Radiation-induced endothelial dysfunction and fibrosis in rat lung: modification by the angiotensin converting enzyme inhibitor CL242817.
The purpose of this study was to evaluate the angiotensin converting enzyme (ACE) inhibitor CL242817 as a modifier of radiation-induced pulmonary endothelial dysfunction and pulmonary fibrosis in rats sacrificed 2 months after a single dose of 60Co gamma rays (0-30 Gy) to the right hemithorax. CL242817 was administered in the feed continuously after irradiation at a regimen of 60 mg/kg/day. Pulmonary endothelial function was monitored by lung ACE activity, plasminogen activator (PLA) activity, and prostacyclin (PGI2) and thromboxane (TXA2) production. Pulmonary fibrosis was evaluated by lung hydroxyproline (HP) content. Lung ACE and PLA activities decreased with increasing radiation dose, and cotreatment with CL242817 significantly ameliorated both responses. CL242817 dose-reduction factors (DRF) were 1.3-1.5 for ACE and PLA activity. Lung PGI2 and TXA2 production increased with increasing radiation dose, and CL242817 almost completely prevented both radiation responses. The slope of the radiation dose-response curves in the CL242817-treated rats was essentially zero, precluding calculation of DRF values for PGI2 and TXA2 production. Lung HP content also increased with increasing radiation dose, and CL242817 significantly attenuated this response (DRF = 1.5). These data suggest that the ability of ACE inhibitors to ameliorate radiation-induced pulmonary endothelial dysfunction is not unique to captopril [Ward et al., Int. J. Radiat. Oncol. Biol. Phys. 15, 135-140 (1988)], rather it is a therapeutic action shared by other members of this class of compounds. These data also provide the first evidence that ACE inhibitors exhibit antifibrotic activity in irradiated rat lung.
Ward
W F
WF
Department of Radiology, Northwestern University Medical School, Chicago, Illinois 60611.
Molteni
A
A
Ts'ao
C H
CH
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D000818:Animals; D003037:Cobalt Radioisotopes; D004727:Endothelium / Q000187:drug effects / Q000528:radiation effects; D005720:Gamma Rays; D008168:Lung / Q000187:drug effects / Q000528:radiation effects*; D008297:Male; D011392:Proline / Q000031:analogs & derivatives* / Q000627:therapeutic use; D011658:Pulmonary Fibrosis / Q000209:etiology* / Q000517:prevention & control; D011833:Radiation Injuries, Experimental / Q000517:prevention & control*; D051381:Rats; D011919:Rats, Inbred Strains
D000806:Angiotensin-Converting Enzyme Inhibitors; D003037:Cobalt Radioisotopes; C048888:CL 242817; D011392:Proline