Effects of the selective inhibition of platelet thromboxane synthesis on the platelet‐subendothelium interaction

• Published in: British journal of pharmacology Vol. 137; no. 7; pp. 1082 - 1088
• Main Authors: De La Cruz, J P, Villalobos, M A, Escalante, R, Guerrero, A, Arrebola, M M, Sánchez de la Cuesta, F
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01-12-2002; Nature Publishing
• Subjects: 6-Ketoprostaglandin F1 alpha - blood; acetylsalicylic acid; Adult; Animals; Aspirin - pharmacology; Biological and medical sciences; Blood Platelets - drug effects; Blood Platelets - metabolism; Blood. Blood coagulation. Reticuloendothelial system; Chlorobenzenes - pharmacology; Cyclooxygenase Inhibitors - pharmacology; dazoxiben; Dinoprost - blood; Dose-Response Relationship, Drug; Endothelium, Vascular - drug effects; Endothelium, Vascular - metabolism; Humans; Imidazoles - pharmacology; Male; Medical sciences; Middle Aged; Pharmacology. Drug treatments; Platelet Aggregation - drug effects; Platelet Aggregation Inhibitors - pharmacology; Pyridines - pharmacology; Rabbits; Receptors, Thromboxane - antagonists & inhibitors; subendothelium; Thromboxane A2; Thromboxane B2 - blood; thromboxane receptor antagonists; thromboxane synthetase inhibitors; Thromboxane-A Synthase - antagonists & inhibitors; Thromboxanes - antagonists & inhibitors; Thromboxanes - blood; Prostaglandin-endoperoxide synthase; thromboxane receptor antagonists; Intramolecular oxidoreductases; Rabbit; Subendothelium; Isomerases; Thromboxane-A synthase; Blood vessel; Aorta; Antagonist; Mechanism of action; Biological receptor; Enzyme; Thromboxane A2; thromboxane synthetase inhibitors; Enzyme inhibitor; Lagomorpha; In vitro; Biological activity; Antiplatelet agent; acetylsalicylic acid; Endothelium; Vertebrata; Platelet; Mammalia; dazoxiben; Animal; Oxidoreductases; Circulatory system; Comparative study
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1038/sj.bjp.0704963

Drugs that inhibit TxA2 synthesis are used to reduce platelet aggregation. The aim of this study was to compare the effects of a cyclo‐oxygenase (COX) inhibitor (acetylsalicylic acid, ASA), a thromboxane synthetase (TxS) inhibitor (dazoxiben) and a dual TxS inhibitor and TxA2 receptor blocker (DT‐TX 30) on platelet aggregation and the platelet‐subendothelium interaction in flow conditions.
The techniques used in this in vitro study were platelet aggregometry in whole blood, and measurement of platelet thromboxane B2 and prostaglandin E2 production and leucocyte production of 6‐keto‐PGF1α. The platelet‐subendothelium interaction was evaluated in rabbit aorta subendothelium preparations exposed to flowing blood at a shear stress of 800 s−1. Morphometric methods were used to calculate the percentage of subendothelium occupied by platelets.
The 50% inhibitory concentration (IC50) of DT‐TX 30 in whole blood was in the range of 10−7 μM (induced with collagen or arachidonic acid) to 10−5 μM (induced with thrombin) or 10−4 (induced with ADP). IC50 values under all experimental conditions were lower with DT–TX 30 than with ASA. For thromboxane B2 the IC50 were: ASA 0.84±0.05 μM, dazoxiben 765±54 μM, DT–TX 30 8.54±0.60 μM. Prostaglandin E2 was inhibited only by ASA (IC50 1.21±0.08 μM). Leucocyte 6‐keto‐PGF1α was inhibited by ASA (IC50 6.58±0.76 μM) and increased by dazoxiben and DT–TX 30. The greatest reduction in percentage subendothelial surface occupied by platelets after blood perfusion was seen after treatment with DT–TX 30 in the range of concentrations that inhibited collagen‐induced platelet aggregation (control group: 31.20±3.8%, DT‐TX 30 at 0.1 μM: 10.71±0.55%, at 1.0 μM: 6.53±0.44%, at 5.0 μM; 1.48±0.07%). All three drugs reduced thrombus formation, although ASA (unlike dazoxiben or DT–TX 30) increased the percentage surface occupied by adhesions.
In conclusion, the effect of specific blockage of TxS together with blockage of membrane receptors for TxA2 can surpass the effect of ASA in inhibiting the platelet‐subendothelium interaction in flow conditions.
British Journal of Pharmacology (2002) 137, 1082–1088. doi:10.1038/sj.bjp.0704963