DIRECT EVIDENCE FOR IN-VIVO NITROXIDE FREE-RADICAL PRODUCTION FROM A NEW ANTIARRHYTHMIC DRUG BY EPR SPECTROSCOPY

The new Class I anti-arrhythmic agent, 2,2,5,5-tetramethyl-3-pyrroline -1-carboxamide derivative, is currently being evaluated in clinical tr ials in patients with a high risk for cardiac arrhythmias. In this stu dy we show that this antiarrhythmic drug can be chemically converted t o the nitroxide free radical analog. Further, using an in vivo Electro n Paramagnetic Resonance (EPR) spectroscopy model by detecting free ra dicals 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 oxid ation products of the drug, namely, the hydroxylamine and the nitroxid e protect against oxidative damage induced by hydrogen peroxide (H2O2) Taken together, our results suggest that, in addition to the antiarrh ythmic effects of the parent drug, sufficient levels of nitroxides may accumulate from the parent drug in vivo to provide antioxidant defens e to cardiac tissue that may be subject to ischemia and oxidation-driv en injury. Copyright (C) 1997 Elsevier Science Inc.