Omidkhoda Seyedeh Farzaneh, Razavi BiBi Marjan, Imenshahidi Mohsen, Rameshrad Maryam, Hosseinzadeh Hossein
Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
Targeted Drug Delivery Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.
Iran J Basic Med Sci. 2020 Mar;23(3):303-310. doi: 10.22038/IJBMS.2019.39604.9389.
One of the most important problems of taking nitroglycerin is the nitrate tolerance phenomenon and endothelial dysfunction. Oxidative stress is a high-emphasized one of tolerance mechanisms. The possible effect of crocin, one of the anti-oxidant ingredients of saffron, on the nitrate tolerance model was investigated.
In the present study, lipid peroxidation and the level of activated and deactivated forms of eNOS were measured. Animals were administered subcutaneously with 25 mg/kg of nitroglycerin, twice a day for 3 days to induce nitrate tolerance model. For evaluation of crocin effects, 20, 40 and 80 mg/kg/day of this compound were injected intraperitoneally in concomitant with nitroglycerin. In the isolated aorta test, after preparation of aorta rings, different concentrations of acetylcholine, sodium nitroprusside and nitroglycerin were added to the organ bath after inducing contraction by phenylephrine and the responsiveness of tissues was recorded.
Findings showed that nitroglycerin administration caused a remarkable overproduction of malondialdehyde (MDA) in the cells and crocin treatment significantly decreased the MDA level. In the nitrate tolerance group, the level of activated eNOS decreased and the level of deactivated eNOS increased. Crocin partly alleviated these changes: however, its effects were not remarkable. Nitroglycerin injection for 3 days developed tolerance to nitroglycerin and cross-tolerance to acetylcholine (endothelial dysfunction) and sodium nitroprusside. Crocin failed to influence significantly on the nitrate tolerance.
Crocin effectiveness is possibly time-dependent; therefore, increasing the duration of treatment with crocin may lead to a significant prevention of nitrate tolerance and endothelial dysfunction.
服用硝酸甘油最重要的问题之一是硝酸盐耐受现象和内皮功能障碍。氧化应激是耐受性机制中备受关注的一个方面。研究了藏红花抗氧化成分之一藏红花素对硝酸盐耐受模型的可能影响。
在本研究中，测量了脂质过氧化以及内皮型一氧化氮合酶（eNOS）的活化和失活形式水平。动物皮下注射25mg/kg硝酸甘油，每天两次，共3天以诱导硝酸盐耐受模型。为评估藏红花素的作用，在给予硝酸甘油的同时腹腔注射20、40和80mg/kg/天的该化合物。在离体主动脉试验中，制备主动脉环后，用去氧肾上腺素诱导收缩后，向器官浴中加入不同浓度的乙酰胆碱、硝普钠和硝酸甘油，并记录组织的反应性。
研究结果表明，给予硝酸甘油会导致细胞中丙二醛（MDA）显著过量产生，而藏红花素处理可显著降低MDA水平。在硝酸盐耐受组中，活化的eNOS水平降低，失活的eNOS水平升高。藏红花素部分缓解了这些变化，但其效果并不显著。注射硝酸甘油3天会产生对硝酸甘油的耐受性以及对乙酰胆碱（内皮功能障碍）和硝普钠的交叉耐受性。藏红花素对硝酸盐耐受性没有显著影响。
藏红花素的有效性可能与时间有关；因此，延长藏红花素治疗时间可能会显著预防硝酸盐耐受和内皮功能障碍。
