Parker J O
Department of Medicine, Queen's University, Kingston, Ontario, Canada.
Eur Heart J. 1991 May;12 Suppl A:13-5.
Tolerance develops during therapy with all organic nitrates, particularly when dosing strategies are designed to provide therapeutic effects throughout 24 h. Such tolerance can be demonstrated by assessing haemodynamic, anti-anginal and anti-ischaemic effects during therapy. The mechanism of nitrate tolerance is not completely understood. Tolerance may be related to depletion of reduced sulfhydryl groups in vascular smooth muscle with resultant reduction in nitric oxide production, adenylate cyclase activation and cyclic guanosine monophosphate (GMP) production. Nitrate exposure also activates counter-regulating influences which lead to fluid retention and augmented vasoconstrictor effects. Intermittent nitrate therapy avoids the problem of tolerance by providing a period of washout. Controlled-release formulations of oral nitrates providing a period of low nitrate exposure should prevent tolerance. This has been documented by studies with a controlled-release formulation of isosorbide-5-mononitrate.
在使用所有有机硝酸盐进行治疗期间都会产生耐受性，尤其是当给药策略旨在提供24小时的治疗效果时。这种耐受性可通过评估治疗期间的血流动力学、抗心绞痛和抗缺血作用来证明。硝酸盐耐受性的机制尚未完全了解。耐受性可能与血管平滑肌中还原巯基的消耗有关，从而导致一氧化氮生成减少、腺苷酸环化酶激活和环磷酸鸟苷（cGMP）生成减少。硝酸盐暴露还会激活反调节作用，导致液体潴留和血管收缩作用增强。间歇性硝酸盐治疗通过提供一段洗脱期来避免耐受性问题。提供低硝酸盐暴露期的口服硝酸盐控释制剂应可预防耐受性。这已在一项关于5-单硝酸异山梨酯控释制剂的研究中得到证实。
