Comparative anti-inflammatory activities of antagonists to C3a and C5a receptors in a rat model of intestinal ischaemia/reperfusion injury.
1. 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. 2. C3aRA (IC(50)=0.15 microm) and C5aRA (IC(50)=0.32 microm) 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. 3. 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 x kg(-1)); the C5aRA (1.0 mg x kg(-1)); the C3aRA+C5aRA (each 1.0 mg x kg(-1)); or vehicle, 45 min prior, or (B) the C3aRA (1.0 mg x kg(-1)) or vehicle, 120 min prior to reperfusion. 4. 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 x kg(-1)) caused transient neutropaenia, and the highest dose (10 mg x kg(-1)) also caused a rapid and transient hypertension. 5. The C3aRA (1.0 mg x 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. 6. 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.
Proctor
Lavinia M
LM
School of Biomedical Sciences, University of Queensland, Brisbane QLD 4072, Australia.
Arumugam
Thiruma V
TV
Shiels
Ian
I
Reid
Robert C
RC
Fairlie
David P
DP
Taylor
Stephen M
SM
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000138:chemical synthesis / Q000627:therapeutic use*; D001120:Arginine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000627:therapeutic use*; D001315:Australia; D001559:Benzhydryl Compounds / Q000008:administration & dosage / Q000138:chemical synthesis / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D007413:Intestinal Mucosa / Q000187:drug effects / Q000473:pathology* / Q000648:ultrastructure; D008565:Membrane Proteins / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000627:therapeutic use; D009503:Neutropenia / Q000139:chemically induced / Q000150:complications; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D010456:Peptides, Cyclic / Q000008:administration & dosage / Q000138:chemical synthesis / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D044087:Receptor, Anaphylatoxin C5a / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000627:therapeutic use; D011951:Receptors, Complement / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000627:therapeutic use; D015427:Reperfusion Injury / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D013997:Time Factors
C438957:AcPhe(ornithine-Pro-cyclohexylamine-Trp-Arg); D000893:Anti-Inflammatory Agents; D001559:Benzhydryl Compounds; D004338:Drug Combinations; D008565:Membrane Proteins; D010456:Peptides, Cyclic; D044087:Receptor, Anaphylatoxin C5a; D011951:Receptors, Complement; C431907:SB 290157; C085567:complement C3a receptor; D001120:Arginine; D000410:Alanine Transaminase