Delayed Captopril Administration Mitigates Hematopoietic Injury in a Murine Model of Total Body Irradiation.

ABSTRACT: The increasing potential for accidental radiation exposure from either nuclear accidents or terrorist activities has escalated the need for radiation countermeasure development. We previously showed that a 30-day course of high-dose captopril, an ACE inhibitor, initiated 1-4?h after total body irradiation (TBI), improved Hematopoietic Acute Radiation Syndrome (H-ARS) and increased survival in mice. However, because of the time likely required for the deployment of a stockpiled radiation countermeasure to a radiation mass casualty site, there is a need for therapies that can be administered 24-48?hours after initial exposure. Using C57BL/6 mice exposed to an LD_50-80/30 of ⁶⁰Co TBI (7.75-7.9?Gy, 0.615?Gy/min), we show that low-dose captopril administration, initiated as late as 48?h post-TBI and continued for 14 days, significantly enhanced overall survival similarly to high-dose, rapid administration. Captopril treatment did not affect radiation-induced cell cycle arrest genes or the immediate loss of hematopoietic precursors. Reduced mortality was associated with the recovery of bone marrow cellularity and mature blood cell recovery at 21-30 days post-irradiation. Captopril reduced radiation-induced cytokines EPO, G-CSF, and SAA in the plasma. Finally, delayed captopril administration mitigated brain micro-hemorrhage at 21 days post-irradiation. These data indicate that low dose captopril administered as late as 48?h post-TBI for only two weeks improves survival that is associated with hematopoietic recovery and reduced inflammatory response. These data suggest that captopril may be an ideal countermeasure to mitigate H-ARS following accidental radiation exposure.

SUBMITTER: McCart EA 

PROVIDER: S-EPMC6379397 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature