BLOOD-CHEMISTRY CHANGES IN THE RAT INDUCED BY HIGH-DOSES OF NITRONYL FREE-RADICAL SPIN TRAPS

For greatest efficacy, it is desirable to use spin trapping agents in the highest concentrations possible. Fifty-four male Sprague-Dawley ra ts were used to explore the relative toxicity of four representative n itronyl spin traps at doses chosen on the basis of earlier lethality s tudies. Most studies were confined to the 3- to 6-h period following d rug injection, because the behavioral signs of toxicity are most evide nt early after injection and because spin trapping studies would typic ally be performed within this time frame. Doses of spin trap were diss olved in a corn oil/buffer vehicle and injected intraperitoneally (LP) . Toxic signs were recorded periodically, and at the time of euthanasi a or spontaneous death a blood sample was collected by cardiac punctur e for clinical chemistry analysis and a necropsy was performed. Both g ross pathology and histopathological examination of the major organs w ere essentially negative in all cases, with no obvious evidence of cel lular damage being observed. Neither DMPO (232 mg/100 g b.wt.) nor PEN (100 mg/100 g b.wt.) were lethal in the present study, while both M(4 )PO (20 and 40 mg/100 g b.wt.) and PyOBN (100 and 200 mg/100 g b.wt.) were lethal. Abnormal clinical chemistry findings were generally confi ned to those animals that died spontaneously or were euthanized early for humane reasons. In most cases, death was associated with marked se izure activity and impaired respiration, and deaths occurred within a few min to a few hours. The mechanism of toxicity was unclear due to t he lack of histopathological evidence and the wide range of abnormal s erum analytes in those rats killed by either M(4)PO or PyOBN. In concl usion, during the first 6 h after IP administration there is little in dication of tissue damage by the nitrone spin traps until the dose is increased to a lethal level, at which point an acute, rapidly occurrin g, wide-spread disruption of tissue integrity seems to occur.