Skip to main content
SpringerLink
Log in

Mechanisms of nitrate tolerance

  • Nitrates
  • Published:
Cardiovascular Drugs and Therapy Aims and scope Submit manuscript

Summary

There is now little dispute that clinical tolerance of organic nitrates occurs, particularly when these drugs are used by themselves to treat patients with stable angina pectoris and congestive heart failure. Classical hypotheses of nitrate tolerance suggest the phenomenon to result from vascular depletion of critical sulfhydryl groups, which are necessary to bring about vasorelaxation from nitrates. While this mechanism of nitrate tolerance probably operates when isolated blood vessels are exposed to high concentrations of nitrate in vitro, there is little evidence to suggest that it contributes to clinical nitrate tolerance. Instead, emerging data suggest that nitrates can cause significant shifts in fluid distribution and secretion of neurohormonal factors that can modulate their vasorelaxant effects. use of angiotensin converting enzyme inhibitors and diuretics in conjunction with nitrates may alleviate the development of tolerance, but the experience has not been universally favorable. Other receptor-effector systems that affect cardiovascular function, such as the adrenergic system, may also be affected by nitrate tolerance. The mechanisms of nitrate tolerance are therefore likely to be multifactorial, involving vascular biochemical changes, physiologic compensation, and possibly receptor regulation.

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

Access this article

Log in via an institution

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. Ahlner J, Andersson RGG, Torfgard K, Axelsson KL. Organic nitrate esters: Clinical use and mechanisms of actions.Pharmacol Rev 1991;43:351–423.

    PubMed  Google Scholar 

  2. Elkayam U. Tolerance to organic nitrates: Evidence, mechanisms, clinical relevance, and strategies for prevention.Ann Intern Med 1991;114:667–677.

    PubMed  Google Scholar 

  3. Cowan JC. Avoiding nitrate tolerance.Br J Clin Pharmacol 1992;34:96–101.

    PubMed  Google Scholar 

  4. Kowaluk E, Hough K, Fung H-L. Effect of intermittent exposure and drug-free intervals on the in vitro vascular tolerance to nitroglycerin.Life Sci 1989;44:1157–1163.

    PubMed  Google Scholar 

  5. Elkayam U, Kulick D, McIntosh N, Roth A, Hsueh W, Rahimtoola SH. Incidence of early tolerance to hemodynamic effects of continuous infusion of nitroglycerin in patients with coronary artery disease and heart failure.Circulation 1987;76:577–584.

    PubMed  Google Scholar 

  6. Packer M, Lee WH, Kessler PD, Gottlieb SS, Medina N, Yushak M. Prevention and reversal of nitrate tolerance in patients with congestive heart failure.N Engl J Med 1987;317:799–804.

    PubMed  Google Scholar 

  7. Olivari MT, Carlyle PF, Levine B, Cohn JN. Hemodynamic and hormonal response to transdermal nitroglycerin in normal subjects and in patients with congestive heart failure.J Am Coll Cardiol 1983;2:872–878.

    PubMed  Google Scholar 

  8. Jordan RA, Seth L, Casebolt P, Hayes MJ, Wilen MM, Franciosa J. Rapidly developing tolerance to transdermal nitroglycerin in congestive heart failure.Ann Intern Med 1986;104:295–298.

    PubMed  Google Scholar 

  9. Elkayam U, Jamison M, Roth A, Kulick D, Vasquez J, Rahimtoola SH. Oral isosorbide dinitrate in chronic heart failure: Tolerance development to QID vs. TID regimen [abstr].J Am Coll Cardiol 1989;13:178.

    Google Scholar 

  10. Zimrin D, Reichek N, Bogin KT, et al. Antianginal effects of intravenous nitroglycerin over 24 hours.Circulation 1988;77:1376–1384.

    PubMed  Google Scholar 

  11. Parker JO, Fung H-L. Transdermal nitroglycerin in angina pectoris.Am J Cardiol 1984;54:471–476.

    PubMed  Google Scholar 

  12. Reicheck N, Priest C, Zimrin D, Chandler T, St. John Sutton M. Antianginal effects of nitroglycerin patches.Am J Cardiol 1984;54:1–7.

    PubMed  Google Scholar 

  13. Poorvin D, Cabot CF, Chi PY, et al. Acute and chronic antianginal efficacy of continuous twenty-four-hour application of transdermal nitroglycerin.Am J Cardiol 1991;68:1263–1273.

    PubMed  Google Scholar 

  14. Thadani U, Fung H-L, Darke AC, Parker JO. Oral isosorbide dinitrate in the treatment of angina pectoris. Dose response relationship and duration of action during acute therapy.Circulation 1980;62:491–502.

    PubMed  Google Scholar 

  15. Thadani U, Fung H-L, Darke AC, Parker JO. Oral isosorbide dinitrate in angina pectoris. Comparison of duration of action and dose response relationship during acute and sustained therapy.Am J Cardiol 1982;49:411–419.

    PubMed  Google Scholar 

  16. Parker JO, VanKoughnett KA, Fung H-L. Transdermal isosorbide dinitrate in angina pectoris. Effect of acute and sustained therapy.Am J Cardiol 1984;54:8–13.

    PubMed  Google Scholar 

  17. Thadani U, Hamilton SF, Olson E, et al. Duration of effects and tolerance of slow-release isosorbide-5-mononitrate for angina pectoris.Am J Cardiol 1987;59:756–762.

    PubMed  Google Scholar 

  18. Curfman GD, Heinsimer JA, Lozner EC, Fung H-L. Intravenous nitroglycerin in the treatment of spontaneous angina pectoris: A prospective, randomized trial.Circulation 1983;67:276–282.

    PubMed  Google Scholar 

  19. Horowitz JD, Henry CA, Syrjanen ML, et al. Combined use of nitroglycerin and N-acetylcysteine in the management of unstable angina pectoris.Circulation 1988;77:787–794.

    PubMed  Google Scholar 

  20. Diodati J, Theroux P, Latour J-G, Lacoste L, Lam JYT, Waters D. Effects of nitroglycerin at therapeutic doses on platelet aggregation in unstable angina pectoris and acute myocardial infarction.Am J Cardiol 1990;66:683–688.

    PubMed  Google Scholar 

  21. Zelis R, Mason DT. Isosorbide dinitrate: Effect on the vasodilator response to nitroglycerin.JAMA 1975;234:166–170.

    PubMed  Google Scholar 

  22. Makhoul N, Dakak N, Flugelman MY, et al. Nitrate tolerance in heart failure—differential venous, pulmonary and systemic arterial effects.Am J Cardiol 1990;65:J28-J32.

    Google Scholar 

  23. Ghio S, Deservi S, Perotti R, Eleuteri E, Montemartine C, Specchia G. Different susceptibility to the development of nitroglycerin tolerance in the arterial and venous circulation in humans—effects of N-acetylcysteine administration.Circulation 1992;86:798–802.

    PubMed  Google Scholar 

  24. Manyari DE, Smith ER, Spragg J. Isosorbide dinitrate and glyceryl trinitrate: Demonstration of cross tolerance in the capacitance vessels.Am J Cardiol 1985;55:927–931.

    PubMed  Google Scholar 

  25. Leier CV, Huss P, Magorien RD, Unverferth DV. Improved exercise capacity and differing arterial and venous tolerance during chronic isosorbide dinitrate therapy for congestive heart failure.Circulation 1983;67:817–822.

    PubMed  Google Scholar 

  26. Stewart DJ, Elsner D, Sommer O, Holtz J, Bassenge E. Altered spectrum of nitroglycerin action in long-term treatment: Nitroglycerin-specific venous tolerance with maintenance of arterial vasodepressor potency.Circulation 1986;74:573–582.

    PubMed  Google Scholar 

  27. Goldberg RK, Lee RW, Olafos M, Goldman S. Development of tolerance to nitroglycerin in the arterial and venous circulation of dogs.J Am Coll Cardiol 1987;10:1335–1341.

    PubMed  Google Scholar 

  28. Chung S-J, Fung H-L. Identification of the subcellular site for nitroglycerin metabolism to nitric oxide in bovine coronary smooth muscle cells.J Pharmacol Exp Ther 1990;253:614–619.

    PubMed  Google Scholar 

  29. Chung S-J, Chong S, Seth P, Jung CY, Fung H-L. Conversion of nitroglycerin to nitric oxide in microsomes of the bovine coronary artery smooth muscle is not primarily mediated by glutathione-S-transferases.J Pharmacol Exp Ther 1992;260:652–659.

    PubMed  Google Scholar 

  30. Chung S-J, Fung H-L. A common enzyme may be responsible for the conversion of organic nitrates to nitric oxide in vascular microsomes.Biochem Biophys Res Commun 1992;185:932–937.

    PubMed  Google Scholar 

  31. Chung S-J, Fung H-L. Relationship between nitroglycerin-induced vascular relaxation and nitric oxide production: Probes with inhibitors and tolerance development.Biochem Pharmacol 1993;45:157–163.

    PubMed  Google Scholar 

  32. Needleman P, Johnson EM, Jr. Mechanisms of tolerance development to organic nitrates.J Pharmacol Exp Ther 1973;184:709–715.

    PubMed  Google Scholar 

  33. Needleman P (ed).Organic Nitrates. New York: Springer-Verlag, 1975.

    Google Scholar 

  34. Fung H-L, Chong S, Kowaluk E. Mechanisms of nitrate action and vascular tolerance.Eur Heart J 1989;10(Suppl A):2–6.

    Google Scholar 

  35. May DC, Popma JJ, Black WH, et al. In vivo induction and reversal of nitroglycerin tolerance in human coronary arteries.N Engl J Med 1987;317:805–809.

    PubMed  Google Scholar 

  36. Bosegaard S, Aldershvile J, Poulsen HE. Preventive administration of intravenous N-acetylcysteine and development of tolerance to isosorbide dinitrate in patients with angina pectoris.Circulation 1992;85:143–149.

    PubMed  Google Scholar 

  37. Dupuis J, Lalonde G, Lemieux R, Rouleau JL. Tolerance to intravenous nitroglycerin in patients with congestive heart failure—Role of increased intravascular volume, neurohumoral activation and lack of prevention with N-acetylcysteine.J Am Coll Cardiol 1990;16:923–931.

    PubMed  Google Scholar 

  38. Bosegaard S, Aldershvile J, Pedersen F, Pietersen A, Madsen JK, Grande P. Continuous oral N-acetylcysteine treatment and development of nitrate tolerance in patients with stable angina pectoris.J Cardiovasc Pharmacol 1991;17:889–893.

    PubMed  Google Scholar 

  39. Parker JO, Farrell B, Lahey KA, Rose BF. Nitrate tolerance: The lack of effect of N-acetylcysteine.Circulation 1987;76:572–576.

    PubMed  Google Scholar 

  40. Hogan JC, Lewis MJ, Henderson AH. N-acetylcysteine fails to attenuate hemodynamic tolerance to glyceryl trinitrate in healthy volunteers.Br J Clin Pharmacol 1989;28:421–427.

    PubMed  Google Scholar 

  41. Hogan JC, Lewis MJ, Henderson AH. Chronic administration of N-acetylcysteine fails to prevent nitrate tolerance in patients with stable angina pectoris.Br J Clin Pharmacol 1990;30:573–577.

    PubMed  Google Scholar 

  42. Levy WS, Katz RJ, Wasserman AG. Methionine restores the venodilative response to nitroglycerin after the development of tolerance.J Am Coll Cardiol 1991;17:474–479.

    PubMed  Google Scholar 

  43. Münzel T, Mülsch A, Holtz J, Just H, Harrison DG, Bassenge E. Mechanisms of interaction between the sulfhydryl precursor L-methionine and glyceryl trinitrate.Circulation 1992;86:995–1003.

    PubMed  Google Scholar 

  44. Münzel T, Mülsch A, Harrison DG, Bassenge E. Mechanisms of interaction between the sulfhydryl precursor L-methionine and glyceryl trinitrate [abstr].Circulation 1992;86:I487.

    Google Scholar 

  45. Katz RJ, Levy WS, Buff L, Wasserman AG. Prevention of nitrate tolerance with angiotensin converting enzyme inhibitors.Circulation 1991;83:1271–1277.

    PubMed  Google Scholar 

  46. Chong S, Fung H-L. Biochemical and pharmacological interactions between nitroglycerin and thiols: Effects of thiol structure on nitric oxide generation and tolerance reversal.Biochem Pharmacol 1991;42:1433–1439.

    PubMed  Google Scholar 

  47. Fung H-L, Chong S, Kowaluk E, Hough K, Kakemi M. Mechanisms for the pharmacologic interaction of organic nitrates with thiols. Existence of an extracellular pathway for the reversal of nitrate vascular tolerance by N-acetylcysteine.J Pharmacol Exp Ther 1988;245:524–530.

    PubMed  Google Scholar 

  48. Lange RL, Reid MS, Tresch DD, Keelan MH, Bernhard VM, Coolidge G. Nonatheromatous ischemic heart disease following withdrawal from chronic industrial nitroglycerin exposure.Circulation 1972;46:666–678.

    PubMed  Google Scholar 

  49. Packer M, Medina N, Yushak M, Lee WH. Hemodynamic factors limiting the response to transdermal nitroglycerin in congestive heart failure.Am J Cardiol 1986;57:260–267.

    PubMed  Google Scholar 

  50. Ferantini M, Pirelli S, Merlina P, Silva P, Pollavini G: Intermittent transdermal nitroglycerin monotherapy in stable exercise-induced angina: A comparison with a continuous schedule.Eur Heart J 1989;10:998–1002.

    PubMed  Google Scholar 

  51. Bauer JA, Fung H-L. Effect of apparent elimination half-life on nitroglycerin-induced hemodynamic rebound in experimental heart failure.Pharm Res 1993;10:1341–1345.

    PubMed  Google Scholar 

  52. Parker JO, Parker JD. Neurohormonal activation during nitrate therapy: A possible mechanism for nitrate tolerance.Am J Cardiol 1992;70:93B-97B.

    PubMed  Google Scholar 

  53. Bauer JA, Fung H-L, Kwon YW, Gopalakrishnan M, Triggle DJ. Continuous versus intermittent nitroglycerin administration in experimental heart failure: Vascular relaxation, adrenoceptor and ion channel effects.J Cardiovasc Pharmacol 1993;22:600–608.

    PubMed  Google Scholar 

  54. Bauer JA, Fung H-L. Effects of chronic glyceryl trinitrate on left ventricular hemodynamics in a rat model of congestive heart failure: Demonstration of a simple model for the study of in vivo nitrate tolerance.Cardiovasc Res 1990;24:198–203.

    PubMed  Google Scholar 

  55. Bauer JA, Fung H-L. Differential hemodynamic effects and tolerance properties of nitroglycerin and an S-nitrosothiol in experimental heart failure.J Pharmacol Exp Ther 1991;256:249–254.

    PubMed  Google Scholar 

  56. Bauer JA, Fung H-L. Concurrent hydralazine administration prevents nitroglycerin-induced hemodynamic tolerance in experimental heart failure.Circulation 1991;84:35–39.

    PubMed  Google Scholar 

  57. Bauer JA, Fung H-L. Pharmacodynamic models of nitroglycerin-induced hemodynamic tolerance in experimental heart failure.Pharm Res 1994;11:816–823.

    PubMed  Google Scholar 

  58. Packer M, Gottlieb SS, Kessler PD, Medina N, Yushak M, Lee WH. What drug-free interval is required to prevent the development of organic nitrate tolerance in heart failure?Circulation 1981;76:IV255.

    Google Scholar 

  59. Cohn JN, Archibald DG, Zeische S, et al. Effect of vasodilator therapy on mortality in chronic congestive heart failure: Results of a Veterans Administration cooperative study (V-HeFT).N Engl J Med 1986;314:1547–1552.

    PubMed  Google Scholar 

  60. Leier CV, Magorien RD, Desch CE, Thompson MJ, Unverferth DV. Hydralazine and isosorbide dinitrate: Comparative central and regional hemodynamic effects when administered alone or in combination.Circulation 1981;63:102–109.

    PubMed  Google Scholar 

  61. Flaim SF. Peripheral vascular effects of nitroglycerin in a conscious rat model of heart failure.Am J Physiol 1982;243:H974-H981.

    PubMed  Google Scholar 

  62. 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;66:608–613.

    PubMed  Google Scholar 

  63. Mehra A, Ostrzega E, Shotan A, Johnson JV, Elkayam U. Persistent hemodynamic improvement with short-term nitrate therapy in patients with chronic congestive heart failure already treated with captopril.Am J Cardiol 1992;70:1310–1314.

    PubMed  Google Scholar 

  64. Varriale P, David WJ, Chryssos BE. Hemodynamic resistance to intravenous nitroglycerin in severe congestive heart failure and restored response after diuresis.Am J Cardiol 1991;68:1400–1402.

    PubMed  Google Scholar 

  65. Parker JD, Farrell B, Fenton T, Parker JO. Effects of diuretic therapy on the development of tolerance during continuous therapy with nitroglycerin.J Am Coll Cardiol 1992;20:616–622.

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmaceutics, School of Pharmacy, State University of New York at Buffalo, 14260, Buffalo, NY, USA

    Ho-Leung Fung Ph.D. & John Anthony Bauer

Authors
  1. Ho-Leung Fung Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. John Anthony Bauer
    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

Fung, HL., Bauer, J.A. Mechanisms of nitrate tolerance. Cardiovasc Drug Ther 8, 489–499 (1994). https://doi.org/10.1007/BF00877927

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00877927

Key Words

Search

Navigation