Skip to main content
SpringerLink
Log in

The Role of Nitric Oxide in Heart Failure

Potential for Pharmacological Intervention

  • Review Article
  • Clinical Pharmacology
  • Published:
Drugs & Aging Aims and scope Submit manuscript

Summary

There is now considerable evidence that nitric oxide (NO) production and action are abnormal in patients with heart failure. Spontaneous NO release from the vascular endothelium is preserved or enhanced in patients with heart failure and this may help to maintain tissue perfusion by blunting the vasoconstriction induced by various neurohumoral factors. On the other hand, endothelial NO release in response to various stimuli including exercise appears to be diminished and this may contribute to the impaired exercise capacity of patients with heart failure.

It is now apparent that NO produced within the heart plays an important role in the modulation of cardiac contractility under physiological conditions. In patients with heart failure, however, increased myocardial NO production in response to cytokines such as tumour necrosis factor-α may contribute to reduced contractility and myocyte injury.

Our understanding of the role of NO in the control of vascular tone has provided an explanation for the efficacy of nitrovasodilators in heart failure and has stimulated novel approaches to augmenting endogenous vascular NO production. There is also evidence that ACE inhibitors act to restore normal endothelial function in patients with heart failure.

Increased NO production within the heart, particularly that produced via the pro-inflammatory inducible NO synthase, may be detrimental. It remains to be determined whether selective inhibition of inducible NO synthase can favourably modify the course of this lethal condition.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Moncada S, Palmer RMJ, Higgs EA. Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol Rev 1991; 43(2): 109–42

    PubMed  CAS  Google Scholar 

  2. Bassenge E. Coronary vasomotor responses: role of endothelium and nitrovasodilators. Cardiovasc Drugs Ther 1994; 8(4): 601–10

    Article  PubMed  CAS  Google Scholar 

  3. Kaiser L, Spickard RC, Olivier NB. Heart failure depresses endothelium-dependent responses in canine femoral artery. Am J Physiol 1989; 256 (4 Pt 2): H962–7

    PubMed  CAS  Google Scholar 

  4. Drexler H, Lu W. Endothelial dysfunction of hindquarter resistance vessels in experimental heart failure. Am J Physiol 1992; 262 (6 Pt 2): H1640–5

    PubMed  CAS  Google Scholar 

  5. Treasure CB, Vita JA, Cox DA, et al. Endothelium-dependent dilation of the coronary microvasculature is impaired in dilated cardiomyopathy. Circulation 1990; 81: 772–9

    Article  PubMed  CAS  Google Scholar 

  6. Kubo SH, Rector TS, Bank AJ, et al. Endothelium-dependent vasodilation is attenuated in patients with heart failure. Circulation 1991; 84: 1589–96

    Article  PubMed  CAS  Google Scholar 

  7. O’Murchu B, Miller VM, Perella MA, et al. Increased production of nitric oxide in coronary arteries during congestive heart failure. J Clin Invest 1994; 93: 165–71

    Article  PubMed  Google Scholar 

  8. Hirooka Y, Imaizumi T, Harada S, et al. Endothelium-dependent forearm vasodilation to acetylcholine but not to substance P is impaired in patients with heart failure. J Cardiovasc Pharmacol 1992; 20 Suppl. 12: S221–5

    Article  PubMed  Google Scholar 

  9. Drexler H, Hayoz D, Munzel T, et al. Endothelial function in chronic congestive heart failure. Am J Cardiol 1992; 69(19): 1596–601

    Article  PubMed  CAS  Google Scholar 

  10. Kubo SH, Rector TS, Bank A, et al. Lack of contribution of nitric oxide to basal vasomotor tone in heart failure. Am J Cardiol 1994; 74: 1133–6

    Article  PubMed  CAS  Google Scholar 

  11. Habib F, Dutka D, Crossman D, et al. Enhanced basal nitric oxide production in heart failure: another failed counter-regulatory vasodilator mechanism? Lancet 1994; 344: 371–3

    Article  PubMed  CAS  Google Scholar 

  12. Winlaw DS, Smythe GA, Keogh AM, et al. Increased nitric oxide production in heart failure. Lancet 1994; 344: 373–4

    Article  PubMed  CAS  Google Scholar 

  13. Winlaw D, Smythe G, Keogh A, et al. Nitric oxide production and heart failure. Lancet 1995; 345: 390–1

    Article  PubMed  CAS  Google Scholar 

  14. Levine B, Kalman J, Mayer L, et al. Elevated circulating levels of tumour necrosis factor in severe chronic heart failure. N Engl J Med 1990; 323: 236–41

    Article  PubMed  CAS  Google Scholar 

  15. McMurray J, Abdullah I, Dargie HJ, et al. Increased concentrations of tumour necrosis factor in ‘cachectic’ patients with severe chronic heart failure. Br Heart J 1991; 66(5): 356–8

    Article  PubMed  CAS  Google Scholar 

  16. Katz SD, Rao R, Berman JW, et al. Pathophysiological correlates of increased serum tumor necrosis factor in patients with congestive cardiac failure: relation to nitric oxide-dependent vasodilation in the forearm circulation. Circulation 1994; 90(1): 12–6

    Article  PubMed  CAS  Google Scholar 

  17. Wiedermann C, Beimpold H, Herold M, et al. Increased levels of serum neopterin and decreased production of neutropil superoxide anions in chronic heart failure with elevated levels of tumour necrosis factor-alpha. J Am Coll Cardiol 1993; 22(7): 1897–1901

    Article  PubMed  CAS  Google Scholar 

  18. Yoshizumi M, Perrella MA, Burnett JC, et al. Tumor necrosis factor downregulates an endothelial nitric oxide synthase messenger RNA by shortening its half-Life. Circ Res 1993; 73(1): 205–9

    Article  PubMed  CAS  Google Scholar 

  19. Matsubara T, Ziff M. Increased superoxide anion release from human endothelial cells in response to cytokines. J Immunol 1986; 137(10): 3295–8

    PubMed  CAS  Google Scholar 

  20. Busse R, Mulsch A. Induction of nitric oxide synthase by cytokines in vascular smooth muscle cells. FEBS Lett 1990; 275(1–2): 87–90

    Article  PubMed  CAS  Google Scholar 

  21. Gross SS, Jaffe EA, Levi R, et al. Cytokine-activated endothelial cells express an isotype of nitric oxide synthase which is tetrahydrobiopterin-dependent, calmodulin-independent and inhibited by arginine analogs with a rank-order of potency characteristic of activated macrophages. Biochem Biophys Res Commun 1991; 178(3): 823–9

    Article  PubMed  CAS  Google Scholar 

  22. Hirooka Y, Imaizumi T, Tagawa T, et al. Effects of L-arginine on impaired acetylcholine-induced and ischemic vasodilation of the forearm in patients with heart failure. Circulation 1994; 90: 658–68

    Article  PubMed  CAS  Google Scholar 

  23. Balligand JL, Kelly RA, Marsden PA, et al. Control of cardiac muscle cell function by an endogenous nitric oxide signalling system. Proc Natl Acad Sci USA 1993; 90: 347–51

    Article  PubMed  CAS  Google Scholar 

  24. Shah AM, Smith JA, Lewis MJ. The role of the endocardium in the modulation of contraction of isolated papillary muscles of the ferret. J Cardiovasc Pharmacol 1991; 17 Suppl. 3: S251–7

    Article  Google Scholar 

  25. Finkel MS, Oddis CV, Jacob TD, et al. Negative inotropic effects of cytokines on the heart mediated by nitric oxide. Science 1992; 257(5068): 387–9

    Article  PubMed  CAS  Google Scholar 

  26. Balligand JL, Ungureanu D, Kelly RA, et al. Abnormal contractile function due to induction of nitric oxide synthesis in rat cardiac myocytes follows exposure to activated macrophage-conditioned medium. J Clin Invest 1993; 91(5): 2314–9

    Article  PubMed  CAS  Google Scholar 

  27. Paulus WJ, Vantrimpont PJ, Shah AM. Acute effects of nitric oxide on left ventricular relaxation and diastolic distensibility in humans. Circulation 1994; 89: 2070–8

    Article  PubMed  CAS  Google Scholar 

  28. De Belder AJ, Radomski MW, Why HJF, et al. Nitric oxide synthase activities in human myocardium. Lancet 1993; 341: 84–5

    Article  PubMed  Google Scholar 

  29. Hatler B, Oddis C, Zeevi A, et al. Regulation of constitutive nitric oxide synthase activity by the human heart. Am J Cardiol 1995; 76: 957–9

    Article  Google Scholar 

  30. Studer R, Käster S, Reinecke H, et al. Myocardial gene expression of endothelial NO synthase in ischaemic and dilative cardiomyopathy [abstract]. Eur Heart J 1994; 15 Suppl. 1: P265

    Google Scholar 

  31. Studer R, Käster S, Just H, et al. Myocardial gene expression of nitric oxide synthase in ischaemic and dilated cardiomyopathy. Circulation 1994; 90 (4 Pt 2): I–547, abstract 2946

    Google Scholar 

  32. Haywood G, Tsao P, Leyen HVD, et al. Expression of inducible nitric oxide synthase in human heart failure. Circulation 1996; 93(6): 1087–94

    Article  PubMed  CAS  Google Scholar 

  33. Moncada S. The L-arginine-nitric oxide pathway. Acta Physiol Scand 1992; 145: 201–7

    Article  PubMed  CAS  Google Scholar 

  34. Pinsky DJ, Cai B, Yang X, et al. Nitric oxide-dependent killing of cardiac myocytes by adjacent macrophages. Circulation 1994; 90 (4 Pt 2): I–192, abstract 1028

    Google Scholar 

  35. Pinsky DJ, Cai B, Yang X, et al. Cytokine-inducible NO-dependent autotoxicity of cardiac myocytes. Circulation 1994; 90 (4 Pt 2): I–192 abstract 1030

    Google Scholar 

  36. Packer M. The development of positive inotropic agents for chronic heart failure: how have we gone astray? J Am Coll Cardiol 1993; 22 (4 Suppl. A): 119A–26A

    Article  PubMed  CAS  Google Scholar 

  37. Waagstein F, Bristow MR, Swedberg K, et al. Beneficial effects of metoprolol in dilated cardiomyopathy. Metoprolol in Dilated Cardiomyopathy (MDC) trial study group. Lancet 1993: 342(8885): 1441–6

    Article  PubMed  CAS  Google Scholar 

  38. Vegh A, Szekeres L, Parratt J. Preconditioning of the ischaemic myocardium: involvement of the L-arginine nitric oxide pathway. Br J Pharmacol 1992; 107: 648–52

    Article  PubMed  CAS  Google Scholar 

  39. Schoelkens BA, Linz W. Bradykinin-mediated metabolic effects in isolated perfused rat hearts. Agents Actions 1992; 38 Suppl. II: 36–42

    CAS  Google Scholar 

  40. Fung HL. Clinical pharmacology of organic nitrates. Am J Cardiol 1993; 72: 9C–13C

    Article  PubMed  CAS  Google Scholar 

  41. Murrell W. Nitroglycerin as a remedy for angina pectoris. Lancet 1879; I: 80–1

    Article  Google Scholar 

  42. Fung HL, Kowalak EA, Chung SJ, et al. Nitric oxide generation from nitrovasodilators in coronary artery smooth muscle cells is mediated by multiple enzymes. In: Moncada MMS, Hibbs Jr JB, Higgs EA, editors. Biology of nitric oxide: Part 1. Physiology and clinical aspects. Colchester: Portland Press, 1992: 139–41

    Google Scholar 

  43. Guiha NH, Cohn JN, Mikulic E, et al. Treatment of refractory heart failure with infusion of nitroprusside. N Engl J Med 1974; 291: 587–92

    Article  PubMed  CAS  Google Scholar 

  44. Leier CV, Bambach D, Thompson MJ, et al. Central and regional hemodynamic effects of intravenous isosorbide dinitrate, nitroglycerin and nitroprusside in patients with congestive heart failure. Am J Cardiol 1981; 48: 1115–23

    Article  PubMed  CAS  Google Scholar 

  45. Franciosa JA, Blank RC, Cohn JN. Nitrate effects on cardiac output and left ventricular outflow resistance in chronic congestive heart failure. Am J Med 1978; 64: 207–13

    Article  PubMed  CAS  Google Scholar 

  46. Ribner HS, Bresnahan D, Hsieh AM, et al. Acute hemodynamic responses to vasodilator therapy in congestive heart failure. Prog Cardiovasc Dis 1982; 25: 1–42

    Article  PubMed  CAS  Google Scholar 

  47. Nelson GIC, Silke B, Ahuya RC, et al. Haemodynamic advantages of isosorbide dinitrate over frusemide in acute heart failure following myocardial infarction. Lancet 1983; I: 730–3

    Article  Google Scholar 

  48. Cohn JN, Archibald DG, Zeische S, et al. Effects of vasodilator therapy on mortality in chronic congestive heart failure: results of a Veterans Administration cooperative study (VHeFT). N Engl J Med 1986; 314: 1547–52

    Article  PubMed  CAS  Google Scholar 

  49. Cohn JN, Johnson G, Zeische S, et al. A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure. N Engl J Med 1991; 325: 303–10

    Article  PubMed  CAS  Google Scholar 

  50. Elkayam U, Mehra A, Shotan A, et al. Nitrate resistance and tolerance: potential limitations in the treatment of congestive heart failure. Am J Cardiol 1992; 70: 98B–104B

    Article  PubMed  CAS  Google Scholar 

  51. Fung HL, Bauer JA. Mechanisms of nitrate tolerance. Cardiovasc Drugs Ther 1994; 8: 489–99

    Article  PubMed  CAS  Google Scholar 

  52. Packer M, Lee WH, Kessler PD, et al. Prevention and reversal of nitrate tolerance in patients with congestive heart failure. N Engl J Med 1987; 317: 799–804

    Article  PubMed  CAS  Google Scholar 

  53. Sharpe N, Coxon R, Wester M, et al. Hemodynamic effects of intermittent transdermal nitroglycerin in chronic congestive heart failure. Am J Cardiol 1987. 59: 895–9

    Article  PubMed  CAS  Google Scholar 

  54. Bauer JA, Fung HL. Concurrent hydralazine administration prevents nitroglycerin-induced tolerance in experimental heart failure. Circulation 1991; 84: 35–9

    Article  PubMed  CAS  Google Scholar 

  55. Unger P, Berkenboom G, Fontaine J. Interaction between hydralazine and nitrovasodilators in vascular smooth muscle. J Cardiovasc Pharmacol 1993; 21: 478–83

    Article  PubMed  CAS  Google Scholar 

  56. Dakak N, Makhoul N, Flugelman MY, et al. Failure of Captopril to prevent nitrate tolerance in congestive heart failure secondary to coronary artery disease. Am J Cardiol 1990; 66: 608–13

    Article  PubMed  CAS  Google Scholar 

  57. Katz RJ, Levy WS, Buff L, et al. Prevention of nitrate tolerance with angiotensin-converting enzyme inhibitors. Circulation 1991. 83: 1271–7

    Article  PubMed  CAS  Google Scholar 

  58. Mehra A, Ostrzega E, Shotan A, et al. Persistent hemodynamic improvement with short-term nitrate therapy in patients with chronic congestive heart failure already treated with Captopril. Am J Cardiol 1992; 70: 1310–4

    Article  PubMed  CAS  Google Scholar 

  59. Han YL, Tong M, Jing QM. A study of Captopril enhancement of nitrate effect in coronary arterial disease patients associated with heart failure. Chin J Intern Med 1994; 33: 455–8

    CAS  Google Scholar 

  60. Mombouli J, Illiano S, Nagao T, et al. The potentiation of endothelium-dependent relaxations to bradykinin by angiotensin converting enzyme inhibitors in canine coronary artery involves both endothelium-derived relaxing and contracting factors. Circ Res 1992; 71: 137–44

    Article  PubMed  CAS  Google Scholar 

  61. Mulder P, Devaux B, Fertak LE, et al. Vascular and myocardial protective effects of converting enzyme inhibition in experimental heart failure. Am J Cardiol 1995; 76 Suppl.: 28E–33E

    Article  PubMed  CAS  Google Scholar 

  62. Drexler H, Kurz S, Jeserich M, et al. Effect of chronic angiotensin-converting enzyme inhibition on endothelial function in patients with chronic heart failure. Am J Cardiol 1995; 76 Suppl.: 13E–8E

    Article  PubMed  CAS  Google Scholar 

  63. Koifman B, Wollman Y, Bogomolny N, et al. Improvement of cardiac performance by intravenous infusion of L-arginine in patients with moderate congestive heart failure. J Am Coll Cardiol 1995; 26: 1251–6

    Article  PubMed  CAS  Google Scholar 

  64. Kubo S, Rector T, Bank A, et al. Chronic oral L- arginine improves forearm blood flow during exercise and reactive hyperemia in patients with heart failure. Circulation 1994; 90(4): I–602

    Google Scholar 

  65. Morley D, Maragos CM, Zhang XY, et al. Mechanism of vascular relaxation induced by the nitric oxide (NO)/nucleophile complexes, a new class of NO-based vasodilators. J Cardiovasc Pharmacol 1993; 21(4): 670–6

    Article  PubMed  CAS  Google Scholar 

  66. Shaffer JE, Lee F, Thomson S, et al. The hemodynamic effects of S-nitrosocaptopril in anesthetized dogs. J Pharmacol Exp Ther 1991; 256(2): 704–9

    PubMed  CAS  Google Scholar 

  67. Rossaint R, Falke KJ, Lopez F, et al. Inhaled nitric oxide for the adult respiratory distress syndrome. N Engl J Med 1993; 328(6): 399–405

    Article  PubMed  CAS  Google Scholar 

  68. Macdonald P, Mundy J, Rogers P, et al. Successful treatment of life-threatening acute reperfusion injury after lung transplantation with inhaled nitric oxide. J Thorac Cardiovasc Surg 1995; 110: 861–3

    Article  PubMed  CAS  Google Scholar 

  69. Kieler-Jensen N, Rickstein S-E, Stenqvist S-E, et al. Inhaled nitric oxide in the evaluation of heart transplant candidates with elevated pulmonary vascular resistance. J Heart Lung Transplant 1994; 13: 366–75

    PubMed  CAS  Google Scholar 

  70. Loh E, Stamler J, Hare J, et al. Cardiovascular effects of inhaled nitric oxide in patients with left ventricular dysfunction. Circulation 1994; 90: 2780–5

    Article  PubMed  CAS  Google Scholar 

  71. Semigran M, Cockrill B, Kacmarek R, et al. Hemodynamic effects of inhaled nitric oxide in heart failure. J Am Coll Cardiol 1994; 24: 982–8

    Article  PubMed  CAS  Google Scholar 

  72. Hayward C, Rogers P, Keogh A, et al. Inhaled nitric oxide in cardiac failure: vascular versus ventricular effects. J Cardiovasc Pharmacol. In press

  73. Bocchi E, Bacal F, Auler JJ. Inhaled nitric oxide leading to pulmonary edema in stable severe heart failure. Am J Cardiol 1994; 74: 70–3

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Cardiopulmonary Transplant Unit, St Vincent’s Hospital, Darlinghurst, New South Wales, 2010, Australia

    Peter Macdonald (Staff Cardiologist), Christopher Schyvens & David Winlaw

Authors
  1. Peter Macdonald
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Christopher Schyvens
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. David Winlaw
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Macdonald, P., Schyvens, C. & Winlaw, D. The Role of Nitric Oxide in Heart Failure. Drugs & Aging 8, 452–458 (1996). https://doi.org/10.2165/00002512-199608060-00007

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00002512-199608060-00007

Keywords

Search

Navigation