De Caterina R, Giannessi D, Mazzone A, Bernini W
CNR Institute of Clinical Physiology, Pisa, Italy.
Eur Heart J. 1988 Jan;9 Suppl A:45-9. doi: 10.1093/eurheartj/9.suppl_a.45.
We investigated two possible reasons for the greater antiplatelet efficacy of isosorbide dinitrate (ISDN) in vivo as compared to in vitro. ISDN and its two main hepatic metabolites, isosorbide-2-mononitrate (IS-2-MN) and isosorbide-5-mononitrate (IS-5-MN) were compared for their ability to inhibit platelet aggregation and thromboxane B2 generation in vitro in response to threshold concentrations of ADP, adrenaline, collagen, thrombin and arachidonic acid. We also determined the concentration of prostacyclin required to inhibit by 50% platelet aggregation (IC50) in response to supra-threshold doses of aggregating agents. Out of the three nitrates tested, IS-2-MN was more effective than ISDN in inhibition of platelet aggregation and thromboxane B2 formation after ADP (minimum effective concentration: 10(-7) M) and adrenaline (minimum effective concentration: 10(-6) M). In addition, ISDN 10(-4)-10(-6) M decreased IC50 for prostacyclin from 2.7 +/- 1.2 to 0.36 +/- 0.2 nM. Generation of a platelet-active species, IS-2-MN, and synergism with prostacyclin are novel properties of ISDN and may account for in vivo-in vitro differences in antiaggregatory properties and in vivo mechanism of action.
我们研究了体内异山梨醇二硝酸酯（ISDN）抗血小板疗效高于体外的两个可能原因。比较了ISDN及其两种主要肝脏代谢产物异山梨醇 - 2 - 单硝酸酯（IS - 2 - MN）和异山梨醇 - 5 - 单硝酸酯（IS - 5 - MN）在体外对阈值浓度的ADP、肾上腺素、胶原、凝血酶和花生四烯酸反应时抑制血小板聚集和血栓素B2生成的能力。我们还测定了响应超阈值剂量聚集剂时抑制50%血小板聚集所需的前列环素浓度（IC50）。在所测试的三种硝酸盐中，IS - 2 - MN在抑制ADP（最低有效浓度：10^(-7) M）和肾上腺素（最低有效浓度：'10^(-6) M）后的血小板聚集和血栓素B2形成方面比ISDN更有效。此外，10^(-4) - 10^(-6) M的ISDN使前列环素的IC50从2.7±1.2降至0.36±0.2 nM。血小板活性物质IS - 2 - MN的生成以及与前列环素的协同作用是ISDN的新特性，可能解释了抗聚集特性的体内 - 体外差异以及体内作用机制。
