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Vol. 291, Issue 1, 194-198, October 1999
Division of Pharmacology, College of Pharmacy, The Ohio State
University, Columbus, Ohio
Nitroglycerin (NTG) is an important cardiovascular agent, but tolerance
during continuous administration limits its clinical utility. Increased
vascular superoxide production may mediate nitrate tolerance via a
reduction in nitric oxide availability. Because superoxide anion and
nitric oxide react avidly to form peroxynitrite, an aggressive
cellular toxicant that nitrates protein tyrosine residues, we tested
the hypotheses that protein nitration, indicative of peroxynitrite
formation, occurs during vascular tolerance, and that protein nitration
participates in tolerance development. Preincubation of rat thoracic
aorta segments with NTG (22 µM, EC95 for 30 min) caused a
significant shift in NTG relaxation response (EC50;
6.7 ± 1.7 versus 0.50 ± 0.13 µM, NTG versus vehicle,
p < .05). After functional evaluations, tissues were fixed in formalin for immunohistochemistry and digital image analysis. NTG-induced vascular tolerance was associated with increased immunoprevalence of 3-nitrotyrosine (3NT, stable biomarker of protein
nitration; 11.41 ± 2.48 versus 0.04 ± 0.02% positive
pixels, NTG versus vehicle, p < .05). Staining was
observed throughout vascular smooth muscle layers. Addition of 500 µM
free tyrosine to the preincubation medium did not alter tolerance
development (NTG EC50 6.5 ± 3.0 µM) but abolished
3NT immunoprevalence (0.16 ± 0.10%). No significant relationship
between NTG potency and 3NT immunoprevalence was observed. These data
support the hypothesis that protein nitration occurs during nitrate
vascular tolerance, however, it apparently does not mediate this phenomenon.
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