heidelberg 1988

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  • K. Chatterjee

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