Elkayam U
University of Southern California School of Medicine, Los Angeles.
Ann Intern Med. 1991 Apr 15;114(8):667-77. doi: 10.7326/0003-4819-114-8-667.
To review the available information about nitrate tolerance, its potential mechanisms, clinical implications, and strategies for prevention.
A survey of the National Library of Medicine MEDLINE database and bibliographies of the reviewed articles.
Studies were selected from the English language literature with an emphasis on recent studies and, when available, randomized placebo-controlled studies. Old studies were selected on the basis of their historical value and originality. A total of 134 retrieved articles were considered relevant and were reviewed in depth.
The available information about the experimental as well as the clinical evidence for tolerance to organic nitrates has been summarized. In addition, information related to potential mechanisms, clinical implications, and possible methods for prevention have been reviewed.
Evidence indicates that prolonged in-vitro exposure to organic nitrates, continuous intravenous or topical administration of nitrates, and frequent in-vivo oral dosing result in the rapid development of tolerance to the peripheral as well as to the coronary vasodilatory effects of the drugs. This phenomenon leads to the rapid attenuation of the hemodynamic and anti-ischemic effects of nitrates in patients with ischemic heart disease or congestive heart failure, or both. Tolerance development seems to be dose- and time-dependent, and its main mechanism seems to be a depletion of sulfhydryl groups at the vascular cell. Although the repletion of sulfhydryl groups with the use of sulfhydryl-containing drugs may help to prevent tolerance, the efficacy and safety of this approach requires further evaluation. Intermittent therapy allowing a sufficiently long, daily nitrate-washout interval seems to be the most effective and the most safe strategy currently available for the prevention of nitrate tolerance.
综述关于硝酸酯类耐受性、其潜在机制、临床意义及预防策略的现有信息。
对美国国立医学图书馆MEDLINE数据库及所综述文章的参考文献进行检索。
从英文文献中选取研究，重点关注近期研究，如有随机安慰剂对照研究则优先选取。旧研究根据其历史价值和原创性进行选取。共检索到134篇相关文章并进行深入综述。
总结了关于硝酸酯类耐受性的实验及临床证据的现有信息。此外，还综述了与潜在机制、临床意义及可能的预防方法相关的信息。
有证据表明，体外长时间暴露于硝酸酯类、持续静脉或局部应用硝酸酯类以及频繁体内口服给药会导致对药物外周及冠状动脉扩张作用的耐受性迅速形成。这种现象会导致硝酸酯类对缺血性心脏病或充血性心力衰竭患者（或两者兼具）的血流动力学及抗缺血作用迅速减弱。耐受性的形成似乎与剂量和时间相关，其主要机制似乎是血管细胞中巯基的耗竭。虽然使用含巯基药物补充巯基可能有助于预防耐受性，但这种方法的疗效和安全性需要进一步评估。允许足够长的每日硝酸酯类洗脱期的间歇疗法似乎是目前预防硝酸酯类耐受性最有效和最安全的策略。
