Protective effects of a potent C5a receptor antagonist on experimental acute limb ischemia-reperfusion in rats.
OBJECTIVE
The capacity of a potent C5a receptor antagonist to inhibit various parameters of local and remote organ injury following lower limb ischemia-reperfusion (I/R) in rats was investigated.


METHODS
Rats were subjected to 2 h bilateral hindlimb ischemia and 4 h reperfusion. Drug-treated rats received AcF-[OPdChaWR] (1 mg/kg) iv either 10 min before ischemia or 10 min prior to reperfusion, or orally (10 mg/kg) 30 min prior to ischemia. Levels of circulating creatine kinase (CK), lactate dehydrogenase (LDH), alanine and aspartate aminotransferase (ALT/AST), creatinine, blood urea nitrogen (BUN), polymorphonuclear leukocytes (PMNs), and calcium (Ca(++)) and potassium (K(+)) ions were determined. Other parameters measured included urinary protein levels, muscle edema, and myeloperoxidase (MPO) concentrations in the lung, liver, and muscle along with liver homogenate tumor necrosis factor-alpha (TNF-alpha) concentrations.L RESULTS: imb I/R injury was characterized by significant elevations of CK, LDH, ALT, AST, creatinine, BUN, proteinuria, PMNs, serum K(+), muscle edema, organ MPO, and liver homogenate TNF-alpha concentrations, but a significant reduction in serum Ca(2+) concentrations. When rats were treated with AcF-[OPdChaWR], there were significant improvements in all these parameters.


CONCLUSIONS
These results indicate a pivotal role for C5a in inducing local and remote organ injury and suggest a possible new drug therapeutic category for preventing anticipated tissue injury associated with I/R.
Woodruff
Trent M
TM
School of Biomedical Sciences, Department of Physiology and Pharmacology, University of Queensland, Brisbane, QLD 4072, Australia.
Arumugam
Thiruma V
TV
Shiels
Ian A
IA
Reid
Robert C
RC
Fairlie
David P
DP
Taylor
Stephen M
SM
D000208:Acute Disease; D000818:Animals; D001806:Blood Urea Nitrogen; D002118:Calcium / Q000037:antagonists & inhibitors / Q000097:blood; D015936:Complement C5a / Q000502:physiology*; D003402:Creatine Kinase / Q000037:antagonists & inhibitors; D003404:Creatinine / Q000097:blood; D019610:Cytoprotection; D005260:Female; D006614:Hindlimb / Q000098:blood supply*; D007770:L-Lactate Dehydrogenase / Q000037:antagonists & inhibitors; D007958:Leukocyte Count; D008099:Liver / Q000378:metabolism; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects; D010456:Peptides, Cyclic / Q000494:pharmacology*; D011188:Potassium / Q000037:antagonists & inhibitors / Q000097:blood; D011507:Proteinuria; D051381:Rats; D017208:Rats, Wistar; D044087:Receptor, Anaphylatoxin C5a / Q000037:antagonists & inhibitors*; D015427:Reperfusion Injury / Q000517:prevention & control*; D000637:Transaminases / Q000037:antagonists & inhibitors; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors
C438957:AcPhe(ornithine-Pro-cyclohexylamine-Trp-Arg); D010456:Peptides, Cyclic; D044087:Receptor, Anaphylatoxin C5a; D014409:Tumor Necrosis Factor-alpha; D015936:Complement C5a; D003404:Creatinine; D007770:L-Lactate Dehydrogenase; D000637:Transaminases; D003402:Creatine Kinase; D011188:Potassium; D002118:Calcium