Radiation pneumotoxicity in rats: modification by inhibitors of angiotensin converting enzyme.
The present study determined whether inhibitors of angiotensin converting enzyme (ACE) can ameliorate radiation-induced pulmonary endothelial dysfunction and pulmonary fibrosis in rats sacrificed 2 months after a range of single doses of 60Co gamma rays to the right hemithorax. Four indices of pulmonary endothelial function were monitored: right lung ACE and plasminogen activator (PLA) activity, and prostacyclin (PGI2) and thromboxane (TXA2) production. Hydroxyproline (HP) content served as an index of pulmonary fibrosis. Rats consumed either control powdered chow or feed containing one of five modifying agents continuously after irradiation. The modifiers included three ACE inhibitors: Captopril, CL242817, and CGS13945, respectively, a thiol, a thioacetate, and a nonthiol compound. All of the ACE inhibitors are analogues of proline. Two additional modifiers were tested: penicillamine, a thiol with no ACE inhibitory activity; and pentoxifylline, a vasodilator that is neither a thiol nor an ACE inhibitor. Radiation produced a dose-dependent decrease in lung ACE and PLA activity, and an increase in PGI2 and TXA2 production and in HP content. All ACE inhibitors attenuated the radiation-induced suppression in lung ACE and PLA activity. All thiol or thioacetate compounds ameliorated the radiation-induced increase in PGI2, TXA2, and HP. The two agents that were both thiols and ACE inhibitors (Captopril and CL242817) spared all of the radiation reactions, while the compound that was neither a thiol nor an ACE inhibitor (pentoxifylline) spared none of the reactions. These data suggest a novel application for ACE inhibitors in general, and for Captopril in particular, as modifiers of radiation pneumotoxicity.
Ward
W F
WF
Department of Radiology, Northwestern University Medical School Chicago, IL 60611.
Molteni
A
A
Ts'ao
C H
CH
Kim
Y T
YT
Hinz
J M
JM
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D000818:Animals; D002216:Captopril / Q000627:therapeutic use; D003037:Cobalt Radioisotopes; D007211:Indoles / Q000627:therapeutic use; D008168:Lung / Q000528:radiation effects*; D008297:Male; D011392:Proline / Q000031:analogs & derivatives / Q000627:therapeutic use; D011658:Pulmonary Fibrosis / Q000188:drug therapy* / Q000209:etiology; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship
D000806:Angiotensin-Converting Enzyme Inhibitors; D003037:Cobalt Radioisotopes; D007211:Indoles; C038810:CGS 13945; C048888:CL 242817; D011392:Proline; D002216:Captopril