Protective effects of a potent C5a receptor antagonist on experimental acute limb ischemia-reperfusion in rats

Abstract

Objectives: 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.