Our paper highlights the past 50 years of research focusing solely on tolerance involving nitroglycerin (glyceryl trinitrate, GTN). It also identifies and discusses inconsistencies in previous mechanistic explanations that have failed to provide a way to administer GTN continuously, free of limitations from tolerance and without the requirement of a nitrate-free interval. We illustrate, for the first time in 135 years, a mechanism whereby nitric oxide, the mediator of vasodilation by GTN, may also be the cause of tolerance. Based on targeting superoxide from mitochondrial complex I, uncoupled by glutathione depletion in response to nitric oxide from GTN, a novel unit dose GTN formulation in glutathione for use as a continuous i.v. infusion has been proposed. We hypothesize that this will reduce or eliminate tolerance seen currently with i.v. GTN. Finally, to evaluate the new formulation we suggest future studies of this new formulation for the treatment of acute decompensated heart failure.

中文翻译：

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一氧化氮是硝酸甘油耐受性的原因：为老狗提供治疗急性心力衰竭的新技巧

我们的论文重点介绍了过去 50 年的研究，仅关注涉及硝酸甘油（三硝酸甘油酯，GTN）的耐受性。它还识别和讨论了以前的机制解释中的不一致之处，这些解释未能提供一种连续管理 GTN 的方法，不受耐受性的限制，也不需要无硝酸盐间隔。我们 135 年来首次阐明了一种机制，即一氧化氮（GTN 血管舒张的介质）也可能是耐受的原因。基于靶向来自线粒体复合物 I 的超氧化物，通过响应来自 GTN 的一氧化氮的谷胱甘肽消耗解耦，已经提出了一种新的谷胱甘肽单位剂量 GTN 制剂，用于连续静脉内输注。我们假设这将减少或消除目前使用 iv GTN 的耐受性。