Sugidachi A, Breiter N, Ogawa T, Asai F, Koike H
Pharmacology and Molecular Biology Research Laboratories, Sankyo Co., Ltd., Tokyo, Japan.
Thromb Haemost. 1996 Nov;76(5):786-90.
Aprosulate sodium, a bis-lactobionic acid amide derivative, is a novel synthetic polyanion with potent anticoagulant activities. In the present study, the effects of aprosulate on platelet aggregation were investigated in a plasma-free system. Aprosulate inhibited thrombin (0.03-0.3 U/ml)-induced aggregation in rat washed platelets in a concentration-dependent manner, with an IC50 value of 0.38 microgram/ml. In contrast, aprosulate, at up to 10 micrograms/ml, did not affect collagen (1 microgram/ml)- or ADP (3 microM)-induced aggregation. In fura 2-loaded platelets, aprosulate (1-10 micrograms/ml) inhibited intracellular Ca2+ mobilization induced by thrombin, but not that by ADP. Protamine, a highly basic protein, abolished aprosulate-mediated inhibition of thrombin-induced platelet aggregation, suggesting that the observed inhibition is primarily due to the negative charge contained on the aprosulate molecule. In human platelets, aprosulate inhibited thrombin-induced aggregation, but failed to inhibit platelet aggregation induced by SFLLRN, a synthetic tethered ligand of a thrombin receptor. Antiplatelet profiles of aprosulate were largely similar to those of heparin, although heparin inhibited both thrombin- and collagen-induced aggregation. These in vitro studies indicate that aprosulate is capable of inhibiting thrombin-induced platelet activation and that this effect is independent of its anticoagulant activity. These results suggest that the polyanionic feature of aprosulate plays an essential role in promoting its antiplatelet activities, and that a plausible mechanism to explain the observed inhibition conferred by this agent, would be one which involves blocking the platelet-thrombin interaction.
阿普罗舒酸钠是一种双乳糖醛酸酰胺衍生物，是一种具有强大抗凝活性的新型合成聚阴离子。在本研究中，在无血浆系统中研究了阿普罗舒酸钠对血小板聚集的影响。阿普罗舒酸钠以浓度依赖的方式抑制凝血酶（0.03 - 0.3 U/ml）诱导的大鼠洗涤血小板聚集，IC50值为0.38微克/毫升。相比之下，高达10微克/毫升的阿普罗舒酸钠不影响胶原蛋白（1微克/毫升）或ADP（3 microM）诱导的聚集。在负载fura 2的血小板中，阿普罗舒酸钠（1 - 10微克/毫升）抑制凝血酶诱导的细胞内Ca2+动员，但不抑制ADP诱导的。鱼精蛋白是一种高度碱性的蛋白质，它消除了阿普罗舒酸钠介导的对凝血酶诱导的血小板聚集的抑制作用，这表明观察到的抑制作用主要是由于阿普罗舒酸钠分子上含有的负电荷。在人血小板中，阿普罗舒酸钠抑制凝血酶诱导的聚集，但未能抑制凝血酶受体的合成拴系配体SFLLRN诱导的血小板聚集。阿普罗舒酸钠的抗血小板谱与肝素的抗血小板谱在很大程度上相似，尽管肝素抑制凝血酶和胶原蛋白诱导的聚集。这些体外研究表明，阿普罗舒酸钠能够抑制凝血酶诱导的血小板活化，并且这种作用与其抗凝活性无关。这些结果表明，阿普罗舒酸钠的聚阴离子特性在促进其抗血小板活性中起重要作用，并且解释该药物观察到的抑制作用的一个合理机制是涉及阻断血小板 - 凝血酶相互作用的机制。
