Connolly T M, Limbird L E
Proc Natl Acad Sci U S A. 1983 Sep;80(17):5320-4. doi: 10.1073/pnas.80.17.5320.
We have previously observed that removal of extraplatelet Na+ markedly diminishes human platelet aggregation and secretion in response to epinephrine. The present studies demonstrate that this effect of the removal of extraplatelet Na+ on platelet function is not unique to activation of platelets by alpha 2-adrenergic agents but represents a phenomenon also evident for other platelet stimuli. Thus, platelet aggregation and secretion in response to maximal concentrations of ADP and lower concentrations of thrombin (less than 0.04 unit/ml) were also markedly reduced in platelets in "Na+-free" medium, suggesting that these agents share an effector mechanism that is similarly inhibited by the removal of extraplatelet Na+. In contrast, platelet aggregation and secretion in response to higher concentrations of thrombin (greater than or equal to 0.04 unit/ml) and to 0.04-1.0 microM (15S)-hydroxy-11 alpha, 9 alpha-(epoxymethano)prosta-5Z,13E-dienoic acid (U46619), an endoperoxide analog, were identical in control platelets and in those suspended in "Na+-free" medium, indicating that platelets suspended in "Na+-free" medium are functionally intact, at least in response to some stimuli. Furthermore, the observation that U46619 can elicit platelet aggregation and secretion independently of extraplatelet Na+ indicates that the loss of platelet responsiveness to epinephrine, ADP, and low concentrations of thrombin cannot be attributed to a loss of sensitivity to the stimulus-provoked secondary mediator(s) of platelet function, endoperoxides or thromboxane A2. Treatment with indomethacin to block the secondary aggregation and secretion pathways of platelets reduced the aggregatory and secretory responses of control platelets induced by epinephrine, ADP, and low concentrations of thrombin to those characteristic of platelets suspended in "Na+-free" medium. In contrast, indomethacin did not alter the functional responses induced by these agents in platelets suspended in "Na+-free" medium, suggesting that "primary" aggregation is intact but that the "secondary" aggregation and secretion mediated by arachidonic acid metabolites are eliminated by removal of extraplatelet Na+. Consistent with this interpretation is the observation that the indomethacin-insensitive aggregation and secretion induced by U46619 and higher concentrations of thrombin were retained in platelets suspended in "Na+-free" medium. Thus, the responses eliminated by removal of extraplatelet Na+ are those eliminated by treating control platelets with indomethacin, suggesting a strong link between the presence of extraplatelet Na+ and the operation of platelet function mediated by the cyclooxygenase pathway.
我们之前观察到，去除血小板外的钠离子会显著降低人类血小板对肾上腺素的聚集和分泌反应。目前的研究表明，去除血小板外钠离子对血小板功能的这种影响并非α2 - 肾上腺素能药物激活血小板所特有，而是一种对其他血小板刺激也明显存在的现象。因此，在“无钠”培养基中的血小板对最大浓度的ADP和较低浓度的凝血酶（小于0.04单位/毫升）的聚集和分泌也明显减少，这表明这些药物共享一种效应机制，该机制同样会因去除血小板外钠离子而受到抑制。相比之下，在对照血小板和悬浮于“无钠”培养基中的血小板中，对较高浓度凝血酶（大于或等于0.04单位/毫升）以及对0.04 - 1.0微摩尔（15S） - 羟基 - 11α，9α - （环氧甲撑）前列腺 - 5Z，13E - 二烯酸（U46619，一种内过氧化物类似物）的血小板聚集和分泌是相同的，这表明悬浮于“无钠”培养基中的血小板功能是完整的，至少对某些刺激有反应。此外，U46619能够独立于血小板外钠离子引发血小板聚集和分泌这一观察结果表明，血小板对肾上腺素、ADP和低浓度凝血酶反应性的丧失不能归因于对刺激引发的血小板功能二级介质（内过氧化物或血栓素A2）敏感性的丧失。用吲哚美辛处理以阻断血小板的二级聚集和分泌途径，可将对照血小板由肾上腺素、ADP和低浓度凝血酶诱导的聚集和分泌反应降低至悬浮于“无钠”培养基中的血小板的特征水平。相比之下，吲哚美辛并未改变这些药物在悬浮于“无钠”培养基中的血小板中诱导的功能反应，这表明“初级”聚集是完整的，但由花生四烯酸代谢产物介导的“二级”聚集和分泌因去除血小板外钠离子而被消除。与这一解释一致的是，观察到U46619和较高浓度凝血酶诱导的对吲哚美辛不敏感的聚集和分泌在悬浮于“无钠”培养基中的血小板中得以保留。因此，因去除血小板外钠离子而消除的反应是用吲哚美辛处理对照血小板时所消除的反应，这表明血小板外钠离子的存在与由环氧化酶途径介导的血小板功能的运作之间存在紧密联系。
