Henry P J, Horowitz J D, Louis W J
Department of Clinical Pharmacology, Austin Hospital, Heidelberg, Victoria, Australia.
J Cardiovasc Pharmacol. 1989 Jul;14(1):31-7. doi: 10.1097/00005344-198907000-00007.
The influence of dose regimen on the induction and reversal of tolerance to nitroglycerin (NTG) is not well understood despite the current widespread clinical use of both sustained and intermittent modes of NTG administration. In an isolated coronary artery preparation both the NTG preexposure concentration and the duration of the NTG preexposure period were positive and independent determinants of the extent of NTG tolerance induction. During a "nitrate-free" or washout period, NTG tolerance was at least partially reversible. The apparent rate of NTG tolerance reversal during a "nitrate-free" period was not dependent on the absolute degree of NTG tolerance induced or on the dose regimen used to induce NTG tolerance. In this isolated vascular preparation, sulfhydryl (SH) supplementation with 1 mM N-acetylcysteine produced no significant augmentation of NTG-induced relaxations in either NTG tolerant or non tolerant tissues. N-acetylcysteine was ineffectual in attenuating the development of NTG tolerance in coronary artery preparations incubated in either Krebs bicarbonate buffer or in 10% human plasma. We conclude that in this model the NTG preexposure concentration, the duration of the NTG preexposure period, and the duration of the "nitrate-free" period are critical and independent determinants of the extent of NTG tolerance but that NTG tolerance is not significantly attenuated by SH supplementation.
尽管目前硝酸甘油（NTG）持续和间歇给药模式在临床上广泛应用，但给药方案对NTG耐受性诱导和逆转的影响尚未完全明确。在离体冠状动脉标本中，NTG预暴露浓度和NTG预暴露时间均为NTG耐受性诱导程度的正向独立决定因素。在“无硝酸盐”或洗脱期，NTG耐受性至少部分可逆。“无硝酸盐”期间NTG耐受性逆转的表观速率不依赖于诱导的NTG耐受性的绝对程度或用于诱导NTG耐受性的给药方案。在这个离体血管标本中，用1 mM N - 乙酰半胱氨酸补充巯基（SH）在NTG耐受或非耐受组织中均未显著增强NTG诱导的舒张作用。在 Krebs 碳酸氢盐缓冲液或10%人血浆中孵育的冠状动脉标本中，N - 乙酰半胱氨酸在减弱NTG耐受性发展方面无效。我们得出结论，在这个模型中，NTG预暴露浓度、NTG预暴露时间和“无硝酸盐”时间是NTG耐受性程度的关键且独立的决定因素，但补充SH并不能显著减弱NTG耐受性。
