Effects of a new C5a receptor antagonist on C5a- and endotoxin-induced neutropenia in the rat.
A new C5a receptor antagonist, the cyclic peptide Phe-[Orn-Pro-D-cyclohexylalanine-Trp-Arg], (F-[OPdChaWR]), was tested for its ability to antagonize the neutropenic effects of both C5a and endotoxin in rats. Human recombinant C5a (2 microg kg(-1) i.v.) caused rapid neutropenia, characterized by an 83% decrease in circulating polymorphonuclear leukocytes (PMNs) at 5 min. Administration of F-[OPdChaWR] (0.3-3 mg kg(-1) i.v.), did not affect the levels of circulating PMNs but, when given 10 min prior to C5a, it inhibited the C5a-induced neutropenia by up to 70%. Administration of E. Coli lipopolysaccharide (LPS, 1 mg kg(-1) i.v.) also caused neutropenia with an 88% decrease in circulating PMNs after 30 min. When rats were pretreated with F-[OPdChaWR] (0.3 - 10 mg kg(-1) i.v.) 10 min prior to LPS, there was a dose-dependent antagonism of the neutropenia caused by LPS, with up to 69% reversal of neutropenia observed 30 min after LPS administration. These findings suggest that C5a receptor antagonists may have therapeutic potential in the many diseases known to involve either endotoxin or C5a.
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Department of Physiology and Pharmacology, University of Queensland, St. Lucia, Australia.
Wong
A K
AK
Finch
A M
AM
Haaima
G
G
Shiels
I A
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Fairlie
D P
DP
Taylor
S M
SM
D000818:Animals; D015703:Antigens, CD / Q000737:chemistry*; D015936:Complement C5a / Q000009:adverse effects* / Q000037:antagonists & inhibitors; D003169:Complement Inactivator Proteins / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004731:Endotoxins / Q000009:adverse effects*; D005260:Female; D006801:Humans; D007958:Leukocyte Count / Q000187:drug effects; D008070:Lipopolysaccharides / Q000009:adverse effects; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000378:metabolism; D009503:Neutropenia / Q000139:chemically induced / Q000517:prevention & control*; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D044087:Receptor, Anaphylatoxin C5a; D011951:Receptors, Complement / Q000737:chemistry*; D011994:Recombinant Proteins / Q000009:adverse effects; D012697:Serine Endopeptidases / Q000737:chemistry / Q000494:pharmacology*
D015703:Antigens, CD; D003169:Complement Inactivator Proteins; D004731:Endotoxins; D008070:Lipopolysaccharides; D044087:Receptor, Anaphylatoxin C5a; D011951:Receptors, Complement; D011994:Recombinant Proteins; C041833:complement C5a-inhibitors; D009240:N-Formylmethionine Leucyl-Phenylalanine; D015936:Complement C5a; D012697:Serine Endopeptidases