Hemodynamics under Basic Conditions and during Ischemic Stress after Inhibition of Thromboxane Synthetase by UK 38.485*

SummaryPlatelet aggregation, secretion of 5-hydroxy tryptamine and production of thromboxane B2 were monitored simultaneously in human platelet suspensions in the absence and presence of cyclooxygenase or thromboxane synthetase inhibitors. Aggregation, secretion and thromboxane B2 formation in response to either sodium arachidonate or epinephrine were blocked by aspirin or by 1-N-butyl imidazole suggesting that thromboxane biosynthesis was an essential requirement for platelet activation by these agents. In contrast, thrombin and collagen could apparently induce aggregation and secretion via two pathways: at low doses involving thromboxane production, but at higher doses by a direct mechanism independent of thromboxane biosynthesis. In the case of ADP, inhibition of thromboxane production blocked secretion but had little effect on aggregation, indicating that secretion was probably dependent on thromboxane biosynthesis which probably occurred as a result of aggregation. Thus it appears that although the processes of thromboxane production, release of dense granule constituents and aggregation may often be intimately linked, each process can occur independently of the other, depending upon the stimulus used.

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Inhibition of Platelet Aggregation by Human Placenta

Thrombosis and Haemostasis ◽

10.1055/s-0038-1657866 ◽

1985 ◽

Vol 54 (02) ◽

pp. 431-437 ◽

Cited By ~ 1

Author(s):

M J Dembélé-Duchesne ◽

A Laghchim Lahlou ◽

H Thaler-Dao ◽

A Crastes de Paulet

Keyword(s):

Fatty Acid ◽

Platelet Aggregation ◽

Human Placenta ◽

Cyclooxygenase Inhibitor ◽

Synthetase Inhibitor ◽

Inhibition Of Platelet Aggregation ◽

Thromboxane Synthetase ◽

Rabbit Platelets ◽

High Doses ◽

Induced Aggregation

SummaryHuman placental cytosol inhibits platelet aggregation induced by high doses of collagen. The aim of this study was to investigate whether this anti-aggregating activity was caused only by the presence of various activities already described in the placenta (an ADP-consuming enzyme, a fatty acid cyclooxygenase inhibitor, and a thromboxane synthetase inhibitor) or whether another factor was present.Heating the cytosol at 50° C for 6 min destroyed the inhibitor of collagen-induced aggregation. ADPase and the AA pathway inhibitors were not modified by this treatment. We therefore show the presence of an additional anti-aggregating factor: it is destroyed by heating at 50° C.We also tested for the presence of an inhibitor of AA release in the placental cytosol using three different methods (rabbit platelets in PRP, washed rabbit platelets, and NRK fibroblasts) but no inhibition could be evidenced.We conclude that this new anti-aggregating factor, which is probably a protein, acts neither through AA release inhibition nor AA cascade inhibition.

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Selective Inhibition of Thromboxane Synthetase with Dazoxiben - Basis of Its Inhibitory Effect on Platelet Adhesion

Thrombosis and Haemostasis ◽

10.1055/s-0038-1657330 ◽

1983 ◽

Vol 49 (02) ◽

pp. 096-101 ◽

Cited By ~ 11

Author(s):

V C Menys ◽

J A Davies

Keyword(s):

Arachidonic Acid ◽

Platelet Adhesion ◽

Fold Increase ◽

Selective Inhibition ◽

Inhibitory Effect ◽

Selective Inhibitor ◽

Coated Glass ◽

Thromboxane Synthetase ◽

Pre Treatment

SummaryPlatelet adhesion to rabbit aortic subendothelium or collagen-coated glass was quantitated in a rotating probe device by uptake of radio-labelled platelets. Under conditions in which aspirin had no effect, dazoxiben, a selective inhibitor of thromboxane synthetase, reduced platelet adhesion to aortic subendothelium by about 40% but did not affect adhesion to collagen-coated glass. Pre-treatment of aortic segments with 15-HPETE, a selective inhibitor of PGI2-synthetase, abolished the inhibitory effect of dazoxiben on adhesion. Concentrations of 6-oxo-PGFlα in the perfusate were raised in the presence of dazoxiben alone, and following addition of thrombin (10 units/ml) there was a 2-3 fold increase in concentration. Perfusion of damaged aorta with platelets labelled with (14C)-arachidonic acid in the presence of thrombin and dazoxiben resulted in the appearance of (14C)-labelled-6-oxo-PGFiα. Inhibition of thromboxane synthetase limits platelet adhesion probably by promoting vascular synthesis of PGI2 from endoperoxides liberated from adherent platelets, which subsequently promotes detachment of cells from the surface.

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Intrathoracic Platelet Accumulation in the Guinea-Pig Induced by Intravenous Administration of Arachidonic Acid - Effect of Cyclooxygenase and Thromboxane Synthetase Inhibitors

Thrombosis and Haemostasis ◽

10.1055/s-0038-1661674 ◽

1986 ◽

Vol 56 (03) ◽

pp. 311-317 ◽

Cited By ~ 1

Author(s):

P A Barrett ◽

K D Butler ◽

R A Shand ◽

R B Wallis

Keyword(s):

Arachidonic Acid ◽

Blood Volume ◽

Intravenous Administration ◽

Guinea Pigs ◽

Human Albumin ◽

Thromboxane Synthetase ◽

Acid Effect ◽

Rapid Accumulation ◽

Platelet Accumulation ◽

High Doses

SummaryIntravenous administration of arachidonic acid to guinea-pigs caused a dose-related, rapid accumulation of 51Cr-labelled platelets in the thorax. Inhibitors of cyclooxygenase inhibited the platelet accumulation, induced by arachidonic acid (30 mg/kg), at doses which did not alter the thoracic blood volume (as measured by 131I-labelled human albumin). Thromboxane synthetase inhibitors had different effects on platelet accumulation depending on the dose. CGS 12970 (3 mg/kg) and N(1-carboxyheptyl) imidazole (100 mg/kg) reduced platelet accumulation. High doses of CGS 12970 and CGS 13080 caused an apparent enhancement of platelet accumulation which was associated with pooling of blood in the thorax, as measured by either 131I-labelled human albumin or 51Cr-labelled erythrocytes. This increase in thoracic blood volume was abolished if the guinea-pigs were also pretreated with diclofenac (1 mg/kg) in addition to the thromboxane synthetase inhibitor. Increases in thoracic blood volume were also obtained following infusions of PGI2 but not PGD2 or PGE2.

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The Effects of Modulation of Prostanoid Metabolism on the Thoracic Platelet Accumulation Induced by Intravenous Administration of Collagen in the Guinea-Pig

Thrombosis and Haemostasis ◽

10.1055/s-0038-1661663 ◽

1986 ◽

Vol 56 (03) ◽

pp. 263-267

Author(s):

K D Butler ◽

R A Shand ◽

R B Wallis

Keyword(s):

Platelet Count ◽

Guinea Pig ◽

Intravenous Administration ◽

Cyclooxygenase Inhibitors ◽

Concomitant Increase ◽

Thromboxane Synthetase ◽

Platelet Accumulation ◽

Related Increase

SummaryThe effects of intravenously administered collagen on the circulatory platelet count, TxB2, 6-keto PGF1α and 51Cr-labelled platelet accumulation in the thorax have been evaluated in the guinea-pig. Administration of collagen induced a dose-related peripheral thrombocytopenia and a concomitant increase in 51Cr-labelled platelets in the thorax. There was also a transient dose-related increase in plasma TxB2 but no change in plasma 6-keto PGF1α levels.The thromboxane synthetase inhibitors tested, reduced the platelet accumulation, but only CGS 13080 significantly inhibited TxB2 production. In contrast all the cyclooxygenase inhibitors tested impaired the elevation of plasma TxB2 after collagen, but only diclofenac inhibited the 51Cr-labelled platelet accumulation.The greater effect of thromboxane synthetase inhibitors compared to cyclooxygenase inhibitors on platelet accumulation in this system cannot be completely explained by the changes measured in the circulating prostanoids.

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