Inhibition of angiotensin-converting enzyme by captopril: a novel approach to reduce ischemia-reperfusion injury after lung transplantation.
OBJECTIVE
Ischemia-reperfusion injury after lung transplantation involves the generation of free radicals. Captopril has been shown to be protective in models of ischemia-reperfusion injury in other organs by acting as a free radical scavenger. The purpose of this study was to assess the protective effects of captopril against ischemia-reperfusion injury and to evaluate the ability of captopril to scavenge free radicals and inhibit neutrophil activation in an experimental model of lung transplantation.


METHODS
A rat single-lung transplant model was used. Donor lungs were flushed and preserved in low-potassium dextran-glucose solution with (n = 5) and without captopril (500 micromol/L; n = 5) for 18 hours at 4 degrees C and then transplanted and reperfused for 2 hours. At the conclusion of the 2-hour reperfusion period, arterial blood gases, blood pressure, and peak airway pressure were measured. Lung tissue biopsy specimens were obtained for assessment of wet/dry weight ratios, histology, and neutrophil sequestration (myeloperoxidase activity). Lipid peroxidation (F(2)-isoprostane assay) was analyzed from plasma samples and tissue lysates.


RESULTS
The addition of captopril to the lung preservation solution significantly improved postreperfusion PO (2) (312 +/- 63.3 mm Hg vs 202 +/- 21.1 mm Hg; P =.006), peak airway pressure (11.4 +/- 1.1 cm H(2)O vs 15.6 +/- 1.5 cm H(2)O; P =.001), and wet/dry weight ratio (4.9 +/- 0.4 vs 15.8 +/- 10.9; P =.008). Blood pressures did not differ significantly between groups. No significant differences were seen in myeloperoxidase activity or F(2)-isoprostane levels.


CONCLUSIONS
The use of captopril in the preservation solution ameliorates ischemia-reperfusion injury in transplanted lungs after an extended cold preservation period. The mechanisms by which captopril is protective remain elusive but do not appear to include inhibition of neutrophil sequestration or lipid peroxidation. This novel approach to ischemia-reperfusion injury may lead to improved lung function after transplantation and provide further insight into the pathogenesis of acute lung injury.
Fischer
S
S
Thoracic Surgery Research Laboratory, Division of Thoracic Surgery, Toronto General Hospital Research Institute, University of Toronto, Toronto, Ontario, Canada.
Maclean
A A
AA
Liu
M
M
Kalirai
B
B
Keshavjee
S
S
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D002216:Captopril / Q000627:therapeutic use*; D003911:Dextrans / Q000494:pharmacology; D015237:Dinoprost / Q000031:analogs & derivatives / Q000032:analysis; D028441:F2-Isoprostanes; D016166:Free Radical Scavengers / Q000494:pharmacology; D005947:Glucose / Q000494:pharmacology; D008168:Lung / Q000098:blood supply* / Q000473:pathology; D016040:Lung Transplantation; D008297:Male; D018375:Neutrophil Activation / Q000187:drug effects; D009926:Organ Preservation / Q000379:methods; D010100:Oxygen / Q000097:blood; D009195:Peroxidase / Q000097:blood; D051381:Rats; D011917:Rats, Inbred Lew; D015427:Reperfusion Injury / Q000517:prevention & control*; D013599:Systole / Q000502:physiology
D000806:Angiotensin-Converting Enzyme Inhibitors; D003911:Dextrans; D028441:F2-Isoprostanes; D016166:Free Radical Scavengers; C083290:low potassium dextran glucose solution; C075750:8-epi-prostaglandin F2alpha; D002216:Captopril; D015237:Dinoprost; D009195:Peroxidase; D005947:Glucose; D010100:Oxygen