Slack C J, McLaughlin B E, Brien J F, Marks G S, Nakatsu K
Department of Pharmacology and Toxicology, Faculty of Medicine, Queen's University, Kingston, Ont., Canada.
Can J Physiol Pharmacol. 1989 Nov;67(11):1381-5. doi: 10.1139/y89-221.
It has been proposed that organic nitrates are prodrugs and biotransformation to a pharmacologically active metabolite (i.e., nitric oxide) must occur before the onset of vasodilation. If this postulated mechanism is correct, tolerance to organic nitrate-induced vasodilation might involve decreased biotransformation of organic nitrates by vascular smooth muscle. In this study, biotransformation of isosorbide dinitrate (ISDN) and glyceryl trinitrate (GTN) was estimated by measuring isosorbide mononitrate (ISMN) and glyceryl dinitrate (GDN), respectively, rather than the nitrate anion, because of a more sensitive method for measurement of ISMN and GDN. To test this hypothesis, isolated rabbit aortic strips (RAS) were made tolerant in vitro by incubation with 500 microM GTN or ISDN for 1 h. After a washout period and submaximal contraction with phenylephrine, the tissues were incubated with either 2.0 microM [14C]ISDN or 0.5 microM [14C]GTN for 2 min. ISDN- or GTN-induced relaxation of RAS was monitored and tissue parent drug and metabolite contents were determined by thin-layer chromatography and liquid scintillation spectrometry. ISDN- and GTN-induced relaxation of RAS and the metabolite concentrations were significantly less for both GTN- and ISDN-tolerant tissue compared with nontolerant tissue. These results are consistent with the hypothesis that organic nitrate biotransformation is required for organic nitrate-induced vasodilation.
有人提出有机硝酸盐是前体药物，在血管舒张开始之前必须发生生物转化形成药理活性代谢物（即一氧化氮）。如果这个假定的机制是正确的，那么对有机硝酸盐诱导的血管舒张的耐受性可能涉及血管平滑肌对有机硝酸盐生物转化的减少。在本研究中，分别通过测量单硝酸异山梨酯（ISMN）和二硝酸甘油酯（GDN）来估计硝酸异山梨酯（ISDN）和硝酸甘油（GTN）的生物转化，而不是测量硝酸根阴离子，因为测量ISMN和GDN有更灵敏的方法。为了验证这一假设，将离体兔主动脉条（RAS）与500微摩尔GTN或ISDN孵育1小时，使其在体外产生耐受性。在洗脱期后，用去氧肾上腺素进行次最大收缩，然后将组织与2.0微摩尔[14C]ISDN或0.5微摩尔[14C]GTN孵育2分钟。监测ISDN或GTN诱导的RAS舒张情况，并通过薄层色谱法和液体闪烁光谱法测定组织中原药和代谢物的含量。与未耐受组织相比，GTN和ISDN耐受组织中ISDN和GTN诱导的RAS舒张以及代谢物浓度均显著降低。这些结果与有机硝酸盐诱导血管舒张需要有机硝酸盐生物转化这一假设一致。
