Axelsson K L, Ahlner J, Ljusegren M E
Acta Pharmacol Toxicol (Copenh). 1986;59 Suppl 6:121-8. doi: 10.1111/j.1600-0773.1986.tb02557.x.
This paper will present a short survey of the literature dealing with nitrate tolerance in experimental animals. Tolerance towards organic nitroesters has been experimentally established in animal models both in vivo and in vitro. However the dose of drug used to provoke tolerance has invariably been very high, which makes it difficult to apply experiences from animal experiments to the clinical setting. Several different hypothesis has been put forward in order to explain the mechanism of tolerance. Today, most evidence seem to point towards an altered metabolism of cGMP as a possible cause of tolerance. Cyclic GMP is the second messenger suggested to mediate the vasodilatory effect of organic nitroesters. The proposed role of critical tissue sulfhydryl groups in mediating the smooth muscle relaxant effect of nitroglycerin (NTG) have made experiments concerning reversal and prevention of tolerance to center on the use of various sulfhydryl reactive compounds. The results of these experiments are as yet ambiguous. Several studies show the existence of cross tolerance between NTG and various other vasodilatory organic nitroesters. In contrast no cross tolerance between NTG and chemically unrelated vasodilator drugs has been observed. The endogenous vasodilators acetylcholine and atrial natriuretic factor are known to induce cGMP increases. In view of this, their effect on NTG-tolerant bovine mesenteric arteries was investigated. However no cross-tolerance appears to exist under in vitro conditions.
本文将对有关实验动物硝酸盐耐受性的文献进行简要综述。在动物模型中，无论是体内还是体外，都已通过实验证实了对有机硝酸酯的耐受性。然而，用于引发耐受性的药物剂量始终非常高，这使得将动物实验的经验应用于临床环境变得困难。为了解释耐受性的机制，已经提出了几种不同的假说。如今，大多数证据似乎都指向cGMP代谢改变是耐受性的一个可能原因。环鸟苷酸（cGMP）是被认为介导有机硝酸酯血管舒张作用的第二信使。关键组织巯基在介导硝酸甘油（NTG）平滑肌松弛作用中所提出的作用，使得关于耐受性逆转和预防的实验集中在使用各种巯基反应性化合物上。这些实验的结果至今仍不明确。多项研究表明NTG与其他各种血管舒张性有机硝酸酯之间存在交叉耐受性。相比之下，未观察到NTG与化学上不相关的血管舒张药物之间存在交叉耐受性。已知内源性血管舒张剂乙酰胆碱和心房利钠因子可诱导cGMP增加。有鉴于此，研究了它们对NTG耐受的牛肠系膜动脉的影响。然而，在体外条件下似乎不存在交叉耐受性。
