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Related Experiment Videos

Tolerance induction by transdermal glyceryl trinitrate in rats.

I S De la Lande1, I Stafford, J D Horowitz

  • 1Cardiology Unit, North Western Adelaide Health Service, The Queen Elizabeth Hospital, University of Adelaide, South Australia, Australia. ilande@tqehsmtp.tqeh.sa.gov.au

European Journal of Pharmacology
|July 28, 1999
PubMed
Summary

Mild tolerance to glyceryl trinitrate in rats is primarily endothelium-independent. This suggests specific mechanisms are involved, with little cross-tolerance to other vasodilators like acetylcholine.

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Area of Science:

  • Pharmacology
  • Cardiovascular Physiology
  • Drug Tolerance Mechanisms

Background:

  • Glyceryl trinitrate (GTN) is a widely used vasodilator.
  • Understanding the mechanisms of GTN tolerance is crucial for optimizing its therapeutic use.
  • Previous studies suggest both endothelium-dependent and -independent pathways may contribute to tolerance.

Purpose of the Study:

  • To investigate the specific mechanisms underlying mild transdermal glyceryl trinitrate tolerance in a rat model.
  • To determine the role of the endothelium in the development of GTN tolerance.
  • To assess cross-tolerance to other vasodilators.

Main Methods:

  • Isolated rat aortic rings were used to assess vascular relaxation.
  • Tolerance was induced via transdermal application of glyceryl trinitrate (15 mg/day for 2 days).

Related Experiment Videos

  • Vessels were pre-contracted with phenylephrine, and relaxation responses to GTN, acetylcholine, and sodium nitroprusside were measured.

    • Main Results:

    • Mild glyceryl trinitrate tolerance was observed, characterized by a 3-4 fold increase in EC50 and reduced maximum relaxation (70-80%).
    • Tolerance was comparable in both endothelium-intact and endothelium-denuded aortic rings, indicating an endothelium-independent mechanism.
    • Minimal cross-tolerance was found for acetylcholine (1.7-fold increase in EC50), and none for sodium nitroprusside.

    Conclusions:

    • Mild glyceryl trinitrate tolerance in rats is predominantly mediated by endothelium-independent mechanisms.
    • These mechanisms do not significantly activate pathways responsible for cross-tolerance to other vasodilators.
    • The findings provide insights into the specific cellular pathways involved in GTN tolerance.