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Vascular peroxynitrite formation during organic nitrate tolerance.
1Division of Pharmacology, College of Pharmacy, The Ohio State University, Columbus, Ohio, USA.
The Journal of Pharmacology and Experimental Therapeutics
|September 22, 1999
Summary
Nitroglycerin tolerance in blood vessels involves protein nitration, a marker of peroxynitrite formation. However, this study found that protein nitration does not cause nitrate tolerance.
Area of Science:
- Cardiovascular Pharmacology
- Biochemistry
- Vascular Biology
Background:
- Nitroglycerin (NTG) is a key cardiovascular drug, but its continuous use leads to tolerance, limiting effectiveness.
- Increased superoxide production in blood vessels may cause nitrate tolerance by reducing nitric oxide availability.
- Superoxide and nitric oxide form peroxynitrite, a toxicant that nitrates tyrosine residues on proteins.
Purpose of the Study:
- To investigate if protein nitration occurs during vascular tolerance to nitroglycerin.
- To determine if protein nitration plays a role in the development of nitrate tolerance.
Main Methods:
- Rat thoracic aorta segments were preincubated with NTG to induce tolerance.
- Functional relaxation responses to NTG were measured.
- Immunohistochemistry and digital image analysis were used to detect 3-nitrotyrosine (3NT), a biomarker of protein nitration.
Main Results:
- NTG preincubation caused significant vascular tolerance, shifting the NTG relaxation response.
- NTG-induced tolerance was associated with increased 3-nitrotyrosine (3NT) immunoprevalence.
- Adding free tyrosine abolished 3NT immunoprevalence but did not affect tolerance development.
Conclusions:
- Protein nitration, indicated by 3NT, occurs during nitroglycerin-induced vascular tolerance.
- Despite its occurrence, protein nitration does not appear to mediate the development of nitrate tolerance.