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An investigation of the purported vasodilation mechanisms of nitroglycerin and nitric oxide prodrugs.

机译：对硝酸甘油和一氧化氮前药的血管舒张作用机理的研究。

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摘要

The reactivity of GTN (nitroglycerin), S-nitrates, putative nitrovasodilator biotransformation intermediates (e.g. RSNO 2), and NO (nitric oxide) donors (e.g. nitrosothiols and NONOates (diazeniumdiolate salts)) was explored with the goal of elucidating the biotransformation mechanism of GTN leading to vasodilation. Finding the popular oxyhemoglobin assay inadequate for the measurement of NO release from organic nitrates and related nitrogen and oxygen containing compounds, an amperometric assay was used to measure NO release. The NO electrode was calibrated in a new way, specifically using DEA/NO (1-(N,N-diethylamine)diazen-1-ium-1,2-diolate, sodium salt) that allowed for the measurement of the rates (and the rate constants) of NO release from a range of NO prodrugs.;Reactivity studies including HPLC kinetics and product studies revealed that the simple reaction of GTN with thiol is likely a clearance-based pathway of GTN metabolism. Investigation of the elusive thionitrate intermediate (from the reaction of GTN with thiol) attested to its high reactivity and probable involvement in a clearance-based pathway. Reaction of GTN with a heme enzyme model (FeIITPP(N-MeIm)2) produced NO, possibly mimicking a mechanism-based pathway. Some S-nitrates rapidly produced NO (in the presence of a thiol) in phosphate buffer solution and activated guanylate cyclase in the presence and absence of thiol. A mechanism (which is based on the results of product studies) is proposed to account for the NO release from one of the S-nitrates. Using plasma as the reaction medium, significant NO release from GTN and other nitrates was measured in the presence of added thiols. Studies of this reactivity indicated that the plasma based reaction is likely mediated by a protein, but not due to hemoglobin, ceruloplasmin, superoxide dismutase, human serum albumin, or glutathione-S-transferase.
机译：探索了GTN（硝酸甘油），S-硝酸盐，假定的硝化血管扩张剂生物转化中间体（例如RSNO 2）和NO（一氧化氮）供体（例如亚硝基硫醇和NONOates（二氮杂二烯二醇盐））的反应性，目的是阐明NTN的生物转化机理。 GTN导致血管扩张。发现流行的氧合血红蛋白测定不足以测量从有机硝酸盐和相关的含氮和氧的化合物中释放出的NO，因此采用安培分析法测量了NO的释放。用新方法校准NO电极，特别是使用DEA / NO（1-（N，N-二乙胺）重氮-1-1,2-二醇盐，钠盐）进行校准，以测量速率（和从一系列NO前药中释放NO的速率常数）;包括HPLC动力学和产物研究在内的反应性研究表明，GTN与硫醇的简单反应可能是基于清除的GTN代谢途径。难以捉摸的硫代硝酸盐中间体的研究（来自GTN与硫醇的反应）证明了其高反应活性和可能参与了基于清除的途径。 GTN与血红素酶模型（FeIITPP（N-MeIm）2）的反应产生NO，可能模仿基于机理的途径。一些硝酸盐在磷酸盐缓冲溶液中迅速产生NO（在巯基存在下），在有和没有巯基的情况下都激活鸟苷酸环化酶。提出了一种机制（基于产品研究的结果）来说明从一种S-硝酸盐中释放NO的原因。使用血浆作为反应介质，在添加硫醇的存在下，从GTN和其他硝酸盐中释放出大量NO。对这种反应性的研究表明，基于血浆的反应可能是由蛋白质介导的，而不是由于血红蛋白，铜蓝蛋白，超氧化物歧化酶，人血清白蛋白或谷胱甘肽-S-转移酶引起的。

著录项

  • 作者

    Artz, Jennifer Dawn.;

  • 作者单位

    Queen's University (Canada).;

  • 授予单位 Queen's University (Canada).;
  • 学科 Chemistry Organic.;Health Sciences Pharmacology.;Chemistry Pharmaceutical.
  • 学位 Ph.D.
  • 年度 1999
  • 页码 289 p.
  • 总页数 289
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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