Hatmi M, Randon J, Faili A, Vargaftig B B
Unité de Pharmacologie Cellulaire, Unité Associée Institut Pasteur, INSERM no. 285, Paris, France.
Br J Haematol. 1993 Feb;83(2):270-5. doi: 10.1111/j.1365-2141.1993.tb08282.x.
Stimulation of washed human platelets by the pro-inflammatory polysaccharide carrageenan is accompanied by shape change, aggregation and release of granule contents and unaccompanied by thromboxane A2 synthesis. Carrageenan triggers platelet activation through a prostaglandin synthetase-independent mechanism. The phospholipase A2 (PLA2) inhibitor, p-bromophenacyl bromide suppresses platelet responses to carrageenan (Vargaftig et al, 1980) probably by mechanism(s) other than those which involve PLA2 activity. Exposure of platelets to carrageenan (2-25 micrograms/ml) induced inositol phosphate formation in a time- and concentration-dependent manner, the level of inositol phosphate formation correlating with the intensity of aggregation. Neomycin, an aminoglycoside antibiotic which inhibits the phospholipase C-mediated phosphatidylinositol 4,5-bisphosphate breakdown, suppressed both platelet activation and inositol phosphate formation. Inhibition was concentration-dependent with an IC50 value of about 180 microM. Platelet-activating factor (PAF) is not responsible for carrageenan-induced platelet activation and inositol phosphate formation, since exposure of platelets to carrageenan (25 micrograms/ml) in the presence of compound WEB 2086 (100 microM), a PAF antagonist, failed to inhibit carrageenan responses. However, compound Ro 19-3704, a structurally related antagonist of PAF reported to be also an inhibitor of phospholipases A2 and C, inhibited concentration-dependently (0.1-10 microM) aggregation and ATP release induced by carrageenan (25 micrograms/ml). These findings indicate that carrageenan activates human platelets through a phospholipase C-dependent mechanism and show that neomycin, at low concentrations, can be a selective inhibitor of phospholipase C-mediated PIP2-breakdown.
促炎多糖角叉菜胶刺激洗涤后的人血小板时，会伴随形状改变、聚集以及颗粒内容物的释放，且不伴有血栓素A2的合成。角叉菜胶通过一种不依赖前列腺素合成酶的机制触发血小板活化。磷脂酶A2（PLA2）抑制剂对溴苯甲酰溴抑制血小板对角叉菜胶的反应（瓦尔加夫蒂格等人，1980年），其抑制机制可能与涉及PLA2活性的机制不同。将血小板暴露于角叉菜胶（2 - 25微克/毫升）会以时间和浓度依赖的方式诱导肌醇磷酸的形成，肌醇磷酸的形成水平与聚集强度相关。新霉素是一种氨基糖苷类抗生素，可抑制磷脂酶C介导的磷脂酰肌醇4,5 - 二磷酸的分解，它能同时抑制血小板活化和肌醇磷酸的形成。抑制作用呈浓度依赖性，IC50值约为180微摩尔。血小板活化因子（PAF）不参与角叉菜胶诱导的血小板活化和肌醇磷酸形成，因为在PAF拮抗剂化合物WEB 2086（100微摩尔）存在的情况下，将血小板暴露于角叉菜胶（25微克/毫升）未能抑制角叉菜胶反应。然而，化合物Ro 19 - 3704是一种结构相关的PAF拮抗剂，据报道也是磷脂酶A2和C的抑制剂，它能浓度依赖性地（0.1 - 10微摩尔）抑制角叉菜胶（25微克/毫升）诱导的聚集和ATP释放。这些发现表明，角叉菜胶通过一种依赖磷脂酶C的机制激活人血小板，并表明低浓度的新霉素可以是磷脂酶C介导的PIP2分解的选择性抑制剂。
