Twomey P, Taira J, DeGraff W, Mitchell J B, Russo A, Krishna M C, Hankovszky O H, Frank L, Hideg K
Radiation Biology Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
Free Radic Biol Med. 1997;22(5):909-16. doi: 10.1016/s0891-5849(96)00477-7.
The new Class I anti-arrhythmic agent 2,2,5,5-tetramethyl-3-pyrroline-1-carboxamide derivative, is currently being evaluated in clinical trials in patients with a high risk for cardiac arrhythmias. In this study we show that this antiarrhythmic drug can be chemically converted to the nitroxide free radical analog. Further, using an in vivo Electron Paramagnetic Resonance (EPR) spectroscopy model by detecting free radicals in the distal portion of the tail of an anesthetized mouse, we demonstrate that the drug is oxidized to the corresponding nitroxide. In vitro studies using Chinese hamster V79 cells suggest that the oxidation products of the drug, namely, the hydroxylamine and the nitroxide protect against oxidative damage induced by hydrogen peroxide (H2O2). Taken together, our results suggest that, in addition to the antiarrhythmic effects of the parent drug, sufficient levels of nitroxides may accumulate from the parent drug in vivo to provide antioxidant defense to cardiac tissue that may be subject to ischemia and oxidation-driven injury.
新型I类抗心律失常药物2,2,5,5-四甲基-3-吡咯啉-1-甲酰胺衍生物目前正在心律失常高危患者中进行临床试验评估。在本研究中，我们表明这种抗心律失常药物可化学转化为氮氧自由基类似物。此外，通过使用体内电子顺磁共振（EPR）光谱模型，检测麻醉小鼠尾巴远端的自由基，我们证明该药物被氧化为相应的氮氧化物。使用中国仓鼠V79细胞进行的体外研究表明，该药物的氧化产物，即羟胺和氮氧化物可保护细胞免受过氧化氢（H2O2）诱导的氧化损伤。综上所述，我们的结果表明，除了母体药物的抗心律失常作用外，母体药物在体内可能积累足够水平的氮氧化物，为可能遭受缺血和氧化驱动损伤的心脏组织提供抗氧化防御。
