Mangione N J, Glasser S P
Division of Clinical Pharmacology, University of South Florida.
Am Heart J. 1994 Jul;128(1):137-46. doi: 10.1016/0002-8703(94)90020-5.
The phenomenon of nitrate tolerance has now been appreciated for almost a century, and our understanding of this process has greatly improved during the past 20 years. Therapeutic nitrates are now recognized as exogenous sources of nitric oxide (or nitrosothiols), which appears to be a primary mediator of natural vasodilatation. Nitrates have been clearly shown to have vasodilatory and antiplatelet effects, both of which diminish during continuous exposure. Nitrate tolerance has been documented with most nitrate preparations when the patient is given continuous nitrate therapy. Tolerance to nitrates may occur in any patient, regardless of underlying illness, medication dose, or serum concentration of NTG. The cause of this phenomenon is multifactorial; there appear to be both cellular and systemic processes involved. To date, no adjuvant pharmacologic intervention has conclusively demonstrated benefit in preventing, abating, or reversing nitrate tolerance. Interruption of nitrate exposure for as little as 8 to 12 hours does appear to be the best means of preventing or reversing tolerance. Nevertheless, some patients with objective tolerance continue to experience relief of symptoms. In addition, despite laboratory-documented cross-tolerance, patients receiving continuous nitrate therapy at usual clinical doses may continue to benefit from the hemodynamic and antianginal effects of SL NTG. Hence, nitrate tolerance is a real entity, but the clinical importance of this phenomenon remains controversial. Finally, further investigation will need to address quality-of-life issues and perhaps assess relief of ischemia by other means.
硝酸盐耐受性现象至今已被认识近一个世纪，在过去20年里，我们对这一过程的理解有了很大提高。治疗性硝酸盐现在被认为是一氧化氮（或亚硝基硫醇）的外源性来源，而一氧化氮似乎是自然血管舒张的主要介质。硝酸盐已被明确证明具有血管舒张和抗血小板作用，但在持续暴露过程中，这两种作用都会减弱。当患者接受持续硝酸盐治疗时，大多数硝酸盐制剂都已证实会出现硝酸盐耐受性。任何患者都可能出现硝酸盐耐受性，无论其潜在疾病、药物剂量或硝酸甘油的血清浓度如何。这一现象的原因是多因素的；似乎涉及细胞和全身过程。迄今为止，尚无辅助药物干预措施能确凿证明在预防、减轻或逆转硝酸盐耐受性方面有获益。将硝酸盐暴露中断短短8至12小时似乎是预防或逆转耐受性的最佳方法。然而，一些有客观耐受性的患者仍会感到症状缓解。此外，尽管有实验室记录的交叉耐受性，但以常规临床剂量接受持续硝酸盐治疗的患者可能仍会从舌下含服硝酸甘油的血流动力学和抗心绞痛作用中获益。因此，硝酸盐耐受性是一个真实存在的情况，但这一现象的临床重要性仍存在争议。最后，需要进一步研究来解决生活质量问题，并可能通过其他方法评估缺血缓解情况。
