MEPACRINE (QUINACRINE) INHIBITION OF THROMBIN-INDUCED PLATELET RESPONSES CAN BE OVERCOME BY LYSOPHOSPHATIDIC ACID
MEPACRINE (QUINACRINE) INHIBITION OF THROMBIN-INDUCED PLATELET RESPONSES CAN BE OVERCOME BY LYSOPHOSPHATIDIC ACID
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DOI：
10.1016/0304-4165(85)90202-8
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发表时间：
1985-01-01
期刊：
影响因子：
--
通讯作者：
GERRARD, JM
中科院分区：
文献类型：
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作者：
MCCREA, JM;ROBINSON, P;GERRARD, JM
将凝血酶添加到人血小板中会导致溶血磷脂酸的产生。溶血磷脂酸的这种合成可以被mepacrine抑制，mepacrine是磷脂酶A2的抑制剂，其攻击磷脂酸以产生溶血磷脂酸。在本研究中，mepacrine的使用浓度为2.5-20μM，足以阻止0.1U/ml凝血酶诱导的聚集和溶血磷脂酸形成。在该浓度下，Mepacrine 还阻断凝血酶诱导的血小板肌球蛋白轻链和 47 kDa 蛋白的磷酸化、凝血酶诱导的分泌以及凝血酶诱导的血小板磷脂中花生四烯酸的释放。然而，mepacrine 还部分抑制了响应凝血酶的磷脂酸的形成，与磷脂酶 C 的某些同时抑制一致。溶血磷脂酸 (2.5-22 μM) 克服了 mepacrine 对凝血酶刺激的聚集、蛋白质磷酸化和分泌的阻碍，而不刺激血小板磷脂中花生四烯酸的释放或溶血磷脂酸的形成，并且仅略微增加磷脂酸形成。结果表明，溶血磷脂酸主要作用于磷脂酶 A2 和磷脂酶 C 的 mepacrine 抑制作用的远端，并且与溶血磷脂酸可能是低剂量凝血酶对人血小板的部分作用的介质的可能性一致。
Addition of thrombin to human platelets results in production of lysophosphatidic acid. Such synthesis of lysophosphatidic acid can be inhibited by mepacrine, an inhibitor of the phospholipase A2 which attacks phosphatidic acid to give lysophosphatidic acid. In the present study, mepacrine was used at a concentration of 2.5-20 .mu.M, sufficient to block aggregation and lysophosphatidic acid formation induced by 0.1 U/ml thrombin. Mepacrine, at this concentration, also blocked thrombin-induced phosphorylation of platelet myosin light chain and a 47 kDa protein, thrombin-induced secretion and thrombin-induced release of arachidonic acid from platelet phospholipids. However, mepacrine also partly inhibited the formation of phosphatidic acid in response to thrombin, consistent with some simultaneous inhibition of phospholipase C. Lysophosphatidic acid (2.5-22 .mu.M) overcame the mepacrine block in thrombin-stimulated aggregation, protein phosphorylation and secretion without stimulating the release of arachidonic acid from platelet phospholipids or the formation of lysophosphatidic acid, and only slightly increasing phosphatidic acid formation. The results suggest that lysophosphatidic acid primarily acts distal to mepacrine inhibition of phospholipase A2 and phospholipase C and are consistent with the possibility that lysophosphatidic acid might be a mediator of part of the effects of low-dose thrombin on human platelets.