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Analytical Techniques for Assaying Nitric Oxide Bioactivity
11:28

Analytical Techniques for Assaying Nitric Oxide Bioactivity

Published on: June 18, 2012

Mechanisms of nitrate action and vascular tolerance

H L Fung1, S Chong, E Kowaluk

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

European Heart Journal
|May 1, 1989
PubMed

Insights

Nitrate tolerance mechanisms remain unclear. While neurohormonal changes occur with nitrate therapy, the exact cause of tolerance, potentially involving vascular metabolism and cyclic GMP, is still under investigation.

Area of Science:

  • Pharmacology
  • Cardiovascular Science

Background:

  • Organic nitrates are widely used for cardiovascular conditions.
  • Nitrate tolerance, a decrease in efficacy over time, is a significant clinical challenge.
  • The precise mechanisms underlying nitrate tolerance are not fully elucidated.

Purpose of the Study:

  • To review and discuss the potential mechanisms contributing to the development of nitrate tolerance.
  • To critically evaluate the evidence for pharmacokinetic, neurohormonal, and cellular mechanisms.

Main Methods:

  • Literature review and synthesis of existing research on organic nitrate pharmacology and tolerance.
  • Analysis of studies investigating pharmacokinetic alterations, neurohormonal responses, and vascular metabolism.
  • Examination of data on intracellular sulfhydryl availability and cyclic guanosine monophosphate (cGMP) production.

Main Results:

  • Pharmacokinetic changes in systemic circulation do not adequately explain nitrate tolerance.
  • Neurohormonal alterations are associated with continuous nitrate therapy but their causal role in tolerance is unconfirmed.
  • Impaired vascular metabolism of organic nitrates occurs in vitro during tolerance, but the role of intracellular sulfhydryl reduction is uncertain.
  • Reduced vascular cyclic GMP production may occur during tolerance, but this may not directly correlate with diminished vascular relaxation.

Conclusions:

  • The exact causative factor for nitrate tolerance remains unidentified.
  • Further research is needed to clarify the roles of vascular metabolism, sulfhydryl availability, and cyclic GMP in the development of nitrate tolerance.

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