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Biochemical mechanisms of nitroglycerin action and vascular tolerance.

机译：硝酸甘油作用和血管耐受性的生化机制。

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摘要

Organic nitrates such as nitroglycerin (NTG) are potent and safe cardiovascular drugs. Although these agents are generally considered as prodrugs of nitric oxide (NO), they differ from other NO donors in their pharmacological action as well as the development of nitrate tolerance. A number of hypotheses have been proposed as the underlying mechanism(s) of nitrate tolerance, but a unifying theory is not yet available. This thesis work, therefore, focused on generating an understanding of the biochemical reaction of NTG, a prototype organic nitrate, in the context of NTG action and vascular tolerance. We demonstrated that NTG reacted with various biochemical target sites in model biomolecules and vascular tissue, consistent with its diverse pharmacological action. Our results also indicated that NTG acts as a chemical/biochemical oxidant in reacting with the biochemical target sites. Thus, NTG induced inactivation of glutathione S-transferase (GST), its own metabolizing enzyme via oxidative reaction. This oxidative reaction appeared to involve the formation of oxidized GST dimer, possibly via −SH oxidation to form disulfide and disulfide S-oxidized product(s). The chemical reaction of NTG with glutathione also provided supportive evidence for the formation of such oxidation products including disulfide with additional oxygen atoms. Consistent with the oxidative property of NTG, the in vitro nitrate vascular tolerance appeared to involve enhanced oxidative stress. Using DNA microarray, we showed that NTG can induce widespread changes in the expression of many genes including those involved in metabolism, cellular signaling and redox regulation. We also observed that NTG can stimulate the vascular release of a neuropeptide, calcitonin gene-related peptide, offering a novel neurogenic mechanism of NTG action. This stimulatory effect of NTG appeared to involve the activation of endothelial NO synthase (eNOS), suggesting that NTG may exert its action via an eNOS-dependent mechanism. This neurogenic component of NTG action appeared to contribute to the anti-aggregatory and cardioprotective effects of NTG. These findings may contribute to a better understanding of NTG pharmacology, and thereby better use of this important drug in the future.
机译：有机硝酸盐，例如硝酸甘油（NTG）是有效且安全的心血管药物。尽管这些试剂通常被认为是一氧化氮（NO）的前药，但它们在药理作用以及对硝酸盐耐受性方面的发展与其他NO供体不同。已经提出了许多假设作为硝酸盐耐受性的潜在机制，但是尚无统一的理论。因此，本论文的工作重点是在NTG作用和血管耐受性的背景下，对NTG（一种有机硝酸盐的原型）的生化反应进行理解。我们证明NTG与模型生物分子和血管组织中的各种生化靶位点反应，与其多样的药理作用一致。我们的结果还表明，NTG在与生化靶位反应中起化学/生化氧化剂的作用。因此，NTG通过氧化反应诱导自身的代谢酶谷胱甘肽S-转移酶（GST）失活。该氧化反应似乎涉及氧化的GST二聚体的形成，可能是通过-SH氧化形成二硫化物和二硫化物S氧化产物。 NTG与谷胱甘肽的化学反应也为形成此类氧化产物（包括带有额外氧原子的二硫化物）提供了支持性证据。与NTG的氧化特性一致，体外硝酸盐血管耐受性似乎涉及增强的氧化应激。使用DNA芯片，我们显示NTG可以诱导许多基因表达的广泛变化，包括那些参与代谢，细胞信号传导和氧化还原调节的基因。我们还观察到NTG可以刺激神经肽降钙素基因相关肽的血管释放，从而提供NTG作用的新型神经发生机制。 NTG的这种刺激作用似乎涉及内皮一氧化氮合酶（eNOS）的激活，这表明NTG可能通过eNOS依赖性机制发挥其作用。 NTG作用的这种神经原性成分似乎有助于NTG的抗聚集和心脏保护作用。这些发现可能有助于更好地理解NTG药理学，从而在将来更好地使用这种重要药物。

著录项

  • 作者

    Lee, Wooin.;

  • 作者单位

    State University of New York at Buffalo.;

  • 授予单位 State University of New York at Buffalo.;
  • 学科 Health Sciences Pharmacology.; Health Sciences Pharmacy.; Biology Molecular.
  • 学位 Ph.D.
  • 年度 2002
  • 页码 248 p.
  • 总页数 248
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 药理学;药剂学;分子遗传学;
  • 关键词

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