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Thiol compounds and organic nitrates

S Boesgaard1

  • 1Department of Medicine B, Rigshospitalet, Copenhagen.

Danish Medical Bulletin
|November 1, 1995
PubMed
Summary
This summary is machine-generated.

Organic nitrates, used for ischemic heart disease, can lose effectiveness over time. This study shows thiol compounds may help maintain nitrate effects by influencing their metabolism and counteracting side effects, potentially improving treatment outcomes.

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Area of Science:

  • Pharmacology
  • Cardiovascular Medicine
  • Biochemistry

Background:

  • Organic nitrates are crucial for treating ischemic heart disease.
  • Tolerance limits the therapeutic efficacy of continuous organic nitrate treatment.
  • The exact mechanisms of nitrate tolerance remain unclear, with thiol depletion being a leading theory.

Purpose of the Study:

  • To investigate in vivo thiol/nitrate interactions in various experimental and clinical settings.
  • To elucidate the role of intracellular thiols in organic nitrate metabolism and tolerance.
  • To explore how exogenous thiol administration affects nitrate efficacy and counter-regulatory mechanisms.

Main Methods:

  • Examined the hypotensive effects of nitroglycerin (NTG) in relation to intracellular glutathione (GSH) levels.

Related Experiment Videos

  • Compared arterial and venous thiol levels in nitrate-tolerant versus non-tolerant animals.
  • Assessed the impact of N-acetylcysteine (NAC) on nitrate effects and the renin-angiotensin system in rats and humans.
  • Main Results:

    • Reduced intracellular GSH levels diminished the acute hypotensive effect of NTG, highlighting GSH's role in nitrate metabolism.
    • Vascular thiol levels were similar in tolerant and non-tolerant animals, questioning thiol depletion as the sole cause of tolerance.
    • Exogenous NAC augmented NTG's hypotensive effect via a non-tolerance-specific mechanism, likely involving extracellular nitrate/thiol interaction and NO formation.
    • NAC inhibited angiotensin-converting enzyme, counteracting nitrate-induced renin-angiotensin system stimulation.
    • In clinical settings, NAC co-administration with isosorbide dinitrate (ISDN) delayed tolerance to antianginal effects and altered the vasodilator profile.

    Conclusions:

    • Cellular thiol levels significantly influence the hemodynamic effects of organic nitrates.
    • Nitrate tolerance may involve altered cellular thiol handling or related enzymes.
    • Exogenous thiols can potentiate nitrate effects through a distinct interaction and attenuate counter-regulatory responses, improving clinical outcomes.