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Mechanisms of nitrate tolerance

H L Fung1, J A Bauer

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

Cardiovascular Drugs and Therapy
|June 1, 1994
PubMed
Summary

Clinical tolerance to organic nitrates is common, especially in stable angina and heart failure. Emerging evidence suggests multifactorial mechanisms beyond simple vascular depletion, involving fluid shifts and neurohormonal factors.

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Area of Science:

  • Cardiovascular Pharmacology
  • Clinical Therapeutics

Background:

  • Clinical tolerance to organic nitrates is a recognized issue in treating stable angina pectoris and congestive heart failure.
  • Classical hypotheses involving vascular sulfhydryl group depletion are insufficient to explain clinical nitrate tolerance.

Purpose of the Study:

  • To explore the emerging mechanisms underlying clinical nitrate tolerance.
  • To investigate factors beyond vascular depletion that contribute to reduced nitrate efficacy.

Main Methods:

  • Review of current literature on nitrate tolerance.
  • Analysis of proposed biochemical and physiological mechanisms.
  • Consideration of adjunctive therapies and their impact.

Main Results:

  • Clinical nitrate tolerance is well-established, particularly with monotherapy.
  • In vitro mechanisms (sulfhydryl depletion) have limited relevance to clinical tolerance.
  • Nitrate tolerance likely involves complex interactions including fluid shifts, neurohormonal modulation, and potential receptor regulation.

Conclusions:

  • Nitrate tolerance is multifactorial, involving vascular, physiological, and potentially receptor-related mechanisms.
  • Adjunctive therapies like ACE inhibitors and diuretics show variable success in mitigating tolerance.
  • Further research is needed to fully elucidate the complex pathophysiology of nitrate tolerance.

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