Hasday J D, Sitrin R G
Blood. 1987 Feb;69(2):660-7.
Dipyridamole, an inhibitor of platelet aggregation, has been shown to have beneficial effects in disorders characterized by extravascular fibrin deposition. Mononuclear phagocytes are present in extravascular sites and are capable of expressing both plasminogen activator and procoagulant activities, which suggests these cells play a central role in extravascular fibrin turnover. We therefore sought to determine whether dipyridamole affects the expression of plasminogen activator and procoagulant activities by rabbit alveolar macrophages cultured in vitro. We found that dipyridamole (10 to 100 mumol/L) caused increases in both cell-associated and released plasminogen activator activity, which reached levels of 240% (P less than .05) and 543% (P less than .01) of controls, respectively. In contrast, dipyridamole decreased the cell-associated procoagulant activity of alveolar macrophages to as little as 21.3% of controls (P less than .01). Similar effects were seen in cells cotreated with lymphokines. The procoagulant activity expressed by these cells functioned as a tissue thromboplastin. The plasminogen activator of control and treated cells was a urokinase as determined by molecular weight characteristics (50 kilodaltons) and by antibody neutralization profiles using polyclonal antibodies against human urokinase and tissue plasminogen activator. These effects of dipyridamole could not be duplicated by structurally dissimilar agents sharing some of the pharmacological actions of dipyridamole; however, two pyrimidopyrimidine compounds structurally similar to dipyridamole effectively mimicked the effects on both procoagulant and plasminogen activator activities. We conclude that dipyridamole may have antithrombotic effects by directly modulating the role of mononuclear phagocytes in fibrin turnover. Thus, dipyridamole may be useful in situations where extravascular fibrin deposition is important to the pathogenesis of tissue injury and repair.
双嘧达莫是一种血小板聚集抑制剂，已被证明在以血管外纤维蛋白沉积为特征的疾病中具有有益作用。单核吞噬细胞存在于血管外部位，能够表达纤溶酶原激活物和促凝活性，这表明这些细胞在血管外纤维蛋白周转中起核心作用。因此，我们试图确定双嘧达莫是否会影响体外培养的兔肺泡巨噬细胞中纤溶酶原激活物和促凝活性的表达。我们发现双嘧达莫（10至100μmol/L）使细胞相关和释放的纤溶酶原激活物活性均增加，分别达到对照水平的240%（P<0.05）和543%（P<0.01）。相比之下，双嘧达莫将肺泡巨噬细胞的细胞相关促凝活性降低至对照的21.3%（P<0.01）。在用淋巴因子共同处理的细胞中也观察到类似的效果。这些细胞表达的促凝活性起组织凝血活酶的作用。根据分子量特征（50千道尔顿）以及使用针对人尿激酶和组织纤溶酶原激活物的多克隆抗体的抗体中和谱确定，对照细胞和处理细胞的纤溶酶原激活物是尿激酶。双嘧达莫的这些作用不能被具有双嘧达莫某些药理作用的结构不同的药物所复制；然而，两种结构与双嘧达莫相似的嘧啶并嘧啶化合物有效地模拟了对促凝和纤溶酶原激活物活性的影响。我们得出结论，双嘧达莫可能通过直接调节单核吞噬细胞在纤维蛋白周转中的作用而具有抗血栓形成作用。因此，双嘧达莫在血管外纤维蛋白沉积对组织损伤和修复的发病机制很重要的情况下可能有用。
