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Vol. 293, Issue 1, 222-229, April 2000
Department of Pharmacology, New York Medical College, Valhalla, New
York
Peroxynitrite (ONOO
), a reactive oxidant produced by the
reaction between nitric oxide and superoxide, was found to diffuse into
the platelet cytosol and inhibit arachidonic acid-induced platelet
aggregations with IC50 value of 5.8 ± 1.2 µM. A
fluorescence assay established that ONOO diffused into
the platelet cytosol in a manner that was inhibited (50-70%) by
4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid, an inhibitor of
HCO3/Cl anion exchanger.
Treatment of platelets with (
)-epigallocatechin gallate (2 µM), a
tea polyphenol and inhibitor of tyrosine nitration, abolished the
inhibitory effect of ONOO on arachidonate-induced
aggregations by 88%. ONOO (50-300 µM), added to
platelets 1 min before arachidonic acid, inhibited (20-100%)
formation of platelet cyclooxygenase (COX) products thromboxane
A2 and 12-hydroxyheptadecatrienoic acid. Interestingly,
simultaneous addition of ONOO and arachidonic acid
stimulated eicosanoid production by 20 to 60%. The inhibition of
thromboxane A2 generation correlated with the 5- to 10-fold
increase in the 3-nitrotyrosine levels of the platelet COX. Experiments
with purified COX-1 and COX-2 also showed 9-fold increase of
3-nitrotyrosine levels, which correlated with decreased (93-98%)
production of prostaglandin H2 when ONOO (50 µM) was added 1 min before arachidonic acid. However, the addition of
ONOO (50-100 µM) simultaneously with arachidonic acid
increased prostaglandin H2 formation by 30 to 60%. Thus,
the inhibitory effect of ONOO involved nitration of COX
tyrosine residues, whereas the stimulatory effect was likely to be a
result of ONOO functioning as a peroxide activator of
eicosanoid signaling. Increasing doses of ONOO not only
inhibited platelet COX but also induced formation of unique
eicosanoids: iso-prostaglandin F2
,
epoxyhydroxyeicosatrienoic acid, and trans-arachidonic
acids, suggesting that OH and NO2 radicals were generated
from ONOO in platelets. Formation of ONOO
from NO and superoxide may function as a platelet hormone-like COX
regulatory mechanism in inflammatory processes in which large amounts
of these molecules are produced.
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