Slack C J, McLaughlin B E, Nakatsu K, Marks G S, Brien J F
Department of Pharmacology and Toxicology, Faculty of Medicine, Queen's University, Kingston, Ont., Canada.
Can J Physiol Pharmacol. 1988 Oct;66(10):1344-6. doi: 10.1139/y88-220.
It is postulated that the organic nitrate vasodilator agents, including glyceryl trinitrate (GTN) and isosorbide dinitrate (ISDN), are prodrugs, such that biotransformation to the active inorganic metabolite, nitric oxide (NO), occurs prior to the onset of vasodilation. Furthermore, it is proposed that organic nitrate tolerance in vascular tissue involves decreased formation of NO. To test this latter hypothesis, we examined vasodilation induced by NO, GTN, and ISDN in non-tolerant, GTN-tolerant, and ISDN-tolerant rabbit aortic rings (RARs). Isolated RARs were contracted submaximally with phenylephrine; the time of onset of relaxation and percent relaxation of tissue were determined in response to NO (0.3 microM), GTN (0.03 microM), and ISDN (0.12 microM) before and after a 1-h treatment with 500 microM GTN, 500 microM ISDN, or buffer only. The data demonstrated that the response to NO was not changed in GTN-tolerant and ISDN-tolerant tissues, in which there was virtually no GTN-induced or ISDN-induced relaxation. These results are consistent with the postulate that organic nitrate vasodilator drugs must undergo biotransformation to NO before vasodilation can occur and that the mechanism of organic nitrate tolerance involves decreased formation of NO.
据推测，包括硝酸甘油（GTN）和异山梨醇二硝酸酯（ISDN）在内的有机硝酸盐血管扩张剂是前体药物，即在血管扩张开始之前会生物转化为活性无机代谢物一氧化氮（NO）。此外，有人提出血管组织中的有机硝酸盐耐受性涉及NO生成减少。为了验证后一个假设，我们检测了在非耐受性、GTN耐受性和ISDN耐受性兔主动脉环（RARs）中由NO、GTN和ISDN诱导的血管扩张情况。将分离的RARs用去氧肾上腺素进行亚最大收缩；在分别用500 microM GTN、500 microM ISDN或仅用缓冲液处理1小时前后，测定组织对NO（0.3 microM）、GTN（0.03 microM）和ISDN（0.12 microM）的舒张起始时间和舒张百分比。数据表明，在GTN耐受性和ISDN耐受性组织中对NO的反应没有改变，在这些组织中几乎没有GTN诱导的或ISDN诱导的舒张。这些结果与以下推测一致，即有机硝酸盐血管扩张药物在血管扩张发生之前必须生物转化为NO，并且有机硝酸盐耐受性的机制涉及NO生成减少。
