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Effects of a new C5a receptor antagonist on C5a‐ and endotoxin‐ induced neutropenia in the rat
Author(s) -
Short Anna,
Wong Allan K,
Finch Angela M,
Haaima Gerald,
Shiels Ian A,
Fairlie David P,
Taylor Stephen M
Publication year - 1999
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0702338
Subject(s) - neutropenia , c5a receptor , antagonist , lipopolysaccharide , receptor antagonist , receptor , pharmacology , medicine , antagonism , leukopenia , granulocyte , immunology , endocrinology , toxicity , complement system , antibody
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 μg 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. British Journal of Pharmacology (1999) 126 , 551–554; doi: 10.1038/sj.bjp.0702338