Nakabayashi S, Uyama O, Nagatsuka K, Uehara A, Wanaka A, Yoneda S, Kimura K, Kamata T
Res Commun Chem Pathol Pharmacol. 1985 Mar;47(3):323-32.
The mechanism by which nitrates produce relaxation of the vascular smooth muscle and anti-aggregatory effect on platelets has not been understood. Several reports have suggested that vasoactive prostaglandin generation may account for part of the pharmacological action of nitroglycerin. However, few studies have been reported that isosorbide dinitrate or its main metabolite, isosorbide-5-mononitrate, directly stimulates prostacyclin (PGI2) generation in blood vessels. We examined the effect of ISDN and 5-ISMN on PGI2 and thromboxane A2 (TXA2) generation in rat thoracic aorta and human thoracic aorta and coronary artery. The stimulation of PGI2 generation was dependent on the concentration of ISDN and the maximum PGI2 generation was effected by ISDN 5.0 ng/ml in both rat and human vessels. The ratio of peak to basal PGI2 generation was about 1.6 with rat thoracic aorta and about 1.6 with human thoracic aorta and about 1.3 with human coronary artery. On the other hand, TXA2 generation showed a smaller increase than that of PGI2 with ISDN used in the therapeutic dose range and 5-ISMN did not significantly affect PGI2 or TXA2 generation. Previous studies of the effect of cyclooxygenase inhibitor, for example indomethacin, on the vasodilating response to nitrates have given conflicting results. It is believed, however, that ISDN is partially, not wholly, associated with the hemodynamic and platelet antiaggregation effects due to vascular PGI2 generation, which may play a beneficial role in inhibiting coronary vasospasm during anginal attacks.
硝酸盐产生血管平滑肌舒张和对血小板抗聚集作用的机制尚未明确。有几份报告表明，血管活性前列腺素的生成可能是硝酸甘油部分药理作用的原因。然而，关于二硝酸异山梨酯或其主要代谢产物5-单硝酸异山梨酯直接刺激血管中前列环素（PGI2）生成的研究报道较少。我们研究了二硝酸异山梨酯（ISDN）和5-单硝酸异山梨酯（5-ISMN）对大鼠胸主动脉、人胸主动脉和冠状动脉中PGI2和血栓素A2（TXA2）生成的影响。PGI2生成的刺激作用取决于ISDN的浓度，在大鼠和人血管中，5.0 ng/ml的ISDN可使PGI2生成达到最大值。大鼠胸主动脉、人胸主动脉和人冠状动脉中PGI2生成的峰值与基础值之比分别约为1.6、1.6和1.3。另一方面，在治疗剂量范围内使用ISDN时，TXA2的生成增加幅度小于PGI2，且5-ISMN对PGI2或TXA2的生成无显著影响。先前关于环氧化酶抑制剂（如吲哚美辛）对硝酸盐血管舒张反应影响的研究结果相互矛盾。然而，据信ISDN部分而非全部与血管PGI2生成导致的血流动力学和血小板抗聚集作用相关，这可能在心绞痛发作期间抑制冠状动脉痉挛中发挥有益作用。
