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Updated: Jun 30, 2026

Analytical Techniques for Assaying Nitric Oxide Bioactivity
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Published on: June 18, 2012

Dissociation between superoxide accumulation and nitroglycerin-induced tolerance.

Pei-Suen Tsou1, Vamsi Addanki, Ho-Leung Fung

  • 1Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, NY 14260-1200, USA.

The Journal of Pharmacology and Experimental Therapeutics
|July 26, 2008
PubMed
Summary

Superoxide accumulation does not cause nitroglycerin (NTG) tolerance. Studies show increased superoxide is an effect, not a cause, of NTG tolerance, with NADPH oxidase subunits not being critical for this process.

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Area of Science:

  • Biochemistry
  • Pharmacology
  • Cell Biology

Background:

  • Nitroglycerin (NTG) tolerance, a decrease in drug efficacy, is a significant clinical challenge.
  • Superoxide (O(2)(*-)) accumulation has been proposed as a key factor in NTG tolerance development.
  • Understanding the precise mechanisms of NTG tolerance is crucial for improving therapeutic outcomes.

Purpose of the Study:

  • To investigate the role of superoxide (O(2)(*-)) accumulation in the development of nitroglycerin (NTG) tolerance.
  • To determine if O(2)(*-) is a causative factor or a consequence of NTG tolerance.
  • To assess the involvement of NADPH oxidase subunits in NTG tolerance.

Main Methods:

  • Experiments were conducted using LLC-PK1 cells and mouse models (p47(phox-/-) and gp91(phox-/-) mice).
  • Assays included measuring O(2)(*-) accumulation, cyclic guanosine monophosphate (cGMP) response, and vascular tolerance.
  • Pharmacological agents like oxypurinol (xanthine oxidase inhibitor) and tiron (O(2)(*-) scavenger) were used.

Main Results:

  • NTG pre-exposure increased O(2)(*-) accumulation and reduced cGMP response in cells.
  • Angiotensin II increased O(2)(*-) but did not affect cGMP response to NTG.
  • Aorta from mice lacking NADPH oxidase subunits showed similar NTG tolerance as wild-type controls.
  • Oxypurinol reduced O(2)(*-) but did not attenuate NTG tolerance in vitro and in vivo.

Conclusions:

  • Superoxide (O(2)(*-)) accumulation is not the initiating cause of nitroglycerin (NTG) tolerance.
  • Increased O(2)(*-) appears to be a consequence, not a cause, of NTG tolerance.
  • The p47(phox) and gp91(phox) subunits of NADPH oxidase are not critically required for NTG tolerance.