Parker J O
Kingston General Hospital, Ontario, Canada.
Am J Cardiol. 1993 Sep 9;72(8):3C-6C; discussion 6C-8C. doi: 10.1016/0002-9149(93)90248-b.
This review discusses the mechanisms of action of the organic nitrates, nitrate tolerance, and the effects of nitrates in patients with stable angina pectoris. The nitrates are prodrugs that enter the vascular smooth muscle, where they are denitrated to form the active agent nitric oxide (NO). NO activates guanylate cyclase, which results in cyclic guanosine monophosphate (cGMP) production and vasodilation as a result of reuptake of calcium by the sarcoplasmic reticulum. NO is identical to endothelium-derived relaxing factor (EDRF), which induces vasodilation, inhibits platelet aggregation, reduces endothelium adhesion, and has anticoagulant and fibrinolytic effects. Thus, the nitrates may be more than vasodilators and, in addition to reducing ischemia, may affect the process of atherosclerosis. The vascular effects of nitrates are attenuated during sustained therapy. Although the basis for the phenomenon of nitrate tolerance is not completely understood, sulfhydryl depletion as well as neurohormonal activation and increased plasma volume may be involved. The administration of N-acetylcysteine, angiotensin-converting enzyme (ACE) inhibitors, or diuretics do not consistently prevent nitrate tolerance. At present, intermittent nitrate therapy is the only way to avoid nitrate tolerance. The intermittent administration of nitrates, however, cannot provide continuous therapeutic benefits, and thus monotherapy with nitrates is not suitable for many patients with stable angina pectoris.
本综述讨论了有机硝酸盐的作用机制、硝酸盐耐受性以及硝酸盐对稳定型心绞痛患者的影响。硝酸盐是前体药物，进入血管平滑肌后被脱硝形成活性剂一氧化氮（NO）。NO激活鸟苷酸环化酶，导致环磷酸鸟苷（cGMP）生成，并因肌浆网对钙的再摄取而引起血管舒张。NO与内皮源性舒张因子（EDRF）相同，可诱导血管舒张、抑制血小板聚集、减少内皮黏附，并具有抗凝和纤溶作用。因此，硝酸盐可能不仅仅是血管扩张剂，除了减轻缺血外，还可能影响动脉粥样硬化进程。在持续治疗期间，硝酸盐的血管效应会减弱。尽管硝酸盐耐受性现象的基础尚未完全了解，但可能涉及巯基耗竭以及神经激素激活和血容量增加。给予N-乙酰半胱氨酸、血管紧张素转换酶（ACE）抑制剂或利尿剂并不能始终预防硝酸盐耐受性。目前，间歇使用硝酸盐疗法是避免硝酸盐耐受性的唯一方法。然而，间歇给予硝酸盐不能提供持续的治疗益处，因此硝酸盐单一疗法不适用于许多稳定型心绞痛患者。
