Pharmacologic inhibition of thromboxane synthetase and platelet aggregation modulatory role of cyclooxygenase products

V. Bertele, A. Falanga, M. Tomasiak

Research output: Contribution to journalArticlepeer-review

Abstract

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, PGF(2α), and PGD2, as shown by radioimmunoassay, thin-layer radiochromatography, and high-resolution gas chromatography mass spectrometry. Even at dazoxiben concentrations (40-80 μM) 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.

Original languageEnglish
Pages (from-to)1460-1466
Number of pages7
JournalBlood
Volume63
Issue number6
Publication statusPublished - 1984

ASJC Scopus subject areas

  • Hematology

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