Comparative anti-inflammatory activities of antagonists to C3a and C5a receptors in a rat model of intestinal ischaemia/reperfusion injury

Authors


School of Biomedical Sciences, University of Queensland, Brisbane QLD 4072, Australia. E-mail: s.taylor@uq.edu.au

Abstract

  • Complement activation is implicated in the pathogenesis of intestinal ischaemia–reperfusion injury (I/R), although the relative importance of individual complement components is unclear. A C3a receptor antagonist N(2)-[(2,2-diphenylethoxy)acetyl]-L-arginine (C3aRA) has been compared with a C5a receptor antagonist (C5aRA), AcF-[OPdChaWR], in a rat model of intestinal I/R.

  • C3aRA (IC50=0.15 μM) and C5aRA (IC50=0.32 μM) bound selectively to human polymorphonuclear leukocyte (PMN) C3a and C5a receptors, respectively. Effects on circulating neutrophils and blood pressure in the rat were also assessed.

  • Anaesthetised rats, subjected to intestinal ischaemia (30 min) and reperfusion (120 min), were administered intravenously with either (A) the C3aRA (0.1–1.0 mg kg−1); the C5aRA (1.0 mg kg−1); the C3aRA+C5aRA (each 1.0 mg kg−1); or vehicle, 45 min prior, or (B) the C3aRA (1.0 mg kg−1) or vehicle, 120 min prior to reperfusion.

  • The C3aRA and C5aRA, administered 45 min prior to reperfusion, displayed similar efficacies at ameliorating several disease markers (increased oedema, elevated ALT levels and mucosal damage) of rat intestinal I/R. The combination drug treatment did not result in greater injury reduction than either antagonist alone. However, doses of the C3aRA (0.01–10 mg kg−1) caused transient neutropaenia, and the highest dose (10 mg kg−1) also caused a rapid and transient hypertension.

  • The C3aRA (1.0 mg kg−1), delivered 120 min prior to reperfusion to remove the global effect of C3aRA-induced neutrophil sequestration, did not attenuate the markers of intestinal I/R, despite persistent C3aR antagonism at this time.

  • C3aR antagonism does not appear to be responsible for the anti-inflammatory actions of this C3aRA in intestinal I/R in the rat. Instead, C3aRA-mediated global neutrophil tissue sequestration during ischaemia and early reperfusion may account for the protective effects observed.

British Journal of Pharmacology (2004) 142, 756–764. doi:10.1038/sj.bjp.0705819

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