Bieroń K, Grodzińska L, Kostka-Trabka E, Gryglewski R J
Department of Pharmacology, University School of Medicine, Cracow, Poland.
Wien Klin Wochenschr. 1993;105(1):7-11.
In vitro prostacyclin (PGI2) and nitric oxide (NO) synergise in their anti-aggregatory actions on blood platelets. Presently, we have studied an interaction of molsidomine (ML--pro-drug for the NO-donor SIN-1) and PGI2 in 20 patients with peripheral arterial disease (PAD) on the plasma fibrinolytic system and platelet aggregability. A synergism of these drugs in their fibrinolytic action as measured by shortening of euglobulin clot lysis time (ECLT) and in their anti-platelet action as measured by an increase in the ratio of free platelets to platelet aggregates was observed. It seems that PGI2 and ML activated the fibrinolytic system by two independent mechanisms i.e. by a PGI2-induced direct release of pro-fibrinolytic t-PA from endothelial cells and by a ML-induced suppression of the release of anti-fibrinolytic PAI-1 from platelets. This may constitute a basis for the synergism. A synergism between PGI2 and ML in their anti-platelet action seems to be rooted in the potentiation by cyclic-GMP on the anti-aggregatory action of cyclic-AMP in platelets. On the other hand, no synergism between PGI2 and ML was observed in their hypotensive effects as measured by systolic and diastolic arterial blood pressure. It may well be that the synergism in fibrinolytic and anti-platelet actions between stimulators of adenylate and guanylate cyclases accompanied by a lack of synergism in their hypotensive actions may allow reduction of the therapeutic doses of either stimulator, thus avoiding hazards of their hypotensive side effects.
体外实验表明，前列环素（PGI2）和一氧化氮（NO）在对血小板的抗聚集作用上具有协同效应。目前，我们研究了20例外周动脉疾病（PAD）患者中，吗多明（ML，一种NO供体SIN-1的前体药物）与PGI2对血浆纤维蛋白溶解系统和血小板聚集性的相互作用。通过缩短优球蛋白凝块溶解时间（ECLT）来衡量，发现这些药物在纤维蛋白溶解作用上具有协同效应；通过游离血小板与血小板聚集体比例的增加来衡量，它们在抗血小板作用上也具有协同效应。似乎PGI2和ML通过两种独立机制激活纤维蛋白溶解系统，即PGI2诱导内皮细胞直接释放促纤维蛋白溶解的组织型纤溶酶原激活剂（t-PA），以及ML诱导血小板释放抗纤维蛋白溶解的纤溶酶原激活物抑制剂-1（PAI-1）受到抑制。这可能构成了协同作用的基础。PGI2和ML在抗血小板作用上的协同效应似乎源于环磷酸鸟苷（cGMP）对血小板中环磷酸腺苷（cAMP）抗聚集作用的增强。另一方面，通过收缩压和舒张压测量发现，PGI2和ML在降压作用上没有协同效应。很可能腺苷酸环化酶和鸟苷酸环化酶刺激剂在纤维蛋白溶解和抗血小板作用上的协同效应，伴随着它们在降压作用上缺乏协同效应，可能允许降低任一刺激剂的治疗剂量，从而避免其降压副作用带来的危害。
