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-cyclohexyl alanine-Trp-Arg], (F-[OPdChaWR]), was tested for its ability to antagonize the neutropenic effects of both C5a and endotoxin in rats. Human recombinan t C5a (2 mu g kg(-1) i.v.) caused rapid neutropenia, characterized by an 83 % decrease in circulating polymorphonuclear leukocytes (PMNs) at 5 min. Adm inistration of F-[OPdChaWR] (0.3-3 mg kg(-1) i.v.), did not affect the leve ls of circulating PMNs but, when given 10 min prior to C5a, it inhibited th e C5a-induced neutropenia by up to 70%. Administration of E. Coli lipopolys accharide (LPS, I mg kg(-1) i.v.) also caused neutropenia with an 88% decre ase in circulating PMNs after 30 min. When rats were pretreated with F-[OPd ChaWR] (0.3-10 mg kg(-1) i.v.) 10 min prior to LPS, there was a dose-depend ent antagonism of the neutropenia caused by LPS, with up to 69% reversal of neutropenia observed 30 min after LPS administration. These findings sugge st that C5a receptor antagonists may have therapeutic potential in the many diseases known to involve either endotoxin or C5a.