Competitive antagonism at thromboxane receptors in human platelets
Competitive antagonism at thromboxane receptors in human platelets
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对人血小板中血栓素受体的竞争性拮抗作用
DOI：
10.1111/j.1476-5381.1985.tb16139.x
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发表时间：
1985
影响因子：
7.3
通讯作者：
N. H. Wilson
中科院分区：
文献类型：
--
作者：
R. Armstrong;R.L. Jonse;V. Peesapati;S. Will;N. H. Wilson
1研究了前列腺素类似物EP 045、EP 092和血栓烷A_2（PTA_2）对体外人血小板聚集的抑制作用。2在稀释的富血小板血浆（PRP）中，EP 045（20 μm）和EP 092（1 μm）完全抑制血栓烷A2（TXA 2）、前列腺素H2（PGH 2）和5种化学稳定的血栓烷模拟物（包括11，9-环氧甲酰基-PGH 2和9，11-偶氮-PGH 2）的不可逆聚集反应。前列腺素类似物CTA 2产生的可逆聚集也受到抑制。稳定激动剂作用的阻断是可以克服的。在无血浆血小板混悬液中，EP 045和EP 092是更有效的拮抗剂。Schild分析表明EP 045具有竞争性拮抗作用（亲和常数为1.1 × 107 m−1）; EP 092阻断的性质尚不清楚。3 EP 045和EP 092不影响ADP、血小板活化因子（Paf）和肾上腺素诱导的初级聚集波，而抑制相应的第二相聚集。EP 045以平行方式抑制PGH 2或11，9-环氧甲烷-PGH 2诱导的聚集和5-羟色胺（5-HT）释放。血栓素生物合成的抑制不参与这些作用。4 EP 045和EP 092未升高血小板悬液中腺苷3′：5′-环磷酸（cAMP）水平。5在无血浆血小板悬浮液中，PTA 2产生形状变化反应，可被EP 045阻断。因此，PTA 2具有血栓烷样激动剂作用。PTA 2阻断11，9-环氧甲酰基-PGH 2的聚集作用似乎主要是由于血栓素受体的竞争。然而，PTA 2使环AMP水平略有上升;这可能是由于对人血小板中存在的PGI 2或PGD 2受体具有非常弱的刺激作用。因此，PTA 2的功能性拮抗作用可能增强其血栓烷受体阻断活性。6根据（a）EP 045、EP 092和PTA 2产生的拮抗作用的特异性，（B）当聚集是生物学反应时受体拮抗剂的亲和常数测定的有效性，和（c）人血小板血栓烷受体与平滑肌中血栓烷受体的特征相比较，讨论了结果。
1 The inhibitory effects of three prostanoid analogues, EP 045, EP 092 and pinane thromboxane A2 (PTA2), on the aggregation of human platelets in vitro have been investigated. 2 In diluted platelet‐rich plasma (PRP), EP 045 (20 μm) and EP 092 (1 μm) completely inhibited irreversible aggregation responses to thromboxane A2 (TXA2), prostaglandin H2 (PGH2) and five chemically stable thromboxane mimetics, including 11,9‐epoxymethano‐PGH2 and 9,11‐azo‐PGH2. Reversible aggregation produced by the prostanoid analogue, CTA2, was also inhibited. The block of the stable agonist action was surmountable. In plasma‐free platelet suspensions EP 045 and EP 092 were more potent antagonists. Schild analysis indicated a competitive type of antagonism for EP 045 (affinity constant of 1.1 × 107 m−1); the nature of the EP 092 block is not clear. 3 Primary aggregation waves induced by ADP, platelet activating factor (Paf) and adrenaline were unaffected by EP 045 and EP 092, whereas the corresponding second phases of aggregation were suppressed. Aggregation and 5‐hydroxytryptamine (5‐HT) release induced by either PGH2 or 11,9‐epoxymethano‐PGH2 were inhibited in a parallel manner by EP 045. Inhibition of thromboxane biosynthesis is not involved in these effects. 4 EP 045 and EP 092 did not raise adenosine 3′:5′‐cyclic monophosphate (cyclic AMP) levels in the platelet suspensions. 5 In plasma‐free platelet suspensions PTA2 produced a shape change response which could be blocked by EP 045. PTA2, therefore, has a thromboxane‐like agonist action. The block of the aggregatory action of 11,9‐epoxymethano‐PGH2 by PTA2 appears to be mainly due to competition at the thromboxane receptor. However, PTA2 produced a slight rise in cyclic AMP levels; this could be due to a very weak stimulant action on either PGI2 or PGD2 receptors present in the human platelet. Functional antagonism by PTA2 may therefore augment its thromboxane receptor blocking activity. 6 The results are discussed in terms of (a) the specificity of antagonism produced by EP 045, EP 092 and PTA2, (b) the validity of affinity constant determinations for receptor antagonists when aggregation is the biological response, and (c) the characteristics of the human platelet thromboxane receptor in comparison with those of thromboxane receptors in smooth muscle.