Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria.
PLoS One. 2012;7(8):e40222. doi: 10.1371/journal.pone.0040222. Epub 2012 Aug 1.
The use of the lipid lowering agent niacin is hampered by a frequent flush response which is largely mediated by prostaglandin (PG) D(2). Therefore, concomitant administration of the D-type prostanoid (DP) receptor antagonist laropiprant has been proposed to be a useful approach in preventing niacin-induced flush. However, antagonizing PGD(2), which is a potent inhibitor of platelet aggregation, might pose the risk of atherothrombotic events in cardiovascular disease. In fact, we found that in vitro treatment of platelets with laropiprant prevented the inhibitory effects of PGD(2) on platelet function, i.e. platelet aggregation, Ca(2+) flux, P-selectin expression, activation of glycoprotein IIb/IIIa and thrombus formation. In contrast, laropiprant did not prevent the inhibitory effects of acetylsalicylic acid or niacin on thrombus formation. At higher concentrations, laropiprant by itself attenuated platelet activation induced by thromboxane (TP) and E-type prostanoid (EP)-3 receptor stimulation, as demonstrated in assays of platelet aggregation, Ca(2+) flux, P-selectin expression, and activation of glycoprotein IIb/IIIa. Inhibition of platelet function exerted by EP4 or I-type prostanoid (IP) receptors was not affected by laropiprant. These in vitro data suggest that niacin/laropiprant for the treatment of dyslipidemias might have a beneficial profile with respect to platelet function and thrombotic events in vascular disease.
使用降脂药物烟酸时，常因潮红反应而受阻，这种反应主要由前列腺素（PG）D2 介导。因此，同时给予 D 型前列腺素（DP）受体拮抗剂 laropiprant 被认为是预防烟酸诱导潮红的有效方法。然而，拮抗 PGD2（一种有效的血小板聚集抑制剂）可能会增加心血管疾病中动脉血栓形成事件的风险。事实上，我们发现 laropiprant 体外处理血小板可防止 PGD2 对血小板功能的抑制作用，即血小板聚集、Ca2+流、P-选择素表达、糖蛋白 IIb/IIIa 激活和血栓形成。相比之下，laropiprant 不能预防阿司匹林或烟酸对血栓形成的抑制作用。在较高浓度下，laropiprant 本身可减弱由血栓烷（TP）和 E 型前列腺素（EP）-3 受体刺激引起的血小板激活，如血小板聚集、Ca2+流、P-选择素表达和糖蛋白 IIb/IIIa 激活测定中所示。EP4 或 I 型前列腺素（IP）受体的血小板功能抑制不受 laropiprant 影响。这些体外数据表明，烟酸/laropiprant 治疗血脂异常可能对血管疾病中的血小板功能和血栓形成事件具有有益的作用。
