选择性血栓素A2受体拮抗剂EP 092对体外和体内全血中血小板聚集的抑制作用。
Inhibitory effect of a selective thromboxane A2 receptor antagonist, EP 092, on platelet aggregation in whole blood ex vivo and in vivo.
作者信息
Booth R F, Honey A C, Lad N, Tuffin D P, Wade P J
机构信息
Searle Research and Development, Buckinghamshire.
出版信息
Br J Pharmacol. 1989 Feb;96(2):395-405. doi: 10.1111/j.1476-5381.1989.tb11830.x.
Abstract
- The inhibitory effect of a selective prostaglandin H2 (PGH2)/thromboxane A2 receptor antagonist, EP 092, on platelet aggregatory responses in whole blood ex vivo (guinea-pig: Rhesus monkey) and intravascular aggregation in vivo (rabbit) has been investigated. 2. Collagen (0.1-10.0 micrograms ml-1) caused a concentration-dependent decrease in single platelet count in samples of both guinea-pig and Rhesus monkey citrated whole blood incubated ex vivo. EP 092 administered to guinea-pigs by intravenous (0.1-3.0 mg kg-1) or oral (1.0-10.0 mg kg-1) routes significantly inhibited the platelet responses to collagen (ED50 values 1.3 +/- 0.2 and 1.4 +/- 0.2 mg kg-1 respectively). Similar potency against collagen-induced whole blood aggregation was observed in Rhesus monkey blood samples following EP 092 given orally (ED50 0.9 +/- 0.3 mg kg-1). 3. The duration of action of EP 092 against collagen aggregatory responses ex vivo in both guinea-pigs and Rhesus monkeys was between 3 and 6 h following oral administration at 3.0 mg kg-1. 4. The inhibitory activity demonstrated by EP 092 against collagen-induced aggregation of Rhesus monkey whole blood ex vivo was not accompanied by any significant reduction in thromboxane A2 formation except at the highest dose tested (10 mg kg-1). 5. The intravascular aggregatory response induced by collagen or thrombin in the anaesthetized rabbit was significantly inhibited by an intravenous infusion of EP 092 (10 mg kg-1). EP 092 appeared less potent and its effect was of shorter duration in this preparation compared with its inhibitory effect on ex vivo aggregation, being evident immediately after infusion of drug but not after a further 30 min. 6. It is concluded that collagen-induced platelet aggregatory response in guinea-pig and Rhesus monkey whole blood ex vivo and rabbit in vivo exhibit a thromboxane-dependent component which can be inhibited in a dose-related fashion by pretreatment with the thromboxane antagonist EP 092. In the rabbit, moreover, the data support the possibility of a role for thromboxane in the intravascular aggregatory response to thrombin.
摘要
- 研究了选择性前列腺素H2（PGH2）/血栓素A2受体拮抗剂EP 092对体外全血（豚鼠：恒河猴）血小板聚集反应及体内血管内聚集（兔）的抑制作用。2. 胶原蛋白（0.1 - 10.0微克/毫升）使体外孵育的豚鼠和恒河猴枸橼酸盐全血样本中的单个血小板计数呈浓度依赖性下降。通过静脉（0.1 - 3.0毫克/千克）或口服（1.0 - 10.0毫克/千克）途径给豚鼠施用EP 092可显著抑制血小板对胶原蛋白的反应（ED50值分别为1.3±0.2和1.4±0.2毫克/千克）。在口服给予EP 092后的恒河猴血样中观察到对胶原蛋白诱导的全血聚集有相似的效力（ED50为0.9±0.3毫克/千克）。3. 在豚鼠和恒河猴中，口服3.0毫克/千克的EP 092后，其对体外胶原蛋白聚集反应的作用持续时间为3至6小时。4. EP 092对恒河猴体外全血胶原蛋白诱导聚集的抑制活性，除了在测试的最高剂量（10毫克/千克）外，并未伴随血栓素A2生成的任何显著减少。5. 静脉输注EP 092（10毫克/千克）可显著抑制麻醉兔中胶原蛋白或凝血酶诱导的血管内聚集反应。与对体外聚集的抑制作用相比，EP 092在该制剂中的效力似乎较低且作用持续时间较短，在输注药物后立即明显，但在进一步30分钟后则不明显。6. 得出结论，胶原蛋白诱导的豚鼠和恒河猴体外全血以及兔体内血小板聚集反应表现出一种血栓素依赖性成分，通过用血栓素拮抗剂EP 092预处理可按剂量相关方式抑制。此外，在兔中，数据支持血栓素在对凝血酶的血管内聚集反应中起作用的可能性。
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