Structure–function analysis of angiotensin-converting enzyme inhibitors as modifiers of radiation-induced pulmonary endothelial dysfunction in rats

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Abstract
We have previously demonstrated that thiol-containing collagen antagonists (penicillamine) and angiotensin-converting enzyme (ACE) inhibitors (Captopril and CL242817) ameliorate endothelial dysfunction in irradiated rat lung. The purpose of the present study was to determine whether the non-thiol ACE inhibitor CGS13945 also modifies radiation-induced pulmonary endothelial dysfunction in rats sacrificed 2 months after a single dose (0-30 Gy) of 60Co .gamma. rays to the right hemithorax. The CGS13945 was administered in the feed continuously after irradiation at a regimen of 30 mg (kg body weight)-1 day-1. Four markers of lung endothelial function were monitored: ACE activity, plasminogen activator (PLA) activity, and prostacyclin (PGI2) and thromboxane (TXA2) production. Right lung ACE and PLA activities decreased with increasing radiation dose, and CGS13945 significantly ameliorated both responses. Dose-reduction factors (DRF) for the inhibitor were 1.80 for ACE activity and 1.41 for PLA activity (p < 0.05). In contrast, lung PGI2 and TXA2 production increased with increasing radiation dose, and CGS13945 did not influence either response significantly. Thus the ACE inhibitor CGS13945 modifies radiation-induced pulmonary endothelial dysfunction in rats, indicating that the presence of a thiol group is not essential for therapeutic efficacy in this class of compounds. On the other hand, CGS13945 exhibits a differential sparing of radiation-induced pulmonary endothelial dysfunction, as does penicillamine. A structure-function analysis of the present and previous data indicates that all of the ACE inhibitors tested (Captopril, CL242817 and CGS13945) spare the radiation-induced suppression in lung ACE and PLA acivity: all of the thiol compounds tested (penicillamine, Captopril and CL242817) spare the radiation-induced elevation in lung PGI2 and TXA2 production; and the thiol ACE inhibitors (Captopril and CL242817) spare all four endothelial responses. These data confirm a novel and potentially important application for ACE inhibitors as modifiers of radiation-induced lung injury, and suggest that there are at least two components to their mechanism of therapeutic action in this model.