Background: Extensive research has been conducted regarding the mechanism o
f action of glyceryl trinitrate (GTN). It is currently believed that GTN un
dergoes a thiol-dependent metabolic pathway and releases its active metabol
ite, nitric oxide (NO) and/or S-nitrosothiols (R-SNO). This activates guany
lyl cyclase (GC) leading to the formation of cGMP, which is responsible for
the relaxation of vascular smooth muscles and the inhibition of platelet a
ggregation. The lack of knowledge as to the precise mechanism of GTN action
and the modulation of its formation has limited the prevention of toleranc
e to GTN. Results: With cultured human vascular endothelial cells (EC), we
showed that nitrite was first formed in endothelial cells whose concentrati
on was dependent on reduced thiols. Cells preexposed to GTN significantly d
ecreased the production of nitrite compared with cells that were not preexp
osed. Furthermore, we showed that thiols in cultured cells were oxidized du
ring interaction with GTN, which correlated with the time of exposure to GT
N. Conclusion: Nitrite is the first active intermediate of GTN metabolism i
n endothelial cells. The analysis of the changes of the blood nitrite and r
educed thiols concentration is helpful for evaluating the vasodilatation ac
tivity of GTN during therapeutic treatments. (C) 2001 Elsevier Science B.V.
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