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V Bertele, A Falanga, M Tomasiak, C Chiabrando, C Cerletti and G de Gaetano
Dazoxiben , an imidazole-derived selective inhibitor of thromboxane A2
(TxA2) synthetase, prevented TxB2 synthesis in vitro in platelet-rich
plasma from 16 normal subjects. Inhibition of TxB2 synthesis was
accompanied by increased generation of PGE2, PGF2 alpha, and PGD2, as shown
by radioimmunoassay, thin-layer radiochromatography, and high- resolution
gas chromatography-mass spectrometry. Even at dazoxiben concentrations
(40-80 microM) above those inhibiting TxB2 synthesis, platelet aggregation
induced by threshold concentrations of arachidonic acid was inhibited in
only 4 of 16 subjects, referred to as responders. The remaining 12
individuals were defined as nonresponders. The aggregating effect of
arachidonic acid and of the prostaglandin- endoperoxide analog U-46619 was
potentiated by PGE2 and prevented by PGD2 at concentrations within the
range of those detected in dazoxiben - treated platelet-rich plasma. The
antiaggregating effect of dazoxiben was counteracted by PGE2 (in
responders) and was potentiated by PGD2 (in nonresponders). Platelets from
responders and nonresponders did not differ in the amount of immunoreactive
PGE2 material or in their sensitivity to U-46619 or PGD2. It is concluded
that inhibition of thromboxane synthetase does not per se prevent platelet
aggregation. The functional result of thromboxane suppression appears to be
modulated by an interplay of the prostaglandin-endoperoxides, PGE2 and
PGD2, which are formed in excess.
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| Copyright © 1984 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
