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


METHODS
C57BL/6 mice were either sham-irradiated or exposed to (60)Co 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 G(0)-G(1) 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.


CONCLUSIONS
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.
Davis
Thomas A
TA
Department of Regenerative Medicine, Naval Medical Research Center, Silver Spring, MD, USA.
Landauer
Michael R
MR
Mog
Steven R
SR
Barshishat-Kupper
Michal
M
Zins
Stephen R
SR
Amare
Mihret F
MF
Day
Regina M
RM
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D002216:Captopril / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D006412:Hematopoietic Stem Cells / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D011835:Radiation Protection / Q000379:methods*; D013997:Time Factors; D014916:Whole-Body Irradiation
D000806:Angiotensin-Converting Enzyme Inhibitors; D002216:Captopril