5 展望 ADP受体结合实验及噻恩并吡啶药理研究资料都显示,在血小板表面可能有两种ADP受体。分子生物学研究也证实了P2X1与P2Y1两种嘌呤受体基因在血小板和巨核细胞的转录与表达。人们已可确定,血小板两种ADP受体有着各自的功能与作用机制。P2X1受体激活时促进钙离子的内流并抑制腺苷酸环化酶活性;P2Y1受体的激活与G蛋白偶联,通过磷脂酰肌醇的水解引起胞内贮存Ca2+的增加和血小板聚集[12]。这两种ADP受体都是血小板活化必不可少的。任何一种受体的缺陷都导致血小板不能活化,血小板的正常功能必须有两种受体的共同参与[13]。血小板ADP受体有独特的性质,ADP是其剌激剂,ATP是竞争性抑制剂;而在其它细胞上ADP和ATP对嘌呤类受体都表现相同的作用。血小板ADP受体类型、结构与功能的最后确定还有待于对先天性血小板ADP受体缺陷患者的基因研究以及对实验动物的血小板ADP受体基因敲除(knock out)的研究结果。血小板ADP受体的确定对于止血与血栓的病理生理研究具有重要的意义。最近有人发现,ADP受体参与了肝素引起的血小板减少性紫癜的发病过程[14]。此外,噻氯匹定已是最常用的一种抗血小板药物,其类似物clopidogrel也进入三期临床试用阶段。一些ADP受体拮抗剂在动物实验也表现出显著的抗血栓效果,有望成为新的抗血栓药物。这将进一步促进抗血小板药物的发展。
作者单位:王兆钺(215006 苏州医学院附属第一医院、江苏省血液研究所)
参考文献
1 Mills DCD. ADP receptors on platelets. Thromb Haemost, 1996, 76:835-856.
2 Hechler B, Leon C, Vial C, et al. The P2Y1 receptor is necessary for adnosine 5′-diphosphate-induced platelet aggregation. Blood,1998, 92:152-159.
3 Gachet C, Cattaneo M, Ohlmann P, et al. Purinoceptors on blood platelets: further pharmacological and clinical evidence to suggest the presence of two ADP receptors. Br J Haematol, 1995, 91:434-444.
4 Cattaneo M, Lecchi A, Randi AM, et al. Identification of a new congenital defect of platelet function characterized by severe impairment of platelet responses to adenosine diphosphate. Blood, 1992, 80:2787-2796.
5 Nurden P, Savi P, Heilmann E, et al. An inherited bleeding disorder linked to a defective interaction between ADP and its receptor on platelets. J Clin invest. 1995, 95:1612-1622.
6 Cachet G, Beatrice H, Catherine L, et al. Activation of ADP receptors and platelet function. Thromb Haemost, 1997, 89:271-275.
7 Hechler B, Eckly A, Ohlmann P, et al. The P2Y1 receptor, necessary but not sufficient to support full ADP-induced platelet aggregation, is not the target of the drug clopidogrel. Br J Haematol, 1998, 103:858-866.
8 Vial C, Hechler B, Leon C, et al. Presence of P2X1 purinoceptors in human platelets and megakaryoblastic cell lines. Thromb Haemost, 1997, 78:1500-1504.
9 Sun B, Li J, Okahara K, et al. P2X1 purinoceptor in human platelets. J Biol chem, 1998, 273:11544-11547.
10 Leon C, Vial C, Cazenave PJ, et al. Cloning and sequencing of a human cDNA encoding endothelial P2Y1 purinoceptor. Gene, 1996, 171:295-297.
11 Leon C, Hechler B, Vial C, et al. The P2Y1 receptor is an ADP receptor antagonized by ATP and expressed in platelets and megakaryoblastic cells. FEBS lett, 1997, 403:26-30.
12 Boyer JL, Mohanram A, Camaioni E, et al. Competitive and selective antagonism of P2Y1 receptors by N6-methyl-2′-deoxyadenosine 3′5′-bisphosphate. br J Pharmacol, 1998, 124:1-3.
13 Jin J, Kunapuli SP. Coactivation of two different G protein-couped receptors is essential for ADP-induced platelet aggregation. Proc Natl Acad Sci uSA, 1998, 95:8070-8074.
14 Polgar J, Eichler P, Greinacher A, et al. Adenosine diphosphate (ADP) and aDP receptor play a major role in platelet activation/aggregation induced by sera from heparin-induced thrombocytopenia patients. Blood, 1998, 91:549-554.