Intracellular and Extracellular Redox Environments Surrounding Redox-Sensitive Contrast Agents under Oxidative Atmosphere

In vivo redox reactions of nitroxyl contrast agents in bile and blood under an oxidative atmosphere were investigated using normal healthy Wistar rats. Differences in intracellular and extracellular volumes in redox environments are discussed. Pharmacokinetic profiles of two nitroxyl contrast agents, 3-carbamoyl-2,2,5,5-tetramethylpyrrolidine-N-oxyl (carbamoyl-PROXYL), 4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPOL), in bile and blood were monitored by an electron paramagnetic resonance spectrometer when the rat was breathing 100% O2 or was subcutaneously administrated 0.2 mmol/kg body weight of ferric citrate. Re-oxidation of hydroxylamines to nitroxyl radicals was caused in bile under 100% O2 breathing, but not in blood. The administration of ferric citrate caused marked re-oxidation in bile, but a slight reduction in blood. Tissue H2O2 level may partly play a role in the intracellular re-oxidation process. Tissue Fe3+ concentration can work more effectively for the intracellular re-oxidation of hydroxylamines. The intracellular environment is susceptible to oxidation compared with the extracellular environment under conditions such as 100% O2 breathing or iron overload.