Timing of captopril administration determines radiation protection or radiation sensitization in a murine model of total body irradiation

Davis, Thomas A.; Landauer, Michael R.; Mog, Steven R.; Barshishat-Kupper, Michal; Zins, Stephen R.; Amare, Mihret F.; Day, Regina M.

doi:10.1016/j.exphem.2010.01.004

« Previous Next »Experimental Hematology
Volume 38, Issue 4 , Pages 270-281, April 2010

Timing of captopril administration determines radiation protection or radiation sensitization in a murine model of total body irradiation

Thomas A. Davis
- Department of Regenerative Medicine, Naval Medical Research Center, Silver Spring, Md., USA
Michael R. Landauer
- Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, Bethesda, Md., USA
Steven R. Mog
- Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, Bethesda, Md., USA
Michal Barshishat-Kupper
- Department of Pharmacology, Uniformed Services University of the Health Sciences, Bethesda, Md., USA
Stephen R. Zins
- Department of Regenerative Medicine, Naval Medical Research Center, Silver Spring, Md., USA
Mihret F. Amare
- Department of Regenerative Medicine, Naval Medical Research Center, Silver Spring, Md., USA
Regina M. Day
- Department of Pharmacology, Uniformed Services University of the Health Sciences, Bethesda, Md., USA
- Offprint requests to: Regina M. Day, Ph.D., Department of Pharmacology, Uniformed Services University of the Health Sciences, Building C, Room 2023, 4301 Jones Bridge Road, Bethesda, MD 20814-4799

Received 5 January 2010; received in revised form 5 January 2010; accepted 20 January 2010. published online 29 January 2010.

Objective

Angiotensin II (Ang II), a potent vasoconstrictor, affects the growth and development of hematopoietic cells. Mixed findings have been reported for the effects of angiotensin-converting enzyme (ACE) inhibitors on radiation-induced injury to the hematopoietic system. We investigated the consequences of different regimens of the ACE inhibitor captopril on radiation-induced hematopoietic injury.

Materials and Methods

C57BL/6 mice were either sham-irradiated or exposed to ⁶⁰Co total body irradiation (0.6 Gy/min). Captopril was provided in the water for different time periods relative to irradiation.

Results

In untreated mice, the survival rate from 7.5 Gy was 50% at 30 days postirradiation. Captopril treatment for 7 days prior to irradiation resulted in radiosensitization with 100% lethality and a rapid decline in mature blood cells. In contrast, captopril treatment beginning 1 hour postirradiation and continuing for 30 days resulted in 100% survival, with improved recovery of mature blood cells and multilineage hematopoietic progenitors. In nonirradiated control mice, captopril biphasically modulated Lin⁻ marrow progenitor cell cycling. After 2 days, captopril suppressed G₀−G₁ transition and a greater number of cells entered a quiescent state. However, after 7 days of captopril treatment Lin⁻ progenitor cell cycling increased compared to untreated control mice.

Conclusion

These findings suggest that ACE inhibition affects hematopoietic recovery following radiation by modulating the hematopoietic progenitor cell cycle. The timing of captopril treatment relative to radiation exposure differentially affects the viability and repopulation capacity of spared hematopoietic stem cells and, therefore, can result in either radiation protection or radiation sensitization.