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

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, 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.

Increased Levels of Prostaglandin D2 Suggest Macrophage Activation in Patients With Primary Pulmonary Hypertension

“…Platelets normally produce little PGD 2 , although they are capable of synthesizing it when TXA 2 synthesis is inhibited. 23 TXA 2 synthesis is increased, Other cells, including eosinophils, endothelial cells, and a variety of antigen-presenting cells in addition to macrophages, have the capacity for PGD 2 synthesis in vitro. 18,24 -26 For example, small amounts of PGD 2 are produced from activated eosinophils in asthmatic patients after stimulation with platelet-activating factor.…”

Inhibition of thromboxane biosynthesis by 3-pyridinol carboxypentyl ethers substituted with a hydroxylated octyl chain

“…Venous blood from healthy volunteers was collected in glass tubes without anticoagulant, immediately mixed with different 4.10(t,2H,OCH2); 2.35(t,2H,CHzCOO); 2.00-7.10(d,l H,Hs); 6.55-5.95 (b.s., 2H,20H); 4.00(t,2H,OCHz); amounts of the compounds to be tested or their solvent (phosphate buffer, pH 7.4) and incubated a t 37'C for 1 h. The serum was separated by centrifugation and stored at -20'C until assayed for TxB2 and PEG2. The two prostanoids were quantitated by specific radioimmunoassays as previously described (Desideri et al 1986;Bertele et al 1984). Cross reactivity of PEG2 antiserum with compounds 3 and 4 was lower than 0.03 and 0.01 'Yo, respectively.…”

“…Concomitantly with TxB2 synthesis inhibition, serum PGE2 rose (18 and 300 times control values for the two compounds). This suggests that 3 and 4 act as selective inhibitors ofTxA2 synthesis, since the cyclic endoperoxides spared by TxA2-synthase inhibitors are diverted to the synthesis of other prostaglandins (Bertele et al 1984).…”

Platelet function, antiplatelet therapy and clinical outcomes: to test or not to test?

“…In 1974, indomethacin, a non‐steroidal anti‐inflammatory drug given to patients with chronic glomerulonephritis, reportedly induced a variable inhibition of platelet aggregation tests: stronger inhibition of platelet function was significantly associated with higher reduction of urinary excretion of protein and fibrinogen/fibrin‐related antigen [13]. A few years later, variability of response to thromboxane A 2 synthase inhibitors was reported by several groups [14–17]. The possibility that salicylate, accumulating in blood during chronic administration of aspirin, could interfere with the antiplatelet effect of the parent compound and induce a variable response to the latter was also proposed [18–21].…”