血小板血栓素合成的选择性抑制对血小板与内皮下相互作用的影响。

Effects of the selective inhibition of platelet thromboxane synthesis on the platelet-subendothelium interaction.

作者信息

De La Cruz J P, Villalobos M A, Escalante R, Guerrero A, Arrebola M M, Sánchez de La Cuesta F

机构信息

Department of Pharmacology and Therapeutics, School of Medicine, University of Málaga, 29071 Málaga, Spain.

出版信息

Br J Pharmacol. 2002 Dec;137(7):1082-8. doi: 10.1038/sj.bjp.0704963.

DOI:10.1038/sj.bjp.0704963

PMID:12429581

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC1573583/

Abstract

Drugs that inhibit TxA(2) 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 TxA(2) receptor blocker (DT-TX 30) on platelet aggregation and the platelet-subendothelium interaction in flow conditions. 2. The techniques used in this in vitro study were platelet aggregometry in whole blood, and measurement of platelet thromboxane B(2) and prostaglandin E(2) production and leucocyte production of 6-keto-PGF(1alpha). 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. 3. The 50% inhibitory concentration (IC(50)) of DT-TX 30 in whole blood was in the range of 10(-7) micro M (induced with collagen or arachidonic acid) to 10(-5) micro M (induced with thrombin) or 10(-4) (induced with ADP). IC(50) values under all experimental conditions were lower with DT-TX 30 than with ASA. For thromboxane B(2) the IC(50) were: ASA 0.84+/-0.05 micro M, dazoxiben 765+/-54 micro M, DT-TX 30 8.54+/-0.60 micro M. Prostaglandin E(2) was inhibited only by ASA (IC(50) 1.21+/-0.08 micro M). Leucocyte 6-keto-PGF(1alpha) was inhibited by ASA (IC(50) 6.58+/-0.76 micro M) 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 micro M: 10.71+/-0.55%, at 1.0 micro M: 6.53+/-0.44%, at 5.0 micro M; 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. 4. In conclusion, the effect of specific blockage of TxS together with blockage of membrane receptors for TxA(2) can surpass the effect of ASA in inhibiting the platelet-subendothelium interaction in flow conditions.

摘要

抑制血栓素A2（TxA2）合成的药物用于减少血小板聚集。本研究的目的是比较环氧化酶（COX）抑制剂（阿司匹林，ASA）、血栓素合成酶（TxS）抑制剂（达唑氧苯）以及双重TxS抑制剂和TxA2受体阻滞剂（DT-TX 30）在流动条件下对血小板聚集和血小板与内皮下相互作用的影响。2. 本体外研究采用的技术包括全血血小板聚集测定法，以及测量血小板血栓素B2和前列腺素E2的生成，还有白细胞生成6-酮-前列腺素F1α。在剪切应力为800 s(-1)的流动血液作用下，对兔主动脉内皮下制剂进行血小板与内皮下相互作用的评估。采用形态计量学方法计算血小板占据内皮下的百分比。3. DT-TX 30在全血中的50%抑制浓度（IC50）范围为10(-7) μM（由胶原或花生四烯酸诱导）至10(-5) μM（由凝血酶诱导）或10(-4)（由ADP诱导）。在所有实验条件下，DT-TX 30的IC50值均低于ASA。对于血栓素B2，IC50分别为：ASA 0.84±0.05 μM，达唑氧苯765±54 μM，DT-TX 30 8.54±0.60 μM。前列腺素E2仅被ASA抑制（IC50 1.21±0.08 μM）。白细胞6-酮-前列腺素F1α被ASA抑制（IC50 6.58±0.76 μM），而被达唑氧苯和DT-TX 可增加。在用抑制胶原诱导的血小板聚集的浓度范围内，DT-TX 30处理后，血液灌注后血小板占据内皮下表面的百分比降低最为显著（对照组：31.20±3.8%，0.1 μM的DT-TX 30：10.71±0.55%，1.0 μM：6.53±0.44%，5.0 μM：1.48±0.07%）。所有三种药物均减少血栓形成，尽管ASA（与达唑氧苯或DT-TX 30不同）增加了黏附占据的表面百分比。4. 总之，特异性阻断TxS并同时阻断TxA2的膜受体，在抑制流动条件下血小板与内皮下相互作用方面的效果可超过ASA。