Kanaho Y, Kometani M, Sato T, Fujii T
Thromb Res. 1983 Sep 15;31(6):817-31. doi: 10.1016/0049-3848(83)90113-5.
The effects of two representative groups of amphiphilic drugs, lysophosphatidylcholine species (myristoyl, palmitoyl and stearoyl) and phenothiazine neuroleptics (promethazine, chlorpromazine and trifluoperazine), on the morphology of intact rabbit platelets, arachidonate release from membrane phospholipids, pseudopod formation and the resulting aggregation of stimulated platelets were examined and compared with those of two known cycloxygenase inhibitors, aspirin and indomethacin. Collagen-induced aggregation was inhibited by relatively low concentrations of amphiphilic drugs in parallel with the prevention of arachidonate release from the membrane phospholipids. Thrombin-and arachidonate-induced aggregations were inhibited by these drugs at higher concentrations, at which they transform intact platelets from discoid to spiny and spherical shape, respectively, and consequently suppress formation of native pseudopods induced by these stimuli. Washing the drug-treated platelets with BSA-Tyrode solution abolished all the effects of drugs. In contrast, the cycloxygenase inhibitors blocked both collagen- and arachidonate-induced aggregations without causing membrane shape change of the intact platelets, although they inhibited thrombin-induced aggregation at extremely high concentrations, at which they did elicit membrane shape change. These observations suggest that these amphiphilic drugs act on the plasma membrane of platelets and impair membrane-linked functions. At lower concentrations they specifically inhibit the arachidonate release from the membrane phospholipids under collagen stimulation; at higher concentrations they drastically perturb the plasma membrane structure, inducing the membrane shape change, and suppressing the native pseudopod formation under thrombin or arachidonate stimulation. The impairment of membrane-linked functions by these amphiphilic drugs is thought to account for their inhibition of stimulus-induced aggregation.
研究并比较了两类具有代表性的两亲性药物，即溶血磷脂酰胆碱类（肉豆蔻酰、棕榈酰和硬脂酰）和吩噻嗪类抗精神病药（异丙嗪、氯丙嗪和三氟拉嗪）对完整兔血小板形态、膜磷脂花生四烯酸释放、伪足形成以及由此导致的刺激血小板聚集的影响，并与两种已知的环氧化酶抑制剂阿司匹林和吲哚美辛进行了比较。相对低浓度的两亲性药物可抑制胶原诱导的聚集，同时可防止膜磷脂释放花生四烯酸。这些药物在较高浓度时可抑制凝血酶和花生四烯酸诱导的聚集，在该浓度下，它们分别使完整血小板从盘状转变为棘状和球形，从而抑制由这些刺激诱导的天然伪足形成。用牛血清白蛋白 - 台氏液洗涤经药物处理的血小板可消除药物的所有作用。相比之下，环氧化酶抑制剂可阻断胶原和花生四烯酸诱导的聚集，且不会引起完整血小板的膜形状改变，尽管它们在极高浓度时可抑制凝血酶诱导的聚集，此时它们确实会引起膜形状改变。这些观察结果表明，这些两亲性药物作用于血小板的质膜并损害膜相关功能。在较低浓度时，它们特异性抑制胶原刺激下膜磷脂花生四烯酸的释放；在较高浓度时，它们会严重扰乱质膜结构，诱导膜形状改变，并抑制凝血酶或花生四烯酸刺激下天然伪足的形成。这些两亲性药物对膜相关功能的损害被认为是其抑制刺激诱导聚集的原因。
