The NIH/NIAID initiated a countermeasure program to develop mitigators for radiation-induced
injuries from a radiological attack or nuclear accident. We have previously characterized and demonstrated mitigation of single organ
injuries, such as
radiation pneumonitis,
pulmonary fibrosis or nephropathy by
angiotensin converting enzyme (
ACE) inhibitors. Our current work extends this research to examine the potential for mitigating multiple organ dysfunctions occurring in the same irradiated rats. Using total body irradiation (TBI) followed by bone marrow transplant, we tested four doses of X radiation (11, 11.25, 11.5 and 12 Gy) to develop lethal late effects. We identified three of these doses (11, 11.25 and 11.5 Gy TBI) that were lethal to all irradiated rats by 160 days to test mitigation by
ACE inhibitors of injury to the lungs and kidneys. In this study we tested three
ACE inhibitors at doses:
captopril (88 and 176 mg/m(2)/day),
enalapril (18, 24 and 36 mg/m(2)/day) and
fosinopril (60 mg/m(2)/day) for mitigation. Our primary end point was survival or criteria for euthanization of morbid animals. Secondary end points included breathing intervals, other assays for lung structure and function and blood
urea nitrogen (BUN) to assess renal damage. We found that
captopril at 176 mg/m(2)/day increased survival after 11 or 11.5 Gy TBI.
Enalapril at 18-36 mg/m(2)/day improved survival at all three doses (TBI).
Fosinopril at 60 mg/m(2)/day enhanced survival at a dose of 11 Gy, although no improvement was observed for
pneumonitis. These results demonstrate the use of a single countermeasure to mitigate the lethal late effects in the same animal after TBI.