Dudek Magdalena, Bednarski Marek, Bilska Anna, Iciek Małgorzata, Sokołowska-Jezewicz Maria, Filipek Barbara, Włodek Lidia
Laboratory of Pharmacological Screening, Jagiellonian University, Collegium Medicum, 9, Medyczna Street, PL 30-688 Kraków, Poland.
Eur J Pharmacol. 2008 Sep 4;591(1-3):203-10. doi: 10.1016/j.ejphar.2008.06.073. Epub 2008 Jun 27.
Besides other organic nitrates, nitroglycerin (glyceryl trinitrate; GTN) has been used to treat acute heart failure particularly due to ischemic heart disease. However, one of serious clinical problems of the GTN therapy, particularly a long-standing medication, is hemodynamic tolerance to GTN, manifested by the decreased therapeutic efficacy of the drug. The most recent studies have suggested that mitochondrial lipoate/dihydrolipoate system-dependent aldehyde dehydrogenase-2 plays a key role in nitric oxide release from GTN. The aldehyde dehydrogenase-2 performs three enzymatic activities of dehydrogenase, esterase and reductase. The reductase activity is responsible for bioactivation of organic nitrates, such as GTN yielding nitrite and dinitrate (1,2-GDN/1,3-GDN, approximately 8:1). In view of a large contribution of dihydrolipoic acid to stabilization and regeneration of thiol groups, necessary for the reductase activity of aldehyde dehydrogenase-2, we conducted studies aimed to determine whether lipoic acid administration to rats is able to prevent GTN tolerance. The studies were conducted on 4 groups of animals: control saline-treated, model GTN-tolerant, GTN + lipoic acid-treated, lipoic acid alone-administered groups. On the 9th day of experiment animals were given i.v. therapeutic dose of GTN. We measured in all animals systolic and diastolic blood pressure before injection of therapeutic dose of GTN into the cadual vein and during 20 min thereafter. Levels of nitric oxide and reactive oxygen species and activities of glutathione peroxidase and superoxide dismutase were assayed in the aorta, plasma and heart of all animals. In addition, levels of malondialdehyde, and non-protein thiols, and activities of glutathione S-transferase and gamma-glutamyl transpeptidase were evaluated in the heart and plasma. The obtained results indicate that treatment of rats with a combination of lipoic acid and GTN can efficiently counteract GTN tolerance.
除其他有机硝酸盐外，硝酸甘油（三硝酸甘油酯；GTN）已被用于治疗急性心力衰竭，尤其是由缺血性心脏病引起的急性心力衰竭。然而，GTN治疗的一个严重临床问题，尤其是长期用药时，是对GTN的血流动力学耐受性，表现为药物治疗效果降低。最近的研究表明，线粒体硫辛酸/二氢硫辛酸系统依赖性醛脱氢酶-2在GTN释放一氧化氮中起关键作用。醛脱氢酶-2具有脱氢酶、酯酶和还原酶三种酶活性。还原酶活性负责有机硝酸盐的生物活化，如GTN生成亚硝酸盐和二硝酸盐（1,2-二硝酸甘油酯/1,3-二硝酸甘油酯，约8:1）。鉴于二氢硫辛酸对醛脱氢酶-2还原酶活性所需的硫醇基团的稳定和再生有很大贡献，我们进行了研究，旨在确定给大鼠施用硫辛酸是否能够预防GTN耐受性。研究在4组动物中进行：对照生理盐水处理组、模型GTN耐受组、GTN+硫辛酸处理组、单独施用硫辛酸组。在实验的第9天，给动物静脉注射治疗剂量的GTN。在向尾静脉注射治疗剂量的GTN之前及之后20分钟内，我们测量了所有动物的收缩压和舒张压。测定了所有动物主动脉、血浆和心脏中的一氧化氮水平、活性氧水平以及谷胱甘肽过氧化物酶和超氧化物歧化酶的活性。此外，还评估了心脏和血浆中的丙二醛水平、非蛋白硫醇水平以及谷胱甘肽S-转移酶和γ-谷氨酰转肽酶的活性。所得结果表明，硫辛酸和GTN联合治疗大鼠能够有效对抗GTN耐受性。
